Pyrimidine based modulators and uses thereof

Abstract

Provided herein are compounds, such as compounds of Formula (I), Formula (l-A), Formula (l-B), or Formula (l-C), or pharmaceutically acceptable salts of any one thereof, useful for modulating KRAS GD12 and / or other G12 mutants.

Description

PYRIMIDINE BASED MODULATORS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U S Provisional Patent Applications Nos. 63 / 507,909 filed on June 13, 2023; the entire contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, Snapshot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292 el). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.

[0003] Despite extensive efforts, small molecules have not been identified which block effector binding or restore GTPase activating protein (GAP) sensitivity, though some have been found which block interaction of Ras with the guanine nucleotide exchange factor (GEF), SOS, which activates Ras at the plasma membrane. KRAS G12C mutations, most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP -bound state. KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Thus, pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state. Additionally, a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification.

[0004] In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability to achieve selective inhibition of cancer cells while sparing normal Ras function, it is attractive for small molecule inhibitors to bind selectively to the GTP-state and stabilize a conformation that is incompetent for oncogenic signaling interactions with effector proteins. Furthermore, it has been shown that only constitutive activation of Raf, MEK and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (e.g., see Drosten, M., et al., Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p. 1091-104). As all evidence has indicated that MAPK signaling is essential for the growth effects of Ras in cancer, KRAS-mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches. Thus, there is a need to develop new inhibitors for KRAS-driven cancers that demonstrate inhibition of MAPK signals via a mechanism of action that is selective for binding to the active GTP-bound state over the inactive GDP-bound state.INCORPORATION BY REFERENCE

[0005] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.SUMMARY OF THE INVENTION

[0006] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein:R100is selected fromB is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15- membered heterocycle and C7-C15 carbocycle are each optionally substituted with one ormore substituents independently selected from halogen, -CN, -NO2, =0, -N(R20)2, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, Ci-6 alkyl-N(R20)2, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-s haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-Ci2carbocycle and 5- to 12-membered heterocycle;R1Ais selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R11A;R1Bis selected from hydrogen, Ci-6 alkyl, C3-C6 carbocycle, 4- to 6-membered heterocycle, wherein the Ci-6 alkyl and C3-C6 carbocycle, and 4- to 6-membered heterocycle, are each independently optionally substituted with one or more R10;R1Cis selected from hydrogen, Ci-6 alkyl, C3-Ci2carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R12A;R1Dis selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R13, and wherein optionally two R13on the same atom of R1Dcome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R13A;Y is selected from a bond, -0-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Cg alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L-aryl, - L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Ci-Ce haloalkyl, -L- OR20, -L-NR20C(O)-aryl, -L-C00H, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L- N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCI-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L- NR20C(O)-aryl, the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, Ci-6 alkyl-N(R20)2, C 1-6 aminoalkyl, Ci-6 alkoxy, C 1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkyl-Ns, C1-C3 alkoxy, cyano, =CH2, =CHF, =CF2, =N0-CI-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSChF, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)-Ci-C3 alkyl-N(R5)2, -CH2OC(O)NCF3(R5), -CH2O-C1-C6 alkyl, -C(O)N(R5)2, tert- butyldimethylsilyloxyCFh-, -N(R5)2, (C1-C3 alkoxy)Ci-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OCI-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, - OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -O-Ci-C6haloalkyl, -C1-C3 alkyl-O-Ci-C6haloalkyl, Ci.6alkyl-N(R20)2, -SF5, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -(CH2)o-iS-heterocycle , - (CH2)o-i-0-heterocycle, -(CH2)o-i-0-phenyl, and -CFtheterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(CI-C3 alkyl)O(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; wherein the alkyl of -CH2O-C1-C6 alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6 carbocycle; wherein the heterocycle of -CH2heterocycle is optionally substituted with oxo; and wherein the phenyl of -(CH2)o-i-0-phenyl is optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-6 haloalkyl, SF5, Ci-6 alkyl-OR20, - OR20;wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)o-i-S-heterocycle are each optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-e haloalkyl, Ci-e alkyl-OR20, and -OR20; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl- N(R20)2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, and Ci-6 haloalkyl; each R10is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(0)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -N02, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl -N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3- C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -0-C 1-10 alkyl, oxo; each R11, R12, and R13is independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(0)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NR20(C=NH)N(R20)2, -NO2, o, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, benzyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -N(R21)2, -SR21, -C(O)N(R21)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-io alkyl, -C(0)R21, -S(O)2F, -S(O)2(R21), -P(O)(OR21)2, -OP(O)(OR21)2, -P(O)(R21)2, 5- to 6-membered heterocycle and oxo; each R11A, R12A, and R13Ais independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -N02, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl -N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3 i2carbocycle, and 3- to 12- membered heterocycle; and each R21is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(Ci- 6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.

[0007] In certain aspects, for a compound or salt of Formula (I).R100is selected fromB is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R20)2, -B(OR20)2, - OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle;R1Ais selected from Ci-6 alkyl, Cs-Ci2carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R11A;R1Bis selected from hydrogen, Ci-6 alkyl, C3-C6 carbocycle, wherein the Ci-6 alkyl and C3- C<> carbocycle are each independently optionally substituted with one or more R10;R1Cis selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R12A;R1Dis selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R13, and wherein optionally two R13on the same atom of R1Dcome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C -C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R13A;Y is selected from a bond, -O-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Ci-Ce haloalkyl, -L- OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L-N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L-NR20C(O)-aryl, the aryl portion of -L- NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 cyanoalkyl, Ci-6 hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH , =N0-CI-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSCLF, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkylsubstituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, - N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, - CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, - CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(Ci- C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-Ci-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, and -CI h heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(CI-C3alkyl)(Ci-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -Ci-C3alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6carbocycle, and 3- to 8-membered heterocycle, wherein the C3-Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl-N(R20)2, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, Ci-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-Ce carbocycle or 3- to 8-membered heterocycle, wherein the C3-Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C 1-6 alkyl -N(R20)2, CI-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, and C 1-6 haloalkyl; each R10is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-Ci2 carbocycle and 5- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, oxo;each R11, R12, and R13is independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-Ci2carbocycle and 5- to 12-membered heterocycle, wherein the C3-Ci2carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -N(R21)2, -C(O)N(R21)2, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, and oxo; each R11A, R12A, and R13Ais independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci -10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R21is independently selected from hydrogen; and Ci-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci -10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0008] In certain embodiments, Formula (I) is represented by Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt thereof.

[0009] In certain embodiments, Formula (I) is represented by Formula (I-B):or a pharmaceutically acceptable salt thereof.

[0010] In certain embodiments, Formula (I) is represented by Formula (I-C):Formula (I-C), or a pharmaceutically acceptable salt thereof.

[0011] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient.

[0012] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient.

[0013] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I- C). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a pharmaceutical composition compromising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C).

[0014] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of Formula (I), Formula (I-A), Formula (I- B), or Formula (I-C). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and / or other G12mutants, using a pharmaceutical composition compromising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient.DETAILED DESCRIPTION OF THE INVENTION

[0015] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.Definitions

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0017] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0018] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “Ci-ealkyl” or “Ci.Cealkyl” refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. For example -Ci-6 alkyl or Ci-Cg alkyl may be selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl, any one of which is optionally substituted. The term -Cx.yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example -Ci-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0019] "Alkyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms i.e., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to twocarbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms i.e., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / / -propyl), 1 -methylethyl (z'so-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl (s c-butyl), 2-methylpropyl ( / .w-butyl), 1,1 -dimethylethyl (Z / Z-butyl). 1-pentyl ( / / -pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0020] "Alkenyl" as used herein 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 preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-G, alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, and the like.

[0021] "Alkynyl" as used herein 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, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0022] The terms “Cx-yalkenyl” and “Cx-yalkynyl” as used herein refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx.yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, -C2-salkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, -C2-ealkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one ofwhich is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0023] “Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, 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 the terminal carbons respectively. In other embodiments, an alkylene comprises one to five carbon atoms (z.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (ie., Ci- C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0024] "Alkenylene" refers to a straight 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 preferably 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. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., Cj-Cs alkenyl ene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene) Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0025] "Alkynylene" refers to a straight 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 preferably having from two to twelve carbon atoms. Thealkynylene 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 alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (z.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms i.e., C5- C« alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0026] "Halo" or "halogen" as used herein refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0027] "Haloalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. Examples of halogen substituted alkanes (“haloalkanes”) include halom ethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., tri chloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens. When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected, for example I-chloro,2-bromoethane.

