KIF modulator compounds and methods of use

Abstract

Provided herein are KIF modulator compounds, pharmaceutical compositions thereof, and methods of use. Also described herein are adducts of KIF18A and KIF modulator compounds.

Description

KIF MODULATOR COMPOUNDS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 590,326, filed Oct.13, 2023; U.S.63 / 553,744, filed Feb.15, 2024; and U.S.63 / 563,021, filed March 8, 2024, each of which is incorporated herein by reference in its entirety. BACKGROUND OF INVENTION

[0002] Kinase-like protein 18A (KIF18A) is a mitotic kinesin motor protein that regulates chromosome positioning during cell division. KIF18A is overexpressed in a subset of human cancers. BRIEF SUMMARY OF THE INVENTION

[0003] Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. In some instances, targeting of CIN-associated vulnerabilities is a therapeutic strategy for treating cancer. In some instances, KIF18A plays a role in maintaining bipolar spindle integrity, such as promoting viability of CIN cancer cells. In some instances, cancer cells with chromosomal instability depend on KIF18A for cell division and survival, making KIF18A a potential therapeutic target.

[0004] Provided in some embodiments herein are KIF18A modulators (e.g., inhibitors). In some embodiments, the compounds provided herein are useful for treating cancer, such as cancers that depend on KIF18A for cell division and survival.

[0005] Provided in some embodiments herein is a compound having the structure of Formula (I-0), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-;L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)R1a1, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, - NH-S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m- OR3b, -NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl; R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge;k is 0 to 2; l is 0 to 2 ; m is 0 to 6; n is 0 to 9; o is 0 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom.

[0006] Provided in some embodiments herein is an adduct comprising a KIF18A and a compound of Formula (B), wherein the structure of Formula (B) is:wherein: ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl, optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; G is -(C=O)-NH- or -NH-(C=O)-; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; andQ is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene.

[0007] Provided in some embodiments herein is a composition comprising a protein and a compound, wherein the protein is KIF18A, the compound is a compound of Formula (B), and the protein and the compound form the adduct described herein. DETAILED DESCRIPTION OF THE INVENTION

[0008] The KIF18A gene is part of the Kinesin-8 subfamily. KIF18A is a plus-end-directed motor. In some instances, KIF18A influences dynamics at the plus end of kinetochore microtubules, such as controlling chromosomal positioning and spindle tension. In some instances, depletion of KIF18A leads to longer spindles, increased chromosome oscillation at metaphase, and activation of the mitotic spindle assembly checkpoint.

[0009] KIF18A is a potential target for treating cancer, such as cancers where KIF18A is overexpressed and / or that depend on KIF18A for cell division and survival. For example, such cancers include colon, breast, lung, pancreas, prostate, bladder, head, neck, cervix, and ovarian cancers. In some instances, genetic deletion, knockdown, or inhibition of KIF18A affects mitotic spindle apparatus. In some instances, inhibition of KIF18A induces mitotic cell arrest. In some instances, mitotic cell arrest is a vulnerability that can promote cell death in mitosis via apoptosis, mitotic catastrophe, or multipolarity driven lethality or death after mitotic slippage in interphase.

[0010] Provided in some embodiments herein are KIF18A modulators. Compounds

[0011] The compounds described herein can be useful as KIF18A modulators. In some embodiments, the compounds described herein are KIF18A inhibitors.

[0012] Provided in some embodiments herein is a compound having the structure of Formula (I-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl;L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)R1a1, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, -CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, - NH-S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m- OR3b, -NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, or optionally substituted C3-C6cycloalkyl; R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle; each R4is independently halogen, -OH, -CN, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, twoor more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1- C3alkylene bridge; or two R4combine to form an oxo; k is 0 to 2; l is 0 to 2 ; m is 1 to 6; n is 0 to 9; o is 0 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom

[0013] In some embodiments, ring B is phenyl or a 6-membered heteroaryl. In some embodiments, ring B is a 6-membered heteroaryl. In some embodiments, ring B is triazine, pyridine, pyrimidine, pyridazine, pyrazinone, pyrazine, or imidazopyrizine.

[0014] In some embodiments, k is 0 or 1.

[0015] In some embodiments, l is 0 or 1.

[0016] In some embodiments, each X3is CH.

[0017] Provided in some embodiments herein, the compound of Formula (I-1) is a compound having the structure of Formula (I-1a):or a pharmaceutical salt or solvate thereof, wherein: each X1is independently CH or N.

[0018] In some embodiments, o is 1; and p is 0 to 1.

[0019] In some embodiments, G is -(C=O)-NH-.

[0020] Provided in some embodiments herein, the compound of Formula (I-1) is a compound having the structure of Formula (II-1):or a pharmaceutical salt or solvate thereof, wherein: each X1is independently CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1- C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; and n is 1 or 2.

[0021] In some embodiments, R2is halogen, -CN, -OR2a, -N(R2a)2, optionally substituted C1-C6alkyl, or -S(O)2N(R2a)2.

[0022] Provided in some embodiments herein, the compound of Formula (I-1) is a compound having the structure of Formula (III-1): (III-1) or a pharmaceutical salt or solvate thereof, wherein: each X1is independently CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1- C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; and n is 1 or 2.

[0023] In some embodiments, R3is -N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, - NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)2-R3c, or optionally substituted 5- to 8- membered heterocycle; each R3ais independently hydrogen, methyl, or ethyl, wherein the ethyl is optionally substituted with one or more substituents selected from methyl and -OH; and R3bis hydrogen, methyl, ethyl, or propyl. In some embodiments, R3is independently - NHSO2(CH2)2OH, -NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2-oxetanyl, -NMeSO2CH3, -N(SO2Me)(CH2)2OH, or

[0024] In some embodiments, each R4is independently halogen, optionally substituted C1- C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge.

[0025] In some embodiments, R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl.

[0026] In some embodiments, each R2is independently halogen, -OR2a, -N(R2a)2, - S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl.

[0027] Provided in some embodiments herein, the compound of Formula (I-1) is a compound having the structure of Formula (I-0), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)R1a1, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, oxo, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5-to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, - NH-S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m- OR3b, -NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl; R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 to 2; l is 0 to 2; m is 1 to 6; n is 0 to 9; o is 1 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom.

[0028] In some embodiments, ring B can be any suitable functional group described herein. In some embodiments, ring B is a 5- to 12- membered heteroaryl or C6-C12aryl. In some embodiments, ring B is a 5- to 12- membered heteroaryl or phenyl. In some embodiments, ring B is a 5- to 8- membered heteroaryl or phenyl. In some embodiments, ring B is a 5- or 6- membered heteroaryl or phenyl. In some embodiments, ring B is a phenyl. In some embodiments, ring B is a 5-membered heteroaryl. In some embodiments, ring B is a 6- membered heteroaryl. In some embodiments, ring B is triazine, pyridine, pyrimidine, pyridazine, pyrazinone, or pyrazine. In some embodiments, ring B is pyridine, pyrimidine,pyridazine, or pyrazine. In some embodiments, ring B is pyridine or pyrimidine. In some embodiments, ring B is pyridine. In some embodiments, ring B is pyrimidine.

[0029] In some embodiments, k can be any suitable integer described herein. In some embodiments, k is 0 to 2. In some embodiments, k is 0 or 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0030] In some embodiments, l can be any suitable integer described herein. In some embodiments, l is 0 to 2. In some embodiments, l is 0 to 1. In some embodiments, l is 0. In some embodiments, l is 1.

[0031] In some embodiments, each X3can be any suitable functional group described herein. In some embodiments, each X3is independently CH or N. In some embodiments, each X3is CH. In some embodiments, each X3is N. In some embodiments, one X3is N and two X3are CH. In some embodiments, one X3is CH and two X3are N. In some embodiments, at least one X3is CH and at least one R3substituent replaces the hydrogen atom on the CH.

[0032] Provided in some embodiments herein is a compound having the structure of Formula (I-0a), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X1is independently CH or N.

[0033] In some embodiments, X1can be any suitable functional group described herein. In some embodiments, each X1is CH. In some embodiments, each X1is N. In some embodiments, one X1is CH, and one X1is N.

[0034] In some embodiments, o is any suitable integer described herein. In some embodiments, o is 1 to 4. In some embodiments, o is 1 to 2. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

[0035] In some embodiments, p is any suitable integer described herein. In some embodiments, p is 0 to 4. In some embodiments, p is 0 to 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0036] In some embodiments, G is any suitable functional group described herein. In some embodiments, G is -(C=X)-NH- or -NH-(C=X)- and X is O or NR, wherein R is hydrogen, C1- C6alkyl, or optionally combined with an R3to form a heterocyclic ring, or optionally combined with an R4to form a heterocyclic ring. In some embodiments, G is -(C=NR)-NH- or -NH- (C=NR)-, R is being combined with an R3to form a heterocyclic ring. In some embodiments, G is -(C=O)-NH- or -NH(C=O)-. In some embodiments, G is -(C=O)NH-. In some embodiments, G is -NH(C=O)-.

[0037] In some embodiments, R is optionally combined with an R3to form a ring. In some embodiments, R is combined with an R3to form a ring (e.g., a heterocycle, such as forming a quinazoline). In some embodiments, R is combined with an R3to form a heterocycle. In some embodiments, R is taken together with an R3and the atoms to which R and R3are attached to form a quinazoline. In some embodiments, R is taken together with an R3and the atoms to which R and R3are attached to form a pyrimidine.

[0038] In some embodiments, G is -(C=NR)-NH- and R is combined with an R3to form a heterocycle. In some embodiments, G is -(C=NR)-NH- and R is taken together with an R3and the atoms to which R and R3are attached to form a quinazoline.

[0039] In some embodiments, o is 2, G is -(C=NR)-NH- and R is combined with an R3to form a heterocycle. In some embodiments, o is 2, G is -(C=NR)-NH- and R is taken together with an R3and the atoms to which R and R3are attached to form a quinazoline.

[0040] In some embodiments, a compound provided herein has the structure of Formula (II), or a pharmaceutical salt or solvate thereof:wherein: X1is CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, - S-, -SO2-, or -SO2-NR1a;R1ais hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, each R3ais independently hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; m is 1 to 3; and n is 1 or 2.

[0041] In some embodiments, X1can be any suitable functional group described herein. In some embodiments, X1is CH or N. In some embodiments, X1is CH. In some embodiments, X1is N.

[0042] In some embodiments, a compound provided herein has the structure of Formula (III-A), or a pharmaceutical salt or solvate thereof:wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, or -NR1a-, or -NR1a-C1-C3alkylene-; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2.

[0043] In some embodiments, a compound provided herein has the structure of Formula (III-B), or a pharmaceutical salt or solvate thereof:wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene- R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2.

[0044] In some embodiments, p is 1. In some embodiments, a compound provided herein has the structure of Formula (III-C), or a pharmaceutical salt or solvate thereof:wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene;R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, - S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R2is halogen, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl; each R2ais independently hydrogen or C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0, 1, or 2.

[0045] In some embodiments, R2is any suitable functional group described herein.

[0046] In some embodiments, each R2is independently halogen, -CN, -OR2a, -N(R2a)2, - S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3- C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, - CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, - CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, - S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, - SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, -OR2a, -N(R2a)2, or -S(O)2N(R2a)2. In some embodiments, R2is -S(O)2N(R2a)2or -SO2-C1-C6alkyl. In some embodiments, R2is - S(O)2N(R2a)2.

[0047] In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionallysubstituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, or - S(O)2N(R2a)2. In some embodiments, R2is -S(O)2N(R2a)2or -SO2-C1-C6alkyl. In some embodiments, R2is -S(O)2N(R2a)2.

[0048] In some embodiments, R2is halogen. In some embodiments, R2is -CN. In some embodiments, R2is -OR2a. In some embodiments, R2is -N(R2a)2. In some embodiments, R2is -S(O)2N(R2a)2. In some embodiments, R2is -SO2-C1-C6alkyl. In some embodiments, R2is optionally substituted C1-C6alkyl. In some embodiments, R2is optionally substituted C3-C8cycloalkyl. In some embodiments, R2is optionally substituted 5- to 8- membered heterocycle. In some embodiments, R2is optionally substituted 5- to 8- membered heteroaryl.

[0049] In some embodiments, each R2ais any suitable functional group described herein. In some embodiments, each R2ais independently hydrogen or optionally substituted C1-C6alkyl. In some embodiments, each R2ais independently optionally substituted C1-C4alkyl. In some embodiments, each R2ais independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, or tert-butyl. In some embodiments, each R2ais methyl. In some embodiments, one R2ais hydrogen and the other R2ais optionally substituted C1-C6alkyl. In some embodiments, R2is -S(O)2N(R2a)2and each R2ais hydrogen. In some embodiments, R2is - S(O)2N(R2a)2and each R2ais independently optionally substituted C1-C6alkyl. In some embodiments, R2is -S(O)2N(R2a)2and each R2ais methyl. In some embodiments, R2is S(O)2NHC(CH3)3.

[0050] In some embodiments, R2is a 5- to 8- membered heteroaryl. In some embodiments, R2is a 5- to 6- membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl. In some embodiments, R2is a furanyl, furanonyl, isothiazolyl, imidazolyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl. In some embodiments, R2is a pyrazolyl.

[0051] In some embodiments, L1can be any suitable linker structure in any combination of variables L1aand L1bdescribed herein. In some embodiments, L1is a linker comprising the structure -L1a-L1b-.

[0052] In some embodiments, L1acan be any suitable functional group described herein. In some embodiments, L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-. In some embodiments, L1ais a bond, -O-, or -NL1a1-. In some embodiments, L1ais a bond or -O-. In some embodiments, L1ais a bond. In some embodiments, L1ais -O-. In some embodiments, L1ais -NL1a1-. In some embodiments, L1ais -S-. In some embodiments, L1ais -SO2-.

[0053] In some embodiments, L1a1is any suitable functional group described herein. In some embodiments, L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1a1is hydrogen, C1- C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1a1is hydrogen, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, L1a1is hydrogen or C1-C6alkyl. In some embodiments, L1a1is hydrogen. In some embodiments, L1a1is C1-C6alkyl. In some embodiments, L1a1is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, L1a1is methyl.

[0054] In some embodiments, L1ais -NL1a1- and L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen or C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen. In some embodiments, L1ais -NL1a1- and L1a1is C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, L1ais -NL1a1- and L1a1is methyl.

[0055] In some embodiments, L1bis any suitable functional group described herein. In some embodiments, L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene. In some embodiments, L1bis optionally substituted C1-C4alkylene. L1bcan be substituted with any suitable substituent described herein. In some embodiments, L1bis C1-C4alkylene substituted with oxo, C3-C6cycloalkyl, or 3- to 6- membered heterocyclyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo or C3-C6cycloalkyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo, cyclopropyl, or cyclobutyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo. In some embodiments, L1bis C1-C4alkylene substituted with cyclopropyl. In some embodiments, L1bis methylene, ethylene, propylene, butylene, or pentylene. In some embodiments, L1bis methylene. In some embodiments, L1bis ethylene. Insome embodiments, L1bis propylene. In some embodiments, L1bis butylene. In some embodiments, L1bis pentylene.

[0056] In some embodiments, L1ais a bond, -O-, or -NL1a1- and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais a bond and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais -O- and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais -NL1a1-, L1a1is hydrogen or C1-C6alkyl, and L1bis optionally substituted C1-C6alkylene.

[0057] In some embodiments, L1is -O(optionally substituted alkylene)-, -(optionally substituted alkylene)O-, or optionally substituted alkylene. In some embodiments, L1is - O(unsubstituted alkylene)-, -(unsubstituted alkylene)O-, unsubstituted alkylene, or substituted alkylene. In some embodiments, L1is -O(unsubstituted alkylene)-. In some embodiments, L1is -(unsubstituted alkylene)O-. In some embodiments, L1is unsubstituted alkylene. In some embodiments, L1is substituted alkylene.

[0058] In some embodiments, L1is –(CH2)4–, –(CH2)3–, –(CH2)2–, –CH2– –cyclopropyl- (CH2)3–, –cyclopropyl-(CH2)2–, –O(CH2)3–, –O(CH2)2–, or –O(CH2)–. In some embodiments, L1is –(CH2)4–, –cyclopropyl-(CH2)3–, –(CH2)3–, –(CH2)2CO–, –(CH2)2–, –O(CH2)2–, or – CH2–.

[0059] In some embodiments, R1is any suitable functional group described herein. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, - SO2-, or -SO2-NR1a. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, - NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, or -SO2-NR1a. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-, -CO-NR1a-, -NR1a- SO2-, or -SO2-NR1a. In some embodiments, R1is a bond. In some embodiments, R1is -O-. In some embodiments, R1is -NR1a-Q-. In some embodiments, R1is -O-. In some embodiments, R1is -NR1a-. In some embodiments, R1is -NR1a-CO-. In some embodiments, R1is -CO-NR1a- . In some embodiments, R1is -NR1a-SO2-. In some embodiments, R1is -SO2-NR1a.

[0060] In some embodiments, R1ais hydrogen, optionally substituted C1-C6alkyl, C1- C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1ais hydrogen, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1ais hydrogen, C1-C3alkyl, C1-C3alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1ais hydrogen. In some embodiments, R1ais optionally substituted C1-C6alkyl. In some embodiments, R1ais methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. Insome embodiments, R1ais methyl. In some embodiments, R1ais substituted C1-C6alkyl. In some embodiments, R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1ais methylene-C3-C6cycloalkyl. In some embodiments, R1ais methylene-cyclopropyl. In some embodiments, R1ais -SO2-C1-C6alkyl. In some embodiments, R1ais -SO2-Me.

[0061] In some embodiments, R1is -NR1a-Q- and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is a -NR1a-Q- and R1ais hydrogen. In some embodiments, R1is -NR1a-Q- and R1ais optionally substituted C1-C6alkyl. In some embodiments, R1is -NR1a-Q- and R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1is -NR1a-Q- and R1ais -SO2-C1-C6alkyl.

[0062] In some embodiments, Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, Q is optionally substituted C1-C6alkylene. In some embodiments, Q is methylene, ethylene, propylene, or butylene. In some embodiments, Q is methylene.

[0063] In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or - SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1- C6alkylene, and R1ais hydrogen. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais optionally substituted C1-C6alkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais -SO2-C1-C6alkyl.

[0064] In some embodiments, R1is -NR1a- and R1ais hydrogen, optionally substituted C1- C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is - NR1a- and R1ais hydrogen. In some embodiments, R1is -NR1a- and R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a- and R1ais C1-C6alkylene-C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a- and R1ais -SO2- C1-C6alkyl (e.g., methyl).

[0065] In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais hydrogen. In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais C1-C6alkylene-C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais -SO2-C1-C6alkyl (e.g., methyl).

[0066] In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais hydrogen. In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais C1-C6alkylene- C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a-SO2- or - SO2-NR1aand R1ais -SO2-C1-C6alkyl (e.g., methyl).

[0067] In some embodiments, an L1described herein is attached to R1to form -L1-R1-, such as tethering two parts of a compound described herein. In some embodiments, L1R1can be any suitable combination of the L1and R1functional groups described herein. In some embodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –(CH2)3–, –(CH2)3–, –(CH2)2–, –CH2–, – O(CH2)3–, –O(CH2)2–, –O(CH2)2O–, –O(CH2)2NH–, –(CH2)3NSO2–, –(CH2)2N(SO2Me)CH2– , -–(CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, –(CH2)2NHCH2–, –(CH2)2CONH– , –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, –(CH2)2SO2NH–, –(CH2)2NHCO–, – (CH2)2N(Me)CO–, –(CH2)2N(CH2-cyclopropyl)CO–, or –(CH2)2NHSO2–. In some embodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –O(CH2)2NH–, –(CH2)3NSO2–, – (CH2)2N(SO2Me)CH2–, -–(CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, – (CH2)2NHCH2–, –(CH2)2CONH–, –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, – (CH2)2NHCO–, –(CH2)2N(Me)CO–, or –(CH2)2N(CH2-cyclopropyl)CO–. In some embodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –O(CH2)2NH–, –(CH2)2N(Me)CH2–, – (CH2)2N(CH2-cyclopropyl)CH2–, or –(CH2)2NHCH2–. In some embodiments, L1-R1is – (CH2)4NH– or –(CH2)3NH–. In some embodiments, L1-R1is:.

[0068] In some embodiments, each R3is any suitable functional group described herein. In some embodiments each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, -NH- S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, -NH-S(O)2- R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, each R3is independently -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, -NH-S(O)(NH)-(CH2)m-R3a, - NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, -NH-S(O)2-R3c, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle. In some embodiments, In some embodiments, each R3is independently -NR3aS(O)2-(CH2)m-OR3bor -NR3a-S(O)2- (CH2)m-R3a.

[0069] In some embodiments, each R3is independently halogen, -CN, -OR3a, -N(R3a)2, - SR3a, -SO2R3a, -NH-S(O)(NH)-R3a, -NH-S(O)2-(CH2)m-R3a, -NH-S(O)2-(CH2)m-OR3b, - B(R3a)3, or -P(R3a)3. In some embodiments, each R3is independently halogen, -CN, -OR3a, - N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b. In some embodiments, each R3is -SO2R3aor - NH-S(O)2-(CH2)m-OR3b. In some embodiments, each R3is -SO2R3a. In some embodiments, each R3is independently -NH-S(O)2-(CH2)m-OR3b. In some embodiments, an R3is a point of attachment to G.

[0070] In some embodiments, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, methoxy, or ethoxy. In some embodiments, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, and methoxy. In some embodiments, the 5- to 8- ,

[0071] In some embodiments, each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2. In some embodiments, each R3ais independently hydrogen or C1-C6alkyl. In some embodiments, each R3ais independently hydrogen methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In some embodiments, each R3ais independently hydrogen, methyl, or ethyl, wherein the ethyl is optionally substituted with one or more substituents selected from methyl and -OH. In some embodiments, each R3ais hydrogen. In some embodiments, each R3ais independently C1-C6alkyl. In some embodiments, R3ais methyl.

[0072] In some embodiments, R3bis hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R3bis hydrogen or C1-C6alkyl. In some embodiments, R3bis hydrogen. In some embodiments, R3bis C1-C6alkyl. In some embodiments, R3bis hydrogen, methyl, ethyl, orpropyl. In some embodiments, R3bis methyl. In some embodiments, R3bis ethyl. In some embodiments, R3bis n-propyl or isopropyl. In some embodiments, R3bis optionally substituted C3-C6cycloalkyl. In some embodiments, R3bis optionally substituted cyclopropyl. In some embodiments, R3bis cyclopropyl optionally substituted with C1-C6alkyl or C1-C6hydroxyalkyl.

[0073] In some embodiments, R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl. In some embodiments, R3bis hydrogen or C1-C6alkyl. In some embodiments, R3bis hydrogen. In some embodiments, R3bis C1-C6alkyl. In some embodiments, R3bis hydrogen, methyl, ethyl, or propyl. In some embodiments, R3bis methyl. In some embodiments, R3bis ethyl. In some embodiments, R3bis n-propyl or isopropyl.

[0074] In some embodiments, R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle. In some embodiments, R3cis C3-C8cycloalkyl. In some embodiments, R3cis 3- to 8- membered heterocycle. In some embodiments, 4- to 6- membered heterocycle. In some embodiments, R3cis oxetanyl, azetidinyl, or thietanyl. In some embodiments, R3cis oxetanyl or azetidinyl. In some embodiments, R3cis oxetanyl.

[0075] In some embodiments, each R3is independently -NHSO2(CH2)2OH, - NHSO2C(CH3)2CH2OH, -NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, - NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -NMeSO2CH3, - N(SO2Me)(CH2)2OH, or

[0076] In some embodiments, each R3is independently -NHSO2(CH2)2OH, - NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2-oxetanyl, -NMeSO2CH3, - N(SO2Me)(CH2)2OH, or

[0077] In some embodiments, R3is -SO2R3aand R3bis methyl. In some embodiments, R3is -NH-S(O)2-(CH2)m-OR3band R3bis hydrogen. In some embodiments, each R3is independently -NHS(O)2-(CH2)2-OH.

[0078] In some embodiments, m is 1 to 6. In some embodiments, m is 1 to 4. In some embodiments, m is 1 to 3. In some embodiments, m is 1 to 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0079] In some embodiments, o is any suitable integer described herein. In some embodiments, o is 1 to 4. In some embodiments, o is 1 to 3. In some embodiments, o is 1 to 2.In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

[0080] In some embodiments, o is 1 and R3is -SO2R3aor -NH-S(O)2-(CH2)m-OR3b.

[0081] In some embodiments, n is any suitable integer described herein. In some embodiments, n is 0 to 9. In some embodiments, n is 1 to 5. In some embodiments, n is 1 to 3. In some embodiments, n is 1 to 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0082] In some embodiments, R4is any suitable functional group described herein.

[0083] In some embodiments, each R4is independently halogen, -OH, -CN, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1- C3alkylene bridge, or two R4combine to form an oxo. In some embodiments, two R4combine to form a C3-C8cycloalkyl. In some embodiments, two R4are on the same carbon atom. In some embodiments, the two R4groups combine to form a cyclopropyl. In some embodiments, the two R4groups combine to form a butyl. In some embodiments, two R4are on different carbon atoms. In some embodiments, two R4groups combine to form a (1R,5S)-8- azabicyclo[3.2.1]octane. In some embodiments, two R4combine to form a C1-C3alkylene bridge. In some embodiments, n is 2 and two R4combine to form a C3-C8cycloalkyl. In some embodiments, two R4combine to form an oxo.

[0084] In some embodiments, each R4is independently halogen, optionally substituted C1- C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge. In some embodiments, two R4combine to form a C3-C8cycloalkyl. In some embodiments, two R4are on the same carbon atom. In some embodiments, the two R4groups combine to form a cyclopropyl. In some embodiments, the two R4groups combine to form a butyl. In some embodiments, two R4are on different carbon atoms. In some embodiments, two R4groups combine to form a (1R,5S)-8-azabicyclo[3.2.1]octane. In some embodiments, two R4combine to form a C1-C3alkylene bridge. In some embodiments, n is 2 and two R4combine to form a C3-C8cycloalkyl.

[0085] In some embodiments of a compound of Formula (I-0) provided herein, each X3is CH; ring B is triazine, pyridine, pyrimidine, pyridazine, pyrazinone, pyrazine, or imidazopyrizine; L1ais a bond or -O-;G is -(C=O)-NH-; R1is -NR1a-; R1ais hydrogen; each R3is independently -NHSO2(CH2)2OH, -NHSO2C(CH3)2CH2OH, - NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, -NMeSO2(CH2)2OH, - NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -NMeSO2CH3, - N(SO2Me)(CH2)2OH, or k is 0 or 1;l is 0 or 1; o is 1; and p is 0 or 1.

[0086] That is, in some embodiments of a compound of Formula (I-0) provided herein, the compound has the structure of Formula (I-a):or a pharmaceutical salt or solvate thereof, wherein: X1is CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl;each R3is independently -NHSO2(CH2)2OH, -NHSO2C(CH3)2CH2OH, - NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, -NMeSO2(CH2)2OH, - NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -NMeSO2CH3, - N(SO2Me)(CH2)2OH, oreach R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 or 1; l is 0 or 1; n is 0 to 9; o is 1; p is 0 or 1; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom.

[0087] In some embodiments, p is 0. In some embodiments, p is 1.

[0088] Accordingly, in some embodiments, the compound of Formula (I-0) has the structure of Formula (I-a):or a pharmaceutical salt or solvate thereof, wherein: X1is CH or N.

[0089] In some embodiments, L1ais a bond. In some embodiments, L1ais -O-.

[0090] In some embodiments, R3is -NHSO2(CH2)2OH, -NMeSO2(CH2)2OH, - NHSO2CH2CH3, -NHSO2-oxetanyl, -NMeSO2CH3, -N(SO2Me)(CH2)2OH, or Insome embodiments, R3is -NHS(O)2-(CH2)2-OH.

[0091] Accordingly, in some embodiments, the compound of Formula (I-0) has the structure of Formula (V), or a pharmaceutical salt or solvate thereof:

[0092] In some embodiments, R2is a 5- to 8- membered heteroaryl. In some embodiments, R2is a 5- to 6- membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl. In some embodiments, R2is a furanyl, furanonyl, isothiazolyl, imidazolyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl. In some embodiments, R2is a pyrazolyl.

[0093] In some embodiments, L1bis optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene. In some embodiments, L1bis optionally substituted C2-C6alkenylene. In some embodiments, L1bis optionally substituted C2-C6alkynylene.

[0094] In some embodiments, each R4is independently halogen, optionally substituted C1- C6alkyl, optionally substituted C1-C6aminoalkyl, or optionally substituted C1-C6alkoxy.

[0095] In some embodiments, n is 0 to 2. In some embodiments, n is 0.

[0096] Provided herein is a compound having the structure of Formula (A), or a pharmaceutically acceptable salt or solvate thereof:

[0097] In some embodiments, ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl. In some embodiments, ring A is optionally substituted C6-C12aryl. In some embodiments, ring A is optionally substituted 5- to 12- membered heteroaryl.

[0098] In some embodiments, ring A is substituted C6-C12aryl. In some embodiments, ring A is optionally substituted phenyl. In some embodiments, ring A is substituted phenyl. In someembodiments, ring A is phenyl substituted with one or more R3, which is described elsewhere herein, such as hereinabove.