[0028] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0029] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0030] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane- 1,2-diamine, pentane- 1, 2, 4-triamine and the like

[0031] "Hydroxy alkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-l-ol, butane- 1 ,4-diol, pentane- 1, 2, 4-triol, and the like.

[0032] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1 -methoxypropane, 2-ethoxypentane, and the like.

[0033] "Cyanoalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.

[0034] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon atom. Carbocycle includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged, or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.

[0035] "Aryl" as used herein refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel 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.

[0036] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0037] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl 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.

[0038] The term “Cx-ycarbocycle” is meant to include groups that contain from x to y carbons in the cycle. For example, the term “C3-6 carbocycle” refers to a saturated, unsaturated, or aromatic ring comprising from 3 to 6 carbons. For example -C3-6 carbocycle- may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any one of which is optionally substituted.

[0039] The term “carbocyclene” refers to a divalent ring, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen atoms. The carbocyclene 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 carbocyclene are to the rest of the molecule and to the radical group are through any two carbons respectively. Carbocyclene includes arylene and cycloalkylene. The term therefore distinguishes carbocyclene from heterocyclene in which the divalent ring comprises at least one atom that is different from a carbon atom. The heterocyclene 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 heterocyclene are to the rest of the molecule and to the radical group through any two atoms respectively, valency permitting. Heterocyclene includes heteroarylene and heterocycloalkylene. Carbocyclene and heterocyclene may each be optionally substituted by one or more substituents such as those substituents described herein.

[0040] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, Se, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles may be fused, bridged, or spiro-ring systems. A spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”. In some cases, spiro-heterocycles, spiro heterocycles, orspiroheterocycles have at least two molecular rings with only one common atom. The spiroheterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.

[0041] “Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) K-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, and imdazopyridine.

[0042] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0043] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0044] “Substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0045] As used herein, the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances wherethe event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0046] As used herein, the term “electrophile” or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and / or an excess of electrons, for example an — SH group). Electrophiles typically are electron poor or comprise atoms which are electron poor. In certain embodiments, an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge or partial positive charge. In some embodiments, an electrophile comprises a conjugated double bond, for example an a,P-unsaturated carbonyl or a,P-unsaturated thiocarbonyl compound.

[0047] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N-NH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-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); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-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); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaryl alkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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(0)tN(Ra)2 (where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0048] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0049] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0050] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0051] As used herein, the phrase "a subject in need thereof' refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0052] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0053] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0054] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in somelevel of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0055] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0056] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0057] As used herein, “sum frequency generation” (SFG) is a nonlinear, optical technique whereby light at one frequency (QI) is mixed with light at another frequency (Q2) to yield a response at the sum frequency (Q1+Q2) (Shen, 1984, 1989). For example, SFG is particularly useful for the detection of molecules at surfaces through their characteristic vibrational transitions and, in this case, is essentially a surface-selective infrared spectroscopy with I and Q2 at visible and infrared frequencies. When the terms “SHG” or “second harmonic generation” are used herein, it is understood that SFG and “sum frequency generation” can substitute and be used in place of SHG with methods well known to one skilled in the art.

[0058] “ Second harmonic-active moiety” or “second harmonic-active moiety,” as used herein, refers to a nonlinear-active moiety, particle or molecule which can be attached (covalently or non-covalently) to a molecule (e.g., a protein, such as an enzyme), particle or phase (e.g., lipid bilayer) in order to render it more nonlinear optical active.

[0059] A “nonlinear active moiety,” as used herein, is a substance which possesses a hyperpolarizability.

[0060] “Hyperpolarizability” or “Nonlinear Susceptibility” as used herein refer to the properties of a molecule, particle, interface, or phase which allow for generation of nonlinear light. The terms “hyperpolarizability,” “second-order nonlinear polarizability,” and “nonlinear susceptibility” are some-times used interchangeably.

[0061] “Allosteric”, “allosteric modulator”, or “allosteric candidate” as used herein, refers to a molecule, moiety or substance which binds predominantly to a site other than the active site and causes conformational change, which can be determined by SHG or SFG, and thus exert their effect via an allosteric mechanism of action.

[0062] The term “inhibit”, “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

[0063] The term “targeted agent” or “targeted therapy” as described herein referred to a therapy that uses specific drugs to target specific genes, protein, or active sites involved in the development, survival, and proliferation of cancer cells.

[0064] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0065] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Compounds

[0066] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein:R100is selected fromB is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R20)2, -B(OR20)2, - OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle;R1Ais selected from C1-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R11A;R1Bis selected from hydrogen, C1-6 alkyl, C3-C6 carbocycle, 4- to 6-membered heterocycle, wherein the C1-6 alkyl and C3-C6 carbocycle, and 4- to 6-membered heterocycle, are each independently optionally substituted with one or more R10;R1Cis selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R12A;R1Dis selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R13, and wherein optionally two R13on the same atom of R1Dcome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R13A;Y is selected from a bond, -O-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Ci-Ce haloalkyl, -L- OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L-N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCi -Ce alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L-NR20C(O)-aryl, the aryl portion of -L- NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(0)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, C 1-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle;each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, C1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkyl-Ns, C1-C3 alkoxy, cyano, =CH2, =CHF, =CF2, =N0-Ci- C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSChF, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)-Ci-C3 alkyl- N(R5)2, -CH2OC(O)NCF3(R5), -CH2O-C1-C6 alkyl, -C(O)N(R5)2, tert-butyldimethylsilyloxyCFh-, -N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, - CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, - CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(Ci- C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -O-Ci-Cg haloalkyl, -C1-C3 alkyl-O-Ci-Ce haloalkyl, Ci-6 alkyl-N(R20)2, -SF5, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -(CH2)o-iS-heterocycle , -(CH2)o-i-0-heterocycle, -(CH2)o-i-0-phenyl, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(CI-C3 alkyl)0(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(0)H and OH, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; wherein the alkyl of -CH2O-CI-C6 alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6 carbocycle; wherein the heterocycle of -CH2heterocycle is optionally substituted with oxo; and wherein the phenyl of -(CH2)o-i-0-phenyl is optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-6 haloalkyl, SF5, C 1-6 alkyl -OR20, -OR20; wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)o-i-S-heterocycle are each optionally substituted with one or more substituents selected from Ci-6 alkyl, C 1-6 haloalkyl, Ci-6 alkyl-OR20, and -OR20; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2;each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C 1-6 alkyl -N(R20)2, CI-6 aminoalkyl, C1-6 alkoxy, Ci-s hydroxyalkyl, and C 1 -6 haloalky 1; each R10is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- Ci2carbocycle and 5- to 12-membered heterocycle, wherein the C3-Ci2carbocycle and 5- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo; each R11, R12, and R13is independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NR20(C=NH)N(R20)2, -N02, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci. 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, benzyl, C3-Ci2carbocycle and 5- to 12-membered heterocycle, wherein the C3-Ci2carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -N(R21)2, - SR21, -C(O)N(R21)2, Ci-10 alkyl, -Ci-io haloalkyl, -0-C 1-10 alkyl, -C(0)R21, -S(O)2F, - S(O)2(R21), -P(O)(OR21)2, -OP(O)(OR21)2, -P(O)(R21)2, 5- to 6-membered heterocycle and oxo; each R11A, R12A, and R13Ais independently selected from halogen, -B(OR20)2, -OR20, -SR20,aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;each R20is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci -10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R21is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci -10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0067] In some embodiments, for a compound or salt of Formula (I),R100is selected fromB is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R20)2, -B(OR20)2, - OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-Ci2carbocycle and 5- to 12-membered heterocycle;R1Ais selected from Ci-6 alkyl, C3-Ci2carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R11A;R1Bis selected from hydrogen, Ci-6 alkyl, C3-C6 carbocycle, wherein the Ci-6 alkyl and C3- C'e carbocycle are each independently optionally substituted with one or more R10;R1Cis selected from hydrogen, Ci-6 alkyl, C3-Ci2carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R12A;R1Dis selected from hydrogen, Ci-6 alkyl, C3-Ci2carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R13, andwherein optionally two R13on the same atom of R1Dcome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R13A;Y is selected from a bond, -O-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Ci-Ce haloalkyl, -L- OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L-N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L-NR20C(O)-aryl, the aryl portion of -L- NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 cyanoalkyl, Ci-6 hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =N0-Ci-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSCLF, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCFL-, - N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, - CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, - CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -0C(0)NH(Ci- C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -0C(0)NH(Ci-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, and -CH? heterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(CI-C3 alkyl)O(Ci-C3 alkyl)phenyl are optionally substituted with one or moresubstituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Cue alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C 1-6 alkyl -N(R20)2, CI-6 aminoalkyl, C1-6 alkoxy, Ci-s hydroxyalkyl, and C 1-6 haloalkyl; each R10is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-s hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(Ci-s alkyl)2, C1-10 alkyl, -Cnio haloalkyl, -O-Ci-10 alkyl, oxo; each R11, R12, and R13is independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-s hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -N(R21)2, -C(O)N(R21)2, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, and oxo;each R11A, R12A, and R13Ais independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20is independently selected from hydrogen; and Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci -10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R21is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, C 1-10 alkyl, -C 1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0068] In some embodiments, Formula (I) is represented by Formula (II).

[0069] In an aspect, the present disclosure provides a compound of Formula (II)Formula (II), or a pharmaceutically acceptable salt thereof wherein:R100is selected fromB is selected from an optionally substituted 8- to 10-membered fused heterocycle, wherein the 8- to 10-membered fused heterocycle is optionally substituted with one or more substituents independently selected from C3 carbocycle, C1-C3 alkyl, halogen, =0, C1-C3 alkyl, -NH2, and - CNR1Ais selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of C1-4 alkyl come together to form a C3-C4 carbocycle;R1Cis selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R12, and wherein optionally two R12on the same atom of C1-4 alkyl come together to form a C3-C4 carbocycle;R2is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R20)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each R6is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl; each R7is independently selected from halogen, and C1-C4 haloalkyl; each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C1-6 haloalkyl;R3is selected from hydrogen, halogen, -CN, -C(O)R20, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 alkoxyalkyl, Ci-ehydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, and C1-6 alkyl; each R11is independently selected from halogen, -OR20, -N(R20)2, -C(O)N(R20)2, -C(O)OR20, - CN, =0, -NH(C=NH)NH2, C2-6 alkenyl, C3-C6 carbocycle, and 4- to 9-membered heterocycle, wherein the 4- to 9-membered heterocycle and C3-C6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -SR21, - S(O)2(R21), -S(O)2F, -C(O)R21, -P(O)(R21)2, -OH, -0CH3, -CN, oxo, -N(R21)2, -C(O)N(R21)2, Ci-10 alkyl, 5- to 6-membered heterocycle, and -C1-10 haloalkyl; and wherein optionally two R11on the same atom of R1Acome together to form a C3-C4 carbocycle;each R12is selected from halogen, -OR20, -N(R20)2, -C(O)N(R20)2, -C(O)OR20, -CN, =0, - NH(C=NH)NH2, C2-6 alkenyl, C3-C6 carbocycle, and 4- to 9-membered heterocycle, wherein the 4- to 9-membered heterocycle and C3-C6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -SR21, -S(O)2(R21), -S(0)2F, - C(O)R21, -P(O)(R21)2, -OH, -OCH3, -CN, oxo, -N(R21)2, -C(O)N(R21)2, CI-IO alkyl, 5- to 6- membered heterocycle, and -C1-10 haloalkyl; and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C4 carbocycle; each R20is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle. each R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle; and n is 0.

[0070] In some embodiments, for a compound or salt of Formula (I) or Formula (II), R100is R1AR1 BR1CRI B R1A selected from -J-- and~L~ . In some cases, R100is ~-L~

[0071] In some embodiments, for a compound or salt of Formula (I), R100is selected from:R1As'N— L- , wherein R1Ais selected from Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to R1CO form an unsubstituted C3 carbocycle; and -J— , wherein R1Cis selected from Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form an unsubstituted C3 carbocycle.R1AN

[0072] In some embodiments, for a compound or salt of Formula (I), R100is selected from: — I—R1ANH and —I— . In some cases, R1Ais selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12- membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more R11A.

[0073] In some embodiments, Formula (I) is represented by Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100,. In some cases,R1Ais selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more R11A.

[0075] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100,, , . In some cases, R1Ais selected from Cn6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more R11A

[0076] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100, 1 B RIA RIB RIAJ- ofR100, or -L is selected from:some cases, R1Ais selected fromC1-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more R11A

[0077] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Bis hydrogen. In some cases, R1Bis selected from an optionally substituted Ci-6 alkyl. In some cases, R1Bis selected from an optionally substituted C3-C6 carbocycle.

[0078] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an optionally substituted Ci-6 alkyl. In some cases, R11is -N(R20)2. In some cases,

[0079] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais C4- Cc, carbocycle, wherein the C4-C6 carbocycle is optionally with one or more R11. In some cases, each R11is selected from -N(R20)2, wherein each R20is selected from hydrogen and optionally

[0080] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R11. In some cases, each R11is selected from halogen, -N(R20)2, - C(O)R20, -C(O)N(R20)2, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally with one or more R11. In some cases, the heterocycle has at least one oxygen atom In some cases, the heterocycle has one oxygen atom. In some cases, R1Ais selected fromwhich is optionally substituted. In some cases, each R11is selected from -OH and Ci-6 hydroxyalkyl. In some cases, each R11is -OH. In some cases, R1Ais selected f

[0081] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), each R11Ais independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, -O, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0082] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), each R11is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- C12 carbocycle and 5- to 12-membered heterocycle. In some cases, each R11is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(0)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl- N(R20)2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle. In some cases, each R11is independently selected from halogen, -OR20, -N(R20)2, =0, =NO(R20), -CN, -NHCN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle. Insome cases, each R11is independently selected from halogen, -OR20, -N(R20)2, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-shydroxyalkyl, C1-6 cyanoalkyl, and C 1-6 haloalkyl.

[0083] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Bis selected from hydrogen, optionally substituted Ci-6 alkyl, and optionally substituted C3-C6 carbocycle. In some cases, R1Bis hydrogen, Ci-6 alkyl, C 1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and C3- C<> carbocycle. In some cases, R1Bis hydrogen, methyl, ethyl, C2 hydroxyalkyl, and cyclopropyl. In some cases, R1Bis hydrogen. In some cases, R1Bis selected from an optionally substituted Ci-6 alkyl. In some cases, R1Bis selected from methyl and ethyl. In some cases, R1Bis methyl. In some cases, R1Bis selected from an optionally substituted C3-C6 carbocycle. In some cases, R1BisIn some cases, R1Bis selected from Ci-6 cyanoalkyl. In some cases, R1Bis selected from Ci-6 hydroxy alkyl.

[0084] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an optionally substituted C1-3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle. In some cases, R11is selected from halogen, - N(R20)2, C3 carbocycle, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N(R21)2, C MO alkyl, and -Ci-io haloalkyl. In some cases, each R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.

[0085] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais

[0087] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100,—1— of R100, or —1— , R1Ais selected from an optionally substituted Ci-6 alkyl. In some cases, R1Ais selected from an optionally substituted C1-3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle. In some cases, R1Ais selected fromcases, R1Ais selected fromR11R11,and. In some cases, R1Ais selected from. In some cases, R1Ais selected from. , . In some cases, R1Aissome cases, R11is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 8-membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 6-membered heteroaryl. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least two nitrogen atoms. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, the heterocycle has only 2 nitrogen atoms and no other heteroatoms.In some cases,which is optionally substituted. In some cases, R11, which is optionally substituted. In some cases,each of which is optionally substituted. In some cases, R11is selected fromeach of which is optionally substituted. In some cases, the optional one or more substituents independently selected from halogen, -OH, -CN, -N(R21)2, -C(O)N(R21)2, CMO alkyl, and -Ci-io haloalkyl. In some cases, R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some cases, the optional one or more substituents of R11is selected from halogen, Ci-6 haloalkyl, -NH2, -NH(CI-6 alkyl), -N(Ci-one or more substituents of R11is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R11is selected from -NH2, and Ci-io alkyl. In some cases, the optional one or more substituents of R11is selected from -NH2. In some

[0088] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100,

[0089] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100,

[0090] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100,hydrogen, Ci-6 alkyl, Ci-6 hydroxyalkyl, and Ci-6 cyanoalkyl. In some cases, R1Bis selected from hydrogen and Ci-s alkyl. In some cases, R1Bis selected from Ci-6 alkyl. In some cases, R1Bis a cyclopropyl. In some cases, R1Bis methyl. In some cases, R1Bis ethyl. In some cases, R100is