[0099] In some embodiments, ring A is substituted 5- to 12- membered heteroaryl. In some embodiments, ring A is optionally substituted quinazoline. In some embodiments, ring A is quinazoline substituted with one or more R3, which is described elsewhere herein, such as hereinabove. [000100] In some embodiments, ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl. In some embodiments, ring B is optionally substituted C6-C12aryl. In some embodiments, ring B is optionally substituted 5- to 12- membered heteroaryl. [000101] In some embodiments, ring B is substituted C6-C12aryl. In some embodiments, ring B is optionally substituted phenyl. In some embodiments, ring B is substituted phenyl. In some embodiments, ring B is phenyl substituted with one or more R2, which is described elsewhere herein, such as hereinabove. [000102] In some embodiments, ring B is substituted 5- to 12- membered heteroaryl. In some embodiments, ring B is optionally substituted pyridinyl. In some embodiments, ring B is substituted pyridinyl. In some embodiments, ring B is pyridinyl substituted with one or more R2, which are each independently described elsewhere herein, such as hereinabove. [000103] In some embodiments, LXis absent, amino, optionally substituted C1-C6alkylene or optionally substituted C1-C6heteroalkylene. In some embodiments, LXis amino, optionally substituted C1-C6alkylene, or optionally substituted C1-C6heteroalkylene. In some embodiments, LXis amino. In some embodiments, LXis optionally substituted C1-C6alkylene. In some embodiments, LXis optionally substituted C1-C6heteroalkylene. In some embodiments, LXis optionally substituted C1-C6aminoalkylene. In some embodiments, LXis described as G elsewhere herein, such as hereinabove. [000104] In some embodiments, LYis or L1-R1. In some embodiments, LYis. In some embodiments, LYis L1-R1. In some embodiments, (L1-R1) is described elsewhere herein (e.g., hereinabove). [000105] In some embodiments, ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl (e.g., spirocyclyl), optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl. In some embodiments, ring C is optionally substituted C3-C10cycloalkyl or optionally substituted 5- to 12 memberedheterocyclyl. In some embodiments, ring C is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl. [000106] In some embodiments, ring C is optionally substituted C3-C10carbocyclyl. In some embodiments, ring C is optionally substituted C3-C10cycloalkyl. In some embodiments, ring C is spirocyclic. [000107] In some embodiments, ring C is optionally substituted 5- to 12 membered heterocyclyl. In some embodiments, ring C is substituted 5- to 12 membered heterocyclyl. In some embodiments, ring C is spirocyclic. [000108] In some embodiments, ring C is piperidinyl. [000109] In some embodiments, ring C is 6-azaspiro[2.5]octanyl. [000110] In some embodiments, ring C is 5-azaspiro[2.5]octanyl. [000111] In some embodiments, ring C is 7-azaspiro[3.5]nonanyl. [000112] In some embodiments, ring C is optionally substituted C6-C12aryl. In some embodiments, ring C is substituted C6-C12aryl. [000113] In some embodiments, ring C is optionally substituted 5- to 12- membered heteroaryl. In some embodiments, ring C is substituted 5- to 12- membered heteroaryl. [000114] In some embodiments, a compound provided herein has the structure of Formula (B), or a pharmaceutical salt or solvate thereof:[000115] In some embodiments, G is -(C=X)-NH- or -NH-(C=X)-. In some embodiments, X is O or NR. In some embodiments, R is optionally combined with an R3to form a ring (e.g., a heterocycle, such as forming a quinazoline), or optionally combined with an R4to form a heterocyclic ring. In some embodiments, G, X, R, R3, and R4are each independently described elsewhere herein, such as hereinabove. [000116] In some embodiments, a compound provided herein has the structure of Formula (C), or a pharmaceutical salt or solvate thereof:[000117] In some embodiments, L1is a linker comprising the structure -L1a-L1b-. In some embodiments, L1is described elsewhere herein, such as hereinabove. [000118] In some embodiments, L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-. In some embodiments, L1ais described elsewhere herein, such as hereinabove. [000119] In some embodiments, L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, -SO2-C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, L1a1is described elsewhere herein, such as hereinabove. [000120] In some embodiments, L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, L1bis described elsewhere herein, such as hereinabove. [000121] In some embodiments, R1is a bond, -O-, -CO-, -NR1a-, -NR1a-Q-, -NR1a-C1- C6alkylene-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a. In some embodiments, R1is described elsewhere herein, such as hereinabove. [000122] In some embodiments, R1ais hydrogen, optionally substituted C1-C6alkyl, -SO2- C1-C6alkyl, optionally substituted C3-C6cycloalkyl, or C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1ais described elsewhere herein, such as hereinabove. [000123] In some embodiments, Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, Q is described elsewhere herein, such as hereinabove. [000124] In some embodiments, the structure of Formula (A) is:wherein: ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; LXis absent, amino, optionally substituted C1-C6alkylene or optionally substituted C1- C6heteroalkylene (e.g., optionally substituted C1-C6aminoalkylene); LYis or L1-R1;ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl (e.g., spirocyclyl), optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, -SO2-C1-C6alkyl, or optionally substituted C3-C6cycloalkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; R1is a bond, -O-, -CO-, -NR1a-, -NR1a-Q-, -NR1a-C1-C6alkylene-, -NR1a-CO-, -CO- NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, optionally substituted C1-C6alkyl, -SO2-C1-C6alkyl, optionally substituted C3-C6cycloalkyl, or C1-C6alkylene-C3-C6cycloalkyl; and Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. [000125] In some embodiments, the structure of Formula (B) is:wherein: ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl, optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; G is -(C=O)-NH- or -NH-(C=O)-; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl;L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; and Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. [000126] In some embodiments, the structure of Formula (C) is:wherein: ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl (e.g., spirocyclyl), optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C6alkylene; R1is a bond, -O-, -CO-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-, -CO-NR1a-, -NR1a- SO2-, -S-, -SO2-, or -SO2-NR1a; and R1ais hydrogen, C1-C6alkyl, -SO2-C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl. [000127] Provided in some embodiments herein is a compound having a structure provided in Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of the compound or the stereoisomer.Table 1Characterization data of compounds in Table 1[000128] In some embodiments, a compound provided herein has the structure of Formula (IV-A), or a pharmaceutically acceptable salt or solvate, thereof:whereinY1is a halogen, cyanide, alcohol, amide, sulfonamide, sulfoxide, ether, cyclic amine, alkyl amine, heteroaryl, saturated heterocycle, organoboranes, or organophosphophorus; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; G2Ais a bond or -(C=O); G2Bis a bond or -(C=O); N is NH; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, Cl, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; D is nitrogen or carbon; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1; and G1is a group configured to extend into a pocket of KIF18 located between an ^^6- helix and a ^^-sheet of KIF18a and to interact with at least one hydrophobic side chain of Ala352 in the ^^6-helix, Met328 in the ^^-sheet, or Tyr112 in the ^^-sheet. [000129] In some embodiments of a compound of Formula (IV-A), G1is further configured to hydrogen bond with Asn293 in an ^^4-helix of KIF18A. [000130] In some embodiments of a compound of Formula (IV-A), G1is further configured to interact with at least one hydrophobic side chain of Leu110, Leu259, and Met328 in the ^^- sheet of KIF18A. [000131] In some embodiments of a compound of Formula (IV-A), G1is -K-(r)-M-(p)-Q-; K is -O- or CRK1RK2; RK1and RK2are independently hydrogen, halogen, F, Cl, or C1-C6alkyl; or RK1and RK2are combined to form a C3-C5cycloalkyl or 3- to 5- membered heterocycle ring; r is 0, 1, or 2; M is CRM3RM4;RM3and RM4are independently hydrogen or C1-C6alkylene optionally substituted with halogen or oxo; p is 0, 1, or 2 Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen, -SO2R6, or C1-C6alkylene optionally substituted with halogen or oxo; and R6is hydrogen or C1-C6alkyl. [000132] In some embodiments of a compound of Formula (IV-A), G1is further configured to hydrogen bond with Asn293 in an ^^4-helix of KIF18A; wherein G1is represented by the formula -K-(r)-M-(p)-Q-; K is -O- or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; r is 0, 1, or 2; M is CRM3RM4; R3and R4are independently hydrogen or C1-C6alkylene optionally substituted with halogen or oxo; p is 0, 1, or 2; and Q is -O-, -NH-, -NHSO2-, or -SO2NH-. [000133] In some embodiments of a compound of Formula (IV-A), G1is further configured to interact with at least one hydrophobic side chain of Leu110, Leu259, and Met328 in the ^^- sheet of KIF18A; wherein G1is -K-(r)-M-(p)-Q-; K is CRK1RK2; RK1and RK2are independently halogen, or C1-C6alkylene; or RK1and RK2are combined to form a ring; r is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkylene optionally substituted with halogen or oxo; p is 0, 1, or 2 Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen or oxo.[000134] In some embodiments of a compound of Formula (IV-A), G2Ais not equal to G2B. [000135] In some embodiments, a compound provided herein has the structure of Formula (IV-B), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y1is a halogen, cyanide, alcohol, amide, sulfonamide, sulfoxide, ether, cyclic amine, alkyl amine, heteroaryl, saturated heterocycle, organoboranes, or organophosphophorus; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, Cl, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a C3-C5cycloalkyl or 3- to 5- membered heterocycle ring; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen, -SO2R6, or C1-C6alkylene optionally substituted with halogen or oxo; and R6is hydrogen or C1-C6alkyl; r is 0, 1, or 2;p is 0, 1, or 2; and G2is a group configured to provide a linkage with Ar / HetAr ring 1 and Ar / HetAr ring 2. [000136] In some embodiments of a compound of Formula (IV-B), G2is further configured to provide a rigid and quasi-planar linkage with Ar / HetAr ring 1 and Ar / HetAr ring 2 to position the Ar / HetAr ring 1 and Ar / HetAr ring 2 in approximately the same plane and allow delocalization of electrons across the entire conjugated system. [000137] In some embodiments of a compound of Formula (IV-B), G2is represented by the formula -G2A-N-G2B; N is NH; G2Aand G2Bare independently a bond or -(C=O)-, provided that G2Aand G2Bare not both -(C=O); Optionally, N may be taken together with D to form a 5 or 6 membered ring. [000138] In some embodiments of a compound of Formula (IV-B), G2is further configured to provide a rigid and quasi-planar linkage with Ar / HetAr ring 1 and Ar / HetAr ring 2 to position the Ar / HetAr ring 1 and Ar / HetAr ring 2 in approximately the same plane and allow delocalization of electrons across the entire conjugated system; wherein G2is represented by the formula -A-N-B-; N is NH or N may be taken together with D to form a 5 or 6 membered ring; A and B are independently a bond or -(C=O), provided that A and B are not both -(C=O). [000139] In some embodiments, a compound provided herein has the structure of Formula (IV-C), or a pharmaceutically acceptable salt or solvate thereof:wherein: Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl;Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or R1and R2are combined to form a ring; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen, -SO2R6, or C1-C6alkylene optionally substituted with halogen or oxo; and R6is hydrogen or C1-C6alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O)-; G2Bis a bond or -(C=O)-; and Y2is a group configured to form one or more hydrogen bonds with one or more of: a back bone of KIF18A, a side chain of Ser262 of KIF18a, or a residue of α-tubulin. [000140] In some embodiments of a compound of Formula (IV-C), G2Ais not equal to G2B. [000141] In some embodiments of a compound of Formula (IV-C), Y2is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle. [000142] In some embodiments, a compound provided herein has the structure of Formula (IV-D), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y1is a halogen, cyanide, alcohol, amide, sulfonamide, sulfoxide, ether, cyclic amine, alkyl amine, heteroaryl, saturated heterocycle, organoboranes, or organophosphophorus; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1; and M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen, -SO2R6, or C1-C6alkylene optionally substituted with halogen or oxo; and R6is hydrogen or C1-C6alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O)-; G2Bis a bond or -(C=O)-; andG4is a group configured to extend between side chains of Leu285 of KIF18A ^^4- helix and Tyr348 of a KIF18A ^^6-helix. [000143] In some embodiments of a compound of Formula (IV-D), G2Ais not equal to G2B. [000144] In some embodiments of a compound of Formula (IV-D), G4is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl and forms a cyclic conjugated π system. [000145] In some embodiments of a compound of Formula (IV-D), G4 is further configured to hydrogen bond with KIF18A or to engage in water-mediated interactions with KIF18A or ^^-tubulin; and more particularly, may be an optionally substituted optionally substituted 5 to 12 membered heteroaryl and form a cyclic conjugated π system. [000146] In some embodiments, a compound provided herein has the structure of Formula (IV-E), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y1is an halogen, cyanide, alcohol, amide, sulfonamide, sulfoxide, ether, cyclic amine, alkyl amine, heteroaryl, saturated heterocycle, organoboranes, or organophosphophorus; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1;M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen or oxo; Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen, -SO2R6, or C1-C6alkylene optionally substituted with halogen or oxo; and R6is hydrogen or C1-C6alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O)-; G2Bis a bond or -(C=O)-; and G5is a group configured to pack against a flat surface on a KIF18A ^^4-helix formed by Gly289 and to interact with a side chain of Asn293 in the KIF18A ^^4-helix, and optionally, to hydrogen bond with the side chain of Asn293. [000147] In some embodiments of a compound of Formula (IV-E), G2Ais not equal to G2B. [000148] In some embodiments of a compound of Formula (IV-E), G5is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl. [000149] In some embodiments, a compound provided herein has the structure of Formula (IV-F), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y1is a halogen, cyanide, alcohol, amide, sulfonamide, sulfoxide, ether, cyclic amine, alkyl amine, heteroaryl, saturated heterocycle, organoboranes, or organophosphophorus; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl;Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; M is CRM3RM4; R3and R4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen, -SO2R6, or C1-C6alkylene optionally substituted with halogen or oxo; and R6is hydrogen or C1-C6alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O)-; G2Bis a bond or -(C=O); and G6is a group configured to interact with hydrophobic side chains of Tyr112, Leu285, and Leu 288 in a KIF18A ^^4-helix and a hydrophobic side chain of Tyr348 in a KIF18a ^^6-helix. [000150] In some embodiments of a compound of Formula (IV-F), G2Ais not equal to G2B. [000151] In some embodiments of a compound of Formula (IV-F), G6is further configured to interact with hydrophobic side chains of Leu110, Leu259, and Met328 in a KIF18A ^^-sheet. [000152] In some embodiments of a compound of Formula (IV-F), G6is represented by the formula:wherein D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; x is 0, 1, or 2; y is 0, 1, or 2; and z is 0 or 1. [000153] In some embodiments of a compound of Formula (IV-F), G6is further configured to interact with hydrophobic side chains of Leu110, Leu259, and Met328 in a KIF18A ^^-sheet; wherein G6is represented by the formula:wherein D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from hydrogen, F, or alkyl, or RJ1and RJ2with the carbon atom it is attached form a C3-C5cycloalkyl, or a 3- to -5-membered heterocycle. x is 0, 1, or 2; y is 0, 1, or 2; and z is 0 or 1. [000154] In some embodiments, a compound provided herein has the structure of Formula (IV-G) or a pharmaceutically acceptable salt or solvate, thereof:wherein Y1is an halogen, cyanide, alcohol, amide, sulfonamide, sulfoxide, ether, cyclic amine, alkyl amine, heteroaryl, saturated heterocycle, organoboranes, or organophosphophorus; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; A is a bond or -(C=O); B is a bond or -(C=O); N is NH; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, Cl, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; D is nitrogen or carbon; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1; andG7represents a means, between ring 2 and ring 3, for extending into a pocket between an ^^6-helix and a ^^-sheet of KIF18a and interacting with at least one hydrophobic side chain of Ala352 in the ^^6-helix, Met328 in the ^^-sheet, and Tyr112 in the ^^-sheet. [000155] In some embodiments of a compound of Formula (IV-G), the means comprises a group having the formula -K-(r)-M-(p)-Q-; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; r is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); p is 0, 1, or 2; and Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; ; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); R6is hydrogen or optionally substituted alkyl. Optionally, Q is -O-, or -NH2-; R5is hydrogen; R6is hydrogen. Optionally, K is CRK1RK2; RK1and RK2are independently halogen (F) or C1-C6alkyl; or RK1and RK2are combined to form a ring. Adducts [000156] The compounds described herein, for example, the compounds described in the “Compound” section above can be useful for forming an adduct with a KIF18A enzyme. The formation of an adduct between the compounds described herein and KIF18A can be useful for treating cancer. In some embodiments, the formation of the adduct inhibits the KIF18A protein, thereby treating cancer. [000157] An adduct can comprise a KIFA18A protein and a compound of any Formula described herein. [000158] Provided in some embodiments herein is an adduct comprising a KIF18A and a compound of Formula (B) as described herein. The compounds of Formula (B) can be any suitable compound described herein, for example the compounds described in the “Compound” section above.[000159] Provided in some embodiments herein is an adduct comprising a KIF18A and a compound of Formula (B), wherein the structure of Formula (B) is:wherein: ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl, optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; G is -(C=O)-NH- or -NH-(C=O)-; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; and Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. [000160] The compounds described herein have structures which are useful for interacting with KIF18A to bind with it and form an adduct. For example, in non-limiting Formula (B), ring A can be sandwiched between the side chains of the KIF18A in the ^^4-helix and ^^6-helix location of the KIF18A. Aromatic rings which have a planar structure are useful for sandwiching between the ^^4-helix and ^^6-helix. Ring A can also be substituted with a diverse range of polar groups that can form hydrogen bonds that an interact with KIF18A. The linker G between ring A and ring B may be useful for keeping rings A and B in the same plane dueto the carbonyl group allowing for delocalization of the aromatic rings. Ring B can interact against the flat surface of KIF18A ^^4-helix, and can also be useful for forming hydrogen bonds. Ring C can interact with hydrophobic KIF18 residues as a saturated cycloalkyl ring or a heterocycloalkyl ring. For example, ring C can interact with the hydrophobic residues within the ^^4-helix and ^^6-helix region of KIF18A. Additionally, if ring C is substituted with halogens, alkyls, or cycloalkyls, it can contact with a deeper layer of the hydrophobic side chains of the KIF18A ^^-sheet. The L1-R1tether can be useful for interacting with the hydrophobic side chains of the KIF18A ^^-sheet region. Additionally, the L1-R1tether can interact with KIF18A via hydrogen bonding in the ^^4-helix region. The L1-R1tether region can weave through the ^^6-helix and ^^-sheet region of KIF18A and interact with the sidechains. [000161] Ring A can be any suitable functional group described herein. In some embodiments, ring A is optionally substituted C6-C12aryl. In some embodiments, ring A is optionally substituted phenyl. [000162] Ring B can be any suitable functional group described herein. In some embodiments, ring B is a 5- to 12- membered heteroaryl or C6-C12aryl. In some embodiments, ring B is a 5- to 12- membered heteroaryl or phenyl. In some embodiments, ring B is a 5- to 8- membered heteroaryl or phenyl. In some embodiments, ring B is a 5- or 6- membered heteroaryl or phenyl. In some embodiments, ring B is a phenyl. In some embodiments, ring B is a 5-membered heteroaryl. In some embodiments, ring B is a 6- membered heteroaryl. In some embodiments, ring B is triazine, pyridine, pyrimidine, pyridazine, pyrazinone, or pyrazine. In some embodiments, ring B is pyridine, pyrimidine, pyridazine, or pyrazine. In some embodiments, ring B is pyridine or pyrimidine. In some embodiments, ring B is pyridine. In some embodiments, ring B is pyrimidine. [000163] Ring C can be any suitable functional group described herein. In some embodiments, ring C is optionally substituted C3-C10cycloalkyl or optionally substituted 5- to 12 membered heterocyclyl. In some embodiments, ring C is optionally substituted 5- to 12 membered heterocyclyl. In some embodiments, ring C is optionally substituted 5- to 8- membered heterocyclyl. In some embodiments, ring C is optionally substituted 5- to 6- membered heterocyclyl. In some embodiments, ring C is optionally substituted piperidinyl. [000164] In some embodiments, the adduct comprises the compound of Formula (B) which has the structure of Formula (I-0):wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, - NH-S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m- OR3b, -NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl; R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 to 2; l is 0 to 2 ; m is 1 to 6; n is 0 to 9; o is 1 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom. [000165] In some embodiments, the adduct comprises the compound of Formula (B) which has the structure of Formula (I-0a):wherein: each X1is independently CH or N. [000166] In some embodiments, the adduct comprises the compound of Formula (B) which has the structure of Formula (I):[000167] In some embodiments, the adduct comprises the compound of Formula (B) which has the structure of Formula (II):wherein: X1is CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, - S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, each R3ais independently hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; m is 1 to 3; and n is 1 or 2. [000168] In some embodiments, the adduct comprises the compound of Formula (B) which has the structure of Formula (III-A):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene-; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2. [000169] In some embodiments, the adduct comprises the compound of Formula (B) which has the structure of Formula (III-B):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene- R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b,R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2. [000170] In some embodiments, the adduct comprises the compound of Formula (B) which has the structure of Formula (III-C):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, - S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl; each R2ais independently hydrogen or C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0, 1, or 2. [000171] In some embodiments, R2is any suitable functional group described herein.[000172] In some embodiments, each R2is independently halogen, -CN, -OR2a, -N(R2a)2, - S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3- C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, - CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, - CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, - S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, - SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, -OR2a, -N(R2a)2, or -S(O)2N(R2a)2. In some embodiments, R2is -S(O)2N(R2a)2or -SO2-C1-C6alkyl. In some embodiments, R2is - S(O)2N(R2a)2. [000173] In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, or - S(O)2N(R2a)2. In some embodiments, R2is -S(O)2N(R2a)2or -SO2-C1-C6alkyl. In some embodiments, R2is -S(O)2N(R2a)2. [000174] In some embodiments, each R2ais any suitable functional group described herein. In some embodiments, each R2ais independently hydrogen or optionally substituted C1-C6alkyl. In some embodiments, each R2ais independently optionally substituted C1-C4alkyl. In some embodiments, each R2ais independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, or tert-butyl. In some embodiments, each R2ais methyl. In some embodiments, one R2ais hydrogen and the other R2ais optionally substituted C1-C6alkyl. In someembodiments, R2is -S(O)2N(R2a)2and each R2ais hydrogen. In some embodiments, R2is - S(O)2N(R2a)2and each R2ais independently optionally substituted C1-C6alkyl. In some embodiments, R2is -S(O)2N(R2a)2and each R2ais methyl. In some embodiments, R2is S(O)2NHC(CH3)3. [000175] In some embodiments, R2is a 5- to 8- membered heteroaryl. In some embodiments, R2is a 5- to 6- membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl. In some embodiments, R2is a furanyl, furanonyl, isothiazolyl, imidazolyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl. In some embodiments, R2is a pyrazolyl. [000176] In some embodiments, L1can be any suitable linker structure in any combination of variables L1aand L1bdescribed herein. In some embodiments, L1is a linker comprising the structure -L1a-L1b-. [000177] In some embodiments, L1acan be any suitable functional group described herein. In some embodiments, L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-. In some embodiments, L1ais a bond, -O-, or -NL1a1-. In some embodiments, L1ais a bond or -O-. In some embodiments, L1ais a bond. In some embodiments, L1ais -O-. In some embodiments, L1ais -NL1a1-. In some embodiments, L1ais -S-. In some embodiments, L1ais -SO2-. [000178] In some embodiments, L1a1is any suitable functional group described herein. In some embodiments, L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1a1is hydrogen, C1- C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1a1is hydrogen, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, L1a1is hydrogen or C1-C6alkyl. In some embodiments, L1a1is hydrogen. In some embodiments, L1a1is C1-C6alkyl. In some embodiments, L1a1is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, L1a1is methyl. [000179] In some embodiments, L1ais -NL1a1- and L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen or C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen. In some embodiments, L1ais -NL1a1- and L1a1is C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, L1ais -NL1a1- and L1a1is methyl.[000180] In some embodiments, L1bis any suitable functional group described herein. In some embodiments, L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene. In some embodiments, L1bis optionally substituted C1-C4alkylene. L1bcan be substituted with any suitable substituent described herein. In some embodiments, L1bis C1-C4alkylene substituted with oxo, C3-C6cycloalkyl, or 3- to 6- membered heterocyclyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo or C3-C6cycloalkyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo, cyclopropyl, or cyclobutyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo. In some embodiments, L1bis C1-C4alkylene substituted with cyclopropyl. In some embodiments, L1bis methylene, ethylene, propylene, butylene, or pentylene. In some embodiments, L1bis methylene. In some embodiments, L1bis ethylene. In some embodiments, L1bis propylene. In some embodiments, L1bis butylene. In some embodiments, L1bis pentylene. [000181] In some embodiments, L1ais a bond, -O-, or -NL1a1- and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais a bond and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais -O- and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais -NL1a1-, L1a1is hydrogen or C1-C6alkyl, and L1bis optionally substituted C1-C6alkylene. [000182] In some embodiments, L1is -O(optionally substituted alkylene)-, -(optionally substituted alkylene)O-, or optionally substituted alkylene. In some embodiments, L1is - O(unsubstituted alkylene)-, -(unsubstituted alkylene)O-, unsubstituted alkylene, or substituted alkylene. In some embodiments, L1is -O(unsubstituted alkylene)-. In some embodiments, L1is -(unsubstituted alkylene)O-. In some embodiments, L1is unsubstituted alkylene. In some embodiments, L1is substituted alkylene. [000183] In some embodiments, L1is –(CH2)4–, –(CH2)3–, –(CH2)2–, –CH2– –cyclopropyl- (CH2)3–, –cyclopropyl-(CH2)2–, –O(CH2)3–, –O(CH2)2–, or –O(CH2)–. In some embodiments, L1is –(CH2)4–, –cyclopropyl-(CH2)3–, –(CH2)3–, –(CH2)2CO–, –(CH2)2–, –O(CH2)2–, or – CH2–. [000184] In some embodiments, R1is any suitable functional group described herein. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, - SO2-, or -SO2-NR1a. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, - NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a. In some embodiments, R1is abond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, or -SO2-NR1a. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-, -CO-NR1a-, -NR1a- SO2-, or -SO2-NR1a. In some embodiments, R1is a bond. In some embodiments, R1is -O-. In some embodiments, R1is -NR1a-Q-. In some embodiments, R1is -O-. In some embodiments, R1is -NR1a-. In some embodiments, R1is -NR1a-CO-. In some embodiments, R1is -CO-NR1a- . In some embodiments, R1is -NR1a-SO2-. In some embodiments, R1is -SO2-NR1a. [000185] In some embodiments, R1ais hydrogen, optionally substituted C1-C6alkyl, C1- C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1ais hydrogen, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1ais hydrogen, C1-C3alkyl, C1-C3alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1ais hydrogen. In some embodiments, R1ais optionally substituted C1-C6alkyl. In some embodiments, R1ais methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, R1ais methyl. In some embodiments, R1ais substituted C1-C6alkyl. In some embodiments, R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1ais methylene-C3-C6cycloalkyl. In some embodiments, R1ais methylene-cyclopropyl. In some embodiments, R1ais -SO2-C1-C6alkyl. In some embodiments, R1ais -SO2-Me. [000186] In some embodiments, R1is -NR1a-Q- and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is a -NR1a-Q- and R1ais hydrogen. In some embodiments, R1is -NR1a-Q- and R1ais optionally substituted C1-C6alkyl. In some embodiments, R1is -NR1a-Q- and R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1is -NR1a-Q- and R1ais -SO2-C1-C6alkyl. [000187] In some embodiments, Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, Q is optionally substituted C1-C6alkylene. In some embodiments, Q is methylene, ethylene, propylene, or butylene. In some embodiments, Q is methylene. [000188] In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or - SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1- C6alkylene, and R1ais hydrogen. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais optionally substituted C1-C6alkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais -SO2-C1-C6alkyl.[000189] In some embodiments, R1is -NR1a- and R1ais hydrogen, optionally substituted C1- C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is - NR1a- and R1ais hydrogen. In some embodiments, R1is -NR1a- and R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a- and R1ais C1-C6alkylene-C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a- and R1ais -SO2- C1-C6alkyl (e.g., methyl). [000190] In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais hydrogen. In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais C1-C6alkylene-C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais -SO2-C1-C6alkyl (e.g., methyl). [000191] In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais hydrogen. In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais C1-C6alkylene- C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a-SO2- or - SO2-NR1aand R1ais -SO2-C1-C6alkyl (e.g., methyl). [000192] In some embodiments, an L1described herein is attached to R1to form -L1-R1-, such as tethering two parts of a compound described herein. In some embodiments, L1R1can be any suitable combination of the L1and R1functional groups described herein. In some embodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –(CH2)3–, –(CH2)3–, –(CH2)2–, –CH2–, – O(CH2)3–, –O(CH2)2–, –O(CH2)2O–, –O(CH2)2NH–, –(CH2)3NSO2–, –(CH2)2N(SO2Me)CH2– , -–(CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, –(CH2)2NHCH2–, –(CH2)2CONH– , –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, –(CH2)2SO2NH–, –(CH2)2NHCO–, – (CH2)2N(Me)CO–, –(CH2)2N(CH2-cyclopropyl)CO–, or –(CH2)2NHSO2–. In some embodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –O(CH2)2NH–, –(CH2)3NSO2–, – (CH2)2N(SO2Me)CH2–, -–(CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, – (CH2)2NHCH2–, –(CH2)2CONH–, –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, – (CH2)2NHCO–, –(CH2)2N(Me)CO–, or –(CH2)2N(CH2-cyclopropyl)CO–. In someembodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –O(CH2)2NH–, –(CH2)2N(Me)CH2–, – (CH2)2N(CH2-cyclopropyl)CH2–, or –(CH2)2NHCH2–. In some embodiments, L1-R1is – (CH2)4NH– or –(CH2)3NH–. In some embodiments, L1-R1is:. [000193] In some embodiments, each R3is any suitable functional group described herein. In some embodiments each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-(CH2)m-R3a, -NH- S(O)(NH)-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, -NH-S(O)2-R3c, - B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, each R3is independently -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, - SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-(CH2)m-R3a, -NH-S(O)(NH)-R3a, - NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, -NH-S(O)2-R3c, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle. In some embodiments, In some embodiments, each R3is independently -NR3aS(O)2-(CH2)m-OR3bor -NR3a-S(O)2- (CH2)m-R3a. [000194] In some embodiments, each R3is independently halogen, -CN, -OR3a, -N(R3a)2, - SR3a, -SO2R3a, -NH-S(O)(NH)-R3a, -NH-S(O)2-(CH2)m-R3a, -NH-S(O)2-(CH2)m-OR3b, - B(R3a)3, or -P(R3a)3. In some embodiments, each R3is independently halogen, -CN, -OR3a, - N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b. In some embodiments, each R3is -SO2R3aor - NH-S(O)2-(CH2)m-OR3b. In some embodiments, each R3is -SO2R3a. In some embodiments, each R3is independently -NH-S(O)2-(CH2)m-OR3b. In some embodiments, an R3is a point of attachment to G. [000195] In some embodiments, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, methoxy, or ethoxy. In some embodiments, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, and methoxy. In some embodiments, the 5- to 8-[000196] In some embodiments, each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2. In some embodiments, each R3ais independently hydrogen or C1-C6alkyl. In some embodiments, each R3ais independently hydrogen methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In some embodiments, each R3ais independently hydrogen, methyl, or ethyl, wherein the ethyl is optionally substituted with one or more substituents selected from methyl and -OH. In some embodiments, each R3ais hydrogen. In some embodiments, each R3ais independently C1-C6alkyl. In some embodiments, R3ais methyl. [000197] In some embodiments, R3bis hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R3bis hydrogen or C1-C6alkyl. In some embodiments, R3bis hydrogen. In some embodiments, R3bis C1-C6alkyl. In some embodiments, R3bis hydrogen, methyl, ethyl, or propyl. In some embodiments, R3bis methyl. In some embodiments, R3bis ethyl. In some embodiments, R3bis n-propyl or isopropyl. In some embodiments, R3bis optionally substituted C3-C6cycloalkyl. In some embodiments, R3bis optionally substituted cyclopropyl. In some embodiments, R3bis cyclopropyl optionally substituted with C1-C6alkyl or C1-C6hydroxyalkyl. [000198] In some embodiments, R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl. In some embodiments, R3bis hydrogen or C1-C6alkyl. In some embodiments, R3bis hydrogen. In some embodiments, R3bis C1-C6alkyl. In some embodiments, R3bis hydrogen, methyl, ethyl, or propyl. In some embodiments, R3bis methyl. In some embodiments, R3bis ethyl. In some embodiments, R3bis n-propyl or isopropyl. [000199] IN some embodiments, R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle. In some embodiments, R3cis C3-C8cycloalkyl. In some embodiments, R3cis 3- to 8- membered heterocycle. In some embodiments, 4- to 6- membered heterocycle. In some embodiments, R3cis oxetanyl, azetidinyl, or thietanyl. In some embodiments, R3cis oxetanyl or azetidinyl. In some embodiments, R3cis oxetanyl. [000200] In some embodiments, each R3is independently -NHSO2(CH2)2OH, - NHSO2C(CH3)2CH2OH, -NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, -NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -NMeSO2CH3, -[000202] In some embodiments, R3is -SO2R3aand R3bis methyl. In some embodiments, R3is -NH-S(O)2-(CH2)m-OR3band R3bis hydrogen. In some embodiments, each R3is independently -NHS(O)2-(CH2)2-OH. [000203] In some embodiments, m is 1 to 6. In some embodiments, m is 1 to 4. In some embodiments, m is 1 to 3. In some embodiments, m is 1 to 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [000204] In some embodiments, o is any suitable integer described herein. In some embodiments, o is 1 to 4. In some embodiments, o is 1 to 3. In some embodiments, o is 1 to 2. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. [000205] In some embodiments, o is 1 and R3is -SO2R3aor -NH-S(O)2-(CH2)m-OR3b. [000206] In some embodiments, n is any suitable integer described herein. In some embodiments, n is 0 to 9. In some embodiments, n is 1 to 5. In some embodiments, n is 1 to 3. In some embodiments, n is 1 to 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. [000207] In some embodiments, R4is any suitable functional group described herein. [000208] In some embodiments, each R4is independently halogen, -OH, -CN, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1- C3alkylene bridge, or two R4combine to form an oxo. In some embodiments, two R4combine to form a C3-C8cycloalkyl. In some embodiments, two R4are on the same carbon atom. In some embodiments, the two R4groups combine to form a cyclopropyl. In some embodiments, the two R4groups combine to form a butyl. In some embodiments, two R4are on different carbon atoms. In some embodiments, two R4groups combine to form a (1R,5S)-8- azabicyclo[3.2.1]octane. In some embodiments, two R4combine to form a C1-C3alkylene bridge. In some embodiments, n is 2 and two R4combine to form a C3-C8cycloalkyl.[000209] In some embodiments, each R4is independently halogen, optionally substituted C1- C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge. In some embodiments, two R4combine to form a C3-C8cycloalkyl. In some embodiments, two R4are on the same carbon atom. In some embodiments, the two R4groups combine to form a cyclopropyl. In some embodiments, the two R4groups combine to form a butyl. In some embodiments, two R4are on different carbon atoms. In some embodiments, two R4groups combine to form a (1R,5S)-8-azabicyclo[3.2.1]octane. In some embodiments, two R4combine to form a C1-C3alkylene bridge. In some embodiments, n is 2 and two R4combine to form a C3-C8cycloalkyl. [000210] The compounds described herein can interact or contact with the protein described herein when there is suitable adjacent distance between the compound and the protein to form an adduct. In some embodiments, the compounds described herein are adjacent to KIF18A. In some embodiments, adjacent can refer to the distance of about 1 to 10 angstroms between the compound and KIF18A. In some embodiments, it can be about 1 to 8 angstroms between the compound and KIF18A. In some embodiments, it can be about 1 to 5 angstroms between the compound and KIF18A. In some embodiments, it can be about 3 to 5 angstroms between the compound and KIF18A. [000211] The compounds described herein have structures which are useful for interacting with KIF18A to bind with it and form an adduct. For example, ring A can be sandwiched between the side chains of the KIF18A in the ^^4-helix and ^^6-helix location of the KIF18A. Aromatic rings which have a planar structure are useful for sandwiching between the ^^4-helix and ^^6-helix. Ring A can also be substituted with a diverse range of polar groups that can form hydrogen bonds that an interact with KIF18A. The linker G between ring A and ring B may be useful for keeping rings A and B in the same plane due to the carbonyl group allowing for delocalization of the aromatic rings. Ring B can interact against the flat surface of KIF18A ^^4- helix, and can also be useful for forming hydrogen bonds. Ring C can interact with hydrophobic KIF18 residues as a saturated cycloalkyl ring or a heterocycloalkyl ring. For example, ring C can interact with the hydrophobic residues within the ^^4-helix and ^^6-helix region of KIF18A. Additionally, if ring C is substituted with halogens, alkyls, or cycloalkyls, it can contact with a deeper layer of the hydrophobic side chains of the KIF18A ^^-sheet. The L1-R1tether can be useful for interacting with the hydrophobic side chains of the KIF18A ^^-sheet region. Additionally, the L1-R1tether can interact with KIF18A via hydrogen bonding in the ^^4-helixregion. The L1-R1tether region can weave through the ^^6-helix and ^^-sheet region of KIF18A and interact with the sidechains. [000212] In some embodiments, ring A is adjacent to the KIF18A between the KIF18 α4- helix and α6-helix. In some embodiments, ring A is adjacent to the KIF18A between Leu285 residue and Tyr348 residue. [000213] In some embodiments, ring B is adjacent to a flat surface of the KIF18A α4-helix. In some embodiments, ring B is adjacent to the KIF18A Gly289 residue or Asn293 residue. In some embodiments, ring B interacts with the KIF18A Asn293 residue via a hydrogen bond. [000214] In some embodiments, ring C is adjacent to hydrophobic residues of the KIF18A. In some embodiments, the hydrophobic residues of the KIF18A are in α4-helix or α6-helix, or a combination thereof. In some embodiments, ring C is adjacent to the KIF18A Tyr112 residue, Leu284 residue, Leu288 residue, and Tyr348 residue. In some embodiments, ring C is adjacent to the KIF18A Leu110 residue, Leu259 residue, Met328 residue, or a combination thereof. [000215] In some embodiments, L1-R1is adjacent to the hydrophobic side chain of the KIF18A α6-helix and β-sheet. L1-R1is adjacent to the Ala352 residue, Met328 residue, and Tyr112 residue of KIF18A. In some embodiments, L1-R1is adjacent to the hydrophobic side chain of the KIF18A β-sheet. In some embodiments, L1-R1is adjacent to the KIF18A Leu110 residue, Leu259 residue, and Met328 residue. [000216] In some embodiments, R1interacts with the KIF18A α4-helix via a hydrogen bond. In some embodiments, R1interacts with the KIF18A Asn293 residue via the hydrogen bond. [000217] In some embodiments, R3interacts with KIF18A via a hydrogen bond. In some embodiments, R3interacts with the KIF18A Ser262 residue via a hydrogen bond. [000218] Provided in some embodiments is an adduct comprising a KIF18A and a compound of Formula (B), wherein the structure of formula (B) is a compound provided in Table 1. Compositions [000219] The compounds described herein, for example, the compounds described in the “Compound” section above can be useful for forming a composition with a protein. In some embodiments, the composition comprising a protein and a compound described herein form an adduct. In some embodiments, the protein is KIF18A. In some embodiments, the compound can be any suitable compound described herein. [000220] The composition can be useful for treating cancer. In some embodiments, the formation of the adduct inhibits the KIF18A protein, thereby treating cancer.[000221] Provided in some embodiments herein is a composition comprising a protein and a compound, wherein the protein is KIF18A, the compound is a compound of Formula (B), and the protein and the compound form an adduct, wherein structure of Formula (B) is:wherein: ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl, optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; G is -(C=O)-NH- or -NH-(C=O)-; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; and Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene.[000222] In some embodiments, the composition comprises the compound of Formula (B) which has the structure of Formula (I-0):wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)R1a1, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)- (CH2)m-R3a, -NH-S(O)(NH)-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, -NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl ; each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl; R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 to 2; l is 0 to 2 ; m is 1 to 6; n is 0 to 9; o is 1 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom. [000223] In some embodiments, the composition comprises the compound of Formula (B) which has a structure of Formula (I-0a):wherein: each X1is independently CH or N. [000224] In some embodiments, the composition comprises the compound of Formula (B) which has a structure of Formula (I):[000225] In some embodiments, the composition comprises the compound of Formula (B) which has a structure of Formula (II):wherein: X1is CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, - S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, each R3ais independently hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; m is 1 to 3; and n is 1 or 2. [000226] In some embodiments, the composition comprises the compound of Formula (B) which has a structure of Formula (III-A):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene-; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2. [000227] In some embodiments, the composition comprises the compound of Formula (B) which has a structure of Formula (III-B):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene- R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b,R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2. [000228] In some embodiments, the composition comprises the compound of Formula (B) which has a structure of Formula (III-C):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, - S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl; each R2ais independently hydrogen or C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0, 1, or 2. [000229] In some embodiments, R2is any suitable functional group described herein.[000230] In some embodiments, each R2is independently halogen, -CN, -OR2a, -N(R2a)2, - S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3- C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, - CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, - CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, - S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, - SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -CN, -OR2a, -N(R2a)2, or -S(O)2N(R2a)2. In some embodiments, R2is -S(O)2N(R2a)2or -SO2-C1-C6alkyl. In some embodiments, R2is - S(O)2N(R2a)2. [000231] In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R2is halogen, -OR2a, -N(R2a)2, or - S(O)2N(R2a)2. In some embodiments, R2is -S(O)2N(R2a)2or -SO2-C1-C6alkyl. In some embodiments, R2is -S(O)2N(R2a)2. [000232] In some embodiments, each R2ais any suitable functional group described herein. In some embodiments, each R2ais independently hydrogen or optionally substituted C1-C6alkyl. In some embodiments, each R2ais independently optionally substituted C1-C4alkyl. In some embodiments, each R2ais independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, or tert-butyl. In some embodiments, each R2ais methyl. In some embodiments, one R2ais hydrogen and the other R2ais optionally substituted C1-C6alkyl. In someembodiments, R2is -S(O)2N(R2a)2and each R2ais hydrogen. In some embodiments, R2is - S(O)2N(R2a)2and each R2ais independently optionally substituted C1-C6alkyl. In some embodiments, R2is -S(O)2N(R2a)2and each R2ais methyl. In some embodiments, R2is S(O)2NHC(CH3)3. [000233] In some embodiments, R2is a 5- to 8- membered heteroaryl. In some embodiments, R2is a 5- to 6- membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl. In some embodiments, R2is a furanyl, furanonyl, isothiazolyl, imidazolyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl. In some embodiments, R2is a pyrazolyl. [000234] In some embodiments, L1can be any suitable linker structure in any combination of variables L1aand L1bdescribed herein. In some embodiments, L1is a linker comprising the structure -L1a-L1b-. [000235] In some embodiments, L1acan be any suitable functional group described herein. In some embodiments, L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-. In some embodiments, L1ais a bond, -O-, or -NL1a1-. In some embodiments, L1ais a bond or -O-. In some embodiments, L1ais a bond. In some embodiments, L1ais -O-. In some embodiments, L1ais -NL1a1-. In some embodiments, L1ais -S-. In some embodiments, L1ais -SO2-. [000236] In some embodiments, L1a1is any suitable functional group described herein. In some embodiments, L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1a1is hydrogen, C1- C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1a1is hydrogen, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, L1a1is hydrogen or C1-C6alkyl. In some embodiments, L1a1is hydrogen. In some embodiments, L1a1is C1-C6alkyl. In some embodiments, L1a1is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, L1a1is methyl. [000237] In some embodiments, L1ais -NL1a1- and L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen or C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is hydrogen. In some embodiments, L1ais -NL1a1- and L1a1is C1-C6alkyl. In some embodiments, L1ais -NL1a1- and L1a1is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, L1ais -NL1a1- and L1a1is methyl.[000238] In some embodiments, L1bis any suitable functional group described herein. In some embodiments, L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, L1bis optionally substituted C1-C6alkylene. In some embodiments, L1bis optionally substituted C1-C4alkylene. L1bcan be substituted with any suitable substituent described herein. In some embodiments, L1bis C1-C4alkylene substituted with oxo, C3-C6cycloalkyl, or 3- to 6- membered heterocyclyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo or C3-C6cycloalkyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo, cyclopropyl, or cyclobutyl. In some embodiments, L1bis C1-C4alkylene substituted with oxo. In some embodiments, L1bis C1-C4alkylene substituted with cyclopropyl. In some embodiments, L1bis methylene, ethylene, propylene, butylene, or pentylene. In some embodiments, L1bis methylene. In some embodiments, L1bis ethylene. In some embodiments, L1bis propylene. In some embodiments, L1bis butylene. In some embodiments, L1bis pentylene. [000239] In some embodiments, L1ais a bond, -O-, or -NL1a1- and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais a bond and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais -O- and L1bis optionally substituted C1-C6alkylene. In some embodiments, L1ais -NL1a1-, L1a1is hydrogen or C1-C6alkyl, and L1bis optionally substituted C1-C6alkylene. [000240] In some embodiments, L1is -O(optionally substituted alkylene)-, -(optionally substituted alkylene)O-, or optionally substituted alkylene. In some embodiments, L1is - O(unsubstituted alkylene)-, -(unsubstituted alkylene)O-, unsubstituted alkylene, or substituted alkylene. In some embodiments, L1is -O(unsubstituted alkylene)-. In some embodiments, L1is -(unsubstituted alkylene)O-. In some embodiments, L1is unsubstituted alkylene. In some embodiments, L1is substituted alkylene. [000241] In some embodiments, L1is –(CH2)4–, –(CH2)3–, –(CH2)2–, –CH2– –cyclopropyl- (CH2)3–, –cyclopropyl-(CH2)2–, –O(CH2)3–, –O(CH2)2–, or –O(CH2)–. In some embodiments, L1is –(CH2)4–, –cyclopropyl-(CH2)3–, –(CH2)3–, –(CH2)2CO–, –(CH2)2–, –O(CH2)2–, or – CH2–. [000242] In some embodiments, R1is any suitable functional group described herein. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, - SO2-, or -SO2-NR1a. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, - NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a. In some embodiments, R1is abond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, or -SO2-NR1a. In some embodiments, R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-, -CO-NR1a-, -NR1a- SO2-, or -SO2-NR1a. In some embodiments, R1is a bond. In some embodiments, R1is -O-. In some embodiments, R1is -NR1a-Q-. In some embodiments, R1is -O-. In some embodiments, R1is -NR1a-. In some embodiments, R1is -NR1a-CO-. In some embodiments, R1is -CO-NR1a- . In some embodiments, R1is -NR1a-SO2-. In some embodiments, R1is -SO2-NR1a. [000243] In some embodiments, R1ais hydrogen, optionally substituted C1-C6alkyl, C1- C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1ais hydrogen, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1ais hydrogen, C1-C3alkyl, C1-C3alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1ais hydrogen. In some embodiments, R1ais optionally substituted C1-C6alkyl. In some embodiments, R1ais methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl. In some embodiments, R1ais methyl. In some embodiments, R1ais substituted C1-C6alkyl. In some embodiments, R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1ais methylene-C3-C6cycloalkyl. In some embodiments, R1ais methylene-cyclopropyl. In some embodiments, R1ais -SO2-C1-C6alkyl. In some embodiments, R1ais -SO2-Me. [000244] In some embodiments, R1is -NR1a-Q- and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is a -NR1a-Q- and R1ais hydrogen. In some embodiments, R1is -NR1a-Q- and R1ais optionally substituted C1-C6alkyl. In some embodiments, R1is -NR1a-Q- and R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1is -NR1a-Q- and R1ais -SO2-C1-C6alkyl. [000245] In some embodiments, Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene. In some embodiments, Q is optionally substituted C1-C6alkylene. In some embodiments, Q is methylene, ethylene, propylene, or butylene. In some embodiments, Q is methylene. [000246] In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or - SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1- C6alkylene, and R1ais hydrogen. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais optionally substituted C1-C6alkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais C1-C6alkylene-C3-C6cycloalkyl. In some embodiments, R1is -NR1a-Q-, Q is optionally substituted C1-C6alkylene, and R1ais -SO2-C1-C6alkyl.[000247] In some embodiments, R1is -NR1a- and R1ais hydrogen, optionally substituted C1- C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is - NR1a- and R1ais hydrogen. In some embodiments, R1is -NR1a- and R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a- and R1ais C1-C6alkylene-C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a- and R1ais -SO2- C1-C6alkyl (e.g., methyl). [000248] In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais hydrogen. In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais C1-C6alkylene-C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a-CO- or -CO-NR1a- and R1ais -SO2-C1-C6alkyl (e.g., methyl). [000249] In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais hydrogen, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl. In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais hydrogen. In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais optionally substituted C1-C6alkyl (e.g., methyl). In some embodiments, R1is -NR1a-SO2- or -SO2-NR1aand R1ais C1-C6alkylene- C3-C6cycloalkyl (e.g., methylene-cyclopropyl). In some embodiments, R1is -NR1a-SO2- or - SO2-NR1aand R1ais -SO2-C1-C6alkyl (e.g., methyl). [000250] In some embodiments, an L1described herein is attached to R1to form -L1-R1-, such as tethering two parts of a compound described herein. In some embodiments, L1R1can be any suitable combination of the L1and R1functional groups described herein. In some embodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –(CH2)3–, –(CH2)3–, –(CH2)2–, –CH2–, – O(CH2)3–, –O(CH2)2–, –O(CH2)2O–, –O(CH2)2NH–, –(CH2)3NSO2–, –(CH2)2N(SO2Me)CH2– , -–(CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, –(CH2)2NHCH2–, –(CH2)2CONH– , –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, –(CH2)2SO2NH–, –(CH2)2NHCO–, – (CH2)2N(Me)CO–, –(CH2)2N(CH2-cyclopropyl)CO–, or –(CH2)2NHSO2–. In some embodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –O(CH2)2NH–, –(CH2)3NSO2–, – (CH2)2N(SO2Me)CH2–, -–(CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, – (CH2)2NHCH2–, –(CH2)2CONH–, –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, – (CH2)2NHCO–, –(CH2)2N(Me)CO–, or –(CH2)2N(CH2-cyclopropyl)CO–. In someembodiments, L1-R1is –(CH2)4NH–, –cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3– , –(CH2)3N-(CH2-cyclopropyl)–, –(CH2)2NH–, –O(CH2)2NH–, –(CH2)2N(Me)CH2–, – (CH2)2N(CH2-cyclopropyl)CH2–, or –(CH2)2NHCH2–. In some embodiments, L1-R1is – (CH2)4NH– or –(CH2)3NH–. In some embodiments, L1-R1is:. [000251] In some embodiments, each R3is any suitable functional group described herein. In some embodiments each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, -NH- S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, -NH-S(O)2- R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl. In some embodiments, each R3is independently -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, - SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, -NH-S(O)(NH)-(CH2)m-R3a, - NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, -NH-S(O)2-R3c, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle. In some embodiments, In some embodiments, each R3is independently -NR3aS(O)2-(CH2)m-OR3bor -NR3a-S(O)2- (CH2)m-R3a. [000252] In some embodiments, each R3is independently halogen, -CN, -OR3a, -N(R3a)2, - SR3a, -SO2R3a, -NH-S(O)(NH)-R3a, -NH-S(O)2-(CH2)m-R3a, -NH-S(O)2-(CH2)m-OR3b, - B(R3a)3, or -P(R3a)3. In some embodiments, each R3is independently halogen, -CN, -OR3a, - N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b. In some embodiments, each R3is -SO2R3aor - NH-S(O)2-(CH2)m-OR3b. In some embodiments, each R3is -SO2R3a. In some embodiments, each R3is independently -NH-S(O)2-(CH2)m-OR3b. In some embodiments, an R3is a point of attachment to G. [000253] In some embodiments, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, ethyl, propyl, methoxy, or ethoxy. In some embodiments, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, and methoxy. In some embodiments, the 5- to 8-[000254] In some embodiments, each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2. In some embodiments, each R3ais independently hydrogen or C1-C6alkyl. In some embodiments, each R3ais independently hydrogen methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In some embodiments, each R3ais independently hydrogen, methyl, or ethyl, wherein the ethyl is optionally substituted with one or more substituents selected from methyl and -OH. In some embodiments, each R3ais hydrogen. In some embodiments, each R3ais independently C1-C6alkyl. In some embodiments, R3ais methyl. [000255] In some embodiments, R3bis hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, or optionally substituted C3-C6cycloalkyl. In some embodiments, R3bis hydrogen or C1-C6alkyl. In some embodiments, R3bis hydrogen. In some embodiments, R3bis C1-C6alkyl. In some embodiments, R3bis hydrogen, methyl, ethyl, or propyl. In some embodiments, R3bis methyl. In some embodiments, R3bis ethyl. In some embodiments, R3bis n-propyl or isopropyl. In some embodiments, R3bis optionally substituted C3-C6cycloalkyl. In some embodiments, R3bis optionally substituted cyclopropyl. In some embodiments, R3bis cyclopropyl optionally substituted with C1-C6alkyl or C1-C6hydroxyalkyl. [000256] In some embodiments, R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl. In some embodiments, R3bis hydrogen or C1-C6alkyl. In some embodiments, R3bis hydrogen. In some embodiments, R3bis C1-C6alkyl. In some embodiments, R3bis hydrogen, methyl, ethyl, or propyl. In some embodiments, R3bis methyl. In some embodiments, R3bis ethyl. In some embodiments, R3bis n-propyl or isopropyl. [000257] IN some embodiments, R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle. In some embodiments, R3cis C3-C8cycloalkyl. In some embodiments, R3cis 3- to 8- membered heterocycle. In some embodiments, 4- to 6- membered heterocycle. In some embodiments, R3cis oxetanyl, azetidinyl, or thietanyl. In some embodiments, R3cis oxetanyl or azetidinyl. In some embodiments, R3cis oxetanyl. [000258] In some embodiments, each R3is independently -NHSO2(CH2)2OH, - NHSO2C(CH3)2CH2OH, -NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, -NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -NMeSO2CH3, - N(SO2Me)(CH2)2OH, or[000259] In some embodiments, each R3is independently -NHSO2(CH2)2OH, - NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2-oxetanyl, -NMeSO2CH3, - N(SO2Me)(CH2)2OH, or[000260] In some embodiments, R3is -SO2R3aand R3bis methyl. In some embodiments, R3is -NH-S(O)2-(CH2)m-OR3band R3bis hydrogen. In some embodiments, each R3is independently -NHS(O)2-(CH2)2-OH. [000261] In some embodiments, m is 1 to 6. In some embodiments, m is 1 to 4. In some embodiments, m is 1 to 3. In some embodiments, m is 1 to 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [000262] In some embodiments, o is any suitable integer described herein. In some embodiments, o is 1 to 4. In some embodiments, o is 1 to 3. In some embodiments, o is 1 to 2. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. [000263] In some embodiments, o is 1 and R3is -SO2R3aor -NH-S(O)2-(CH2)m-OR3b. [000264] In some embodiments, n is any suitable integer described herein. In some embodiments, n is 0 to 9. In some embodiments, n is 1 to 5. In some embodiments, n is 1 to 3. In some embodiments, n is 1 to 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. [000265] In some embodiments, R4is any suitable functional group described herein. [000266] In some embodiments, each R4is independently halogen, -OH, -CN, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1- C3alkylene bridge, or two R4combine to form an oxo. In some embodiments, two R4combine to form a C3-C8cycloalkyl. In some embodiments, two R4are on the same carbon atom. In some embodiments, the two R4groups combine to form a cyclopropyl. In some embodiments, the two R4groups combine to form a butyl. In some embodiments, two R4are on different carbon atoms. In some embodiments, two R4groups combine to form a (1R,5S)-8- azabicyclo[3.2.1]octane. In some embodiments, two R4combine to form a C1-C3alkylene bridge. In some embodiments, n is 2 and two R4combine to form a C3-C8cycloalkyl.[000267] In some embodiments, each R4is independently halogen, optionally substituted C1- C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge. In some embodiments, two R4combine to form a C3-C8cycloalkyl. In some embodiments, two R4are on the same carbon atom. In some embodiments, the two R4groups combine to form a cyclopropyl. In some embodiments, the two R4groups combine to form a butyl. In some embodiments, two R4are on different carbon atoms. In some embodiments, two R4groups combine to form a (1R,5S)-8-azabicyclo[3.2.1]octane. In some embodiments, two R4combine to form a C1-C3alkylene bridge. In some embodiments, n is 2 and two R4combine to form a C3-C8cycloalkyl. [000268] The composition described herein comprises compounds described herein which can interact or contact with the protein described herein when there is suitable adjacent distance between the compound and the protein to form an adduct. In some embodiments, the compounds described herein are adjacent to KIF18A. [000269] The compounds described herein have structures which are useful for interacting with KIF18A to bind with it and form an adduct in the composition. For example, ring A can be sandwiched between the side chains of the KIF18A in the ^^4-helix and ^^6-helix location of the KIF18A. Aromatic rings which have a planar structure are useful for sandwiching between the ^^4-helix and ^^6-helix. Ring A can also be substituted with a diverse range of polar groups that can form hydrogen bonds that an interact with KIF18A. The linker G between ring A and ring B may be useful for keeping rings A and B in the same plane due to the carbonyl group allowing for delocalization of the aromatic rings. Ring B can interact against the flat surface of KIF18A ^^4-helix, and can also be useful for forming hydrogen bonds. Ring C can interact with hydrophobic KIF18 residues as a saturated cycloalkyl ring or a heterocycloalkyl ring. For example, ring C can interact with the hydrophobic residues within the ^^4-helix and ^^6-helix region of KIF18A. Additionally, if ring C is substituted with halogens, alkyls, or cycloalkyls, it can contact with a deeper layer of the hydrophobic side chains of the KIF18A ^^-sheet. The L1-R1tether can be useful for interacting with the hydrophobic side chains of the KIF18A ^^- sheet region. Additionally, the L1-R1tether can interact with KIF18A via hydrogen bonding in the ^^4-helix region. The L1-R1tether region can weave through the ^^6-helix and ^^-sheet region of KIF18A and interact with the sidechains. [000270] In some embodiments, ring A is adjacent to the KIF18A between the KIF18 α4- helix and α6-helix. In some embodiments, ring A is adjacent to the KIF18A between Leu285 residue and Tyr348 residue.[000271] In some embodiments, ring B is adjacent to a flat surface of the KIF18A α4-helix. In some embodiments, ring B is adjacent to the KIF18A Gly289 residue or Asn293 residue. In some embodiments, ring B interacts with the KIF18A Asn293 residue via a hydrogen bond. [000272] In some embodiments, ring C is adjacent to hydrophobic residues of the KIF18A. In some embodiments, the hydrophobic residues of the KIF18A are in α4-helix or α6-helix, or a combination thereof. In some embodiments, ring C is adjacent to the KIF18A Tyr112 residue, Leu284 residue, Leu288 residue, and Tyr348 residue. In some embodiments, ring C is adjacent to the KIF18A Leu110 residue, Leu259 residue, Met328 residue, or a combination thereof. [000273] In some embodiments, L1-R1is adjacent to the hydrophobic side chain of the KIF18A α6-helix and β-sheet. L1-R1is adjacent to the Ala352 residue, Met328 residue, and Tyr112 residue of KIF18A. In some embodiments, L1-R1is adjacent to the hydrophobic side chain of the KIF18A β-sheet. In some embodiments, L1-R1is adjacent to the KIF18A Leu110 residue, Leu259 residue, and Met328 residue. [000274] In some embodiments, R1interacts with the KIF18A α4-helix via a hydrogen bond. In some embodiments, R1interacts with the KIF18A Asn293 residue via the hydrogen bond. [000275] In some embodiments, R3interacts with KIF18A via a hydrogen bond. In some embodiments, R3interacts with the KIF18A Ser262 residue via a hydrogen bond. [000276] Provided in some embodiments herein is composition comprising a protein and a compound, wherein the protein is KIF18A, the compound is a compound of Formula (B), and the protein and the compound form an adduct, wherein structure of Formula (B) is a compound provided in Table 1. Pharmaceutical Compositions [000277] Provided in some embodiments herein is a pharmaceutical composition comprising a compound provided herein, or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. [000278] Provided in some embodiments herein is a method for preparing a pharmaceutical composition described herein. In some embodiments, the method comprises mixing a pharmaceutically acceptable carrier and a compound provided herein, or pharmaceutically acceptable salt or solvate thereof. [000279] In some embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.[000280] In some embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [000281] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses. [000282] In some embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. [000283] The pharmaceutically acceptable excipients in the pharmaceutical composition described herein can be any suitable pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient is sodium lauryl sulfate, partially pre-gelatinized maize starch, microcrystalline cellulose, sodium starch glycolate,hydroxypropylcellulose LF, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the sodium lauryl sulfate is Kolliphore SLS fine, the partially pre-gelatinized maize starch is Starch 1500, the microcrystalline cellulose is Avicel PH 101, the sodium starch glycolate is type A, the hydroxypropyl cellulose LF is Klucel HPC LF, and the colloidal silicon dioxide is Aerosil Pharma 200. Methods of Treatment [000284] In some embodiments, a compound provided herein, or pharmaceutically acceptable salt or solvate thereof is used in a method for treating cancer. [000285] Provided in some embodiments herein is a method for treating cancer in an individual, the method comprising administering to the individual a compound provided herein or pharmaceutically acceptable salt or solvate thereof. [000286] Provided in some embodiments is a method of inhibiting KIF18A, comprising forming an adduct by contacting KIF18A with any compound of Formula (B). The adduct can comprise any adduct described herein. In some embodiments, the adduct comprising a KIF18A and a compound as provided in Table 1. [000287] Provided in some embodiments in a method of treating cancer in a patient by forming an adduct as described herein. [000288] Cancer is often characterized by unregulated cell proliferation. Damage to one or more genes, responsible for the cellular pathways, which control progress of proliferation through the cell cycle and centrosome cycle, can cause the loss of normal regulation of cell proliferation. These deregulated genes can code for various tumor suppressor or oncogene proteins, which participate in a cascade of events, leading to unchecked cell-cycling progression and cell proliferation. Various kinase and kinesin proteins have been identified, which play key roles in cell cycle and mitotic regulation and progression of normal dividing cells and cancer cells. [000289] In some embodiments, the cancer is mediated by KIF18A. In some embodiments, the cancer is mediated by a misregulation of KIF18A. In some embodiments, the cancer is treated by modulating KIF18A. In some embodiments, the cancer is treated by inhibiting KIF18A. [000290] Provided in some embodiments herein is a method of inhibiting KIF18A with a compound provided herein, or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method comprises contacting KIF18A with the compound. [000291] KIF18A belongs to the Kinesin-8 subfamily and is a plus-end directed motor protein. KIF18A is believed to influence dynamics at the plus end of kinetochore microtubulesto control correct chromosome positioning and spindle tension. Depletion of human KIF18A leads to longer spindles, increased chromosome oscillation at metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells. KIF18A is overexpressed in various types of cancers, including but not limited to colon, breast, lung, pancreas, prostate, bladder, head, neck, cervix, and ovarian cancers. Further, genetic deletion or knockdown, or inhibition of KIF18A affects the mitotic spindle apparatus in cancer cell lines. Particularly, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote cell death in mitosis via apoptosis, mitotic catastrophe, or multipolarity driven lethality or death after mitotic slippage in interphase. [000292] In some embodiments, the cancer is (a) a solid or hematologically derived tumor selected from cancer of the bladder, endometrial, lung squamous cell, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall-bladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, (b) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer or Kaposi's sarcoma. [000293] In some embodiments, the cancer is bladder cancer, endometrial cancer, lung squamous cell cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophagus cancer, gall-bladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreas cancer, stomach cancer, cervix cancer, thyroid cancer, prostate cancer or skin cancer. In some embodiments, the cancer is leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma. In some embodiments, the cancer is acute and chronic myelogenous leukemias, myelodysplastic syndrome or promyelocytic leukemia. In some embodiments, the cancer is fibrosarcoma or rhabdomyosarcoma. In some embodiments, the cancer is melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer or Kaposi's sarcoma. In some embodiments, the cancer is melanoma,prostate cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, sarcoma, or leukemia. [000294] In treatment methods according to embodiments of the invention, an effective amount of at least one compound described herein is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. Definitions [000295] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. [000296] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. [000297] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Theterm "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of" the described features. [000298] “Amino” refers to the –NH2radical. [000299] “Cyano” refers to the -CN radical. [000300] “Nitro” refers to the NO2 radical. [000301] “Oxo” refers to the =O radical. [000302] “Hydroxyl” refers to the -OH radical. [000303] "Alkyl" generally refers to an acyclic (e.g., straight or branched) or cyclic hydrocarbon (e.g., chain) radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C15alkyl). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” unless otherwise stated. Alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as “alkylene” or “alkylenyl” groups). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. In general, alkyl groups are each independently substituted or unsubstituted. In someinstances, an alkyl group provided herein is substituted or further substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [000304] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula –O- alkyl, where alkyl is an alkyl group as defined above. [000305] “Aminoalkyl” refers to a radical bonded through a nitrogen atom of the formula – NH-alkyl, where alkyl is an alkyl group as defined above. [000306] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group provided herein is substituted or further substituted as described for “alkyl” hereinabove. [000307] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, analkynyl group provided herein is substituted or further substituted as described for “alkyl” hereinabove. [000308] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is substituted or further substituted as described for “alkyl” hereinabove. [000309] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5alkenylene). Unless stated specifically otherwise in the specification, the alkenylene is substituted or further substituted as described for “alkyl” hereinabove.[000310] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5alkynylene). Unless stated specifically otherwise in the specification, the alkynylene is substituted or further substituted as described for “alkyl” hereinabove. [000311] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. In some instances, an aryl group provided herein is substituted or further substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [000312] “Aralkyl” or “aryl-alkyl” refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. Unless stated specifically otherwise in the specification, the alkylene chain part of the aralkyl radical is substituted or unsubstituted as described above for an alkylene chain. Unless stated specifically otherwise in the specification, the aryl part of the aralkyl radical is substituted or unsubstituted as described above for an aryl group. [000313] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. In some instances, a carbocyclyl group provided herein is substituted or further substituted with one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated. [000314] “Carbocyclylalkyl” refers to a radical of the formula –Rc-carbocyclyl where Rcis an alkylene chain as defined above. Unless stated specifically otherwise in the specification, the alkylene chain and the carbocyclyl radical are independently substituted or further substituted as defined hereinabove. [000315] “Carbocyclylalkenyl” refers to a radical of the formula –Rc-carbocyclyl where Rcis an alkenylene chain as defined above. Unless stated specifically otherwise, the alkenylene chain and the carbocyclyl radical are independently substituted or further substituted as defined hereinabove. [000316] “Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. Unless stated specifically otherwise, the alkylene chain and the carbocyclyl radical are independently substituted or further substituted as defined hereinabove. [000317] “Halo" or “halogen” refers to fluoro, bromo, chloro, or iodo substituents. [000318] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above, for example, trihalomethyl, dihalomethyl, halomethyl, and the like. In some embodiments, the haloalkyl is a fluoroalkyl, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is substituted or further substituted as defined above for an alkyl group. [000319] The term “heteroalkyl” refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriatenumber of substituents or valencies – for example, -CH2- may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, sulfur, or other suitable heteroatom. In some instances, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)- or having another substituent contemplated herein), or sulfur (e.g. -S-, -S(=O)-, or -S(=O)2-). In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1-C18heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, a heteroalkyl is a C1-C4heteroalkyl. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, heteroalkyl does not include alkoxy as defined herein. Unless stated specifically otherwise, a heteroalkyl group is substituted or further substituted as defined above for an alkyl group. [000320] “Heteroalkylene” refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is substituted or further substituted, as defined above for an alkyl group. [000321] “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl radical is saturated (i.e., containing single C-C bonds only) or unsaturated (e.g., containing one or more double bonds or triple bonds in the ring system). In some instances, the heterocyclyl radical is saturated. In some instances, the heterocyclyl radical is saturated and substituted. In some instances, the heterocyclyl radical is unsaturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In some instances, a heterocyclyl group is substituted or further substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb- O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [000322] “Heterocyclylalkyl” refers to a radical of the formula –Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. Unless stated specifically otherwise in the specification, the heterocyclyl part of the heterocyclylalkyl radical is substituted or further substituted as defined above for a heterocyclyl group. [000323] “Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionallysubstituted as defined above for an alkylene chain. Unless stated specifically otherwise in the specification, the heterocyclyl part of the heterocyclylalkoxy radical is substituted or further substituted as defined above for a heterocyclyl group. [000324] “Heteroaryl” or “aromatic heterocycle” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^– electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, pyrazinone, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). In some instances, a heteroaryl group is substituted or further substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb- O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [000325] “Heteroarylalkyl” refers to a radical of the formula –Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. Unless specifically stated otherwise in the specification, the heteroaryl part of the heteroarylalkyl radical is substituted or further substituted as defined above for a heteroaryl group. [000326] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted asdefined above for an alkylene chain. Unless specifically stated otherwise in the specification, the heteroaryl part of the heteroarylalkoxy radical is substituted or further substituted as defined above for a heteroaryl group. [000327] “Adduct” refers to the combined product of two or more compounds and / or proteins to form a larger structure. For example, the adduct may comprise a protein and a compound described herein which forms a new singular structure. The protein and the compound may bind by protein-compound interactions which include, but are not limited to electrostatic interactions, van der Waals forces, hydrophobic interactions, hydrogen bonding, or covalent bonding. [000328] “Adjacent” refers to being within a specific space and distance of a compound or protein. For example, a compound adjacent to a protein can be within a specific distance such as 20 angstroms or less, or 10 angstroms or less between the compound and protein. In some embodiments, a compound adjacent lies within a distance of about 1 to 6 Angstroms. In some embodiments, a compound adjacent lies within a distance of about 2 to 5 Angstroms. In some embodiments, a compound adjacent lies within a distance of about 3 to 5 Angstroms. In some embodiments, a compound adjacent lies within a distance of about 3 to 6 Angstroms. [000329] In general, optionally substituted groups are each independently substituted or unsubstituted. Each recitation of a optionally substituted group provided herein, unless otherwise stated, includes an independent and explicit recitation of both an unsubstituted group and a substituted group (e.g., substituted in certain embodiments, and unsubstituted in certain other embodiments). In some instances, a substituted group provided herein (e.g., substituted alkyl) is substituted by one or more substituent, each substituent being independently selected from the group consisting of halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (e.g., optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [000330] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. EXAMPLES [000331] The following illustrative examples are representative of embodiments of the stimulation, systems, and methods described herein and are not meant to be limiting in any way. General Synthesis [000332] In some instances, a compound provided herein (e.g., a compound provided in Table 1) is synthesized as described herein. General Synthetic Schemes General synthetic route 1A[000333] In this route key intermediate 3 can be obtained via two alternative approaches. In the first approach starting from acid 1 amide coupling with 6-nitropyridin-2-amine using either a coupling agent, such as HATU, or activating acid by transforming into acid chloride resulted in intermediate 2 which in turn was reduced to aniline 3. In second approach starting from amine 4 and 2-bromo-6-nitopyridine, Pd-catalyzed coupling using PEPPSI and base such asCesium carbonate or similar reagents produced compound 3. After acid-promoted Boc-group removal compound 5 was produced and further underwent base- or heat-mediated SNAr coupling with 2-fluoro-4-iodobenzoic acid to give 6. Boc protection of aniline nitrogen followed by iron-mediated nitro group reduction produced compound 8. Next, a macrocyclization via amide bond formation was forged by coupling agents such us T3P, HATU or other suitable agent. Finally, Cu-or Pd-catalyzed coupling with an appropriate nucleophile in Step 8 followed by acid-promoted Boc removal in Step 9 afforded compound 11. General synthetic route 1B[000334] This route followed the same sequence of transformations as General synthetic route 1A with exception for omitting Boc protection and de-protection of the aniline nitrogen (Steps 5 and 9 in Route 1A).General synthetic route 2A[000335] Acid 1 underwent HATU or other appropriate coupling agent mediated amide coupling with aniline 10 in Step 1 to produce 2. Reduction of amide functionality to aniline 3 followed by acid-catalyzed Boc-protecting group removal yielded intermediate 4. Subsequent SNAr with 2-fluoro-4-iodo-1-nitrobenzene produced 5 and the nitro group reduction using iron gave intermediate 6. The ester was saponificated to carboxylic acid 7 which was subjected to amide coupling reagent such as HATU or similar agents to produce macrocycle 8. Cu- or Pd- catalyzed coupling afforded target compound 9.General synthetic route 2B[000336] Amine 1 and aryl halide 10 underwent base- or heat-mediated SNAr or, alternatively, Pd-catalyzed reaction in Step 1 to produce intermediate 2. Acid-catalyzed selective Boc removal following by base-catalyzed SNAr with fluoro arene 9 gave intermediate 4. Iron-mediated reduction of the nitro group afforded compound 5 which in turn underwent intramolecular amide bond formation facilitated by NaHMDS producing macrocyclic 6. Acid- catalyzed PMB protecting group removal in Step 6 followed by Cu-or Pd-catalyzed couplingin Step 7 with an appropriate nucleophile afforded compound 8.General synthetic route 3A[000337] Intermediate 1 was employed in base-promoted SNAr with aryl fluoride or aryl chloride 6 to afford intermediate 2. Intramolecular amide coupling utilizing HATU, TCFH orother suitable reagent gave macrocycle 3. Following that PMB group was removed under acidic conditions in Step 3 and Cu-or Pd-catalyzed coupling in Step 4 with an appropriate nucleophile afforded final compound 5. General synthetic route 3B[000338] The route followed the same sequence of transformations as General synthetic route 3A with exception for Step 2 which in this route employed Lewis Acid-catalyzed transformation of an ester to an amid thus forging the macrocycle formation. General synthetic route 3C[000339] Intermediate 1 was employed in base-promoted SNAr with aryl fluoride or aryl chloride 7 to afford intermediate 2. The ester group in 2 was hydrolyzed under basic conditions to produce acid 3. Intramolecular amide coupling utilizing HATU, TCFH or other suitable reagent gave macrocycle 4. Following that PMB group was removed under acidic conditions in Step 4 and Cu-or Pd-catalyzed coupling in Step 5 with an appropriate nucleophile afforded final compound 6.General synthetic route 3D[000340] Intermediate 1 was employed in base-promoted SNAr with aryl fluoride or aryl chloride 6 to afford intermediate 2. The ester group in 2 was hydrolyzed under basic conditions, such as LiOH in water-THF to produce acid 3. Intramolecular amide coupling utilizing HATU, TCFH or another suitable reagent gave macrocycle 4. Following that Cu-or Pd-catalyzed coupling in Step 5 with an appropriate nucleophile afforded final compound 5. General synthetic route 3E[000341] Intermediate 1 was employed in base-promoted SNAr with aryl fluoride 2 to afford intermediate 3. Cu-catalyzed reaction with azole 4 resulted in intermediate 5 which was benzylated in with benzoyl chloride 6 to produce amide 7. Deprotection of amine, followed by intramolecular SNAr produce macrocycle 9. Following that Cu-or Pd-catalyzed coupling in Step 6 with an appropriate nucleophile afforded final compound 10 General synthetic route 4A[000342] In Step 1 base- (such as KF and DIPEA) or heat-promoted SNAr between amine 1 and intermediate 2 produced compound 3. Boc group was removed in step 2 under acidic conditions. For compound 4 intramolecular SNAr, promoted by a base such as potassium carbonate in ACN or DMSO, was accomplished in Step 3 to produce macrocycle 5. Finally, Cu-or Pd-catalyzed coupling in Step 4 with an appropriate nucleophile afforded final compound 6.General synthetic route 4B[000343] In Step 1 base-or heat-promoted SNAr between amine 1 and intermediate 2 produced compound 3. Both PMB and Boc groups were removed in step 2 under acidic conditions. For compound 4 intramolecular SNAr, promoted by a base such as potassium carbonate in ACN or DMS, was accomplished in Step 3 to produce macrocycle 5. Finally, Cu- or Pd-catalyzed coupling in Step 4 with an appropriate nucleophile afforded final compound 6.General synthetic route 4C[000344] In Step 1 base-or heat-promoted SNAr between amine 1 and intermediate 2 produced compound 3. Selective Boc group were removal in step 2 under mild acidic conditions furnished 4. Intramolecular SNAr, promoted by a base such as potassium carbonate in ACN or DMSO, was accomplished in Step 3 to produce macrocycle 5. Cu-or Pd-catalyzed coupling in Step 4 with an appropriate nucleophile afforded compound 6. PMB group removal in Step 5 lead to final compound 7. General synthetic route 5[000345] Fully elaborated compound 1 underwent one pot coupling / reduction sequence with a carboxylic acid in presence of sodium borohydride upon reflux in DCE to yield compound 2 or 3 (when formic acid was used). General synthetic route 6[000346] In Step 1 base-or heat-promoted SNAr between amine 1 and aryl halide 2 produced compound 3. Benzamide 4 was incorporated via Cu-mediated coupling in Step 2. Following that Boc was removed under acidic conditions in Step 3. Compound 7 was prepared via intramolecular SNAr, promoted by a base such as potassium carbonate in ACN or DMSO. Finally, Cu-or Pd-catalyzed coupling in Step 5 with an appropriate nucleophile afforded final compound 8. General synthetic route 7A[000347] In Step 1 aniline 1 and ester 2 undergo base-(such as NaHMDS) or Lewis acid- (such as AlMe3) promoted amidation. Following that compound 3 is subjected to Grubbs or similar catalyst to promote macrocyclization via RCM (ring-closing metathesis) to produce amixture of cis and trans isomers 4 (which can be separated at this step or carried forward and separated after step 4). Acid-catalyzed protecting group removal followed by Cu-or Pd- catalyzed coupling in Step 4 with an appropriate nucleophile afforded compound 6 which can be either 1) used as desired final compound or 2) further hydrogenated in step 5 using hydrogen (gas) over Pd / C or other appropriate reductant (such as tosylhydrazide) to reduce the olefine and produce final compound 7. General synthetic route 7B[000348] Same synthetic sequence was employed as in General synthetic route 7A except for in Step 1 amide coupling between aniline 1 and acid 2 was used. General synthetic route 8[000349] In Step 1 aniline 1 and acid 2 undergo amide coupling utilizing HATU, TCFH, oxalyl chloride or other coupling agent. Following that compound 3 is subjected to Grubbs or similar catalyst to promote macrocyclization via RCM (ring-closing metathesis) to produce a mixture of cis and trans isomers 4 (which can be separated at this step or carried forward and separated after step 3). Cu-or Pd-catalyzed coupling in Step 4 with an appropriate nucleophileafforded compound 5 which can be either 1) used as desired final compound or 2) further hydrogenated in step 4 using hydrogen (gas) over Pd / C or other appropriate reductant (such as tosylhydrazide) to reduce the olefine and produce final compound 6. Intermediate A.3-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-4-yl)propanoic acidStep 1: tert-butyl 3-(3-ethoxy-3-oxopropyl)-4-oxopiperidine-1-carboxylate [000350] TsOH-H2O (11.9 g, 62.7 mmol) was added to a mixture of tert-butyl 4- oxopiperidine-1-carboxylate (50 g, 250.9 mmol) and pyrrolidine (71.3 g, 1 mol) in toluene (600 mL). The resulting mixture was heated to 120°C and stirred overnight. After cooling to room temperature, the resulting mixture was concentrated under vacuum to afford the crude product. The residue was dissolved in MeCN (500 mL) and treated with ethyl acrylate (37.7 g, 376 mmol). The resulting mixture was heated to 90 °C and stirred at for 3 hours. After cooling to room temperature, the resulting mixture was concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with PE:EA = 9:1 to afford the desired product tert-butyl 3-(3-methoxy-3-oxopropyl)-4-oxopiperidine-1- carboxylate (20 g, 22.5% yield). LCMS (ESI-MS) m / z = 300.2 [M+H]+. Step 2: tert-butyl 3-(3-ethoxy-3-oxopropyl)-4-methylenepiperidine-1-carboxylate [000351] Potassium tert-butoxide (22.5 g, 200 mmol) was added to mixture of methyltriphenylphosphonium bromide (71.6 g, 200 mmol)^in THF (210 mL). The resulting mixture was stirred at 25 °C for 1 hour, followed by addition of a mixture of tert-butyl 3-(3- ethoxy-3-oxopropyl)-4-oxopiperidine-1-carboxylate (20 g, 66.8 mmol) in THF (100 mL). The resulting mixture was stirred at room temperature overnight, quenched by addition of water (500 mL) and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (3 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with PE:EA = 10:1 to afford the desired product tert-butyl 3-(3-ethoxy-3-oxopropyl)-4- methylenepiperidine-1-carboxylate (16 g, 80.5% yield). LCMS (ESI-MS) m / z = 298.2 [M+H]+.Step 3: tert-butyl 4-(3-ethoxy-3-oxopropyl)-6-azaspiro [2.5] octane-6-carboxylate [000352] A solution of diethyl zinc in toluene (2 M, 100.1 mL, 200.2 mmol) was added to 1,2-dichloroethane (50 mL) followed by addition of diiodomethane (67.5 g, 252.2 mmol) slowly under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 hour. Then a mixture of tert-butyl 3-(3-ethoxy-3-oxopropyl)-4-methylenepiperidine-1-carboxylate (15 g, 50.4 mmol) in 1,2-dichloroethane (50 mL) was added to the reaction mixture above and the resulting mixture was stirred at room temperature overnight. Then Boc2O (22.02 g, 100 mmol), Et3N (20.42 g, 201.7mmol) and EA (100 mL) was added to the resulting mixture above and stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of water (200 mL) and filtered. The filter cake was washed with EA (3 x 100 mL). The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers (3 x 100 mL + 2 x 200 mL) were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE:EA = 9:1 to afford a mixture of tert-butyl 4-(3-ethoxy-3-oxopropyl)-6- azaspiro[2.5]octane-6-carboxylate and tert-butyl 3-(3-ethoxy-3-oxopropyl)-4-methyli- denepiperidine-1-carboxylate (8 g crude with 30% of desired product based on LCMS). LCMS (ESI-MS) m / z = 312.2 [M+H]+. Step 4: 3-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-4-yl)propanoic acid [000353] LiOH (3.7 g, 154.1 mmol) was added to tert-butyl 4-(3-ethoxy-3-oxopropyl)-6- azaspiro[2.5]octane-6-carboxylate (8 g crude, 30% purity based on LCMS) in water (40 mL) and THF (40 mL). The resulting mixture was stirred at 60°C for 2 hours. After removing THF under vacuum, the aqueous phase was acidified to pH 6 by addition of aqueous HCl (1 N). The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and was concentrated under vacuum to afford a mixture of 3-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-4- yl)propanoic acid and 3-(1-(tert-butoxycarbonyl)-4-methylenepiperidin-3-yl)propanoic acid, Intermediate A (7.5 g crude with 30% of desired product based on LCMS).Intermediate B. N2-(4-methoxybenzyl)-6-methyl-N2-(4-(piperidin-3- yl)butyl)pyrimidine-2,4-diamineStep 1: tert-butyl 3-(4-((4-methoxybenzyl)amino)-4-oxobutyl)piperidine-1-carboxylate [000354] DIEA (8.72 g, 67.4 mmol) was added to a stirred mixture of 4-(1-(tert- butoxycarbonyl)piperidin-3-yl)butanoic acid (6.1 g, 22.5 mmol), (4- methoxyphenyl)methanamine (3.08 g, 22.5 mmol) and HATU (12.8 g, 33.7 mmol) in DMF (50 mL). The resulting mixture was stirred at room temperature for 2 hours, diluted with EA (500 ml) and washed with brine (3 x 500 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with EA:PE=1:1 to afford tert-butyl 3-(4-((4-methoxybenzyl)amino)-4-oxobutyl)piperidine-1-carboxylate (7.4 g, 84.2% yield). LCMS (ESI-MS) m / z = 391.2 [M+H]+. Step 2: tert-butyl 3-(4-((4-methoxybenzyl)amino)butyl)piperidine-1-carboxylate [000355] NaBH4(1.74 g, 46.0 mmol) was added to a stirred mixture of tert-butyl 3-(4-((4- methoxybenzyl)amino)-4-oxobutyl)piperidine-1-carboxylate (6 g, 15.4 mmol) and AcOH (2.77 g, 46.0 mmol) in THF (60 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was heated to 70 °C and stirred for 2 hours. After cooling to room temperature, the reaction was quenched with saturated aqueous NaHCO3and diluted with water (200 mL). The resulting mixture was extracted with EA (3 x 200 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under vacuum to afford a crude product. The residue was purified by silica gel column chromatography, eluted with EA:PE=3:2 to afford tert-butyl 3-(4-((4-methoxybenzyl)amino)butyl)piperidine-1-carboxylate (2.8 g, 48.4% yield). LCMS (ESI-MS) m / z = 377.2 [M+H]+. Step 3: tert-butyl 3-(4-((4-amino-6-methylpyrimidin-2-yl)(4- methoxybenzyl)amino)butyl)piperidine-1-carboxylate [000356] DIEA (3.84 g, 29.7 mmol) was added to a stirred mixture of tert-butyl 3-(4-((4- methoxybenzyl)amino)butyl)piperidine-1-carboxylate (2.8 g, 7.43 mmol) and 2-chloro-6-methylpyrimidin-4-amine (1.71 g, 11.9 mmol) in DMSO (30 mL). The resulting mixture was heated to 140 °C and stirred for 16 hours. After cooling to room temperature, the resulting mixture was diluted with EA (500 ml) and washed with brine (3 x 500 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with EA:PE=1:3 to afford tert-butyl 3-(4-((4-amino-6-methylpyrimidin-2-yl)(4- methoxybenzyl)amino)butyl)piperidine-1-carboxylate (1.7 g, 47.2% yield). LCMS (ESI-MS) m / z = 484.3 [M+H]+. Step 4: N2-(4-methoxybenzyl)-6-methyl-N2-(4-(piperidin-3-yl)butyl)pyrimidine-2,4- diamine [000357] TFA (1 mL) was added to a stirred solution of tert-butyl 3-(4-((4-amino-6- methylpyrimidin-2-yl)(4-methoxybenzyl)amino)butyl)piperidine-1-carboxylate (600 mg, 1.24 mmol) in DCM (10 mL). The resulting mixture was cooled to 0 °C and stirred for 2 hours. The reaction was quenched by addition of aqueous saturated NaHCO3(100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford a crude product N2-(4-methoxybenzyl)-6-methyl-N2- (4-(piperidin-3-yl)butyl)pyrimidine-2,4-diamine, Intermediate B (500 mg crude). The crude product was used for next step without purification. LCMS (ESI-MS) m / z = 384.4 [M+H]+. Intermediate C.2-hydroxy-N-(3-oxo-4,6-diaza-5(2,6)-pyridina-1(1,3)-piperidina-2(1,2)- benzenacyclononaphane-25-yl)ethane-1-sulfonamideStep 1.4-(1-(tert-butoxycarbonyl)piperidin-3-yl)butanoic acid [000358] To a RBF with stir bar was added 4-(1-boc-piperidin-3-yl)butyric acid (2.00 g, 1 Eq, 7.37 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (2.12 g, 1.5 Eq, 11.1 mmol), DMAP (450 mg, 0.5 Eq, 3.69 mmol), DCM (80mL), and Benzenemethanamine, 4-methoxy (1.21 g, 1.15 mL, 1.2 Eq, 8.84 mmol). The reaction mixture was then stirred at rt overnight. After 18 h, the reaction mixture was washed with sat. aq. NaHCO3 and water, then the aq. layer was extracted with DCM (3 x). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-100% EtOAc in heptane) provided tert-butyl 3-(4-((4- methoxybenzyl)amino)-4-oxobutyl)piperidine-1-carboxylate (2.857 g, 7.316 mmol, 99.3 %). LCMS M+1 / Z = 391.1 [000359] 1H NMR (499 MHz, CHLOROFORM-d) δ ppm 7.16 - 7.23 (m, 2 H) 6.83 - 6.88 (m, 2 H) 5.70 (br s, 1 H) 4.36 (d, J=5.5 Hz, 2 H) 3.82 - 3.99 (m, 2 H) 3.79 (s, 3 H) 2.74 (ddd, J=13.1, 11.5, 3.0 Hz, 1 H) 2.43 (br s, 1 H) 2.17 (td, J=7.6, 2.1 Hz, 2 H) 1.59 - 1.87 (m, 4 H) 1.33 - 1.48 (m, 11 H) 1.15 - 1.29 (m, 2 H) 0.97 - 1.10 (m, 1 H). Step 2. tert-butyl 3-(4-((4-methoxybenzyl)amino)-4-oxobutyl)piperidine-1-carboxylate [000360] To a RBF was added tert-butyl 3-(4-((4-methoxybenzyl)amino)-4- oxobutyl)piperidine-1-carboxylate (1.85 g, 1 Eq, 4.74 mmol), NaBH4 (591 mg, 3.3 Eq, 15.6 mmol), and THF (20 mL). The reaction mixture was cooled to 0 °C stirred 5 min then acetic acid (939 mg, 894 μL, 3.3 Eq, 15.6 mmol) was added slowly. The reaction mixture was then warmed to 66 °C. After 4 h, the reaction mixture was cooled to rt, diluted with DCM, and quenched with aq. NaHCO3. The aq. layer was extracted with DCM (3 x), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-10% MeOH in DCM with 1% TEA) provided tert-butyl 3-(4- ((4-methoxybenzyl)amino)butyl)piperidine-1-carboxylate (1.283 g, 3.407 mmol, 71.9 %). LCMS M+1 / Z = 377.2 Step 3. tert-butyl 3-(4-((4-amino-6-methylpyrimidin-2-yl)(4- methoxybenzyl)amino)butyl)piperidine-1-carboxylate [000361] To a vial was added tert-butyl 3-(4-((4-methoxybenzyl)amino)butyl)piperidine-1- carboxylate (2.0 g, 1 Eq, 5.3 mmol), 2-Chloro-6-methylpyrimidin-4-yl-amine (0.76 g, 1 Eq, 5.3 mmol), DIPEA (2.1 g, 2.8 mL, 3 Eq, 16 mmol), and dry Isopropanol (10.0 mL). The reaction mixture was then heated to 160 °C in a microwave reactor. After 18 h, the reaction mixture was concentrated and purified directly via Isco column chromatography (0-100% EtOAc in heptane) to provide tert-butyl 3-(4-((4-amino-6-methylpyrimidin-2-yl)(4- methoxybenzyl)amino)butyl)piperidine-1-carboxylate (1.816 g, 3.755 mmol, 71 %). LCMS M+1 / Z = 484.3.1H NMR (499 MHz, CHLOROFORM-d) δ ppm 7.15 - 7.20 (m, 2 H) 6.79 - 6.84 (m, 2 H) 5.63 (s, 1 H) 4.79 (s, 2 H) 4.40 (br s, 2 H) 3.89 (br d, J=13.1 Hz, 2 H) 3.78 (s, 3H) 3.40 - 3.52 (m, 2 H) 2.73 (br s, 1 H) 2.19 (s, 3 H) 1.77 (br dd, J=13.3, 3.4 Hz, 1 H) 1.49 - 1.65 (m, 7 H) 1.34 - 1.48 (m, 13 H). Step 4. N2-(4-methoxybenzyl)-6-methyl-N2-(4-(piperidin-3-yl)butyl)pyrimidine-2,4- diamine hydrochloride [000362] To a vial was added tert-butyl 3-(4-((4-amino-6-methylpyrimidin-2-yl)(4- methoxybenzyl)amino)butyl)piperidine-1-carboxylate (310 mg, 1 Eq, 641 μmol), dioxane (4.0 mL), and Hydrogen chloride in dioxane (117 mg, 801 μL, 4.0 molar, 5 Eq, 3.20 mmol). The reaction mixture was stirred at rt. After 90 min the solvent was removed in vacuo and the crude material was used for the next step without further purification. LCMS M+1 / Z = 384.2 Step 5.2-(3-(4-((4-amino-6-methylpyrimidin-2-yl)(4- methoxybenzyl)amino)butyl)piperidin-1-yl)-4-bromobenzoic acid [000363] To the crude material from the previous step was added 4-bromo-2-fluorobenzoic acid (211 mg, 1.5 Eq, 961 μmol), K2CO3 (443 mg, 5 Eq, 3.20 mmol), DMSO (4.0 mL) were added. The reaction mixture was heated to 140 °C. After 48 h, the reaction mixture was diluted with EtOAc and washed with brine (5 x), dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-10% MeOH in DCM) provided 2-(3-(4-((4-amino-6- methylpyrimidin-2-yl)(4-methoxybenzyl)amino)butyl)piperidin-1-yl)-4-bromobenzoic acid (180 mg, 309 μmol, 48.2 % over 2 steps). LCMS M+1 / Z = 582.2.1H NMR (499 MHz, CHLOROFORM-d) δ ppm 8.15 (d, J=8.5 Hz, 1 H) 7.49 - 7.55 (m, 2 H) 7.13 - 7.20 (m, 2 H) 6.78 - 6.83 (m, 2 H) 5.62 (s, 1 H) 4.72 - 4.82 (m, 2 H) 4.43 (br s, 2 H) 3.77 (s, 3 H) 3.39 - 3.52 (m, 2 H) 2.95 - 3.10 (m, 2 H) 2.79 (br t, J=11.4 Hz, 1 H) 2.61 (s, 2 H) 2.40 - 2.54 (m, 1 H) 2.16 (s, 3 H) 1.87 - 1.95 (m, 2 H) 1.74 - 1.84 (m, 2 H) 1.53 (br dd, J=12.6, 6.3 Hz, 2 H) 1.18 - 1.32 (m, 4 H). Step 6.25-bromo-6-(4-methoxybenzyl)-56-methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,3)- piperidina-2(1,2)-benzenacyclodecaphan-3-one [000364] To a vial was added 2-(3-(4-((4-amino-6-methylpyrimidin-2-yl)(4- methoxybenzyl)amino)butyl)piperidin-1-yl)-4-bromobenzoic acid (150 mg, 1 Eq, 257 μmol), triethylamine (104 mg, 144 μL, 4 Eq, 1.03 mmol), DCE (8.0 mL), and HATU (196 mg, 2 Eq, 515 μmol). The reaction mixture was then stirred at 85 °C. After 18 h, the reaction mixture was concentrated and purified directly via Isco column chromatography (0-50% EtOAc in heptane) to provide25-bromo-6-(4-methoxybenzyl)-56-methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,3)- piperidina-2(1,2)-benzenacyclodecaphan-3-one (50.5 mg, 89.5 μmol, 34.7 %). LCMS M+1 / Z = 564.1.1H NMR (499 MHz, CHLOROFORM-d) δ ppm 13.32 - 13.80 (m, 1 H) 11.98 - 12.47 (m, 1 H) 8.03 - 8.31 (m, 1 H) 7.47 (br d, J=5.7 Hz, 1 H) 7.32 - 7.41 (m, 1 H) 7.24 (d, J=8.5 Hz,3 H) 6.84 (d, J=8.5 Hz, 2 H) 5.05 - 5.25 (m, 1 H) 4.84 (br d, J=17.2 Hz, 1 H) 4.41 - 4.59 (m, 1 H) 3.79 (s, 3 H) 2.84 - 3.84 (m, 2 H) 2.27 - 2.62 (m, 4 H) 2.04 - 2.20 (m, 1 H) 1.86 (br s, 2 H) 1.69 (br s, 2 H) 1.54 (s, 2 H) 0.85 - 1.58 (m, 5 H). Step 7.25-bromo-56-methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,3)-piperidina-2(1,2)- benzenacyclodecaphan-3-one [000365] To a solution of 25-bromo-6-(4-methoxybenzyl)-56-methyl-4,6-diaza-5(4,2)- pyrimidina-1(1,3)-piperidina-2(1,2)-benzenacyclodecaphan-3-one (1.32 g, 1 Eq, 2.34 mmol) in DCM (4.0 mL) was added TFA (5.33 g, 3.60 mL, 20 Eq, 46.8 mmol). The reaction mixture was stirred at rt. After 18 hours, the reaction mixture was concentrated in vacuo and directly purified via Isco column chromatography (0-70% EtOAc in heptane) to provide 25-bromo-56- methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,3)-piperidina-2(1,2)-benzenacyclodecaphan-3-one, Intermediate C (541 mg, 1.22 mmol, 52.1 %). LCMS M+1 / Z = 444.0 Intermediate D.3-(1-(1-(tert-butoxycarbonyl) piperidin-4-yl)cyclopropyl)propanoic acidStep 1. ethyl 1-(pyridin-4-yl)cyclopropane-1-carboxylate [000366] NaH (60% in mineral oil, 7.26 g, 303 mmol) was added to a stirred mixture of ethyl 2-(pyridin-4-yl)acetate (10 g, 60.5 mmol) in DMF (100 mL) and THF (100 mL) at 0 °C. After stirring for 30 minutes, dibromoethane (34.1 g, 182 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours, quenched by addition of saturated aqueous NH4Cl (200 mL) and extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified with silica gel column, eluted with EA:PE = 1:1 to afford the desiredproduct ethyl 1-(pyridin-4-yl)cyclopropane-1-carboxylate (8 g, 64.7%, yield). LCMS (ESI- MS) m / z =192.2 [M+H]+. Step 2. ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate [000367] PtO2(0.95 g, 4.18 mmol) was added to a stirred mixture of ethyl 1-(pyridin-4- yl)cyclopropane-1-carboxylate (8 g, 41.8 mmol) and conc. HCl (5 mL, 165 mmol) in EtOH (100 mL) under nitrogen atmosphere. The resulting mixture stirred at room temperature for 16 hours under hydrogen atmosphere, filtered and the filtrate was concentrated under vacuum to afford the crude product ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate (6.2 g crude). The crude product was used for next step without further purification. LCMS (ESI-MS) m / z = 198.2 [M+H]+. Step 3. tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperidine-1-carboxylate [000368] A solution of NaHCO3(7.92 g, 94.3 mmol) in water (50 mL) was added to a stirred mixture of ethyl 1-(piperidin-4-yl)cyclopropane-1-carboxylate (6.2 g, 31.4 mmol) and Boc2O (6.86 g, 31.4 mmol) in dioxane (100 mL). The resulting mixture was stirred at room temperature for 5 hours, diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The residue was purified with silica gel column, eluted with PE:EA = 3:1 to afford the desired product tert-butyl 4-(1- (ethoxycarbonyl)cyclopropyl)piperidine-1-carboxylate (4.2 g, 42.7% yield). LCMS (ESI-MS) m / z = 298.3 [M+H]+. Step 4. tert-butyl 4-(1-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate [000369] LiAlH4(1.61 g, 42.4 mmol) was added to stirred mixture of tert-butyl 4-(1- (ethoxycarbonyl)cyclopropyl) piperidine-1-carboxylate (4.2 g, 14.1 mmol) in THF (80 mL) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 3 hours, carefully quenched by addition of saturated aqueous NH4Cl (50 mL) dropwise at 0 °C and then extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, evaporated to afford the crude product tert-butyl 4-(1- (hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (3.2 g crude). The crude product was used for next step without further purification. LCMS (ESI-MS) m / z = 256.3 [M+H]+. Step 5. tert-butyl 4-(1-formylcyclopropyl)piperidine-1-carboxylate [000370] Dess-Martin periodinane (11.5 g, 27.0 mmol) was added to a stirred mixture of tert- butyl 4-(1-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (3.2 g, 13.5 mmol) in DCM(60 mL). The resulting mixture was stirred at room temperature for 16 hours and concentrated directly under vacuum. The residue was purified with silica gel column, eluted with PE:EA = 1:1 to afford the desired product tert-butyl 4-(1-formylcyclopropyl)piperidine-1-carboxylate (3 g, 78.9% yield). LCMS (ESI-MS) m / z = 254.2 [M+H]+. Step 6. tert-butyl (E)-4-(1-(3-ethoxy-3-oxoprop-1-en-1-yl)cyclopropyl)piperidine-1- carboxylate [000371] LiCl (0.65 g, 15.4 mmol) and DBU (5.00 g, 32.8 mmol) was added to a stirred mixture of tert-butyl 4-(1-formylcyclopropyl)piperidine-1-carboxylate (2.6 g, 10.3 mmol) and triethyl phosphonoacetate (2.76 g, 12.6 mmol) in MeCN (50 mL). The resulting mixture was stirred at room temperature for 16 hours and concentrated under vacuum. The residue was purified with silica gel column, eluted with PE:EA = 1:1 to afford the desired product tert-butyl (E)-4-(1-(3-ethoxy-3-oxoprop-1-en-1-yl)cyclopropyl)piperidine-1-carboxylate (2.4 g, 67.9% yield). LCMS (ESI-MS) m / z = 324.2 [M+H]+. Step 7. tert-butyl 4-(1-(3-ethoxy-3-oxopropyl)cyclopropyl)piperidine-1-carboxylate [000372] A solution of NaOAc (1.83 g, 22.3 mmol) in water (20 mL) was added to a stirred mixture of tert-butyl (E)-4-(1-(3-ethoxy-3-oxoprop-1-en-1-yl)cyclopropyl)piperidine-1- carboxylate (2.4 g, 7.42 mmol) and 4-toluenesulfonyl hydrazide (2.76 g, 14.8 mmol) in THF (20 mL). The resulting mixture was heated to 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product tert-butyl 4-(1-(3- ethoxy-3-oxopropyl)cyclopropyl)piperidine-1-carboxylate (2.4 g crude). The crude product was used for next step without further purification. LCMS (ESI-MS) m / z = 326.2 [M+H]+. Step 8.3-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)cyclopropyl)propanoic acid [000373] A solution of NaOH (0.88 g, 22.1 mmol) in water (40 mL) was added to stirred mixture of tert-butyl 4-(1-(3-ethoxy-3-oxopropyl)cyclopropyl)piperidine-1-carboxylate (2.4 g, 7.37 mmol) in THF (40 mL). The resulting mixture was stirred at room temperature for 16 hours and THF was evaporated off under vacuum. The PH value of the aqueous phase was adjusted to around 5~6 by addition of aqueous HCl (1 M). Then the resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified with silica gel column, eluted with DCM:MeOH = 10:1 to afford the desired product3-(1-(1-(tert-butoxycarbonyl) piperidin-4-yl)cyclopropyl)propanoic acid, Intermediate D (2.1 g, 91.8% yield). LCMS (ESI-MS) m / z = 298.3 [M+H]+. Intermediate E. tert-butyl 4-(4-aminobutyl)-6-azaspiro[2.5]octane-6-carboxylateStep 1. tert-butyl (Z)-4-(4-ethoxy-4-oxobutylidene)-6-azaspiro[2.5]octane-6-carboxylate [000374] A solution of 1M NaHMDS in THF (44.5 ml) was added to (4-ethoxy-4- oxobutyl)triphenylphosphanium bromide (20.3 g, 44.5 mmol) in THF (50 mL) under nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 1 hour. Tert-butyl 4-oxo-6- azaspiro[2.5]octane-6-carboxylate (5 g, 22.1 mmol) was added to the reaction mixture and the resulting solution was stirred at room temperature overnight. The reaction was quenched with sat. NH4Cl (aq.) (100 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl (4Z)-4-(4-ethoxy-4-oxobutylidene)-6-azaspiro[2.5]octane-6-carboxylate(2 g, 27.8% yield). LCMS (ESI-MS) m / z = 223.2 [M+H-Boc]+. Step 2. tert-butyl (Z)-4-(4-hydroxybutylidene)-6-azaspiro[2.5]octane-6-carboxylate [000375] LiAlH4(0.65 g, 17 mmol) was added to tert-butyl (4Z)-4-(4-ethoxy-4- oxobutylidene)-6-azaspiro[2.5]octane-6-carboxylate in THF (60 mL) under nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with sat. NH4Cl (aq.) (120mL) at 0°C. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3x1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product tert-butyl (Z)-4-(4-hydroxybutylidene)-6- azaspiro[2.5]octane-6-carboxylate(4.6 g crude). LCMS (ESI-MS) m / z = 282.2 [M+H]+.Step 3. tert-butyl 4-(4-hydroxybutyl)-6-azaspiro[2.5]octane-6-carboxylate [000376] NaOAc (4 g, 49 mmol) in water (40 mL) was added to a mixture of tert-butyl (Z)- 4-(4-hydroxybutylidene)-6-azaspiro[2.5]octane-6-carboxylate (4.6 g, 16.3 mmol) and TsNHNH2(18.3 g, 98 mmol) in DME (40 mL). The resulting mixture was heated to 95°C and stirred for 16 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (40 mL) at room temperature. The resulting mixture was extracted with EA (3 x 40mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford tert-butyl 4-(4-hydroxybutyl)-6-azaspiro[2.5]octane-6-carboxylate (4.2 g, 90% yield). LCMS (ESI-MS) m / z = 284.2 [M+H]+. Step 4. tert-butyl 4-(4-(1,3-dioxoisoindolin-2-yl)butyl)-6-azaspiro[2.5]octane-6- carboxylate [000377] DIAD (10.1 g, 50.2 mmol) was added to a mixture of tert-butyl 4-(4-hydroxybutyl)- 6-azaspiro[2.5]octane-6-carboxylate (9.5 g, 33.5 mmol), phthalimide (5.4 g, 36.8 mmol) and PPh3(13.2 g, 50.3 mmol) in THF (100 mL) under nitrogen atmosphere at 0°C. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl 4-[4-(1,3-dioxoisoindol-2-yl)butyl]-6-azaspiro[2.5]octane-6- carboxylate (12 g, 82.4% yield). LCMS (ESI-MS) m / z = 413.2 [M+H]+. Step 5. tert-butyl 4-(4-aminobutyl)-6-azaspiro[2.5]octane-6-carboxylate [000378] Hydrazine hydrate (0.61 g, 12.1 mmol) was added to a stirred mixture of tert-butyl 4-[4-(1,3-dioxoisoindol-2-yl)butyl]-6-azaspiro[2.5]octane-6-carboxylate (2 g, 4.85 mmol) in EtOH (30 mL) at rt. The resulting mixture was stirred heated to 80 °C and stirred for 1 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product (700 mg crude), intermediate E. The crude product was used in the next step directly without further purification. LCMS (ESI-MS) m / z = 283.2 [M+H]+.Intermediate F. tert-butyl 4-(4-((4-methoxybenzyl)amino)butyl)-6-azaspiro[2.5]octane-6- carboxylate[000379] To a solution of Intermediate E (22.00 g, 77.898 mmol, 1.0 eq) in MeOH (220 mL) was added p-Anisaldehyde (11.14 g, 81.793 mol, 1.05 eq) and CH3COOH (46.78 mg, 0.779 mmol, 0.01 eq). The reaction was stirred at 20 °C for 1 h, then STAB (41.27 g, 194.745 mmol, 2.5 eq) was added at 10 °C. The reaction was condensed under reduced pressure. The crude residue was added to NaOH aqueous solution (200 mL, 8% in water) and MTBE (200 mL), stirred well for 10 min, separated the solution, extracted the aqueous phase with MTBE (200 mL). Combined the organic phase, washed with saturated saline (50 mL), dried over MgSO4, filtered and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel flash chromatography (Heptane:THF=20:1~5:1~1:1) to afford tert-butyl 4-(4-((4- methoxybenzyl)amino)butyl)-6-azaspiro[2.5]octane-6-carboxylate, Intermediate F (22.06 g, 54.798 mmol, 70.35% yield). LC-MS[M+H]+=403.4.1HNMR (CDCl3, 400 MHz) 6.86-7.28 (m, 4H), 3.77-4.05 (m, 6H), 2.60-3.14 (m, 7H), 1.79-2.01 (m, 1H), 1.22-1.65 (m, 14H), 0.58- 0.95 (m, 2H), 0.20-0.41 (m, 4H). Intermediate G.4-bromo-N-(2-chloro-6-methylpyrimidin-4-yl)-2-fluorobenzamide[000380] (COCl)2(1.51 g, 11.9 mmol) was added to a stirred mixture of 4-bromo-2- fluorobenzoic acid (2 g, 9.13 mmol) in DCM (20 mL) at 0 °C, followed by addition of DMF (0.1 mL). After stirring for 1 hour, the reaction mixture was evaporated under vacuum and dissolved in DMF (5 mL). At the same time, NaH (60% in mineral oil, 280 mg, 11.9 mmol) was added to a stirred mixture of 2-chloro-6-methylpyrimidin-4-amine (1.31 g, 9.13 mmol) in DMF (20 mL) at 0 °C. After stirring for 1 hours, the former solution was added. The resulting mixture was stirred at 0 °C for 1 hours, quenched by addition of saturated aqueous NH4Cl (20 mL) and extracted with EA (2 x 50 mL). The combined organic layers were washed with brine(20 x 2mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified with silica gel column, eluted with EA:PE = 3:1 to afford the desired product 4-bromo-N-(2-chloro-6-methylpyrimidin-4-yl)-2-fluorobenzamide (1.3 g, 41.3 % yield). LCMS (ESI-MS) m / z = 344.1 [M+H]+. Intermediate H.4-bromo-N-(2-chloropyrimidin-4-yl)-2-fluorobenzamide[000381] Intermediate H was synthesized via the same procedure as Intermediate G using 2- chloropyrimidin-4-amine in place of 2-chloro-6-methylpyrimidin-4-amine. Intermediate I. N4-(4-methoxybenzyl)-6-methyl-N4-(4-(piperidin-3-yl)butyl)pyridine- 2,4-diamine[000382] Intermediate I was synthesized via the same procedure as Intermediate B using 4- chloro-6-methylpyridin-2-amine in place of 2-chlro-6-methylpyrimidin-4-amine in Step 3.Intermediate J. tert-butyl 4-(1-(3-((4- methoxybenzyl)amino)propyl)cyclopropyl)piperidine-1-carboxylateStep 1. tert-butyl 4-(1-(3-(benzyloxy)propyl)-2,2-dibromocyclopropyl)piperidine-1- carboxylate [000383] In two batches to a solution of tert-butyl 4-(5-(benzyloxy)pent-1-en-2- yl)piperidine-1-carboxylate (90.0 g, 250 mmol, 1.00 eq) and t-BuOK (140 g, 1.25 mol, 5.00 eq) in hexane (900 mL) was slowly added CHBr3(316 g, 1.25 mol, 5.00 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hr. The reaction was quenched by addition Sat.NH4Cl 500 mL for 2 hrs, then extracted with EtOAc 500 mL x 3. The combined organic layers were washed with brine 500 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC(0.1% FA condition) to produce tert-butyl 4-(1-(3-(benzyloxy)propyl)-2,2-dibromocyclopropyl)piperidine-1- carboxylate (64.9 g, 123 mmol, 49.0% yield). LCMS: m / z = 271.0 (M+H+-100) Step 2. tert-butyl 4-(1-(3-(benzyloxy)propyl)cyclopropyl)piperidine-1-carboxylate [000384] Two batches: To a solution of tert-butyl 4-(1-(3-(benzyloxy)propyl)-2,2- dibromocyclopropyl)piperidine-1-carboxylate (60.0 g, 113 mmol, 1.00 eq), Ni(OAc)2-H2O (1.41 g, 5.67 mmol, 0.05 eq), 3.4,7,8-tetramethyl-1,10-phenanthroline (2.67 g, 11.3 mmol, 0.10 eq), pyridine (13.4 g, 171 mmol, 1.50 eq) and TPGS-750-M (2.00% w / w) in THF (600 mL) and H2O (120 mL) was slowly NaBH4(21.5 g, 565 mmol, 5.00 eq) added under Ar atmosphere. The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition 1MHCl to adjust pH to 7, then extracted with EtOAc 200 mL x 3. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 10 / 1, Rf of P1 = 0.6) to produce tert-butyl 4-(1- (3-(benzyloxy)propyl)cyclopropyl)piperidine-1-carboxylate (27.3 g, 73.1 mmol, 64.3% yield). LCMS: m / z = 274.1 (M+H+-100) Step 3. tert-butyl 4-(1-(3-hydroxypropyl)cyclopropyl)piperidine-1-carboxylate [000385] Two batches: To a solution of tert-butyl 4-(1-(3- (benzyloxy)propyl)cyclopropyl)piperidine-1-carboxylate (21.0 g, 56.3 mmol, 1.00 eq) in i- PrOH (210 mL) was added Pd(OH)2 / C (20% purity, 20% w / w) under Ar atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(50.0 Psi) at 60 °C for 24 hr. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-(1-(3-hydroxypropyl)cyclopropyl)piperidine-1-carboxylate (12.8 g, 45.2 mmol, 80.5% yield). LCMS: m / z = 184 (M+H+-100) Step 4. tert-butyl 4-(1-(3-oxopropyl)cyclopropyl)piperidine-1-carboxylate [000386] Two batches: To a solution of tert-butyl 4-(1-(3- hydroxypropyl)cyclopropyl)piperidine-1-carboxylate (20.0 g, 70.6 mmol, 1.00 eq) in DCM (200 mL) was slowly added DMP (59.8 g, 141 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. TLC (Petroleum ether : Ethyl acetate = 3:1, Rf of R1 = 0.4, Rf of P1 = 0.6) indicated Reactant 1 was consumed completely and one new spots formed. The reaction was quenched by addition Sat.Na2S2O3300 mL, then extracted with DCM 150 mL x 3. The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1, Rfof P1 = 0.6) to produce tert-butyl 4-(1-(3-oxopropyl)cyclopropyl)piperidine-1-carboxylate (14.6 g, 50.1 mmol, 73.7%yield) was obtained. Step 5. tert-butyl 4-(1-(3-((4-methoxybenzyl)amino)propyl)cyclopropyl)piperidine-1- carboxylate [000387] Two batches: To a solution of tert-butyl 4-(1-(3-oxopropyl)cyclopropyl)piperidine- 1-carboxylate (18.0 g, 64.0 mmol, 1.00 eq) and PMBNH2(9.65 g, 70.4 mmol, 1.1 eq) in MeOH (180 mL) was added NaBH(OAc)3(27.1 g, 128mmol, 2.00 eq) at 0 °C, then the reaction mixture was stirred at 25 °C for 1 hr. TLC (Petroleum ether : Ethyl acetate = 3:1, Rf of R1 = 0.6, Rf of P1 = 0.05) indicated Reactant 1 was consumed completely and one new spots formed. The reaction was concentrated under reduced pressure to remove EtOH. The residue wasquenched by addition Sat.NaHCO3200 mL , then extracted with EtOAc 100 mL * 3. The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC, column: Welch Ultimate XB-CN 250*70*10um;mobile phase: [Hexane-EtOH（0.1% NH3.H2O）];gradient:5%-45% B over 15 min to afford tert-butyl 4-(1-(3-((4- methoxybenzyl)amino)propyl)cyclopropyl)piperidine-1-carboxylate, Intermediate J (11.0 g, 27.3 mmol, 42.7% yield). LCMS: m / z = 403.3 (M+H+) [000388]1H NMR (400 MHz, DMSO-d6) δ 7.19 - 7.24 (m, 2H), 6.83 - 6.88 (m, 2H), 3.91 - 4.01 (m, 2H), 3.72 (s, 3H), 3.57 - 3.63 (m, 2H), 2.54 (s, 1H), 2.41 (t, J=6.82 Hz, 2H), 1.50 (br d, J=11.88 Hz,2 H), 1.38 (s, 9H), 1.30 - 1.36 (m, 2H), 1.21 - 1.30 (m, 3H), 1.12 (br d, J=11.88 Hz, 1H), 1.04 (td, J=12.2, 4.00 Hz, 2H), 0.23 - 0.29 (m, 2H), 0.13 - 0.20 (m, 2H). Intermediate K. N4-(4-methoxybenzyl)-N4-(3-(1-(piperidin-4- yl)cyclopropyl)propyl)pyrimidine-2,4-diamine[000389] Intermediate K was synthesized from Intermediate J via the same procedure as for Intermediate B steps 3 and 4 using 4-chloropyrimidin-2-amine in place of 2-chlro-6- methylpyrimidin-4-amine in Step 3. Intermediate L. N4-(4-methoxybenzyl)-6-methyl-N4-(3-(1-(piperidin-4- yl)cyclopropyl)propyl)pyrimidine-2,4-diamine[000390] Intermediate L was synthesized from Intermediate J via the same procedure as Intermediate B steps 3 and 4.Intermediate M. N2-(4-(6-azaspiro[2.5]octan-4-yl)butyl)-N2-(4-methoxybenzyl)-6- methylpyrimidine-2,4-diamine[000391] Intermediate M was synthesized from Intermediate F via the same procedure as Intermediate B steps 3 and 4. Intermediate N. N2-(4-(6-azaspiro[2.5]octan-4-yl)butyl)-N2-(4- methoxybenzyl)pyrimidine-2,4-diamine[000392] Intermediate N was synthesized from Intermediate F and 2-chloropyrimidin-4- amine via the same procedure as Intermediate B steps 3 and 4. Intermediate O.6-bromo-N-(2-chloropyrimidin-4-yl)-2-fluoronicotinamide was prepared following the synthetic scheme outlined below.[000393] To a vial was added 2-Chloro-pyrimidin-4-ylamine (1.18 g, 4 Eq, 9.09 mmol), 6- bromo-2-fluoronicotinic acid (500 mg, 1 Eq, 2.27 mmol), N- (chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (765 mg, 1.2 Eq, 2.73 mmol), DIPEA (1.18 g, 1.58 mL, 4 Eq, 9.09 mmol), and THF (10 mL). The reaction mixture was then heated to 50 °C. After 18 h, the reaction mixture was diluted with water and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0- 40% EtOAc in heptanes) followed by purification via prepHPLC (10-100% MeCN in 0.1%TFA water) provided 6-bromo-N-(2-chloropyrimidin-4-yl)-2-fluoronicotinamide (214 mg, 645 μmol, 28.4 %) as a white solid after neutralization and extraction. LCMS M+1 / Z = 332.9 Intermediate P.4-bromo-N-(6-chloro-5-cyanopyridin-2-yl)-2-fluorobenzamideIntermediate P [000394] To a stirred solution of 4-bromo-2-fluorobenzoic acid (856 mg, 3.91 mmol) in DCM (2 mL) were added (COCl)2(645 mg, 5.08 mmol) and DMF (2 mL) dropwise at 0 °C. Then the reaction mixture was stirred for 2 hours. After completion of reaction, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride. To a stirred solution of 6-amino-2-chloropyridine-3-carbonitrile (600 mg, 3.91 mmol) in anhydrous DMF (2 mL) was added NaH (281 mg, 11.7 mmol) at 0 °C and the resulting was stirred for 1 hour before being treated with a solution of the acid chloride in DMF (1mL). The resulting mixture was stirred for 2 hours and then was quenched with H2O (10 mL) and the aqueous layer was extracted with EA (2 x 10 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA 4 : 1 to afford 4-bromo-N-(6-chloro-5-cyanopyridin-2-yl)-2- fluorobenzamide (470 mg, 29.5% yield). LCMS (ESI-MS) m / z =353.9 [M+H]+. Intermediate Q. N2-(but-3-en-1-yl)-N2-(4-methoxybenzyl)-6-methylpyrimidine-2,4- diamine.Step 1. N-(4-methoxybenzyl)but-3-en-1-amine [000395] To a solution of 3-buten-1-amine (10 g, 140 mmol) in DCM (150 mL) was added anisaldehyde (19.1 g, 140 mmol) and TEA (42.7 g, 422 mmol). The resulting solution was stirred at room temperature for 16 hours. Then the reaction mixture was cooled to 0 °C. MeOH (50 mL) and NaBH4(5.32 g, 140 mmol) were added. The resulting mixture was stirred at 0 °C for 2 hours and pH of the mixture was adjusted to 2.0 by adding 1 N HCI (aq). The reaction mixture was extracted with DCM (100 mL x 2) and the water phase was collected. The pH ofthe water phase was adjusted to 8.0 by adding aq. NaHCO3solution and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford N-(4-methoxybenzyl)but-3-en-1- amine (6.7 g crude). LCMS (ESI-MS) m / z = 192.1 [M+H]+. Step 2. N2-(but-3-en-1-yl)-N2-(4-methoxybenzyl)-6-methylpyrimidine-2,4-diamine [000396] DIEA (8.11 g, 62.7 mmol) was added to a mixture of N-(4-methoxybenzyl)but-3- en-1-amine (3 g, 15.7 mmol) and 2-chloro-6-methylpyrimidin-4-amine (2.25 g, 15.7 mmol) in DMSO (50 mL). The resulting solution was heated to 140 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE 1:1 to afford the desired product N2-(but-3-en-1-yl)-N2-(4-methoxybenzyl)-6-methylpyrimidine-2,4-diamine (1.4 g, 28.6% yield). LCMS (ESI-MS) m / z = 299.0 [M+H]+. Intermediate R. Methyl 2-(4-allylpiperidin-1-yl)-4-bromobenzoate.Step 1. tert-butyl 4-allylpiperidine-1-carboxylate [000397] DBU (13.4 g, 88.0 mmol) was added to a mixture of tert-butyl 4-(2- oxoethyl)piperidine-1-carboxylate (10 g, 44.0 mmol) and methyltriphenylphosphonium bromide (31.4 g, 88.0 mmol) in ACN (100 mL). The resulting solution was heated to reflux and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (200 mL x 2) and water (150 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE 5:1 to afford the desired product tert-butyl 4- allylpiperidine-1-carboxylate (8 g, 79.1% yield). LCMS (ESI-MS) m / z = 226.1 [M+H]+. Step 2.4-allylpiperidine [000398] Into a 250-mL round-bottom flask, was placed tert-butyl 4-allylpiperidine-1- carboxylate (8 g, 35.5 mmol) and HCl in 1,4-dioxane (4M, 100 mL, 400 mmol). The resultingsolution was stirred at room temperature for 3 hours. The residue was evaporated and dried under vacuum to afford 4-allylpiperidine (4.2 g crude). LCMS (ESI-MS) m / z = 126.1 [M+H]+. Step 3. methyl 2-(4-allylpiperidin-1-yl)-4-bromobenzoate [000399] K2CO3(11.0 g, 79.9 mmol) was added to a mixture of 4-allylpiperidine (2 g, 16.0 mmol) and methyl 4-bromo-2-fluorobenzoate (3.72 g, 16.0 mmol) in DMSO (40 mL, 563 mmol). The resulting solution was heated to 140 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE 1:2 to afford methyl 2-(4-allylpiperidin- 1-yl)-4-bromobenzoate (5 g, 72.8% yield). LCMS (ESI-MS) m / z = 338.0 [M+H]+. Intermediate S. N2-allyl-N2-(4-methoxybenzyl)pyrimidine-2,4-diamineStep 1. N-(4-methoxybenzyl)prop-2-en-1-amine [000400] Et3N (5.41 g, 53.4 mmol) was added to a mixture of 4-methoxybenzaldehyde (7.28 g, 53.4 mmol) and prop-2-en-1-amine hydrochloride (5 g, 53.4 mmol) in DCM (150 mL). The mixture was stirred at room temperature overnight. NaBH4(13.6 g, 64.1 mmol) and MeOH (150 mL) were added to the reaction mixture at 0 °C and the resulting was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum. The resulting mixture was quenched with sat. NaHCO3(aq.) (400 mL) at room temperature. The resulting mixture was extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford N-(4-methoxybenzyl)prop-2-en-1-amine (5 g, 47.5% yield). LCMS (ESI-MS) m / z =178.1 [M+H]+. Step 2. N2-allyl-N2-(4-methoxybenzyl)pyrimidine-2,4-diamine [000401] DIEA (5.99 g, 46.3 mmol) was added to a mixture of 2-chloropyrimidin-4-amine (2 g, 15.4 mmol) and N-(4-methoxybenzyl)prop-2-en-1-amine (2.74 g, 15.4 mmol) in DMSO (20 mL). The mixture was stirred at 140 °C overnight. The reaction was quenched with water(100 mL) at room temperature. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (450 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford N2-allyl-N2-(4- methoxybenzyl)pyrimidine-2,4-diamine (1.2 g, 25.8% yield). LCMS (ESI-MS) m / z = 271.1 [M+H]+. Intermediate T. tert-butyl 4-(3-aminopropoxy)-6-azaspiro[2.5]octane-6-carboxylateStep 1. tert-butyl 4-(3-(benzyloxy)propoxy)-6-azaspiro[2.5]octane-6-carboxylate [000402] A solution of tert-butyl 4-hydroxy-6-azaspiro[2.5]octane-6-carboxylate (4.6 g, 20.2 mmol) in DMF (50 mL) was treated with NaH (728 mg, 30.4 mmol) for 1 hour at 0 °C under nitrogen atmosphere followed by the addition of ((3-bromopropoxy)methyl)benzene (5.1 g, 22.3 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with EA (500 ml) and washed with brine (3 x 500 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with EA / PE 1:8 to afford tert-butyl 4-(3-(benzyloxy)propoxy)-6-azaspiro[2.5]octane-6-carboxylate (1.5 g, 19.7% yield). LCMS (ESI-MS) m / z = 376.2 [M+H]+. Step 2. tert-butyl 4-(3-hydroxypropoxy)-6-azaspiro[2.5]octane-6-carboxylate [000403] Pd / C (1 g, 9.39 mmol) was added to a stirred solution of tert-butyl 4-(3- (benzyloxy)propoxy)-6-azaspiro[2.5]octane-6-carboxylate (1.5 g, 3.99 mmol) in MeOH (20 mL). The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction mixture was filtered off and the filtrate was concentrated to afford tert-butyl 4-(3- hydroxypropoxy)-6-azaspiro[2.5]octane-6-carboxylate (1 g crude). LCMS (ESI-MS) m / z = 286.2 [M+H]+.Step 3. tert-butyl 4-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-6-azaspiro[2.5]octane-6- carboxylate [000404] DIAD (1.06 g, 5.25 mmol) was added to a stirred mixture of tert-butyl 4-(3- hydroxypropoxy)-6-azaspiro[2.5]octane-6-carboxylate (1 g, 3.50 mmol), isoindoline-1,3- dione (620 mg, 4.20 mmol) and PPh3(1.38 g, 5.25 mmol) in THF (15 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with EA / PE 2:3 to afford tert-butyl 4-(3-(1,3-dioxoisoindolin- 2-yl)propoxy)-6-azaspiro[2.5]octane-6-carboxylate (1.2 g, 82.6% yield). LCMS (ESI-MS) m / z = 415.1 [M+H]+. Step 4. tert-butyl 4-(3-aminopropoxy)-6-azaspiro[2.5]octane-6-carboxylate [000405] Hydrazine hydrate (15 mL) was added to a solution of tert-butyl 4-(3-(1,3- dioxoisoindolin-2-yl)propoxy)-6-azaspiro[2.5]octane-6-carboxylate (1.2 g, 2.89 mmol) in EtOH (20 mL). The resulting mixture was heated to 60 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in EA (200 ml) and washed with brine (3 x 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl 4-(3-aminopropoxy)-6-azaspiro[2.5]octane-6-carboxylate (700 mg crude). LCMS (ESI-MS) m / z = 285.3 [M+H]+.Intermediate U. tert-butyl 3-(4-aminobutyl)-4,4-difluoropiperidine-1-carboxylate.Step 1. tert-butyl 3-(3-ethoxy-3-oxopropyl)-4-oxopiperidine-1-carboxylate [000406] Pyrrolidine (21.4 g, 301 mmol) was added to a mixture of tert-butyl 4- oxopiperidine-1-carboxylate (20 g, 100 mmol) and 4-methylbenzenesulfonic acid (2.6 g, 15.1 mmol) in toluene (1 L). The resulting solution was heated to 120 °C and stirred for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under vacuum to afford a crude product. The residue was dissolved in ACN (200 mL) and ethyl acrylate (10 g, 100 mmol). The resulting solution was heated to 90 °C and stirred for 2 hours. Then water (66.6 mL) was added. The resulting solution was heated to 100 °C and stirred for 20 hours. After cooling to room temperature, the reaction mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the desired product tert-butyl 3-(3-ethoxy-3-oxopropyl)-4-oxopiperidine-1-carboxylate (18 g crude) as a yellow oil. LCMS (ESI-MS) m / z =300.1 [M+H]+. Step 2. tert-butyl 3-(3-ethoxy-3-oxopropyl)-4,4-difluoropiperidine-1-carboxylate [000407] DAST (29.1 g, 180 mmol) was added to a mixture of tert-butyl 3-(3-ethoxy-3- oxopropyl)-4-oxopiperidine-1-carboxylate (18 g, 60.1 mmol) in DCM (240 mL). The resultingsolution was stirred for 10 h at -78 °C under nitrogen atmosphere, quenched by addition of 10 % sodium bicarbonate (1000 mL) at 0 °C and then extracted with DCM (2 x 1000 mL). The combined organic layers were washed with brine (2 x 1000 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA 8:1 to afford the desired product tert-butyl 3-(3-ethoxy-3- oxopropyl)-4,4-difluoropiperidine-1-carboxylate (11 g, 57 % yield). LCMS (ESI-MS) m / z = 322.1 [M+H]+. Step 3. tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)piperidine-1-carboxylate [000408] LiAlH4(2.6 g, 68.5 mmol) was added to a mixture of tert-butyl 3-(3-ethoxy-3- oxopropyl)-4,4-difluoropiperidine-1-carboxylate (11 g, 34.2 mmol) and in THF (110 mL). The resulting mixture was stirred for 4 h at 0 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (300 mL) at 0 °C. The resulting mixture was extracted with EA (2 x 300 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl 4,4- difluoro-3-(3-hydroxypropyl)piperidine-1-carboxylate (6 g crude). LCMS (ESI-MS) m / z = 280.2 [M+H]+. Step 4. tert-butyl 4,4-difluoro-3-(3-(tosyloxy)propyl)piperidine-1-carboxylate [000409] TsCl (4.91 g, 25.7 mmol) was added to a mixture of tert-butyl 4,4-difluoro-3-(3- hydroxypropyl)piperidine-1-carboxylate (6 g, 21.5 mmol) , and Et3N (6.52 g, 64.4 mmol) in DCM (120 mL) at 0 °C. The resulting mixture was stirred for 4 h at 0 °C under nitrogen atmosphere. The reaction mixture was diluted with water (120 mL) ,extracted with EA (2 x 120 mL). The combined organic layers were washed with brine (2 x 120 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA 8:1 to afford the desired product tert-butyl 4,4- difluoro-3-(3-(tosyloxy)propyl)piperidine-1-carboxylate (6 g, 64.4 % yield). LCMS (ESI-MS) m / z = 434.1 [M+H]+. Step 5. tert-butyl 3-(3-cyanopropyl)-4,4-difluoropiperidine-1-carboxylate [000410] Bu4N+CN-(3.06 g, 11.4 mmol) was added to a mixture of tert-butyl 4,4-difluoro-3- (3-(tosyloxy)propyl)piperidine-1-carboxylate (6 g, 13.8 mmol) in ACN (150 mL). The resulting mixture was heated to 65 °C and stirred for 3 hours under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) and extracted with EA (2 x 250 mL). The combined organic layers were washed with brine (5 x 200 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl 3-(3-cyanopropyl)-4,4-difluoropiperidine-1-carboxylate (4.2 g crude). LCMS (ESI-MS) m / z = 289.1 [M+H]+. Step 6. tert-butyl 3-(4-aminobutyl)-4,4-difluoropiperidine-1-carboxylate [000411] BH3in THF (1 M, 36.4 mL, 36.4 mmol) was added to a mixture of tert-butyl 3-(3- cyanopropyl)-4,4-difluoropiperidine-1-carboxylate (4.2 g, 14.6 mmol) in THF (50 mL). The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched with MeOH (20 ml) at 0 °C. The residue was diluted with water (300 mL) and extracted with EA (2 x 300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH 7:2 to afford the desired product tert-butyl 3-(4-aminobutyl)-4,4-difluoropiperidine-1-carboxylate (1.7 g, 39.9 % yield). LCMS (ESI-MS) m / z = 293.2 [M+H]+. Intermediate V. tert-butyl (6-(but-3-en-1-yl(4-methoxyphenyl)methyl)amino)-4- methylpyridin-2-yl)carbamateStep 1. tert-butyl (6-bromo-4-methylpyridin-2-yl)carbamate [000412] Boc2O (13.7 mL, 64.2 mmol) was added to a mixture of 6-bromo-4-methylpyridin- 2-amine (10 g, 53.5 mmol) and DMAP (1.31 g, 10.7 mmol) and TEA (9.7mL, 69.5 mmol) in DCM (100 mL) at room temperature. The resulting mixture was stirred for 2 days at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 200 mL). The combined organic layers were washed with brine(3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA 1 : 1 to afford tert-butyl (6-bromo-4-methylpyridin-2-yl)carbamate (11.3 g, 73.6% yield). LCMS (ESI-MS) m / z =287.0 [M+H]+. Step 2. tert-butyl (6-(but-3-en-1-yl(4-methoxyphenyl)methyl)amino)-4-methylpyridin-2- yl)carbamate [000413] To a stirred mixture of tert-butyl (6-bromo-4-methylpyridin-2-yl)carbamate (3.0 g, 10.4 mmol) and but-3-en-1-yl[(4-methoxyphenyl)methyl]amine (2.0 g, 10.4 mmol) in dioxane (30 mL) was added Pd-PEPPSI-IPent catalyst (414 mg, 0.52 mmol) and t-BuOK (3.5 g, 31.2 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was heated to 120 °C and stirred for overnight. After cooling to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE : EA = 5 : 1 to afford tert-butyl (6-(but-3-en-1-yl(4-methoxyphenyl)methyl)amino)-4-methylpyridin-2-yl)carbamate (1.5 g, 36.1% yield) LCMS (ESI-MS) m / z = 398.2 [M+H]+. Step 3. N2-(but-3-en-1-yl)-N2-(4-methoxybenzyl)-4-methylpyridine-2,6-diamine [000414] TFA (0.5 mL) was added to a stirred mixture of tert-butyl (6-(but-3-en-1-yl(4- methoxyphenyl)methyl)amino)-4-methylpyridin-2-yl)carbamate (500 mg, 1.26 mmol) in DCM (5 mL). The resulting mixture was stirred for overnight at room temperature, and concentrated to afford the crude product N2-(but-3-en-1-yl)-N2-(4-methoxybenzyl)-4- methylpyridine-2,6-diamine (300 mg, crude). LCMS (ESI-MS) m / z = 298.2 [M+H]+. Intermediate W.2-(4-allylpiperidin-1-yl)-4-bromobenzoic acid.Intermediate W [000415] K2CO3(7.12 g, 51.5 mmol) was added to a mixture of 4-allylpiperidine (4.57 g, 17.2 mmol) and 4-bromo-2-fluorobenzoic acid (4.3 g, 17.2 mmol) in DMSO (80 mL). Theresulting mixture was heated to 140 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with PE / EA 4 : 1 to afford the desired product 2-(4-allylpiperidin-1-yl)-4-bromobenzoic acid (2.6 g, 30.5% yield). LCMS (ESI-MS) m / z = 324.1 [M+H]+. Intermediate X. N2-(but-3-en-1-yl)-N2-(4-methoxybenzyl)pyridine-2,6-diamine.[000416] Intermediate X was synthesized using the same procedure as Intermediate V, steps 1-3 using 6-bromopyridin-2-amine in step 1. Intermediate Y.4-bromo-N-(2-chloro-6-cyanopyrimidin-4-yl)-2-fluorobenzamideStep 1.2-chloro-6-((4-methoxybenzyl)amino)pyrimidine-4-carbonitrile [000417] (4-methoxyphenyl)methanamine (6.3 g, 45.98 mmol) was added to a solution of 2,6-dichloropyrimidine-4-carbonitrile (4 g, 22.99 mmol) in DCM (80 mL) and the resulting mixture was stirred at room temperature overnight. After cooling to room temperature, the reaction mixture was diluted with DCM (300 mL) and washed with 1 N HCl (3 x 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE 1: 3 to afford 2-chloro-6-((4-methoxybenzyl)amino)pyrimidine-4-carbonitrile (4.6 g, 72.8% yield). LCMS (ESI-MS) m / z =274.9 [M+H]+. Step 2.6-amino-2-chloropyrimidine-4-carbonitrile [000418] TFA (20 mL) was added to a solution of 2-chloro-6-((4- methoxybenzyl)amino)pyrimidine-4-carbonitrile (4.6 g, 16.74 mmol) in DCE (50 mL). The resulting solution was heated to 70 °C and stirred for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with EA / PE 1 : 2 to afford 6-amino-2- chloropyrimidine-4-carbonitrile (1.8 g, 65.7% yield). LCMS (ESI-MS) m / z =154.9 [M+H]+. Step 3.4-bromo-N-(2-chloro-6-cyanopyrimidin-4-yl)-2-fluorobenzamide [000419] A solution of 4-bromo-2-fluorobenzoic acid (1.25 g, 5.69 mmol) in DCM (20 mL) was treated with oxalic dichloride (985.45 mg, 7.76 mmol) at room temperature for 2 hours. The mixture was concentrated under vacuum, the residue was re-dissolved in DCM (10 mL) and added to a mixture of Et3N (2.1 g, 20.70 mmol) and 6-amino-2-chloropyrimidine-4- carbonitrile (800 mg, 5.17 mmol) in DCM (20 mL). The resulting mixture was heated to 35 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with EA / PE 1 : 8 to afford 4-bromo-N-(2-chloro-6-cyanopyrimidin-4-yl)-2-fluorobenzamide (550 mg, 29.9% yield). LCMS (ESI-MS) m / z =354.8 [M+H]+.Intermediate Z.4-methyl-N2-(4-(piperidin-3-yl)butyl)pyridine-2,6-diamineStep 1. N,N-dibenzyl-6-chloro-4-methylpyridin-2-amine [000420] DIEA (16.0 g, 123 mmol) was added to a stirred mixture of 2,6-dichloro-4- methylpyridine (10 g, 61.7 mmol) and dibenzylamine (12.2 g, 61.7 mmol) in NMP (100 mL). The resulting mixture was heated to 140 °C and stirred for 2 days. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with DCM / PE 10:1 to afford N,N-dibenzyl-6-chloro-4-methylpyridin-2-amine (1.7 g, 8.1% yield). LCMS (ESI-MS) m / z =543.8 [M+H]+. Step 2. tert-butyl 3-(4-((6-(dibenzylamino)-4-methylpyridin-2- yl)amino)butyl)piperidine-1-carboxylate [000421] Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (0.22 g, 0.26 mmol) was added to a stirred mixture of N,N-dibenzyl-6-chloro-4-methylpyridin-2-amine (1.7 g, 5.27 mmol) and tert-butyl 3-(4-aminobutyl)piperidine-1-carboxylate (1.62 g, 6.32 mmol) in dioxane (20 mL). The resulting mixture was heated to 100 °C and stirred for 16 hours. After cooling to roomtemperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the residue. The residue was purified by silica gel column chromatography, eluted with PE / EA 5:1 to afford tert-butyl 3-(4-((6-(dibenzylamino)-4-methylpyridin-2- yl)amino)butyl)piperidine-1-carboxylate (2.0 g, 66.8% yield). LCMS (ESI-MS) m / z = 379.2 [M+H]+. Step 3. tert-butyl 3-(4-((6-amino-4-methylpyridin-2-yl)amino)butyl)piperidine-1- carboxylate [000422] Pd / C (500 mg, 10% Pd on carbon) was added to a stirred mixture of tert-butyl 3-(4- ((6-(dibenzylamino)-4-methylpyridin-2-yl)amino)butyl)piperidine-1-carboxylate (2.0 g, 1.84 mmol) in MeOH (20 mL) under nitrogen atmosphere. The mixture was stirred for 2 days at room temperature under hydrogen atmosphere. The reaction mixture was filtered, the filter cake was washed with MeOH (3 x 30 mL). The filtrate was concentrated under reduced pressure to afford the crude product tert-butyl 3-(4-((6-amino-4-methylpyridin-2- yl)amino)butyl)piperidine-1-carboxylate (1.2 g crude)The crude product mixture was used in the next step directly without further purification. LCMS (ESI-MS) m / z = 363.3 [M+H]+. Step 4.4-methyl-N2-(4-(piperidin-3-yl)butyl)pyridine-2,6-diamine [000423] TFA (10 mL) was added to a stirred mixture of tert-butyl 3-(4-((6-amino-4- methylpyridin-2-yl)amino)butyl)piperidine-1-carboxylate (1.2 g, 3.31 mmol) in DCM (20 mL). The resulting mixture was stirred for 1 hour at room temperature. The reaction was quenched with sat. NaHCO3(20 mL) at room temperature. The resulting mixture was diluted with EA (2 x 50 ml) and washed with brine (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product 4- methyl-N2-(4-(piperidin-3-yl)butyl)pyridine-2,6-diamine (600 mg crude). LCMS (ESI-MS) m / z = 263.4 [M+H]+. Intermediate AA. N2-(but-3-en-1-yl)-N2-(4-methoxybenzyl)pyrimidine-2,4-diamine.