[0091] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100,

[0092] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an C1-3 alkyl, which is optionally substituted with one or more R11, wherein each R11is selected from C3-C6 carbocycle, and 5- to 6-membered heterocycle, wherein the 5- to 6- membered heterocycle and C3-C6 carbocycle are each optionally substituted. In some cases, R1Ais selected from an C1-3 alkyl, which is substituted with one or more R11, wherein each R11is selected from phenyl, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle and phenyl are each optionally substituted. In some cases, R11is phenyl, which is optionally substituted.In some cases, R11is selected from a 5- to 6-membered heterocycle, which is optionally substituted.In some cases, R11is pyridine, which is optionally substituted. In some cases, R1Ais selected from, . , y y . n some cases, the one or more substituents are independently selected from halogen, -P(O)(R21)2, -S(O)2F, -OH, -CN, -N(R21)2, - C(O)N(R21)2, CI -io alkyl, and -C1-10 haloalkyl. In some cases, the one or more substituents are independently selected from halogen, -P(O)(R21)2, -OH, -CN, -N(R21)2, -C(O)N(R21)2, Ci-io alkyl, and -Ci-10 haloalkyl. In some cases, the one or more substituents are independently selected from -P(O)(R21)2, -N(R21)2, and Ci -10 alkyl. In some cases, the one or more substituents are independently selected from -P(O)(R21)2, and -N(R21)2. In some cases, the one or more substituents are independently selected from -P(O)(R21)2. In some cases, each R21is independently selected from hydrogen and Ci-6 alkyl. In some cases, each R21is independently selected from C1.3 alkyl. In. In some cases,selected fromsome cases, R1Bis selected from hydrogen and Ci-6 alkyl. In some cases, R100is selected from In some cases,some cases, R100is —J— . In some cases, R100is selected from —I— . In some cases, B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and Ci-6 alkyl. In some cases, B is selected from an 8-membered heterocycle, wherein the 8-membered heterocycle is substituted with one or more substituents independentlyselected from halogen, -CN, -NH2, and Ci-6 alkyl. In some cases, the heterocycle of B has one sulfur atom and no other heteroatoms. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, B is selected fromeach of which is optionally substituted. In some cases, B is selected from, each of which is substituted with at least one substituent.. In some cases, Y is O. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, Ci-shaloalkyl. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some-L-heterocycle. In some cases, R2is selected from optionally substituted -L-heterocycle, wherein the heterocycle is a saturated heterocycle. In some cases, the heterocycle is selected from, each of which is optionally substituted with one or more R6. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, - N(R5)S(O)2(R5), -OC(O)N(R5)2, -CH2, OXO, =NO-CI-C3alkyl, -CH2OC(O)heterocycle, - CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, each R6is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some cases, each R6is independently selected from halogen. In some cases, Y-R2is selected from,

[0094] In some embodiments, for a compound or salt of Formula (I), Formula (I- A), Formula (I- B), or Formula (I-C), B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, and selenium. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from selenium. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from sulfur and selenium. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium. In some cases, B is an optionally substituted 8-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium.

[0095] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Bis hydrogen. In some cases, R1Bis selected from an optionally substituted Ci-6 alkyl. In some cases, R1Bis selected from an optionally substituted C3-C6 carbocycle. In some cases, R1Bis selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, and C3-C6 carbocycle. In some cases, R1Bis hydrogen, methyl, ethyl, and cyclopropyl. In some cases, R1Bis hydrogen. In some cases, R1Bis selected from an optionally substituted C1-6 alkyl. In some cases, R1Bis selected from an optionally substituted C1-2 alkyl. In some cases, R1Bis selected from methyl and ethyl. In some cases, R1Bis methyl. Insome cases, R1Bis selected from an optionally substituted C3-C6 carbocycle. In some cases, R1Bis

[0096] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an optionally substituted C1.3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle. In some cases, R11is selected from halogen, -N(R20)2, C3 carbocycle, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N(R21)2, Ci-io alkyl, and -C1-10 haloalkyl. In some cases, each R21is independently selected from hydrogen; and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some cases, R1Ais selected from

[0098] In some embodiments, for a compound or salt of Formula (I), R1Ais selected from an optionally substituted Ci-6 alkyl. In some cases, R1Ais selected from an optionally substituted C1-3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle. In some cases, R1Ais selected from an optionally substituted C1-2 alkyl. In some cases,R11R11R11In some cases, R1Ais selected fromIn some cases, R1Ais selected from. In some cases, R11is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 8-membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 6-membered heteroaryl. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least two nitrogen atoms. In some cases, the heterocycle has one nitrogen atom and no other heteroatoms. In some cases, the heterocycle has two nitrogen atoms and no other heteroatoms. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl has one nitrogen atom and no other heteroatoms. In some cases, the heteroaryl has two nitrogen atoms and no other heteroatoms. In some cases, R11iseach of which is optionallysubstituted. In some cases,each of which is optionally substituted. In some cases, R11is selected fromeach of which is optionally substituted. In some cases, the optional one or more substituents of R11are each independently selected from halogen, -OH, -CN, -N(R21)2, -C(O)N(R21)2, Ci-io alkyl, and -Ci-io haloalkyl. In some cases, each R21is independently selected from hydrogen; and Ci-6 alkyl,C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6- membered heterocycle. In some cases, the optional one or more substituents of R11is selected from halogen, Ci-6 haloalkyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,, and Ci-io alkyl. In some cases, the optional one or more substituents of R11is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci -10 alkyl. In some cases, the optional one or more substituents of R11is selected from -NH2, and Ci-io alkyl. In some cases, the optional one or more substituents of R11is selected from -NH2. In some cases, R11is selected fromselected from hydrogen and Ci-6 alkyl. In some cases, R1Bis selected from Ci-6 alkyl. In some cases, R1Bis a cyclopropyl. In some cases, R1Bis methyl. In some cases, R1Bis ethyl. In some cases, R100some cases,some cases, R100is selected from

[0100] In some embodiments, for a compound or salt of Formula (I), R100is selected fromsome cases, R100is selected fromsome cases, R1Bis selected from hydrogen and Ci-6 alkyl. In some cases, R100is selected from In some cases,some cases, R100is — I— . In some cases, R100is selected from —I— . In some cases, B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl. In some cases, B is selected from an 8-membered heterocycle, wherein the 8-membered heterocycle is substituted with one or more substituents independently selected from halogen, -CN, -NH2, and Ci-6 alkyl. In some cases, the heterocycle of B has one sulfur atom and no other heteroatoms. In some cases, the heterocycle of B is an unsaturatedheterocycle. In some cases, B is selected fromeach of which is optionally substituted. In some cases, B is selected fromeach of which is substituted with at least one substituent.some cases, R3is selected from hydrogen, -CN, -C(O)H, Ci hydroxyalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, fluorine, and -CN. In some cases, R3is selected from fluorine. In some cases, R3is selected from hydrogen. In some cases, R3is selected from -CN. In some cases, Y is O. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, Ci-ehaloalkyl. In some cases, two substituents on the same carbon atom ofL come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is selected from. , s selected from optionally substituted -L-heterocycle. In some cases, R2is selected from optionally substituted -L-heterocycle, wherein the heterocycle is asaturated heterocycle. In some cases, the heterocycle is selected fromeach of which is optionally substituted with one or more R6. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, OXO, =N0-CI-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, - CH2OC(O)N(R5)2, and-O-Ci-Cs alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, each R6is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some cases, each R6is independently selected from halogen. In some cases, Y-R2is selected from,

[0101] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an optionally substituted C1-6 alkyl. In some cases, R11is -N(R20)2. In some cases,R1Ais selectedH,. In some cases, R11is selected from an optionally substituted 5- to 6- membered heteroaryl. In some cases, R11is selected from an optionally substituted 6-membered heteroaryl. In some cases, R11is selected from an optionally substituted pyridine. In some cases, the heteroaryl (e.g., pyridine) is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -NH2, -NH(CI-6 alkyl), - N(CI-6 alkyl)2, C1-10 alkyl, and -Ci-10 haloalkyl. In some cases, the heteroaryl (e.g., pyridine) is optionally substituted with one or more substituents independently selected from -NH2, -NH(CI-6 alkyl), and -N(Ci-s alkyl)2. In some cases, the heteroaryl (e.g., pyridine) is substituted with at least one -NH2. In some cases, there heteroaryl has at least one nitrogen atom. In some cases, thereheteroaryl has one nitrogen atom and no other heteroatoms. In some cases, R1Ais selected from

[0102] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais C4-C6 carbocycle, wherein the C4-C6 carbocycle is optionally with one or more R11. In some cases, the carbocycle is a saturated carbocycle. In some cases, each R11is selected from -N(R20)2, wherein each R20is selected from hydrogen and optionally substituted Ci-6 alkyl. In some cases,R1Ais selected

[0103] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R11. In some cases, the heterocycle is a saturated heterocycle. In some cases, each R11is selected from halogen, -N(R20)2, -C(O)R20, -C(O)N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, R1Ais

[0104] In some embodiments, for a compound or salt of Formula (I), R100is selected from

[0105] In some embodiments, for a compound or salt of Formula (I) or (I-A), R1Bis hydrogen. In some cases, R1Bis selected from an optionally substituted Ci-6 alkyl. In some cases, R1Bis selected from an unsubstituted Ci-6 alkyl. In some cases, R1Bis methyl. In some cases, R1Bis selected from an optionally substituted C3-C6 carbocycle.

[0106] In some embodiments, for a compound or salt of Formula (I) or (I-A), R1Ais selected from an optionally substituted C1-6 alkyl. In some cases, R11is -N(R20)2. In some cases,wherein the C4-C6 carbocycle is optionally with one or more R11. In some cases, R11is selected from -N(R20)2, and wherein each R20is selected from hydrogen and optionally substituted C1-6selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R11. In some cases, each R11is independently selected from C1-6 aminoalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, -C(O)R20, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, and oxo. In some cases, each R11is selected from halogen, -OH, -N(R20)2, -C(O)R20, -C(O)N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-shydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, R1Ais selected from, , y . ,R1Ais selected fromwhich is optionally substituted. In some cases, each R11is independently selected from Ci-6 aminoalkyl, Ci-g cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, -C(O)R20,C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-io alkyl, and oxo. In some cases, each R11is selected from halogen, -N(R20)2, - C(O)R20, -C(O)N(R20)2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R11is selected from halogen, -N(R20)2,C(O)N(R20)2, CI-6 haloalkyl, and Ci-6 alkyl. In some cases, R1Ais selected fromwherein optionally two R11on the same atom of R1Acome together to form an optionally substituted C3-C6 carbocycle. In some cases, R11is selected from -OH and -CN, and wherein two R11on the same atom of R1Acome together to form an unsubstituted C3 carbocycle. In some cases,

[0107] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally with one or more R11. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle has one oxygen atom. In some cases, R1Ais selected from, which is optionally substituted. In some cases, each R11is selected from -OH and C1-6 hydroxyalkyl. In some cases, each R11is -OH. In some cases, R1Ais selected from

[0108] In some embodiments, for a compound or salt of Formula (I) or (I-A), R1Bis selected from hydrogen, C1-6 alkyl, C3 carbocycle, 4- to 5-membered heterocycle, wherein the C1-6 alkyl, C3 carbocycle, and 4-to 5-membered heterocycle, are each optionally substituted with one or more R10, wherein each R10is independently selected from halogen, -OR20, -C(O)N(R20)2, -N(R20)2, -C(O)OR20, =0, -CN, C2-6 alkenyl, Ci-6 haloalkyl, C3-C6 carbocycle, and 4-memberedsome cases, R1Bis selected from unsubstituted C1-6 alkyl . In some cases, R1Bis,

[0109] In some embodiments, for a compound or salt of Formula. In some cases, R100is from

[0110] In some embodiments, for a compound or salt of Formula (I), R100is selected from

[0111] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Aisselected fromIn some cases, R1Ais selected fromIn some cases, R1Ais selected from

[0112] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an optionally substituted Ci-6 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form an optionally substituted C3-C6 carbocycle. In some cases, R11is selected from -OH, -CN, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -NH(CI-6 alkyl), -N(Ci-6 alkyl)2, Ci- 10 alkyl, -Ci-io haloalkyl, and -O-Ci- 10 alkyl; and wherein two R11on the same atom of R1Acome together to form an unsubstituted C3

[0113] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R11is selected from, which is optionally substituted. In some cases, R11is selected fromwhich is optionally substituted.

[0114] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100

[0115] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an Ci-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom ofR1Acome together to form a C3 carbocycle. In some cases, R1Ais selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle. In some cases, R11is selected from halogen, -OR20, -N(R20)2, -C(O)N(R20)2, - C(O)OR20, -CN, =0, -NH(C=NH)NH2, C2-6 alkenyl, C3-Cs carbocycle, and 4- to 9-membered heterocycle, wherein the 4- to 9-membered heterocycle and C3-C6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -SR21, -S(O)2(R21), -S(O)2F, -C(0)R21, -P(O)(R21)2, -OH, -0CH3, -CN, oxo, -N(R21)2, -C(O)N(R21)2, C1-10 alkyl, 5- to 6-membered heterocycle, and -C1-10 haloalkyl; and wherein optionally two R11on the same atom of R1Acome together to form a C3-C4 carbocycle. In some cases, each R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered

[0116] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1A

[0117] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0118] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0119] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0120] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0121] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0122] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Bis selected from Ci-6 alkyl, and 4- to 5-membered heterocycle, wherein the Ci-6 alkyl, and 4-to 5- membered heterocycle, are each optionally substituted with one or more R10, wherein each R10is independently selected from halogen, -OR20, -C(O)N(R20)2, -N(R20)2, -C(O)OR20, =0, -CN, C2-6 alkenyl, Ci-e haloalkyl, C3-C6 carbocycle, and 4-membered heterocycle.

[0123] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Bis

[0124] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0125] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100

[0126] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0127] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from an optionally substituted Ci-6 alkyl. In some cases, R1Ais selected from an optionally substituted C1-3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle. In some cases, R1Ais selected from an optionally substituted C1.3 alkyl. In some cases, R1Ais selected from an optionally substituted C1-2 alkyl. In some cases, R1Ais selected from an optionally substituted Ci alkyl. In some cases, R1Ais selected from an optionally substituted C2 alkyl. In some cases, R1Ais not a C2 alkyl. In some cases, R1Ais not a linear C2 alkyl.In some cases, R1Ais not a branched C3 alkyl. In some cases, R1Ais not. In some cases,R11R1Ais not. In some cases, R1Ais notsome cases, R1Ais selected fromcases, R1Ais not selected from. In some cases, R1Ais not. In some cases, R1Ais notnot a heteroaryl. In some cases, R1Ais not a linear C2 alkyl or a branched C3 alkyl. In some cases, R1Ais not a linear C2 alkyl or a branched C3 alkyl, and R11is not a heteroaryl. In some cases, R1Ais not a linear C2 alkyl or a branched C3 alkyl, and R11is not a 5- to 6-membered heteroaryl. In some cases, R11is selected from an optionally substituted 5- to 12- membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 8- membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 6- membered heterocycle. In some cases, R11is selected from an optionally substituted 5- to 6- membered heteroaryl. In some cases, R11each of which is optionally substituted. In some cases,R11is selected from, each of which is optionally substituted. In some cases, R11is selected from, each of which is optionally substituted. In some cases, the optional one or more substituents independently selected from halogen, -OH, -CN, -N(R21)2, Ci-io alkyl, and -CMO haloalkyl. In some cases, each R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some cases, the optional one or more substituents of R11is selected from halogen, C1-6 haloalkyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,, , , and Ci -io alkyl. In some cases, the optional one or more substituents ofR11is selected from -NH2, -NH(CI-6 alkyl), -N(Ci-e alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R11is selected from -NH2, and Ci-io alkyl. In some cases, the optional one or more substituents of R11is selected from -NH2. In some cases, R11

[0128] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0129] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100orwherein R1Bis selected from hydrogen and Ci-6 alkyl. In some cases, R1Bis selected from Ci-6 alkyl.

[0130] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100

[0131] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0132] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0133] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0134] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0135] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R11is selected from, / =N / ^NS. MU < 1, and vx-|Nn, each of which is optionally substituted. In some cases, ), R is, each of which is optionally substituted. In some cases,R11is selected fromeach of which is optionally substituted. In some cases, the optional one or more substituents independently selected from halogen, oxo, -OH, -OCH3, -CN, -N(R21)2, - C(O)N(R21)2, -P(O)(R21)2, -SCH3, Ci-10 alkyl, and -Ci-io haloalkyl. In some cases, the optional one or more substituents of R11is selected from halogen, oxo, -OH, -OCH3, C1-6 haloalkyl, -NH2, -

[0136] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R100or

[0139] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of C1-6 alkyl come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R11A.

[0140] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B), R1Cis selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of Ci-6 alkyl come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R12A;

[0141] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R1Ais selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R11. In some cases, R1Ais selected from, ,each of which is optionally substituted with one or more R11, and wherein each R11is independently selected from -OH, C 1.6 aminoalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, C1-6 alkyl, -C(O)R20, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NHz, -NH(CI-6 alkyl), -N(CI-6 alkyl h, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, and oxo. In some cases, R11is selected from halogen, -OH, -N(R20)2, - C(O)R20, -C(O)N(R20)2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, R1Ais selected from

[0142] In some embodiments, for a compound or salt of Formula (I), R100is selected from

[0143] In some embodiments, Formula (I) is represented by Formula (I-B):Formula (I-B), or a pharmaceutically acceptable salt thereof

[0144] In some embodiments, for a compound or salt of Formula (I), R100is different thanY-R2. In some cases, —I— is different than Y-R2.