[000424] Intermediate AA was synthesized following the same procedure as Intermediate Q and using 2-chloropyrimidin-4-amine in step 2 in place of 2-chloro-6-methylpyrimidin-4- amine.Intermediate AB. Methyl 2-(4-allyl-4-methylpiperidin-1-yl)-4-bromobenzoateStep 1. tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate [000425] DIBAl-H (1 M in hexane, 20.98 mL, 21 mmol) was added to a solution of tert-butyl 4-(cyanomethyl)-4-methylpiperidine-1-carboxylate (2 g, 8.39 mmol) in DCM (50 mL) dropwise at -30 °C. The resulting solution was stirred at -30 °C for 30 min. The reaction was quenched with MeOH and filtered. The filtrated was diluted with DCM (50 mL), washed with brine (50 mL x 2), dried with anhydrous Na2SO4and evaporated under vacuum to give tert- butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate (1 g, crude). LCMS (ESI-MS) m / z = 242.0 [M+H]+. Step 2. tert-butyl 4-allyl-4-methylpiperidine-1-carboxylate [000426] DBU (1.26 g, 8.29 mmol) was added to a solution of tert-butyl 4-methyl-4-(2- oxoethyl)piperidine-1-carboxylate (1 g, 4.14 mmol) and methyltriphenylphosphanium bromide (2.96 g, 8.29 mmol) in ACN (20 mL) . The resulting solution was heated to reflux and stirred for 16 hours. The reaction mixture was diluted with water (30 mL), extracted with EA (30 mL x 2). The combined organic layers were combined, washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered and evaporated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE 3 : 1 to afford tert-butyl 4-allyl-4- methylpiperidine-1-carboxylate (500 mg, 47.9%). LCMS (ESI-MS) m / z = 140.4 [M-Boc]+.Step 3.4-allyl-4-methylpiperidine [000427] Into a 25-mL round-bottom flask, was placed tert-butyl 4-allyl-4-methylpiperidine- 1-carboxylate (500 mg, 2.09 mmol) and HCl in 1,4-dioxane (4 M, 5 mL, 20 mmol). The resulting solution was stirred at room temperature for 3 hours. The mixture was evaporated and dried under vacuum to give 4-allyl-4-methylpiperidine (280 mg, crude). LCMS (ESI-MS) m / z = 140.1 [M+H]+. Step 4. methyl 2-(4-allyl-4-methylpiperidin-1-yl)-4-bromobenzoate [000428] K2CO3(834 mg, 6.03 mmol) was added to a solution of 4-allyl-4-methylpiperidine (280 mg, 2.01 mmol) and methyl 4-bromo-2-fluorobenzoate (469 mg, 2.01 mmol) in DMSO (3 mL). The resulting solution was heated to 140 °C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (10 mL), extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and evaporated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE 1 : 2 to give methyl 2-(4-allyl-4- methylpiperidin-1-yl)-4-bromobenzoate (400 mg, 55.7%). LCMS (ESI-MS) m / z = 352.0 [M+H]+. Intermediate AC. N2-(4-(6-azaspiro[2.5]octan-4-yl)butyl)-4-methylpyridine-2,6-diamineStep 1. tert-butyl 4-(4-((6-(dibenzylamino)-4-methylpyridin-2-yl)(4- methoxybenzyl)amino)butyl)-6-azaspiro[2.5]octane-6-carboxylate [000429] Pd-PEPPSI-IPent catalyst (260 mg, 0.310 mmol) was added to a stirred mixture of N,N-dibenzyl-6-chloro-4-methylpyridin-2-amine (2 g, 6.12 mmol) , Intermediate F (2.49 g, 6.20 mmol) and Cs2CO3(4.04 g, 12.4 mmol) in dioxane (30 mL). The resulting mixture washeated to 100 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the residue. The residue was purified by silica gel column chromatography, eluted with PE / EA 5:1 to afford tert-butyl 4-(4-((6-(dibenzylamino)-4-methylpyridin-2-yl)(4-methoxybenzyl)amino)butyl)-6- azaspiro[2.5]octane-6-carboxylate (2.1 g, 49.2% yield). LCMS (ESI-MS) m / z = 689.9 [M+H]+. Step 2. tert-butyl 3-(4-((6-amino-4-methylpyridin-2-yl)amino)butyl)piperidine-1- carboxylate [000430] Pd / C (1 g, 9.39 mmol) was added to a stirred mixture of tert-butyl 4-(4-((6- (dibenzylamino)-4-methylpyridin-2-yl)(4-methoxybenzyl)amino)butyl)-6- azaspiro[2.5]octane-6-carboxylate (1 g, 1.45 mmol) in MeOH (20 mL) under nitrogen atmosphere. The mixture was stirred for 2 days at room temperature under hydrogen atmosphere. The reaction mixture was filtered, the filter cake was washed with MeOH (3 x 30 mL). The filtrate was concentrated under reduced pressure to afford the crude product tert- butyl 3-(4-((6-amino-4-methylpyridin-2-yl)amino)butyl)piperidine-1-carboxylate (500 mg crude). The crude product mixture was used in the next step directly without further purification. LCMS (ESI-MS) m / z =509.3 [M+H]+. Step 3. N2-(4-(6-azaspiro[2.5]octan-4-yl)butyl)-4-methylpyridine-2,6-diamine [000431] TFA (5 mL) was added to a stirred mixture of tert-butyl 4-(4-((6-amino-4- methylpyridin-2-yl)(4-methoxybenzyl)amino)butyl)-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 0.983 mmol) in DCM (5 mL). The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was stirred at room temperature for 2 hours and concentrated to afford the crude product N2-(4-(6-azaspiro[2.5]octan-4-yl)butyl)-4- methylpyridine-2,6-diamine (200 mg crude) as yellow oil. LCMS (ESI-MS) m / z = 289.2 [M+H]+. Intermediate AD.2-(4-allylpiperidin-1-yl)-4-chlorobenzoic acid[000432] Intermediate AD was synthesized using the same procedure as intermediate W using 4-chloro-2-fluorobenzoic acid. LCMS (ESI-MS) m / z =280.1 [M+H]+.Intermediate AE.25-chloro-55-iodo-4,6-diaza-5(2,6)-pyridina-1(1,4)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-oneStep 1. N2-(but-3-en-1-yl)-3-iodopyridine-2,6-diamine [000433] To a vial was added 3-Buten-1-amine, hydrochloride (90.4 mg, 840 μmol), 6- fluoro-5-iodopyridin-2-amine (100 mg, 420 μmol), DMSO (0.50 mL), and K2CO3(232 mg, 1.68 mmol). The reaction mixture was then heated to 140 °C. After 18 hour, the reaction mixture was diluted with water and extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-100% EtOAc in heptane) provided N2-(but-3-en-1-yl)-3-iodopyridine-2,6- diamine (30 mg, 25 %). LCMS (ESI-MS) m / z = 290.0 [M+H]+. Step 2.2-(4-allylpiperidin-1-yl)-N-(6-(but-3-en-1-ylamino)-5-iodopyridin-2-yl)-4- chlorobenzamide [000434] To a vial was added 2-(4-allylpiperidin-1-yl)-4-chlorobenzoic acid (80 mg, 0.29 mmol), N2-(but-3-en-1-yl)-3-iodopyridine-2,6-diamine (91 mg, 0.31 mmol), N- (chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (0.10 g, 0.37 mmol), 1-Methylimidazole (82 mg, 1.0 mmol), and MeCN (1.5 mL). The reaction was then stirred at rt. After 2.5 hour the reaction mixture was quenched with water and diluted with EtOAc. The organic layer was separated and washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-20% EtOAc on heptane)provided 2-(4-allylpiperidin-1-yl)-N-(6-(but-3-en-1-ylamino)-5-iodopyridin-2-yl)-4- chlorobenzamide (80 mg, 51 %). LCMS (ESI-MS) m / z =551.0 [M+H]+. Step 3.25-chloro-55-iodo-4,6-diaza-5(2,6)-pyridina-1(1,4)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-one, Intermediate AE [000435] To a vial was added 2-(4-allylpiperidin-1-yl)-N-(6-(but-3-en-1-ylamino)-5- iodopyridin-2-yl)-4-chlorobenzamide (80 mg, 0.15 mmol) and Benzylidene(dichloro)(1,3- dimesityl-2-imidazolidinylidene)ruthenium - tricyclohexylphosphine (1:1) (25 mg, 29 μmol). The reaction was placed under a N2atmosphere, then toluene (4.0 mL) was added via syringe. The reaction was then heated to 100 °C. After 2.5 hour the reaction was quenched with water and diluted with EtOAc. The organic layer was separated and washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-20% EtOAc on heptane) provided 25-chloro-55-iodo-4,6-diaza-5(2,6)-pyridina-1(1,4)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-one, intermediate AE (32 mg, 42 %). LCMS (ESI-MS) m / z =523.0 [M+H]+. Intermediate AF.2-(4-allylpiperidin-1-yl)-4-nitrobenzoic acid[000436] Intermediate AF was synthesized using the same procedure as intermediate W using 4-nitro-2-fluorobenzoic acid. LCMS (ESI-MS) m / z =291.1 [M+H]+.Intermediate AG. N-(55-bromo-3-oxo-4,6-diaza-5(2,6)-pyridina-1(1,4)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-25-yl)ethanesulfonamideStep 1.3-bromo-N2-(but-3-en-1-yl)pyridine-2,6-diamine [000437] To a flask was added 3-Buten-1-amine, hydrochloride (5.63 g, 52.4 mmol) and 5- Bromo-6-fluoro-pyridin-2-ylamine (5.00 g, 26.2 mmol). The vial was placed under a N2atmosphere and DMSO (100 mL) and K2CO3(12.7 g, 91.6 mmol) were added. The reaction was then heated to 120 °C. After 24 hour, the reaction mixture was diluted with EtOAc and washed with brine (5 x), dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-20% EtOAc in heptane) provided 3-bromo-N2-(but-3-en-1-yl)pyridine-2,6- diamine (4.29 g, 67.7 %). LCMS (ESI-MS) m / z = 242.0 [M+H]+. Step 2.2-(4-allylpiperidin-1-yl)-N-(5-bromo-6-(but-3-en-1-ylamino)pyridin-2-yl)-4- nitrobenzamide [000438] To a flask was added 2-(4-allylpiperidin-1-yl)-4-nitrobenzoic acid (5.00 g, 17.2 mmol), 3-bromo-N2-(but-3-en-1-yl)pyridine-2,6-diamine (5.00 g, 20.7 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (6.28 g, 22.4 mmol), DIPEA (6.00 mL, 34.4 mmol), and 2-MeTHF (90.0 mL). The reaction was then stirred at rt. After 24 hour the reaction mixture was quenched with 1 M aq. NaOH, diluted with water, and extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-20% EtOAc on heptane) provided 2-(4-allylpiperidin-1-yl)-N-(5-bromo-6-(but-3-en-1- ylamino)pyridin-2-yl)-4-nitrobenzamide (5.77 g, 65.1 %). LCMS (ESI-MS) m / z = 514.1 [M+H]+. Step 3.2-(4-allylpiperidin-1-yl)-4-amino-N-(5-bromo-6-(but-3-en-1-ylamino)pyridin-2- yl)benzamide [000439] To a flask was added 2-(4-allylpiperidin-1-yl)-N-(5-bromo-6-(but-3-en-1- ylamino)pyridin-2-yl)-4-nitrobenzamide (6.99 g, 13.6 mmol), Hypodiboric acid (4.87 g, 54.4 mmol) and 4,4'-Dipyridyl (53.1 mg, 340 μmol). The reaction vial was placed under a N2atmosphere, then DMF (60 mL) was added. The reaction was then stirred at 23 °C. After 1 hour the reaction mixture was diluted with water and extracted with EtOAc (3 x). The combined organic layers were washed with sat. aq. NaHCO3, then brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-100% EtOAc on heptane) provided 2-(4-allylpiperidin-1-yl)-4-amino-N-(5-bromo-6-(but-3-en-1-ylamino)pyridin-2- yl)benzamide (6.00 g, 91.1 %). LCMS (ESI-MS) m / z = 484.1 [M+H]+. Step 4.2-(4-allylpiperidin-1-yl)-N-(5-bromo-6-(but-3-en-1-ylamino)pyridin-2-yl)-4- (ethylsulfonamido)benzamide [000440] To a flask was added 2-(4-allylpiperidin-1-yl)-4-amino-N-(5-bromo-6-(but-3-en-1- ylamino)pyridin-2-yl)benzamide (6.0 g, 12 mmol),THF (50 mL), and 4-methylmorpholine (8.2 mL, 74 mmol). Ethylsulfonyl Chloride (6.4 g, 4.7 mL, 50 mmol) in THF (10 mL) was added slowly and the reaction was stirred at rt. After 18 hour, K2CO3(17 g, 0.12 mol) and MeOH (30 mL) were added and the reaction mixture heated to 40 °C. After 4 hour, the reaction mixture was diluted with brine and extracted with DCM (5 x). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification via Isco column chromatography (0-10% MeOH in DCM) provided 2-(4-allylpiperidin-1-yl)-N-(5-bromo-6- (but-3-en-1-ylamino)pyridin-2-yl)-4-(ethylsulfonamido)benzamide (2.1 g, 29 %). LCMS (ESI- MS) m / z = 577.6 [M+H]+.Step 5. N-(55-bromo-3-oxo-4,6-diaza-5(2,6)-pyridina-1(1,4)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-25-yl)ethanesulfonamide [000441] To a flask was added 2-(4-allylpiperidin-1-yl)-N-(5-bromo-6-(but-3-en-1- ylamino)pyridin-2-yl)-4-(ethylsulfonamido)benzamide (2.1 g, 3.6 mmol), toluene (300 mL) and Benzylidene(dichloro)(1,3-dimesityl-2-imidazolidinylidene)ruthenium - tricyclohexylphosphine (1:1) (0.62 g, 0.73 mmol) under a N2atmosphere. The reaction was then heated to 60 °C. After 3 hour the reaction mixture was cooled to rt and DMSO (5.2 mL, 73 mmol) was added and stirred at rt. After 18 h, reaction mixture was concentrated in vacuo. Purification via Isco column chromatography (0-100% EtOAc on heptane) provided N-(55- bromo-3-oxo-4,6-diaza-5(2,6)-pyridina-1(1,4)-piperidina-2(1,2)-benzenacycloundecaphan-9- en-25-yl)ethanesulfonamide, intermediate AG (1.5 g, 75 %). LCMS (ESI-MS) m / z = 548.1 [M+H]+. Intermediate AH-rac.55-bromo-25-chloro-4,6-diaza-5(2,6)-pyridina-1(1,3)-piperidina- 2(1,2)-benzenacycloundecaphan-3-oneStep 1. tert-butyl 3-(5-((6-amino-3-bromopyridin-2-yl)amino)pentyl)piperidine-1- carboxylate [000442] K2CO3(21 g, 0.16 mol) was added to a solution of tert-butyl 3-(5- aminopentyl)piperidine-1-carboxylate (14 g, 52 mmol) and 5-bromo-6-fluoropyridin-2-amine (9.9 g, 52 mmol) in DMSO (150 mL). The resulting solution was stirred at 140 °C for 16 hours. After cooling to room temperature, the reaction was diluted with water (200 mL), extracted with EA (3 x 200 mL). The combined layers were washed with brine (2 x 200 mL), dried with anhydrous Na2SO4, filtered and evaporated to give a crude. The crude was purified with silica gel column, eluted with EA / PE 1 : 2 to afford tert-butyl 3-(5-((6-amino-3-bromopyridin-2-yl)amino)pentyl)piperidine-1-carboxylate (15 g, 66 % yield), LCMS (ESI-MS) m / z =441.2 [M+H]+. Step 2. tert-butyl 3-(5-((3-bromo-6-(4-chloro-2-fluorobenzamido)pyridin-2- yl)amino)pentyl)piperidine-1-carboxylate [000443] Into a solution of tert-butyl 3-(5-((6-amino-3-bromopyridin-2- yl)amino)pentyl)piperidine-1-carboxylate (15 g, 34 mmol)in DCM (300 mL)was added DIEA (13 g, 18 mL, 0.10 mol) . The mixture was cooled to 0 °C, 4-chloro-2-fluorobenzoyl chloride (6.6 g, 34 mmol) was added dropwise. The resulting solution was stirred at room temperature for 1 hours. The reaction mixture was evaporated and purified with silica gel column, eluted with EA : PE= 1 : 2 to afford tert-butyl 3-(5-((3-bromo-6-(4-chloro-2- fluorobenzamido)pyridin-2-yl)amino)pentyl)piperidine-1-carboxylate (14.5 g, 71 % yield), LCMS (ESI-MS) m / z =597.2 [M+H]+. Step 3. N-(5-bromo-6-((5-(piperidin-3-yl)pentyl)amino)pyridin-2-yl)-4-chloro-2- fluorobenzamide [000444] TFA (13.7 g, 120 mmol) was added to a solution of tert-butyl 3-(5-((3-bromo-6-(4- chloro-2-fluorobenzamido)pyridin-2-yl)amino)pentyl)piperidine-1-carboxylate (14.4 g, 24.1 mmol) in DCM (150 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was evaporated to afford N-(5-bromo-6-((5-(piperidin-3- yl)pentyl)amino)pyridin-2-yl)-4-chloro-2-fluorobenzamide (10 g, crude), LCMS (ESI-MS) m / z =497.1 [M+H]+. Step 4.55-bromo-25-chloro-4,6-diaza-5(2,6)-pyridina-1(1,3)-piperidina-2(1,2)- benzenacycloundecaphan-3-one [000445] Cs2CO3(19 g, 58 mmol) was added to a solution of N-(5-bromo-6-((5-(piperidin-3- yl)pentyl)amino)pyridin-2-yl)-4-chloro-2-fluorobenzamide (9.7 g, 19 mmol) in DMSO (100 mL). The resulting solution was stirred at 120 °C for 5 hours. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), dried with anhydrous Na2SO4, filtered and evaporated to give 55-bromo-25-chloro-4,6-diaza-5(2,6)-pyridina-1(1,3)- piperidina-2(1,2)-benzenacycloundecaphan-3-one (4 g, crude), LCMS (ESI-MS) m / z =477.1 [M+H]+.Intermediate AH and Intermediate AH-1. Enantiopure 55-bromo-25-chloro-4,6-diaza- 5(2,6)-pyridina-1(1,3)-piperidina-2(1,2)-benzenacycloundecaphan-3-one[000446] 55-bromo-25-chloro-4,6-diaza-5(2,6)-pyridina-1(1,3)-piperidina-2(1,2)- benzenacycloundecaphan-3-one (4 g, 8 mmol) was dissolved in DCM (60 mL) and purified with the following conditions: Column: CHIRALPAK IG 3*25 cm, 5um; Mobile Phase A: CO2, Mobile Phase B: DCM: MeOH=1: 1(0.1% 2M NH3-MEOH); Flow rate: 85 mL / min; Gradient: isocratic 40% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 7.2; RT2(min): 8.15; Sample Solvent: MEOH; Injection Volume: 3 mL; Number Of Runs: 40. The fractions were collected, evaporated and lyophilized to afford: First eluting isomer (Intermediate AH): [000447] Enantiopure 55-bromo-25-chloro-4,6-diaza-5(2,6)-pyridina-1(1,3)-piperidina- 2(1,2)-benzenacycloundecaphan-3-one (1.2 g, 30 % yield).1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.4, 0.8 Hz, 1H), 7.51 (d, J =8.4 Hz, 1H), 7.40 (s, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 6.62 (s, 1H), 3.54-3.47 (m, 1H), 3.32-3.26 (m, 1H), 3.17-3.09 (m, 1H), 3.09-2.89 (m, 2H), 2.68-2.64 (m, 1H), 2.22-2.09 (m, 1H), 2.08-1.91 (m, 2H), 1.81-1.72 (m, 1H), 1.59-1.39 (m, 6H), 1.39-1.20 (m, 2H), 1.19-1.08 (m, 1H). LCMS (ESI- MS) m / z = 477.1 [M+H]+. Second eluting isomer (Intermediate AH-1): [000448] (13S)-55-bromo-25-chloro-4,6-diaza-5(2,6)-pyridina-1(1,3)-piperidina-2(1,2)- benzenacycloundecaphan-3-one (1.1 g, 30 % yield).1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.51 (d, J =8.4 Hz, 1H), 7.40 (s, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 6.62 (s, 1H), 3.59-3.45 (m, 1H), 3.32-3.26 (m, 1H), 3.18-3.09 (m, 1H), 3.03-2.95 (m, 1H), 2.94-2.88 (m, 1H), 2.68-2.59 (m, 1H), 2.23-2.08 (m, 1H), 2.07- 1.88 (m, 2H), 1.87-1.72 (m, 1H), 1.65-1.38 (m, 6H), 1.37-1.21 (m, 2H), 1.20-1.05 (m, 1H). LCMS (ESI-MS) m / z = 477.1 [M+H]+.Intermediate AI.4-bromo-N-(3-chloro-1,2,4-triazin-5-yl)-2-fluorobenzamide[000449] Intermediate AI was synthesized via the same procedure as Intermediate G using 3- chloro-1,2,4-triazin-5-amine in place of 2-chloro-6-methylpyrimidin-4-amine. LCMS (ESI- MS) m / z = 330.9 [M+H]+. Intermediate AJ.6-amino-2-(but-3-en-1-yl(4-methoxybenzyl)amino)pyrimidine-4- carbonitrile[000450] DIEA (2.5 g, 19.4 mmol) was added to a mixture of 6-amino-2-chloropyrimidine- 4-carbonitrile (1 g, 6.47 mmol) and N-(4-methoxybenzyl)but-3-en-1-amine (1.24 g, 6.47 mmol) in DMSO (15 mL). The resulting mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (300 ml) and washed with brine (3 x 300 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE 1 : 3 to afford 6-amino-2-(but-3-en-1-yl(4- methoxybenzyl)amino)pyrimidine-4-carbonitrile (700 mg, 34.9% yield). LCMS (ESI-MS) m / z =310.1 [M+H]+.4A Intermediate AK.6-amino-2-(but-3-en-1-ylamino)nicotinonitrile[000451] Intermediate AK was synthesized via the same procedure as Intermediate AJ using 6-amino-2-chloronicotinonitrile in place of 6-amino-2-chloropyrimidine-4-carbonitrile.Intermediate AL. tert-butyl 4-(5-aminopentyl)-6-azaspiro[2.5]octane-6-carboxylate.Step 1. tert-butyl (Z)-4-(4-ethoxy-4-oxobutylidene)-6-azaspiro[2.5]octane-6-carboxylate [000452] NaHMDS (34 mL, 2.0M in THF) was added to (4-ethoxy-4- oxobutyl)triphenylphosphonium bromine (12.57 g, 33.30 mmol) in THF (50 mL) in THF (50 mL) under nitrogen atmosphere. The mixture was stirred at 0 °C for 3 hours. Tert-butyl 4-oxo- 6-azaspiro[2.5]octane-6-carboxylate (5 g, 22.19 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction was poured into aq. NH4Cl (200 mL) at room temperature. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 200mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA 10 : 1 to afford tert-butyl (Z)-4-(4- ethoxy-4-oxobutylidene)-6-azaspiro[2.5]octane-6-carboxylate (2.6 g, 32.6% yield). LCMS (ESI-MS) m / z =324.2 [M+H]+. Step 2. tert-butyl (Z)-4-(4-hydroxybutylidene)-6-azaspiro[2.5]octane-6-carboxylate [000453] LiAlH4(0.46 g, 12.06 mmol) was added to tert-butyl (Z)-4-(4-ethoxy-4- oxobutylidene)-6-azaspiro[2.5]octane-6-carboxylate (2.6 g, 8.04 mmol in THF (50 mL) under nitrogen atmosphere at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), driedover anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product tert-butyl (Z)-4-(4-hydroxybutylidene)-6-azaspiro[2.5]octane-6- carboxylate (2.2 g, 97.3%yield), LCMS (ESI-MS) m / z =282.2 [M+H]+. Step 3. tert-butyl 4-(4-hydroxybutyl)-6-azaspiro[2.5]octane-6-carboxylate [000454] NaOAc (3.85 g, 46.91 mmol) was added to a mixture of 4-methylbenzene-1- sulfonohydrazide (17.47 g, 93.81 mmol) and tert-butyl (Z)-4-(4-hydroxybutylidene)-6- azaspiro[2.5]octane-6-carboxylate (2.2 g, 7.82 mmol) in DME (40 mL). The mixture was stirred at 95°C for 16 hours. The resulting mixture was concentrated under vacuum to afford the residue. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl 4-(4-hydroxybutyl)-6-azaspiro[2.5]octane-6-carboxylate (1 g, 45.1%yield), LCMS (ESI-MS) m / z =284.2 [M+H]+. Step 4. tert-butyl 4-(4-(tosyloxy)butyl)-6-azaspiro[2.5]octane-6-carboxylate [000455] Et3N (0.27 g, 2.65 mmol) was added to tert-butyl 4-(4-hydroxybutyl)-6- azaspiro[2.5]octane-6-carboxylate (0.25 g, 0.88 mmol) and 4-Methylbenzenesulfonyl chloride (0.42 g, 2.20 mmol) in DCM (50 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel column chromatography, eluted with PE / EA 10 : 1 to afford tert-butyl 4-(4-(tosyloxy)butyl)-6-azaspiro[2.5]octane-6-carboxylate (150 mg, 38.9%yield), LCMS (ESI-MS) m / z =438.2 [M+H]+. Step 5. tert-butyl 4-(4-cyanobutyl)-6-azaspiro[2.5]octane-6-carboxylate [000456] formonitrile; tetrabutylamine (138 mg, 0.52 mmol) was added to tert-butyl 4-(4- (tosyloxy)butyl)-6-azaspiro[2.5]octane-6-carboxylate (150 mg, 0.34 mmol) in ACN (5 mL) . The mixture was stirred at 65 °C for 2 hour. The reaction was poured into aq.NaHCO3(50 mL) at room temperature. The resulting mixture was extracted with EA (3 x 50 mL). dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product tert-butyl 4-(4-cyanobutyl)-6-azaspiro[2.5]octane-6-carboxylate (110 mg, crude), LCMS (ESI-MS) m / z =293.2 [M+H]+. Step 6. tert-butyl 4-(5-aminopentyl)-6-azaspiro[2.5]octane-6-carboxylate [000457] Borane-tetrahydrofuran complex (4.7 mL, 1.0M in THF) was added to tert-butyl 4- (4-cyanobutyl)-6-azaspiro[2.5]octane-6-carboxylate (110 mg, 0.38 mmol) in THF (1 mL). The mixture was stirred at room temperature overnight. The reaction was poured into MeOH(5mL) at room temperature. The resulting mixture was concentrated under vacuum to afford the crudeproduct tert-butyl 4-(5-aminopentyl)-6-azaspiro[2.5]octane-6-carboxylate (90 mg, crude), LCMS (ESI-MS) m / z =297.2 [M+H]+. Intermediate AM.25-iodo-14-methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,4)-piperidina- 2(1,2)-benzenacycloundecaphan-9-en-3-oneStep 1. tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate [000458] Diisobutylaluminum hydride (53 mL, 1.0 M in DCM) was added dropwise to a solution of tert-butyl 4-(cyanomethyl)-4-methylpiperidine-1-carboxylate (5 g, 20.98 mmol) in DCM (200 mL) under nitrogen atmosphere at -30 °C. The mixture was stirred at -30 °C for 2 hours. The reaction was quenched with MeOH (8 mL) and 15 mL of saturated citric acid aqueous solution and then stirred for 15 minutes. The resulting mixture was filtered and the filtrate was washed with brine (3 x 200 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum to afford tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1- carboxylate (2.8 g crude), LCMS (ESI-MS) m / z = 142.1 [M-boc+H]+.Step 2. tert-butyl 4-allyl-4-methylpiperidine-1-carboxylate [000459] Methyltriphenylphosphonium bromide (8.3 g, 23.20 mmol) was added to a solution of tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate (2.8 g, 11.60 mmol) and DBU (3.5 g, 23.20 mmol) in MeCN (40 mL). The resulting mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under vacuum, then the residue was diluted with ethyl acetate (300 ml) and washed with brine (3 x 300 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE (1 : 4) to afford tert-butyl 4-allyl-4-methylpiperidine-1-carboxylate (1.4 g, 50.4% yield), LCMS (ESI-MS) m / z = 140.2 [M-boc+H]+. Step 3.4-allyl-4-methylpiperidine [000460] A solution of tert-butyl 4-allyl-4-methylpiperidine-1-carboxylate (1.3 g, 5.43 mmol) in HCl in 1,4-dioxane (15 mL 4.0 M) was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum to afford 4-allyl-4-methylpiperidine (1 g crude) as a white solid. LCMS (ESI-MS) m / z = 140.1 [M+H]+. Step 4. N-(2-(but-3-en-1-ylamino)pyrimidin-4-yl)-2-fluoro-4-iodobenzamide [000461] DIEA (8.22 g, 63.57 mmol) was added to a solution of N-(2-chloropyrimidin-4-yl)- 2-fluoro-4-iodobenzamide (3 g, 7.95 mmol) and but-3-en-1-amine hydrochloride (4.27 g, 39.73 mmol) in DMSO (40 mL). The resulting mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with EA (500 ml) and washed with brine (3 x 500 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:2) to afford N-(2-(but-3-en-1-ylamino)pyrimidin-4- yl)-2-fluoro-4-iodobenzamide (1.5 g, 45.8% yield), LCMS (ESI-MS) m / z = 413.3 [M+H]+. Step 5.2-(4-allyl-4-methylpiperidin-1-yl)-N-(2-(but-3-en-1-ylamino)pyrimidin-4-yl)-4- iodobenzamide [000462] K2CO3(2.1 g, 15.08 mmol) was added to a solution of 4-allyl-4-methylpiperidine (700 mg, 5.02 mmol) and N-(2-(but-3-en-1-ylamino)pyrimidin-4-yl)-2-fluoro-4- iodobenzamide (1.5 g, 5.02 mmol) in DMSO (15 mL). The resulting mixture was heated to 140 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EA (500 ml) and washed with brine (3 x 500 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:4) to afford 2-(4-allyl-4-methylpiperidin-1-yl)-N-(2-(but-3-en-1-ylamino)pyrimidin-4-yl)-4-iodobenzamide (600 mg, 22.5% yield), LCMS (ESI-MS) m / z = 532.1 [M+H]+. Step 6. (E)-25-iodo-14-methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,4)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-one [000463] Hoveyda-Grubb’s catalyst 2nd G (3.3 g, 5.27 mmol) was added to a solution of 2- (4-allyl-4-methylpiperidin-1-yl)-N-(2-(but-3-en-1-ylamino)pyrimidin-4-yl)-4-iodobenzamide (560 mg, 1.05 mmol) in toluene (10 mL) and the resulting mixture was heated to 100 °C and stirred overnight. After cooling to room temperature, the resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with EA / PE 1 : 2 to afford (E)-25-iodo-14-methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,4)-piperidina- 2(1,2)-benzenacycloundecaphan-9-en-3-one (200 mg crude). LCMS (ESI-MS) m / z = 504.1 [M+H]+. Intermediate AN.2-(4-allyl-4-methylpiperidin-1-yl)-4-chlorobenzoic acid[000464] Intermediate AN was synthesized from 4-allyl-4-methylpiperidine (described in synthesis of Intermediate AB) and 4-chloro-2-fluorobenzoic acid following the same procedure as used in synthesis of intermediate AO, LCMS (ESI-MS) m / z = 294.1 [M+H]+. Intermediate AO.2-(4-(1-allylcyclopropyl)piperazin-1-yl)-4-chlorobenzoic acidStep 1. methyl 2-(4-(1-allylcyclopropyl)piperazin-1-yl)-4-chlorobenzoate [000465] K2CO3(661 mg, 4.79 mmol) was added to a mixture of methyl 4-chloro-2- fluorobenzoate (300 mg, 1.60 mmol) and 1-(1-allylcyclopropyl)piperazine (264 mg, 1.60 mmol) in DMSO (5 mL). The resulting mixture was heated to 140 °C and stirred for 2 hours.After cooling to room temperature, the reaction mixture was diluted with water (5 mL) and extracted with EA (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with PE / EA 4 : 1 to afford methyl 2-(4-(1-allylcyclopropyl)piperazin-1-yl)-4-chlorobenzoate (310 mg, 58.3% yield), LCMS (ESI-MS) m / z = 335.1 [M+H]+. Step 2.2-(4-(1-allylcyclopropyl)piperazin-1-yl)-4-chlorobenzoic acid [000466] LiOH (215 mg, 8.90 mmol) was added to a mixture of methyl 2-(4-(1- allylcyclopropyl)piperazin-1-yl)-4-chlorobenzoate (300 mg, 0.89 mmol) in THF (5 mL). The resulting mixture was heated to 60 °C and stirred for 16 hours. Then, the reaction mixture was filtered and concentrated under vacuum to afford the crude product 2-(4-(1- allylcyclopropyl)piperazin-1-yl)-4-chlorobenzoic acid (270 mg, crude), LCMS (ESI-MS) m / z = 321.1 [M+H]+. Intermediate AP. Methyl 2-(4-(but-3-en-1-yl)piperazin-1-yl)-4-chlorobenzoate[000467] Intermediate AP was synthesized from 4-chloro-2-fluorobenzoic acid and 1-(but-3- en-1-yl)piperazine using the procedure described in step 4 of preparation of Intermediate AB. Intermediate AR.2-(4-(allyloxy)piperidin-1-yl)-4-chlorobenzoic acid[000468] Intermediate AR was synthesized from tert-butyl 4-hydroxy-piperidine-1- carboxylate following the same route and procedure as for intermediate AW-1.Intermediate AS. (Z)-25-amino-4,6-diaza-5(4,2)-pyrimidina-1(1,3)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-one.Step 1. 2-(3-allylpiperidin-1-yl)-4-nitrobenzoic acid. [000469] 2-fluoro-4-nitrobenzoic acid (2.74 g, 14.79 mol, 1.0 eq), K2CO3(5.111 g, 36.978 mmol, 2.5 eq) and DMSO (12V) were charged into a reactor with stirring. 3-allylpiperidine (2.778 g, 22.187 mmol, 1.5 eq) was dropped into the mixture. The reaction mixture was warmed up to 110~130 ℃ and stirred for 2~4 h. The reaction was monitored by HPLC. After the reaction was completed, the reactor was cooled to 20-30 ℃ and the mixture was poured into the water (15 V). After adjusting the pH to 1-2 with 6M HCl, the mixture was filtered and the filter cake was rinsed with H2O (2 V). The filter cake was collected and dried under reduced pressure at < 60 ℃ to produce 2-(3-allylpiperidin-1-yl)-4-nitrobenzoic acid (3.70 g, 86% yield) Step 2. 2-(3-allylpiperidin-1-yl)-4-nitrobenzamide. [000470] DCM(10V) and 2-(3-allylpiperidin-1-yl)-4-nitrobenzoic acid (17.65 g, 60.796 mmol, 1.0 eq) were charged into a reactor with stirring. (COCl)2(19.292 g, 151.991 mmol, 2.5 eq) was dropped into the mixture. The reaction mixture was stirred at 20~30 ℃ for 1~2 h. The reaction was monitored by HPLC. After the reaction was completed, the solvent was removed under reduced pressure at < 40 ℃ until no significant distillate observed. The residue was dissolved with 10V DCM and added dropwise to the 10V ammonia water. The mixture wasfiltered and the filter cake was rinsed with 2V DCM. The filter cake was collected and dried under reduced pressure at < 50 ℃. 2-(3-allylpiperidin-1-yl)-4-nitrobenzamide (17.00 g, 97% yield) was obtained. Step 3. 2-(3-allylpiperidin-1-yl)-N-(2-chloropyrimidin-4-yl)-4-nitrobenzamide. [000471] 2-(3-allylpiperidin-1-yl)-4-nitrobenzamide (5.000g, 17.28mmol, 1.0 eq), PB125249 (2.832g, 19.01mmol, 1.1eq), Cs2CO3(6.194g, 19.01mmol ,1.1 eq), PD2(DBA)3(158.2 mg,172.8 μmol, 0.01 eq), Xantphos (300.0mg, 518.4 μmol, 0.03 eq) and toluene (100ml) were charged to a reactor under nitrogen. The reaction mixture was stirred at 70-90oC for 2 h. The reaction was monitored by HPLC. After the reaction was completed, it was cooled to 20- 30°C and filtered. The filter cake was washed with 3V toluene, the filtrate was concentrated under reduced pressure, and 2-(3-allylpiperidin-1-yl)-N-(2-chloropyrimidin-4-yl)-4- nitrobenzamide (7.5g > 100% yield) was obtained. Step 4. 2-(3-allylpiperidin-1-yl)-N-(2-(but-3-en-1-yl(4- methoxybenzyl)amino)pyrimidin-4-yl)-4-nitrobenzamide. [000472] 2-(3-allylpiperidin-1-yl)-N-(2-chloropyrimidin-4-yl)-4-nitrobenzamide (5.000 g, 12.411 mmol, 1 eq), H2O (5V) and toluene (5V) were charged to a reactor, followed by KF (2.884 g, 49.646 mmol, 4.0 eq) and DIPEA (4.812 g, 37.234 mmol, 3.0 eq). N-(4- methoxybenzyl)but-3-en-1-amine (2.849 g, 14.894 mmol, 1.2 eq) was added, and the mixture was stirred at 100°C for 60 h. The reaction was monitored by HPLC. After the reaction was completed, the mixture was concentrated under reduced pressure. The aqueous phase was extracted with 10V MTBE, and the organic phase was concentrated under reduced pressure. Column chromatography was performed and 2-(3-allylpiperidin-1-yl)-N-(2-(but-3-en-1-yl(4- methoxybenzyl)amino)pyrimidin-4-yl)-4-nitrobenzamide (4.5g, 65.1% yield) was obtained Step 5. (Z)-56-methyl-25-nitro-4,6-diaza-5(4,2)-pyrimidina-1(1,3)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-one . [000473] 2-(3-allylpiperidin-1-yl)-N-(2-(but-3-en-1-yl(4-methoxybenzyl)amino)pyrimidin- 4-yl)-4-nitrobenzamide (3.000 g, 5.389 mmol, 1 eq) and toluene (100V) were charged to a reactor， and the solution was heated to 80-90oC. Toluene (100V) solution of Grubbs II (686.317 mg, 808.402 μmol, 0.15 eq) was added, the mixture was stirred at 80-90°C for 2h.2- (3-allylpiperidin-1-yl)-N-(2-(but-3-en-1-yl(4-methoxybenzyl)amino)pyrimidin-4-yl)-4- nitrobenzamide (1.500 g, 2.695 mmol, 1 eq) and toluene (100V) were charged to a reactor and the solution was heated to 80-90oC. Toluene (100V) solution of Grubbs II (343.158 mg,404.201 μmol, 0.15 eq) was added, the mixture was stirred at 80-90°C for 2h.[000474] The reaction was monitored by HPLC. After the reaction was completed, the mixture of 015# and 016# experiments were combined and concentrated under reduced pressure. Column chromatography purification was performed, and (Z)-56-methyl-25-nitro- 4,6-diaza-5(4,2)-pyrimidina-1(1,3)-piperidina-2(1,2)-benzenacycloundecaphan-9-en-3-one (2.5 g, 58.5% yield) was obtained. Step 6. ((Z)-25-amino-4,6-diaza-5(4,2)-pyrimidina-1(1,3)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-one. [000475] (Z)-56-methyl-25-nitro-4,6-diaza-5(4,2)-pyrimidina-1(1,3)-piperidina-2(1,2)- benzenacycloundecaphan-9-en-3-one (1.5000 g, 2.838 mmol, 1eq), CH3COOH (1.363 g, 22.701 mmol, 8 eq), Fe (3.169 g, 56.754 mmol, 20 eq) and THF (20V) were charged to a reactor, and the reaction mixture was stirred at 10-20°C for 3hr. The reaction was monitored by HPLC. After the reaction was completed, the mixture was concentrated under reduced pressure. To the residue was added 20V DCM and 20V H2O, and the mixture was filtered. The organic phase was separated and concentrated under reduced pressure. Column chromatography purification was performed and (Z)-25-amino-4,6-diaza-5(4,2)-pyrimidina- 1(1,3)-piperidina-2(1,2)-benzenacycloundecaphan-9-en-3-one (860mg) was obtained. Intermediate AT. (Z)-25-amino-56-methyl-4,6-diaza-5(4,2)-pyrimidina-1(1,3)- piperidina-2(1,2)-benzenacycloundecaphan-9-en-3-one.[000476] Intermediate AT was obtained following the same procedure as Intermediate AS, 2,4-dichloro-6-methylpyrimidine was used in step 3. Intermediate AU.5-amino-3-(but-3-en-1-ylamino)pyrazine-2-carbonitrile[000477] K2CO3(5 g, 0.04 mol) was added to the mixture of 5-amino-3-chloropyrazine-2- carbonitrile (2 g, 0.01 mol) and but-3-en-1-amine hydrochloride (3 g, 4 Eq, 0.03 mol) in DMSO(50 mL). The mixture was stirred at 140 °C for 16 hours. The reaction mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE 1:2 to afford 5-amino-3-(but-3-en-1- ylamino)pyrazine-2-carbonitrile (2 g, 80 % yield), LCMS (ESI-MS) m / z =190.2[M+H]+. Intermediate AV. N2-allyl-N2-(4-methoxybenzyl)-6-methylpyrimidine-2,4-diamine[000478] DIEA (8 g, 0.06 mol) was added to the mixture of 2-chloro-6-methylpyrimidin-4- amine (3 g, 0.02 mol) and N-(4-methoxybenzyl)prop-2-en-1-amine (4 g, 0.03 mol) in DMSO (60 mL). The mixture was stirred at 140 °C for 1 hour. The reaction mixture was diluted with water (600 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 1.2 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:5) to afford N2-allyl-N2-(4- methoxybenzyl)-6-methylpyrimidine-2,4-diamine (2.2 g, 40 % yield), LCMS (ESI-MS) m / z =285.2 [M+H]+. Intermediate AW.2-(4-(allyloxy)-4-methylpiperidin-1-yl)-4-chlorobenzoic acidStep 1. tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate [000479] To a stirred solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (3 g, 13.93 mmol) in anhydrous DMF (30 mL) was added NaH (1 g, 41.80 mmol) at 0 °C and stirred for 1 hour. Then add dropwise 3-bromoprop-1-ene (2.53 g, 20.92 mmol) dissolved in DMF. The resulting mixture was stirred. After 2 hours, the reaction was quenched with water (10 mL) and the aqueous layer was extracted with EA (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with PE : EA = 4 : 1 to afford tert-butyl 4-(allyloxy)-4- methylpiperidine-1-carboxylate (2.6 g, 73% yield). LCMS (ESI-MS) m / z = 256.2 [M+H]+. Step 2. 4-(allyloxy)-4-methylpiperidine [000480] 4M HCl in 1,4-dioxane (10 mL) was added to a stirred mixture of tert-butyl 4- (allyloxy)-4-methylpiperidine-1-carboxylate (2.6 g, 10.18 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated to afford the crude product 4-(allyloxy)-4-methylpiperidine (1.5 g), which was used for the next step without further purification. LCMS (ESI-MS) m / z = 156.1 [M+H]+. Step 3. Methyl 2-(4-(allyloxy)-4-methylpiperidin-1-yl)-4-chlorobenzoate (intermediate AW) [000481] K2CO3(3.7 g, 27.05 mmol) was added to a mixture of 4-(allyloxy)-4- methylpiperidine (1.4 g, 9.02 mmol) and methyl 4-chloro-2-fluorobenzoate (1.7 g, 9.02 mmol) in DMSO (10 mL). The resulting mixture was heated to 140 °C and stirred for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography, eluted with PE : EA = 4 : 1 to afford methyl 2-(4-(allyloxy)-4-methylpiperidin-1-yl)-4-chlorobenzoate (2 g, 68% yield). LCMS (ESI-MS) m / z = 324.1 [M+H]+. Step 4. 2-(4-(allyloxy)-4-methylpiperidin-1-yl)-4-chlorobenzoic acid (Intermediate AW-1) [000482] LiOH (1.4 g, 58.6 mmol) was added to a mixture of methyl 2-(4-(allyloxy)-4- methylpiperidin-1-yl)-4-chlorobenzoate (1.9 g, 5.87 mmol) in THF (15 mL) and H2O (5 mL). The resulting mixture was heated to 50 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrousNa2SO4, filtered and concentrated under vacuum to afford 2-(4-(allyloxy)-4-methylpiperidin- 1-yl)-4-chlorobenzoic acid (1.8 g, 99% yield). LCMS (ESI-MS) m / z = 310.1 [M+H]+. Intermediate AX.25-chloro-14-methyl-55-(1H-pyrazol-1-yl)-4,6-diaza-5(2,6)-pyridina- 1(1,4)-piperidina-2(1,2)-benzenacycloundecaphan-9-en-3-oneStep 1. 2-(4-allyl-4-methylpiperidin-1-yl)-N-(6-(but-3-en-1-ylamino)-5-(1H-pyrazol-1- yl)pyridin-2-yl)-4-chlorobenzamide [000483] Intermediate AN (6.5 g, 0.022 mol) was added to a stirred mixture of HATU (12.6 g, 0.033 mol), Intermediate AY (5.1 g, 0.022 mol) and DIPEA (8.5 g, 0.066 mol) in DMF (50 mL) .The resulting mixture was stirred at room temperature. After 2 hour, the reaction mixture was diluted with H2O (50 mL) and extracted with EA (2 x 2 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified with silica gel column, eluted with PE : DCM = 2 : 1 to afford methyl 2-(4-allyl-4-methylpiperidin-1-yl)-4-chlorobenzoate (10 g, 89.6% yield). LCMS (ESI-MS) m / z = 505.2 [M+H]+. Step 2. 25-chloro-14-methyl-55-(1H-pyrazol-1-yl)-4,6-diaza-5(2,6)-pyridina-1(1,4)- piperidina-2(1,2)-benzenacycloundecaphan-9-en-3-one [000484] 2-(4-allyl-4-methylpiperidin-1-yl)-N-(6-(but-3-en-1-ylamino)-5-(1H-pyrazol-1- yl)pyridin-2-yl)-4-chlorobenzamide (10 g, 0.020 mol) was added to a stirred mixture of Dichloro(1,3-dimesityl-2-imidazolidinylidene)(2-isopropoxybenzylidene)ruthenium (1.25 g, 0.002 mol) in Toluene (400 mL). The resulting mixture was stirred for 1 hours at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE : EA =6:1 to afford 25-chloro-14-methyl-55-(1H- pyrazol-1-yl)-4,6-diaza-5(2,6)-pyridina-1(1,4)-piperidina-2(1,2)-benzenacycloundecaphan-9- en-3-one (6 g, 63.6% yield). LCMS (ESI-MS) m / z = 477.2 [M+H]+. Intermediate AY. N2-(but-3-en-1-yl)-3-(1H-pyrazol-1-yl)pyridine-2,6-diamine[000485] CuI (47 g, 0.25 mol) was added to the mixture of 3-bromo-N2-(but-3-en-1- yl)pyridine-2,6-diamine (40 g, 0.17 mol), K3PO4(110 g, 0.51 mol), 1H-pyrazole (34 g, 0.50 mol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (35 g, 0.25 mol) in DMSO (400 mL) under N2atmosphere. The mixture was stirred at 100°C overnight. The reaction mixture was diluted with water (2 L). The resulting mixture was extracted with EA (3 x 2 L). The combined organic layers were washed with brine (3 L), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, eluted with EA : PE = 1:4 to afford N2-(but-3-en-1-yl)-3-(1H-pyrazol-1-yl)pyridine-2,6-diamine (20.1 g, 53% yield). LCMS (ESI-MS) m / z = 230.1 [M+H]+. Intermediate AZ. N2-allyl-3-(1H-pyrazol-1-yl)pyridine-2,6-diamine[000486] Intermediate AZ was synthesized using the same procedure as Intermediate AY with N2-allyl-3-bromopyridine-2,6-diamine (synthesized from allyl amine in similar manner as described in Step 1 of Intermediate AG) being used in place of 3-bromo-N2-(but-3-en-1- yl)pyridine-2,6-diamine. Intermediate BA.2-(3-(allyloxy)piperidin-1-yl)-4-chlorobenzoic acidStep 1. tert-butyl 3-(allyloxy)piperidine-1-carboxylate [000487] NaH (0.9 g, 0.04 mol) was added to the mixture of 3-bromoprop-1-ene (3 g, 0.02 mol) and tert-butyl 3-hydroxypiperidine-1-carboxylate (5 g, 0.02 mol) in DMF (25 mL). Themixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with aq. NH4Cl (200 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous Na2SO4. After...