[0145] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B),different than Y-R2.

[0146] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B), R1Cis selected from an optionally substituted Ci-6 alkyl. In some cases, R1Cis selected from an optionally substituted Ci-6 alkyl, and wherein optionally two R12on the same atom of R1Ccome together to form an optionally substituted C3-C6 carbocycle. In some cases, R12is selected from -OH and -CN, and wherein two R12on the same atom of R1Ccome together to form an unsubstituted C3

[0147] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B), R1Cis selected from an optionally substituted C1-6 alkyl. In some cases, R1Cis selected from an optionally substituted C1-6 alkyl, and wherein optionally two R12on the same atom of R1Ccome together to form an optionally substituted C3-C6 carbocycle. In some cases, R12is selected from -OH, -CN, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-io haloalkyl, and -O-Ci-io alkyl; and wherein two R12on the same atom of R1Ccome together to form an unsubstituted C3 carbocycle. In some cases,some embodiments, for a compound or salt of Formula

[0150] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B), R1Cis selected from an optionally substituted C1.3 alkyl. In some cases, R1Cis selected from

[0151] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B), R1CisR12R12selected fromIn some cases, R12is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, R12is selected from an optionally substituted 5- to 8- membered heterocycle. In some cases, R12is selected from an optionally substituted 5- to 6- membered heterocycle. In some cases, R12is selected from an optionally substituted 5- to 6- membered heteroaryl. In some cases, R12CNINH, each of which is optionally substituted. In some cases, R12is selected fromthe optional one or more substituents of R12is selected from -NH2, -NH(CI-6 alkyl), -N(Ci-6alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R12is selected from -NH2,-NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R12is selected from -NH2, and C1-10 alkyl. In some cases, the optional one or moresubstituents of R12is selected from -NH2. In some cases, R12is selected fromsome embodiments, for a compound or salt of Formula (I), R100is selected from

[0153] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B), R1Cis selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R1Cis selected from an optionally substituted 5-membered heterocycle having at least one oxygen atom, o-^In some cases, R1Cis selected , which is optionally substituted. In some cases, each R12is selected from halogen, -OR20, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. Insome cases, R12is selected from -OH. In some cases, R1Cis HO

[0154] In some embodiments, for a compound or salt of Formula (I) or Formula (I-B), R1Cis selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R1Cis selected from an optionally substituted 5-membered heterocycle. In some cases, R1Cis selectedfrom an optionally substituted 5-membered heterocycle having at least one oxygen atom. In some cases, R1Cis selectedwhich is optionally substituted. In some cases, R12is selected from halogen, -OR20, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, and Ci-6 alkyl. In some cases,each R12is selected from -OH. In some cases, R1C1S HO

[0155] In some embodiments, for a compound or salt of Formula (I), R100is selected from

[0156] In some embodiments, for a compound or salt of Formula (I) or Formula (I-C), R1Cis selected from an optionally substituted Ci-6 alkyl. In some cases, R1Cis selected from an optionally substituted C1-3 alkyl, and wherein optionally two R11on the same atom of R1Ccome together to form a C3 carbocycle. In some cases, R1Cis selected from an optionally substituted C1-3 alkyl. InR11R1Cis selected from. In some cases, R1Cis selected fromIn some cases, R1Cis selected from

[0157] In some embodiments, for a compound or salt of Formula (I) or Formula (I-C), R1Cis selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3 carbocycle. In some cases, R1Cis selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one ormore R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3 carbocycle. In some cases, R12is selected from halogen, -OR20, -N(R20)2, -C(O)N(R20)2, - C(O)OR20, -CN, =0, -NH(C=NH)NH2, C2-6 alkenyl, C3-C6 carbocycle, and 4- to 9-membered heterocycle, wherein the 4- to 9-membered heterocycle and C3-C6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -SR21, -S(O)2(R21), -S(O)2F, -C(0)R21, -P(O)(R21)2, -OH, -OCH3, -CN, oxo, -N(R21)2, -C(O)N(R21)2, Ci-10 alkyl, 5- to 6-membered heterocycle, and -C1-10 haloalkyl; and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C4 carbocycle. In some cases, each R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.

[0158] In some embodiments, for a compound or salt of Formula (I) or Formula (I-C), R1Cis

[0159] In some embodiments, for a compound or salt of Formula (I) or Formula (I-C), R1Cis selected from C1.3 alkyl, and 5- to 6-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C4 carbocycle or 4-membered heterocycle. In some cases, each R12is independently selected from -OH, -CN, 5- to 6-membered heterocycle, wherein the 5- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, and Ci-io alkyl.

[0160] In some embodiments, for a compound or salt of Formula (I) or Formula (I-C), R1Cis

[0161] In some embodiments, Formula (I) is represented by Formula (I-C):Formula (I-C), or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, for a compound or salt of Formula (I) or Formula (I-C), R1Dis selected from an optionally substituted Ci-6 alkyl. In some cases, R is selected fromsome cases, R13is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, R13is selected from an optionally substituted 5- to 8-membered heterocycle. In some cases, R13is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R13is selected from an optionally substituted 5- to 6-membered heteroaryl. In some cases, R13is selected fromeach of which is optionally substituted. In some cases,selected fromeach of which is optionally substituted. In some cases, the optional one or more substituents of R12is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R12is selected from -NH2,-NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R12is selected from -NH2, and C1-10 alkyl In some cases, the optional one or more substituents of R12is selected from -NIL. In some cases, R13is selected from

[0163] In some embodiments, for a compound or salt of Formula (I) or Formula (I-C), R1Dis selected from an optionally substituted C1-6 alkyl, and wherein optionally two R13on the same atom of R1Dcome together to form an optionally substituted C3-C6 carbocycle. In some cases, R13is selected from -OH, -CN, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -NH(CI-6alkyl), -N(Ci-6alkyl)2, Ci-io alkyl, -C1-10 haloalkyl, and -O-Ci-10 alkyl; and wherein two R13on the same atom of R1Dcome together to form an unsubstituted C3 carbocycle. In some cases, R1Dis selected from

[0165] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), B is selected from an optionally substituted 7- to 15-membered fused heterocycle and optionally substituted C7-C15 fused carbocycle. In some cases, and optionally substituted C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 7- to 15-membered fused heteroaryl and optionally substituted C7-C15 fused aryl. In some cases, B is an optionally substituted unsaturated C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0166] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Ci5 fused carbocycle. In some cases, and optionally substituted Cs-Cis fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 8- to 15-membered fused heteroaryl and optionally substituted Cs-Cis fused aryl. In some cases, B is an optionally substituted unsaturated Cs-Ci5 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. Insome cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0167] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining three rings (e.g., tricyclic). In some cases, B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining two rings (e.g., bicyclic). In some cases, for B the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Ci5 fused carbocycle are each independently bicyclic or tricyclic. In some cases, for B the optionally substituted 8- to 15-membered fused heterocycle is bicyclic. In some cases, for B the optionally substituted 8- to 15-membered fused heterocycle is tricyclic.

[0168] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), the heterocycle or carbocycle of B is bicyclic. In some cases, the heterocycle or carbocycle of B is tricyclic. In some cases, the tricyclic heterocycle contains three interconnected rings of atoms.

[0169] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), for B, the heterocycle and carbocycle are each independently selected from bicyclic and tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently bicyclic.

[0170] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selected frommore substituents. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Ci5 fused carbocycle are selected, each of which is optionally substituted with one or more substituents. In some cases, B is selected fromwhich is optionally substituted with one or more substituents.

[0171] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),each of which is optionally substituted with one or more substituents. In some cases, B is selectedoptionally substituted with one or more substituents.