Claims

CLAIMS What is claimed is:

1. A compound having the structure of Formula (I-0), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)R1a1, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, -NH-S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m- OR3b, -NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl; R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 to 2; l is 0 to 2 ; m is 1 to 6; n is 0 to 9; o is 0 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom.

2. The compound of claim 1, wherein ring B is phenyl.

3. The compound of claim 1, wherein ring B is a 5-membered heteroaryl, 6-membered heteroaryl, or 9 membered bicyclic heteroaryl.

4. The compound of claim 1, wherein ring B is a 6-membered heteroaryl.

5. The compound of claim 4, wherein ring B is triazine, pyridine, pyrimidine, pyridazine, pyrazinone, pyrazine, or imidazopyrizine.

6. The compound of any one of claims 1 to 5, wherein k is 0 or 1.

7. The compound of any one of claims 1 to 6, wherein l is 0 or 1.

8. The compound of any one of claims 1 to 7, wherein each X3is CH.

9. The compound of any one of claims 1 to 8, wherein at least one of X3is N.

10. The compound of claim 1, having the structure of Formula (I-0a), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X1is independently CH or N.

11. The compound of claim 1 or 2, having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

12. The compound of any one of claims 1 to 11, wherein o is 1.

13. The compound of any one of claims 1 to 12, wherein p is 0 to 2.

14. The compound of claim 13, wherein p is 0 or 1.

15. The compound of claim 14, wherein p is 0.

16. The compound of any one of claims 1 to 15, wherein G is -NH-(C=O)-.

17. The compound of any one of claims 1 to 15, wherein G is -(C=O)-NH-.

18. The compound of claim 17, wherein the compound has the structure of Formula (II), or a pharmaceutical salt or solvate thereof:wherein: X1is CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene;R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, -NR3a- S(O)2-(CH2)m-OR3b, -NH-S(O)2-R3c, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R3ais independently hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; m is 1 to 3; and n is 1 or 2.

19. The compound of any one of claims 10 to 18, wherein X1is N.

20. The compound of any one of claims 10 to 18, wherein X1is CH.

21. The compound of claim 19, wherein the compound has the structure of Formula (III- A), or a pharmaceutical salt or solvate thereof:wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene-; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, -NR3a-S(O)2- (CH2)m-OR3b, -NH-S(O)2-R3c, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl;each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2.

22. The compound of claim 10, wherein the compound has the structure of Formula (III- B), or a pharmaceutical salt or solvate thereof:wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene- R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, -NR3a-S(O)2- (CH2)m-OR3b, -NH-S(O)2-R3c, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2.

23. The compound of claim 10, wherein the compound has the structure of Formula (III- C), or a pharmaceutical salt or solvate thereof:wherein:L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl; each R2ais independently hydrogen or C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, -NR3a- S(O)2-(CH2)m-OR3b, -NH-S(O)2-R3c, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; R3ais hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0, 1, or 2.

24. The compound of any one of claims 1 to 23, wherein R2is halogen, -OR2a, -N(R2a)2, optionally substituted C1-C6alkyl, or -S(O)2N(R2a)2.

25. The compound of claim 23 or 24, wherein R2is C1-C6alkyl.

26. The compound of any one of claims 1 to 25, wherein R2is methyl.

27. The compound of any one of claims claim 1 to 24, wherein each R2ais independently optionally substituted C1-C4alkyl.

28. The compound of claim 27, wherein each R2ais independently methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.

29. The compound of any one of claims 1 to 28, wherein L1ais a bond or -O-.

30. The compound of any one of claims 1 to 29, wherein L1ais a bond.

31. The compound of any one of claims 1 to 30, wherein L1bis optionally substituted C1- C4alkylene.

32. The compound of claim 31, wherein L1bis C1-C4alkylene substituted with oxo or C3- C6cycloalkyl.

33. The compound of claim 32, wherein L1bis C1-C4alkylene substituted with oxo or cyclopropyl.

34. The compound of any one of claims 1 to 33, wherein L1is –(CH2)4–, –(CH2)3–, – (CH2)2–, –CH2– –cyclopropyl-(CH2)3–, –cyclopropyl-(CH2)2–, –O(CH2)3–, – O(CH2)2–, or –O(CH2)–.

35. The compound of any one of claims 1 to 34, wherein R1is a bond, -O-, -NR1a-, -NR1a- C1-C6alkylene-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, or -SO2-NR1a.

36. The compound of claim 35, wherein R1is -NR1a-.

37. The compound of claim 35, wherein R1is a bond.

38. The compound of any one of claims 1 to 36, wherein R1ais hydrogen, -C(=O)H, C1- C3alkyl, C1-C3alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl.

39. The compound of claim 38, wherein R1ais hydrogen.

40. The compound of claim 38, wherein R1ais -CH2-cyclopropyl.

41. The compound of claim 38, wherein R1ais -SO2-CH3.

42. The compound of any one of claims 1 to 35, wherein L1-R1is:.

43. The compound of any one of claims 1 to 35, wherein L1-R1is –(CH2)4NH–, – cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3–, –(CH2)3N-(CH2- cyclopropyl)–, –(CH2)2NH–, –(CH2)3–, –(CH2)3–, –(CH2)2–, –CH2–, –O(CH2)3–, – O(CH2)2–, –O(CH2)2O–, –O(CH2)2NH–, –(CH2)3NSO2–, –(CH2)2N(SO2Me)CH2–, -– (CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, –(CH2)2NHCH2–, – (CH2)2CONH–, –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, – (CH2)2SO2NH–, –(CH2)2NHCO–, –(CH2)2N(Me)CO–, –(CH2)2N(CH2- cyclopropyl)CO–, or –(CH2)2NHSO2–.