[0172] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), for B, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, -NCh, =0, -N(R20)2, -B(OR20)2, - OR20, -SR20, Ci-6 aminoalkyl, C1-6 alkoxy, Ci-6 alkoxyalkyl, Ci-shydroxyalkyl, C 1-6 cyanoalkyl, Ci-ehaloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, -NO2, =0, -N(R20)2, -B(OR20)2, -OH, -SR20, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-s alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(0H)2, -OH, -O-C1-C3 haloalkyl, -C(0)NH2, -NH2, =0, -CN, Ci-6alkoxy, Ci-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, =0, -NH2, -N(Ci-6 alkyl)H - N(CI-6 alkyl)2, -OH, C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, C1-C3 alkyl. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are selected from

[0173] In some embodiments, for a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), B is selected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle. In some cases, the heterocycle of B has at least one sulfur atom. In some cases, the heterocycle of B has one or sulfur atoms. In some cases, the heterocycle of B has at least one nitrogen atom. In some cases, Bone or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =0, -CN, -NHCN, Ci-6aminoalkyl, C1-6 alkoxy, Ci-shydroxyalkyl, C1-6 cyanoalkyl, Ci-6 haloalkyl, C2.6 alkenyl, and C2.6 alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OH, -NH2, =0, and -CN. In some cases, B is

[0174] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula(I-B), or Formula (I-C), B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom. In some cases, B is selected from, each of which is optionally substituted. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, Ci- C3alkyl, -OR20, -C(O)N(R20)2, -N(R20)2, =0, -CN, -NHCN, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, Cnehaloalkyl, C2-6 alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, Ci- C3alkyl, -NH2, and -CN. In some cases, B is substituted. In some cases, B is substituted with at least one -NH2. In some cases, B is selected from. In some cases, B is substituted with at least one -NH2at leastone -CN. In some cases, B is selected from

[0175] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), B is an optionally substituted 7- to 11-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle. In some cases, B is an optionally substituted 7-membered fused heterocycle. In some cases, B is an optionally substituted 8-membered fused heterocycle. In some cases, B is an optionally substituted 9-membered fused heterocycle. In some cases, B is an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, the heterocycle of B is a non-aromatic heterocycle. In some cases, B has at least one sulfur atom. In some cases, B has at two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 heteroatom. In some cases, B has at least 2 heteroatoms. In some cases,SX of which is optionally substituted. In some cases, B is selected from S J , each of which is optionally substituted. In some cases, B is selected fromeach of which is optionally substituted. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(0H)2, -OH, -O-C1-C3 haloalkyl, - C(0)NH2, -NH2, =0, -CN, Ci-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least three substituents. In some cases, B is substituted with at least two substituents. In some cases, B is substituted with at least one substituent. In some cases, B is substituted with at least one substituent selected from halogen,C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from -CN. In some cases, B is

[0176] In some embodiments, for a compound or salt of Formula (I), Formula (I- A),Formula (I-B), or Formula (I-C), B is an optionally substituted 8- to 10-membered fused carbocycle. In some cases, B is a substituted 8- to 10-membered fused carbocycle. In some cases, B is an optionally substituted 9-membered fused carbocycle. In some cases, B is a substituted 9- membered fused carbocycle. In some cases,, which is optionally substituted with one or more substituents. In some cases,, which is substituted with one or more substituents. In some cases, for B, the one or more substituents are independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =0, -CN, Ci-6alkoxy, Ci-6hydroxyalkyl, and C2-6 alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selected fromwith one or more substituents selected from halogen and C 1.6 haloalky 1. In some cases, B is, which is substituted with one or more substituents selected from halogen. In someselected from fluorine. In some cases, B is selected fromIn some cases,which is substituted with one or more substituents selected from chlorine. In some cases, B is selected from

[0177] In some embodiments, a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and Ci-6 alkyl. In some cases, the heterocycle of B is selectedis optionally substituted with one or more substituents independently selected from halogen, -CN,

[0178] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), B is an optionally substituted 7- to 11-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, the heterocycle of B is a non-aromatic heterocycle. In some cases, B has at least one sulfur atom. In some cases, B has at two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 heteroatom. In some cases, B has at least 2 heteroatoms. In some cases, B is selectedeach of which is optionally substituted. In some cases, B is selected from, which is optionally substituted.In some cases, B is selected fromwhich is optionally substituted. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, - O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =0, -CN, Ci-6 alkoxy, C1-6 hydroxyalkyl, and C2-e alkynyl. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from CN. In some cases, B is substituted with at least one substituent. In some cases, B is selected

[0179] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, - OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6aminoalkyl, Ci-6 alkoxy, Ci-e alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl. In some cases, R3is selected from hydrogen, halogen, -CN, - NO2, -N(R20)2, -OR20, -SR20, -C(O)N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, CI-6 aminoalkyl, Ci-6 alkoxy, C 1-6 alkoxy alkyl, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl. In some cases, R3is selected from hydrogen, halogen, -CN, -NO2, -NH2, - N(Ci.6 alkyl)H -N(Ci.6alkyl)2,-OH, -C(O)N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R3is selected from hydrogen, -CN, -C(O)R20, -C(O)OR20, C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci- 6 haloalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, -CN, -C(O)R20, - C(O)OR20, Ci-6 hydroxyalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, -CN, - C(O)H, -C(O)OCH3, CI hydroxyalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, -F, -CN, -C(O)H, -C(O)OCH3, Ci hydroxyalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, -CN, -C(O)H, Ci hydroxyalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, fluorine, and -CN. In some cases, R3is selected from fluorine. In some cases, R3is selected from hydrogen. In some cases, R3is selected from -CN. In some cases, R3is selected from -NO2. In some cases, R3is selected from C1.3 haloalkyl. In some cases, R3is selected from -CF3.

[0180] In some embodiments, a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), R3is -CN.

[0181] In some embodiments, for a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), Y is -O-. In some cases, Y is a bond. In some cases, Y is -S-. In some cases, Y is -N(R5)-.

[0182] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 haloalkyl. In some cases, two substituents on the same carbon atom ofL come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.

[0183] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), L is selected from C1-C4 alkylene. In some cases, L is selectedfrom unsubstituted C1-C4 alkylene. In some cases, each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3- Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, Ci-e haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. In some cases, L is selected, each L is independently selected from a substitutedC1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle 3- to 5-membered heterocycle. In some cases, each L is independently selected from a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each Lsome cases, each L is independently selected from, and. In some cases, each L is independently selected from. In some cases, each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen and C1-C4 alkyl. In some cases, L is selected from

[0184] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each L is independently selected from an unsubstituted C1-C4alkylene. In some cases, L is selected from ' '. In some cases, L is selected from

[0185] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is selected from heterocycle, Ci-Ce alkyl, -L-heterocycle, -L- N(R20)2, -L-OR20, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, - L-CI-C6haloalkyl, -L-OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L-N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCI-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L-NR20C(O)- aryl, the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L- heteroaryl are each optionally substituted with one or more R7

[0186] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is selected from heterocycle, -L-heterocycle, -L-aryl, -L- heteroaryl, and -L-N(R20)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

[0187] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (LB), or Formula (I-C), R2is selected from heterocycle, -L-heterocycle, -L-N(R20)2, -L-OR20, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-CI-C6haloalkyl, -L- NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L-N(R20)C(O)(OR20), -L- OC(O)N(R20)2, and -L-C(=O)OCi -Ce alkyl, wherein the heterocycle, the heterocycle portion of - L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; and wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the heteroaryl of -L-heteroaryl each have at least one heteroatom selected from nitrogen, oxygen, silicon, and sulfur.

[0188] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (LB), or Formula (LC), R2is -L-heterocycle, wherein the heterocycle portion is optionally substituted. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a monocyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a saturated heterocycle. In some cases, R2is selected from a -L-5- to 10-membered heterocycle. In some cases, R2is selected from a -(Ci-C2alkylene)-5- to 10-membered heterocycle. In some cases, R2is selected from a -L-5- to 8-membered heterocycle. In some cases, R2is selected from a-L-5- to 8-membered saturated heterocycle. In some cases, R2is a -L-5-membered heterocycle. In some cases, R2is a -L-8-membered heterocycle. In some cases, the heterocycle contains at least 1 nitrogen atom. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, the heterocycle contains 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom. In some cases, the heterocycle has a silicon atom. In some cases, the heterocycle portion of -L- heterocycle has at least one heteroatom selected from nitrogen, oxygen, silicon, and sulfur. In some cases, the bicyclic heterocycle contains 1 nitrogen atom. In some cases, Y-R2is selectedoptionally substituted In some cases, Y-R2is selected fromwherein the heterocycle portion is optionally substituted. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 aminoalkyl. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and halogen. In some cases, Y-R2is selected from

[0189] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R2isselected from, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected fromwherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =CH2, =NO-CI-C3alkyl, - CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, Y-R2is selected from

[0190] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is -L-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7In some cases, the heteroaryl is selected from a 5- to 6- membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl is selected from a 5-membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has two nitrogen atoms. In some cases, the heteroaryl has three nitrogen atoms. In some cases, the heteroaryl is selected from -which isoptionally substituted. In some cases, the heteroaryl is, which is optionally substituted. In some cases, Y-R2is selected from, wherein the heteroaryl portion is optionally substituted with one or more R7.In some cases, each R7is independently selected from C1-C4 alkyl, halogen, and C1-C4 haloalkyl.In some cases, Y-R2is selected fromIn some cases, Y-R2is selected fromjn some caseSjY-R2is selected from

[0191] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is -L-aryl, optionally substituted with one or more R7In some cases, wherein Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R7. In some cases, Y-R2is selected from

[0192] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is -L-N(R20)2. In some cases, Y-R2is selected from