44. The compound of claim 43, wherein L1-R1is –(CH2)4NH– or –(CH2)3NH–.

45. The compound of any one of claims 1 to 44, wherein each R3is independently - N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH- S(O)2-R3c, or optionally substituted 5- to 8- membered heterocycle.

46. The compound of any one of claims 1 to 45, wherein each R3is independently - NR3aS(O)2-(CH2)m-OR3bor -NR3a-S(O)2-(CH2)m-R3a.

47. The compound of claim 45, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, and methoxy.

48. The compound of claim 45 or 46, wherein each R3ais independently hydrogen, methyl, or ethyl, wherein the ethyl is optionally substituted with one or more substituents selected from methyl and -OH.

49. The compound of any one of claims 45 or 46, wherein R3bis hydrogen, methyl, ethyl, or propyl.

50. The compound of claim 45, wherein R3cis oxetanyl.

51. The compound of claim 45, wherein m is 2.

52. The compound of claim 45, wherein each R3is independently -NHSO2(CH2)2OH, - NHSO2C(CH3)2CH2OH, -NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, - NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -53. The compound of claim 52, wherein each R3is independently -NHS(O)2-(CH2)2-OH.

54. The compound of any one of claims 1 to 53, wherein n is 2.

55. The compound of any one of claims 1 to 54, wherein two R4combine to form a C3-C8cycloalkyl.

56. The compound of claim 55, wherein the two R4are attached to the same carbon atom.

57. The compound of claim 54 or 55, wherein the two R4groups combine to form a cyclopropyl.

58. The compound of claim 54 or 55, wherein the two R4groups combine to form a cyclobutyl.

59. The compound of claim 54, wherein the two R4are attached to different carbon atoms.

60. The compound of claim 59, wherein the two R4groups combine to form a (1R,5S)-8- azabicyclo[3.2.1]octane.

61. The compound of claim 1, wherein the compound,,,pharmaceutically acceptable salt or solvate of any one thereof.

62. The compound of claim 1, wherein the compound is ,,, , ,pharmaceutically acceptable salt or solvate of any one thereof.

63. The compound of claim 1, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

64. The compound of claim 1, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

65. The compound of claim 1, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

66. The compound of claim 1, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

67. The compound of claim 1, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

68. The compound of claim 1, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

69. The compound of claim 1, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

70. The compound of claim 1, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

71. A compound having the structure of a compound of Table 1 or a pharmaceutically acceptable salt thereof.

72. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1 to 70 and a pharmaceutically acceptable excipient.

73. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1 to 70.

74. The method of claim 73 wherein the cancer is bladder cancer, endometrial cancer, lung squamous cell cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophagus cancer, gall-bladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreas cancer, stomach cancer, cervix cancer, thyroid cancer, prostate cancer or skin cancer.

75. A method of inhibiting KIF18A comprising contacting the enzyme with a compound of any one of claims 1 to 70 or a composition of claim 71, or a pharmaceutically acceptable salt or solvate thereof.

76. A compound of any one of claims 1 to 70 or a composition of claim 71, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.

77. An adduct comprising a KIF18A and a compound of Formula (B), wherein the structure of Formula (B) is:wherein: ring A is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; ring B is optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl;ring C is optionally substituted C3-C10cycloalkyl, optionally substituted 5- to 12 membered heterocyclyl, optionally substituted C6-C12aryl or optionally substituted 5- to 12- membered heteroaryl; G is -(C=O)-NH- or -NH-(C=O)-; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; and Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene.

78. The adduct of claim 77, wherein ring A is optionally substituted C6-C12aryl.

79. The adduct of claim 78, wherein ring A is optionally substituted phenyl.

80. The adduct of any one of claims 77 to 79, wherein ring B is optionally substituted C6aryl or optionally substituted 5- to 6- membered heteroaryl.

81. The adduct of claim 80, wherein ring B is optionally substituted 6- membered heteroaryl.

82. The adduct of claim 80, wherein ring B is optionally substituted phenyl or optionally substituted pyridinyl.

83. The adduct of any one of claims 77 to 82, wherein ring C is optionally substituted C3- C10cycloalkyl or optionally substituted 5- to 12 membered heterocyclyl.

84. The adduct of claim 83, wherein ring C is optionally substituted 5- to 12- membered heterocyclyl.

85. The adduct of claim 84, wherein ring C is optionally substituted 5- to 8- membered heterocyclyl.

86. The adduct of claim 85, wherein ring C is optionally substituted 5- to 6- membered heterocyclyl.

87. The adduct of claim 86, wherein ring C is optionally substituted piperidinyl.

88. The adduct of claim 77, wherein the compound of Formula (B) has a structure of Formula (I-0):wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-(CH2)m- R3a, -NH-S(O)(NH)-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m-OR3b, - NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl3;each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 to 2; l is 0 to 2 ; m is 1 to 6; n is 0 to 9; o is 1 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom.

89. The adduct of claim 88, wherein the compound of Formula (B) has the structure of Formula (I-0a):wherein: each X1is independently CH or N.

90. The adduct of any one of claims 77 to 89, wherein the compound of Formula (B) has a structure of Formula (I):

91. The adduct of any one of claims 77 to 90, wherein the compound of Formula (B) has a structure of Formula (II):wherein: X1is CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, each R3ais independently hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; m is 1 to 3; and n is 1 or 2.

92. The adduct of any one of claims 77 to 91, wherein the compound of Formula (B) has a structure of Formula (III-A):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-;L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene-; R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2.

93. The adduct of any one of claims 77 to 89, wherein the compound of Formula (B) has a structure of Formula (III-B):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, or -NR1a-C1-C3alkylene- R1ais hydrogen, -C(=O)H, optionally substituted C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R3is halogen, -NH-S(O)2-(CH2)m-R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0 to 2.

94. The adduct of any one of claims 77 to 90, wherein the compound of Formula (B) has a structure of Formula (III-C):wherein: L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, or -NL1a1-; L1a1is hydrogen, C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene; R1is a bond, -O-, -NR1a-, -NR1a-C1-C6alkylene-, -NR1a-CO-,-CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)H, C1-C6alkyl, or C1-C6alkylene-C3-C6cycloalkyl; R2is halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, or optionally substituted C3-C6cycloalkyl; each R2ais independently hydrogen or C1-C6alkyl; R3is halogen, -CN, -OR3a, -N(R3a)2, -SO2R3a, or -NH-S(O)2-(CH2)m-OR3b, R3ais hydrogen or C1-C6alkyl; R3bis hydrogen or C1-C6alkyl; each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, or two or more R4combine to form a C3-C8cycloalkyl; m is 1 to 3; and n is 0, 1, or 2.

95. The adduct of any one of claims 77 to 94, wherein R2is halogen, -OR2a, -N(R2a)2, optionally substituted C1-C6alkyl, or -S(O)2N(R2a)2.

96. The adduct of claim 95, wherein R2is C1-C6alkyl.

97. The adduct of any one of claims 1 to 96, wherein R2is methyl.

98. The adduct of claim 95, wherein each R2ais independently optionally substituted C1- C4alkyl.

99. The adduct of claim 98, wherein each R2ais independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.

100. The adduct of any one of claims 77 to 99, wherein L1ais a bond or -O-.

101. The adduct of claim 100, wherein L1ais a bond.

102. The adduct of any one of claims 77 to 101, wherein L1bis optionally substituted C1-C4alkylene.

103. The adduct of claim 102, wherein L1bis C1-C4alkylene substituted with oxo or C3-C6cycloalkyl.

104. The adduct of claim 103, wherein L1bis C1-C4alkylene substituted with oxo or cyclopropyl.

105. The adduct of any one of claims 77 to 104, wherein L1is –(CH2)4–, –(CH2)3–, – (CH2)2–, –CH2– –cyclopropyl-(CH2)3–, –cyclopropyl-(CH2)2–, –O(CH2)3–, – O(CH2)2–, or –O(CH2)–.

106. The adduct of any one of claims 77 to 105, wherein R1is a bond, -O-, -NR1a-, -NR1a- C1-C6alkylene-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, or -SO2-NR1a.

107. The adduct of claim 106, wherein R1is -NR1a-.

108. The adduct of claim 107, wherein R1is a bond.

109. The adduct of any one of claims 77 to 107, wherein R1ais hydrogen, C1-C3alkyl, C1- C3alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl.

110. The adduct of claim 109, wherein R1ais hydrogen.

111. The adduct of claim 109, wherein R1ais -CH2-cyclopropyl.

112. The adduct of claim 109, wherein R1ais -SO2-CH3.

113. The adduct of any one of claims 77 to 106, wherein L1-R1is:.

114. The adduct of any one of claims 77 to 105, wherein L1-R1is –(CH2)4NH–, – cyclopropyl-(CH2)3NH–, –(CH2)3NH–, –(CH2)3NCH3–, –(CH2)3N-(CH2- cyclopropyl)–, –(CH2)2NH–, –(CH2)3–, –(CH2)3–, –(CH2)2–, –CH2–, –O(CH2)3–, – O(CH2)2–, –O(CH2)2O–, –O(CH2)2NH–, –(CH2)3NSO2–, –(CH2)2N(SO2Me)CH2–, -– (CH2)2N(Me)CH2–, –(CH2)2N(CH2-cyclopropyl)CH2–, –(CH2)2NHCH2–, – (CH2)2CONH–, –(CH2)2CONMe–, –(CH2)2CON(CH2-cyclopropyl)–, – (CH2)2SO2NH–, –(CH2)2NHCO–, –(CH2)2N(Me)CO–, –(CH2)2N(CH2- cyclopropyl)CO–, or –(CH2)2NHSO2–.

115. The adduct of claim 114, wherein L1-R1is –(CH2)4NH– or –(CH2)3NH–.

116. The adduct of any one of claims 77 to 115, wherein each R3is independently - N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH- S(O)2-R3c, or optionally substituted 5- to 8- membered heterocycle.

117. The adduct of any one of claims 116, wherein each R3is independently -NR3aS(O)2- (CH2)m-OR3bor -NR3a-S(O)2-(CH2)m-R3a.

118. The adduct of claim 116, wherein R3is optionally substituted 5- to 8- membered heterocycle, which is optionally substituted with one or more substituents selected from oxo, methyl, and methoxy.

119. The adduct of claim 116 or 117, wherein each R3ais independently hydrogen, methyl, or ethyl, wherein the ethyl is optionally substituted with one or more substituents selected from methyl and -OH.

120. The adduct of any one of claims 116 or 117, wherein R3bis hydrogen, methyl, ethyl, or propyl.

121. The adduct of claim 115, wherein R3cis oxetanyl.

122. The adduct of claim 116, wherein m is 2.

123. The adduct of claim 116, wherein each R3is independently -NHSO2(CH2)2OH, - NMeSO2(CH2)2OH, -NHSO2CH2CH3, -NHSO2-oxetanyl, -NMeSO2CH3, -124. The adduct of claim 123, wherein each R3is independently -NHS(O)2-(CH2)2-OH.

125. The adduct of any one of claims 88 to 124, wherein n is 2.

126. The adduct of claim 125, wherein two R4combine to form a C3-C8cycloalkyl.

127. The adduct of claim 126, wherein the two R4are attached to the same carbon atom.

128. The adduct of claim 127, wherein the two R4groups combine to form a cyclopropyl.

129. The adduct of claim 125, wherein the two R4are attached to different carbon atoms.

130. The adduct of claim 129, wherein two R4groups combine to form a (1R,5S)-8- azabicyclo[3.2.1]octane.

131. The adduct of any one of claims 77 to 130, wherein the compound of Formula (B) is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

132. The adduct of any one of claims 77 to 131, wherein ring A is adjacent to the KIF18A between the KIF18 α4-helix and α6-helix.

133. The adduct of claim 132, wherein ring A is adjacent to the KIF18A between Leu285 residue and Tyr348 residue.

134. The adduct of any one of claims 77 to 133, wherein ring B is adjacent to a flat surface of the KIF18A α4-helix.

135. The adduct of claim 134, wherein ring B is adjacent to the KIF18A Gly289 residue or Asn293 residue.

136. The adduct of claim 135, wherein ring B interacts with the KIF18A Asn293 residue via a hydrogen bond.

137. The adduct of any one of claims 77 to 136, wherein ring C is adjacent to hydrophobic residues of the KIF18A.

138. The adduct of claim 137, wherein the hydrophobic residues of the KIF18A are in α4- helix or α6-helix, or a combination thereof.

139. The adduct of claim 138, wherein ring C is adjacent to the KIF18A Tyr112 residue, Leu284 residue, Leu288 residue, and Tyr348 residue.

140. The adduct of claim 137, wherein ring C is adjacent to the KIF18A Leu110 residue, Leu259 residue, Met328 residue, or a combination thereof.

141. The adduct of any one of claims 77 to 140, wherein L1-R1is adjacent to the hydrophobic side chain of the KIF18A α6-helix and β-sheet.

142. The adduct of claim 141, wherein L1-R1is adjacent to the Ala352 residue, Met328 residue, and Tyr112 residue of KIF18A.

143. The adduct of claim 141, wherein L1-R1is adjacent to the hydrophobic side chain of the KIF18A β-sheet.

144. The adduct of claim 143, wherein the L1-R1is adjacent to the KIF18A Leu110 residue, Leu259 residue, and Met328 residue.

145. The adduct of any one of claims 77 to 144, wherein R1interacts with the KIF18A α4- helix via a hydrogen bond.

146. The adduct of claim 145, wherein R1interacts with the KIF18A Asn293 residue via the hydrogen bond.

147. The adduct of any one of claims 88 to 145, wherein R3interacts with KIF18A via a hydrogen bond.

148. The adduct of claim 147, wherein R3interacts with the KIF18A Ser262 residue via a hydrogen bond.

149. A method of treating cancer in a patient in need thereof, comprising administering to the patient an adduct as described in any one of claims 77 to 148.

150. The method of claim 149 wherein the cancer is bladder cancer, endometrial cancer, lung squamous cell cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophagus cancer, gall-bladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreas cancer, stomach cancer, cervix cancer, thyroid cancer, prostate cancer or skin cancer.

151. A method of inhibiting KIF18A, comprising forming an adduct as described in any one of claims 77 to 148, by contacting KIF18A with a compound of Formula (B).

152. A compound of any one of claims 77 to 148, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.

153. A composition comprising a protein and a compound, wherein the protein is KIF18A, the compound is a compound of Formula (B), and the protein and the compound form the adduct of any one of claims 77 to 148.

154. A compound having the structure of Formula (IV-A), or a pharmaceutically acceptable salt or solvate, thereof:wherein: Y1is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; G2Ais a bond or -(C=O); G2Bis a bond or -(C=O), wherein G2Ais not equal to G2B; N is NH; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; D is nitrogen or carbon; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1; and G1is a group configured to extend into a pocket of KIF18 located between an ^^6- helix and a ^^-sheet of KIF18a and to interact with at least one hydrophobic side chain of Ala352 in the ^^6-helix, Met328 in the ^^-sheet, and Tyr112 in the ^^-sheet.

155. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 154, wherein G1is further configured to hydrogen bond with Asn293 in an ^^4-helix of KIF18A.

156. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 154, wherein G1is further configured to interact with at least one hydrophobic side chain of Leu110, Leu259, and Met328 in the ^^-sheet of KIF18A.

157. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 154, wherein: G1is -K-(r)-M-(p)-Q-; K is -O- or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; r is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); p is 0, 1, or 2 Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); and R6is hydrogen or optionally substituted alkyl.

158. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 155, wherein: G1is represented by the formula -K-(r)-M-(p)-Q-; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; r is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); p is 0, 1, or 2; Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); and R6is hydrogen.

159. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 156, wherein: G1is -K-(r)-M-(p)-Q-; K is CRK1RK2; RK1and RK2are independently halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; r is 0, 1, or 2;M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); p is 0, 1, or 2; Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); and R6is hydrogen or optionally substituted alkyl.

160. A compound having the structure of Formula (IV-B), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y1is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; x is 0, 1, or 2; z is 0 or 1; y is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, or – OR6-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine);R6is hydrogen or optionally substituted alkyl; r is 0, 1, or 2; p is 0, 1, or 2; and G2is a group configured to provide a linkage with Ar / HetAr ring 1 and Ar / hetAr ring 2.

161. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 160, wherein G2is further configured to provide a rigid and quasi-planar linkage with Ar / HetAr ring 1 and Ar / HetAr ring 2 to position the Ar / HetAr ring 1 and Ar / HetAr ring 2 in approximately a same plane and allow delocalization of electrons across the G2, Ar / HetAr ring 1, and Ar / HetAr ring 2 in a conjugated system.

162. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 160, wherein G2is represented by the formula -G2A-N-G2B-; N is NH or N is taken together with D to form a 5 or 6 membered ring; G2Aand G2Aare independently a bond or -(C=X), provided that A and B are not both -(C=O).

163. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 160, wherein G2is represented by the formula -G2A-N-G2B- wherein N is NH; and G2Aand G2Bare independently a bond or -(C=O), provided that A and B are not both - (C=O).

164. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 160, wherein N is taken together with D to form a 5 or 6 membered ring.

165. A compound having the structure of Formula (IV-C), or a pharmaceutically acceptable salt or solvate thereof:wherein: Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl;Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; x is 0, 1, or 2; z is 0 or 1; y is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); R6is hydrogen or optionally substituted alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O); G2Bis a bond or -(C=O) , wherein G2Ais not equal to G2B; and Y2is a group configured to form one of more hydrogen bonds with one or more of: a backbone of KIF18A, a side chain of Ser262 of KIF18a, or a residue of α-tubulin.

166. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 165 wherein Y2is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle.

167. A compound having the structure of Formula (IV-D), or a pharmaceutically acceptable salt or solvate thereof:wherein:Y1is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; x is 0, 1, or 2; z is 0 or 1; y is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); R6is hydrogen or optionally substituted alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O); G2Bis a bond or -(C=O), wherein G2Ais not equal to G2B; and G4is a group configured to extend between side chains of Leu285 of a KIF18A ^^4- helix and Tyr348 of a KIF18A ^^6-helix.

168. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 167, wherein G4is further configured to hydrogen bond with KIF18A or to engage in water-mediated interactions with KIF18A or ^^-tubulin.

169. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 167, wherein G4is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl and forms a cyclic conjugated π system.

170. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 168, wherein G4is an optionally substituted 5 to 12 membered heteroaryl and forms a cyclic conjugated π system.

171. A compound having the structure of Formula (IV-E), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y1is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; x is 0, 1, or 2; z is 0 or 1; y is 0, 1, or 2; M is CRm3Rm4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); R6is hydrogen or optionally substituted alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O); G2Bis a bond or -(C=O), wherein G2Ais not equal to G2B; andG5is a group configured to pack against a flat surface on a KIF18A ^^4-helix formed by Gly289 and to interact with a side chain of Asn293 in an KIF18A ^^4-helix, and optionally, to hydrogen bond with the side chain of Asn293.

172. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 171, wherein G5is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl.

173. A compound having the structure of Formula (IV-F), or a pharmaceutically acceptable salt or solvate thereof:wherein: Y1is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; M is CRM3RM4; R3and R4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); R6is hydrogen or optionally substituted alkyl; r is 0, 1, or 2; p is 0, 1, or 2; G2Ais a bond or -(C=O); G2Bis a bond or -(C=O), wherein G2Ais not equal to G2B; and G6is a group configured to interact with hydrophobic side chains of Tyr112, Leu285, and Leu 288 in a KIF18A ^^4-helix and a hydrophobic side chain of Tyr348 in a KIF18a ^^6-helix.

174. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 173, wherein G6is further configured to interact with hydrophobic side chains of Leu110, Leu259, and Met328 in a KIF18A ^^-sheet.

175. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 174, wherein G6is represented by the formula:wherein D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; x is 0, 1, or 2; z is 0 or 1; and y is 0, 1, or 2.

176. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 175, wherein G6is represented by the formula:wherein D is nitrogen or carbon; J is CRJ1RJ2, where RJ1and RJ2are independently selected from F or alkyl. x is 0, 1, or 2; z is 0 or 1; and y is 0, 1, or 2.

177. A compound having the structure of Formula (IV-G) or a pharmaceutically acceptable salt or solvate, thereof:wherein Y1is an amide, sulfonamide, ether, cyclic amine, alkyl amine, aromatic heterocycle, or saturated heterocycle; Ring 1 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl;Ring 2 is an optionally substituted C6-C12aryl or optionally substituted 5 to 12 membered heteroaryl; G2Ais a bond or -(C=O); G2Bis a bond or -(C=O), wherein G2Ais not equal to G2B; N is NH; J is CRJ1RJ2, where RJ1and RJ2are independently selected from H, F, alkyl, or wherein RJ1and RJ2can be taken together to form a ring; D is nitrogen or carbon; x is 0, 1, or 2; y is 0, 1, or 2; z is 0 or 1; and G7represents a means, between ring 2 and ring 3, for extending into a pocket between an ^^6-helix and ^^-sheet of KIF18a and interacting with at least one hydrophobic side chain of Ala352 in the ^^6-helix, Met328 in the ^^-sheet, and Tyr112 in the ^^-sheet.

178. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 177, wherein the means is a group having the formula -K-(r)-M-(p)-Q-; K is O or CRK1RK2; RK1and RK2are independently hydrogen, halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring; r is 0, 1, or 2; M is CRM3RM4; RM3and RM4are independently hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); p is 0, 1, or 2; Q is -O-, -NR5-, -SO2-, -SO2NR5- or -NR5SO2-; R5is hydrogen or C1-C6alkyl optionally substituted with halogen (fluorine); and R6is hydrogen or optionally substituted alkyl.

179. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 177, wherein Q is -O-, or -NH2-; R5is hydrogen; and R6is hydrogen.

180. The compound, or pharmaceutically acceptable salt or solvate thereof, of claim 177, wherein K is CRK1RK2; and RK1and RK2are independently halogen (F), or C1-C6alkyl; or RK1and RK2are combined to form a ring.

181. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein: each X3is CH; ring B is triazine, pyridine, pyrimidine, pyridazine, pyrazinone, pyrazine, or imidazopyrizine; L1ais a bond or -O-; G is -(C=O)-NH-; R1is -NR1a-; R1ais hydrogen; each R3is independently -NHSO2(CH2)2OH, -NHSO2C(CH3)2CH2OH, - NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, -NMeSO2(CH2)2OH, - NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -NMeSO2CH3, -k is 0 or 1; l is 0 or 1; o is 1; and p is 0 or 1.

182. The compound of claim 181, wherein the compound has the structure of Formula (I- a):or a pharmaceutical salt or solvate thereof, wherein: X1is CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-;L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently -NHSO2(CH2)2OH, -NHSO2C(CH3)2CH2OH, - NHSO2C(cyclopropyl)CH2OH, -NHSO2CH(CH3)CH2OH, -NMeSO2(CH2)2OH, - NHSO2CH2CH3, -NHSO2CHCH2, -NHSO2-oxetanyl, -NMeSO2CH3, -each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 or 1; l is 0 or 1; n is 0 to 9; o is 1; p is 0 or 1; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom.

183. The compound of claim 181 or claim 182, or a pharmaceutical salt or solvate thereof, wherein p is 1.

184. The compound of any one of claims 181 to 183, wherein the compound has the structure of Formula (II-a):or a pharmaceutical salt or solvate thereof, wherein: X1is CH or N.

185. The compound of any one of claims 181 to 184, or a pharmaceutical salt or solvate thereof, wherein L1ais a bond.

186. The compound of any one of claims 181 to 185, or a pharmaceutical salt or solvate thereof, wherein R3is -NHS(O)2-(CH2)2-OH.

187. The compound of any one of claims 181 to 186, wherein the compound has the structure of Formula (V), or a pharmaceutical salt or solvate thereof:

188. The compound of any one of claims 181 to 187, or a pharmaceutical salt or solvate thereof, wherein R2is a 5- to 8- membered heteroaryl.

189. The compound of any one of claims 181 to 188, or a pharmaceutical salt or solvate thereof, wherein R2is a furanyl, furanonyl, isothiazolyl, imidazolyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl.

190. The compound of any one of claims 181 to 189, or a pharmaceutical salt or solvate thereof, wherein R2is a pyrazolyl.

191. The compound of any one of claims 181 to 190, or a pharmaceutical salt or solvate thereof, wherein L1bis optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene.

192. The compound of any one of claim 191, or a pharmaceutical salt or solvate thereof, wherein L1bis optionally substituted C2-C6alkenylene.

193. The compound of any one of claims 181 to 190, or a pharmaceutical salt or solvate thereof, wherein each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, or optionally substituted C1-C6alkoxy.

194. The compound of any one of claims 181 to 190, or a pharmaceutical salt or solvate thereof, wherein n is 0.

195. A compound having the structure of Formula (I-1), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X3is independently CH or N; ring B is a 5- or 6- membered heteroaryl or phenyl; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond, -O-, -NL1a1-, -S-, or -SO2-; L1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; G is -(C=O)-NH- or -NH-(C=O)-; R1is a bond, -O-, -NR1a-, -NR1a-Q-, -NR1a-CO-, -CO-NR1a-, -NR1a-SO2-, -S-, -SO2-, or -SO2-NR1a; R1ais hydrogen, -C(=O)R1a1, optionally substituted C1-C6alkyl, C1-C6alkylene-C3-C6cycloalkyl, or -SO2-C1-C6alkyl; R1a1is hydrogen, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; Q is optionally substituted C1-C6alkylene, optionally substituted C2-C6alkenylene, or optionally substituted C2-C6alkynylene; each R2is independently halogen, -CN, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl; each R2ais independently hydrogen or optionally substituted C1-C6alkyl; each R3is independently halogen, -CN, -(CH2)m-N(R3a)2-, -OR3a, -N(R3a)2, - N(SO2R3b)R3a, -SR3a, -SO2R3a, -NR3a-S(O)2-(CH2)m-R3a, -NH-S(O)(NH)-R3a, - NH-S(O)(NH)-(CH2)m-R3a, -NR3a-S(O)2-(CH2)m-OR3b, -NH-S(O)R3a-(CH2)m- OR3b, -NH-S(O)2-R3c, -B(R3a)3, -P(R3a)3, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl;each R3ais independently hydrogen, -C(O)OR3b, optionally substituted C1-C6alkyl, or -N(R3b)2; R3bis hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, or optionally substituted C3-C6cycloalkyl; R3cis C3-C8cycloalkyl or 3- to 8- membered heterocycle; each R4is independently halogen, -CN, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge; k is 0 to 2; l is 0 to 2 ; m is 1 to 6; n is 0 to 9; o is 0 to 4; p is 0 to 4; and wherein when any one of variable G, L1, R1, R2, R3, or R4are present, the bond to variable G, L1, R1, R2, R3or R4replaces a hydrogen on a carbon or nitrogen atom.

196. The compound of claim 195, or a pharmaceutical salt or solvate thereof , wherein ringB is phenyl or a 6-membered heteroaryl.

197. The compound of claim 195 or 196, or a pharmaceutical salt or solvate thereof, wherein ring B is a 6-membered heteroaryl.

198. The compound of any one of claims 195 to 197, or a pharmaceutical salt or solvate thereof, wherein ring B is triazine, pyridine, pyrimidine, pyridazine, pyrazinone, pyrazine, or imidazopyrizine.

199. The compound of any one of claims 195 to 198, or a pharmaceutical salt or solvate thereof, wherein k is 0 or 1.

200. The compound of any one of claims 195 to 199, or a pharmaceutical salt or solvate thereof, wherein l is 0 or 1.

201. The compound of any one of claims 195 to 200, or a pharmaceutical salt or solvate thereof, wherein each X3is CH.

202. The compound of claim 195, having the structure of Formula (I-1a):or a pharmaceutical salt or solvate thereof, wherein: each X1is independently CH or N.

203. The compound of any one of claims 195 to 202, or a pharmaceutical salt or solvate thereof, wherein o is 1; and p is 0 to 1.

204. The compound of any one of claims 195 to 203, or a pharmaceutical salt or solvate thereof, wherein G is -(C=O)-NH-.

205. The compound of claim 195, wherein the compound has the structure of Formula (II- 1):or a pharmaceutical salt or solvate thereof, wherein: each X1is independently CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; and n is 1 or 2.

206. The compound of any one of claims 195 to 205, or a pharmaceutical salt or solvate thereof, wherein R2is halogen, -CN, -OR2a, -N(R2a)2, optionally substituted C1-C6alkyl, or -S(O)2N(R2a)2.

207. The compound of claim 195, wherein the compound has the structure of Formula (III- 1):or a pharmaceutical salt or solvate thereof, wherein: each X1is independently CH or N; L1is a linker comprising the structure -L1a-L1b-; L1ais a bond or -O-; L1bis optionally substituted C1-C8alkylene, optionally substituted C2-C8alkenylene, or optionally substituted C2-C8alkynylene; and n is 1 or 2.

208. The compound of any one of claims 195 to 207, or a pharmaceutical salt or solvate thereof, wherein R3is -N(R3a)2, -N(SO2R3b)R3a, -NR3a-S(O)2-(CH2)m-R3a, -NR3a- S(O)2-(CH2)m-OR3b, -NH-S(O)2-R3c, or optionally substituted 5- to 8- membered heterocycle; each R3ais independently hydrogen, methyl, or ethyl, wherein the ethyl is optionally substituted with one or more substituents selected from methyl and -OH; and R3bis hydrogen, methyl, ethyl, or propyl.

209. The compound of any one of claims 195 to 208, or a pharmaceutical salt or solvate thereof, wherein R3is independently -NHSO2(CH2)2OH, -NMeSO2(CH2)2OH, - NHSO2CH2CH3, -NHSO2-oxetanyl, -NMeSO2CH3, -N(SO2Me)(CH2)2OH, or.

210. The compound of claim 195, or a pharmaceutical salt or solvate thereof, wherein each R4is independently halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6aminoalkyl, optionally substituted C1-C6alkoxy, two or more R4combine to form a C3-C8cycloalkyl, or two R4combine to form a C1-C3alkylene bridge.

211. The compound of claim 195, or a pharmaceutical salt or solvate thereof, wherein R3bis hydrogen, optionally substituted C1-C6alkyl, or optionally substituted C2-C6alkenyl.

212. The compound of claim 195, or a pharmaceutical salt or solvate thereof, wherein each R2is independently halogen, -OR2a, -N(R2a)2, -S(O)2N(R2a)2, -SO2-C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8-membered heteroaryl, or two R2are taken together to form an oxo, an optionally substituted C3-C8cycloalkyl, an optionally substituted 5- to 8- membered heterocycle, or optionally substituted 5- to 8- membered heteroaryl.

213. The compound of claim 195, wherein the compound is a compound of Formula (I-0), as described in claim 1, or a pharmaceutical salt or solvate thereof.

214. A compound selected from:acceptable salt or solvate thereof.

215. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

216. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

217. The compound of claim 214, wherein the compound ior a pharmaceutically acceptable salt or solvate thereof.

218. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

219. The compound of claim 214, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

220. The compound of claim 214, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

221. The compound of claim 214, wherein the compoundpharmaceutically acceptable salt or solvate thereof.

222. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

223. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

224. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

225. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

226. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

227. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

228. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

229. The compound of claim 214, wherein the compoundor a pharmaceutically acceptable salt or solvate thereof.

230. The compound of claim 214, wherein the compound ior a pharmaceutically acceptable salt or solvate thereof.

231. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 195 to 230, and a pharmaceutically acceptable excipient.

232. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 195 to 230.

233. The method of claim 232 wherein the cancer is bladder cancer, endometrial cancer, lung squamous cell cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophagus cancer, gall-bladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreas cancer, stomach cancer, cervix cancer, thyroid cancer, prostate cancer or skin cancer.

234. A method of inhibiting KIF18A comprising contacting the enzyme with a compound of any one of claims 195 to 230 or a composition of claim 231, or a pharmaceutically acceptable salt or solvate thereof.

235. A compound of any one of claims 195 to 230 or a composition of claim 231, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.

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