[0193] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is heterocycle, optionally substituted with one or more R6. In some cases, the heterocycle, which is optionally substituted. In some cases, the heterocyclesome cases,

[0194] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-I), or Formula (I-J), R2is heterocycle, optionally substituted with oneOk or more R6. In some cases, the heterocycle of R6is , which is optionally substituted. In some cases, the heterocyclesome cases,

[0195] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),A°'yQFormula (I-B), or Formula (I-C), Y-R2is selected from > — ' , wherein the heterocycle portion is optionally substituted, where the optional one or more substituents are selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-CI-C3alkyl, - CH2OC(O)heterocycle, -CFFheterocycle, -CH2OC(O)N(R5)2, -(CH2)o-i-0-heterocycle, and -O-Ci- C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy, and wherein the heterocycle of -(CH2)o-i-0-heterocycle is optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkyl-OR20, and -OR20. In some cases, the optional one or more substituents are selected from:Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, each R6is selected from -(CH2)o-iS-heterocycle, and -(CH2)o-i-0-heterocycle, wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)O-I-S- heterocycle are each optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-ehaloalkyl, Ci-6 alkyl-OR20, and -OR20. In some cases, each R6is selected from -CH2-S- heterocycle, and -CI b-O-heterocycle, wherein the heterocycle of -CH2-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected from C1-6 alkyl, Ci-e haloalkyl, Ci-6 alkyl-OR20, and -OR20. In some cases, each R20is independently selected from hydrogen; and Ci-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen. In some cases, each R20is independently selected from Ci-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen. In some cases, the heterocycle has one or two nitrogen atoms. In some cases, the heterocycle is a heteroaryl. In some cases, the heterocycle is selectedheterocycle, and -CH2-O-heterocycle, wherein the heterocycle of -CH2-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected fromsubstituted with one or more R6. In some cases, R6is selected from -CH2O-C1-C6 alkyl, wherein the alkyl of -CH2O-C1-C6 alkyl is optionally substituted with one or more substituents selected

[0197] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is selected from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6; -L-aryl, and -L-heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of - L-heteroaryl are each optionally substituted with one or more R7; and -L-N(R20)2. In some cases, the heterocycle of R2is selected from, wherein the heterocycle ofR2is optionally substituted with one or more R6; wherein the aryl and heteroaryl of R2is selected from, wherein the aryl and the heteroaryl are each optionally substituted with one or more R7;In some cases, the heterocycle of R2isheterocycle is optionally substituted with one or more R6; wherein the aryl and heteroaryl of R2is selected fromwherein the aryl and the heteroaryl are each optionally substituted with one or more R7; and. In some cases, each R6is independently selected from halogen, hydroxy, Ci-C3alkyl, C1-C3 haloalkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, OXO, =NO-CI-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and-O-Ci-C3alkyl, wherein the alkyl of -O-Ci-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from C1-C3 alkyl, halogen and C1-C3 haloalkyl. In some cases, the heterocycle of R2, the aryl and heteroaryl of R2, and -N(R20)2of R2is selected from;wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6;the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more

[0198] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, C1-C4 hydroxyalkyl and C1-C4 alkyl. In some cases, L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from C1-C4 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from C1-C2 alkylene.In some cases, L is. In some cases, L is

[0199] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each L is independently selected from an optionally substituted C1-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-ehydroxyalkyl, C 1 -6 haloalky 1. In some cases, the optional substituents ofL are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl.

[0200] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, Ci-e haloalkyl.

[0201] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), each L is independently selected from a substituted C1-C4 alkylene, and two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from

[0202] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), R2is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0203] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (LB), or Formula (LC), R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0204] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0205] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or moreR6.

[0206] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),portion is optionally substituted with one or more R6.

[0207] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R2is selected from -L-saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R2is selected from

[0208] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), Y is a bond. In some cases, R2is selected from an optionally substituted heteroaryl and optionally substituted aryl. In some cases, R2is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl only contain nitrogen atom(s). In some cases, the heteroaryl is a 6-membered heteroaryl. In some cases, the heteroaryl is a 5-membered heteroaryl. In some cases, the heteroaryl is selected fromeach of which is optionally substituted. In some cases, the heteroaryl is selectedeach of which is optionally substituted. In some cases,R2is selected from an optionally substituted aryl. In some cases, the aryl is a phenyl. In some cases, the heteroaryl is optionally substituted with one or more R6, wherein each R6is selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, - CH2 heterocycle, -C1-C3 alkyl-N(R5)2, and -C(O)N(R5)2. In some cases, R6is selected from C1-C3 alkyl, -CHiheterocycle, and -C(O)N(R5)2. In some cases, the aryl is optionally substituted with one

[0209] In some embodiments, for a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), each R6is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q- phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)Ci-Ce alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(CI-C3 alkyl)O(Ci-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0210] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each R6is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, each R6is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0211] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6is independently selected from Ci- C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO- C1-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from C1-C3 alkyl, halogen and Ci- C3 haloalkyl.

[0212] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R6is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6is selected from halogen and C1-C3 alkyl. In some cases, R6is halogen. In some cases, R6is C1-C3 alkyl. In some cases, R6is selected from halogen and C1-C3 alkyl. In some cases, R6is selected from methyl and fluorine.

[0213] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), R2is selected from

[0214] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), Y-R2is selected from

[0215] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),

[0216] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula

[0217] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), L is selected from unsubstituted C1-C4 alkylene.

[0218] In some embodiments, for a compound or salt of Formula (I), Formula (I- A),Formula (I-B), or Formula (I-C), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0219] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and Ci- C3 aminoalkyl.

[0220] In some embodiments, for a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), R6of R2is independently selected at each occurrence from Ci-C3 alkyl and halogen.

[0221] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), Y-R2is selected from

[0222] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), n is selected from 0 to 4. In some cases, n is selected from 0 to3. In some cases, n is selected from 0 to 2. In some cases, n is selected from 0 and 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2.

[0223] In some embodiments, for a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkynyl, C1-6 cyanoalkyl, and C1-6 haloalkyl. In some cases, R4is independently selected from halogen, =0, -CN, Ci-6 cyanoalkyl, C2-6 alkynyl, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, and Ci-6 haloalkyl. In some cases, R4is independently selected from halogen, =0, -CN, Ci-6 cyanoalkyl, C2-6 alkynyl, and Ci-6 haloalkyl. In some cases, R4is independently selected from -CN, Ci-6 cyanoalkyl, and C2-6 alkynyl. In some cases, each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 aminoalkyl, Ci-6 alkoxy, C 1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and C 1-6 haloalkyl.

[0224] In some embodiments, for a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), Q is a bond. In some cases, Q is a S. In some cases, Q is a O.

[0225] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2. In some cases, each R7is independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0226] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), Y is -O-. In some cases, each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, and C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 4- to 6-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen. In some cases, each L is selected from^^^^ ,

[0227] In some embodiments, for a compound or salt of Formula (I), Formula (I-A),Formula (I-B), or Formula (I-C), Y-R2is selected from

[0228] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formulawith one or more R6. In some cases, each R6is selected from -(CH2)o-iS-heterocycle, and - (CH2)o-i-0-heterocycle, wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)O-I-S- heterocycle are each optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-ehaloalkyl, Ci-6 alkyl-OR20, and -OR20. In some cases, each R6is selected from -CH2-S- heterocycle, and -CH2-O-heterocycle, wherein the heterocycle of -CH2-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected from C1-6 alkyl, Ci-e haloalkyl, Ci-6 alkyl-OR20, and -OR20. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen. In some cases, each R20is independently selected from Ci-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen. In some cases, the heterocycle has one or two nitrogen atoms. In some cases, the heterocycle is a heteroaryl. In some cases, the heterocycle is selectedfrom:. In some cases, each R6is selected from -CH2-S- heterocycle, and -CJfr-O-heterocycle, wherein the heterocycle of -CHa-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected fromsubstituted with one or more R6. In some cases, R6is selected from -CH2O-C1-C6 alkyl, whereinthe alkyl of -CH O-C1-C6 alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6 carbocycle. In some cases, Y-R2is selected from

[0229] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R1Bis selected from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen; R1Ais selected from Ci-6 alkyl, and 5- membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle; and each R11is independently selected from -OR20, -C(O)N(R20)2, -N(R20)2, -C(O)R20, =0, -CN, C2-6 alkynyl, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected R1 BR1AN from -NH2, and -C1-10 haloalkyl. In some cases, R100oris selected fromoptionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom. Insome cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OR20, -N(R20)2, -CN, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the optional substituents of B are independently selected at each occurrence from C1-C3 alkyl, -NH2, and -CN. In some cases, B is selected,and, , . In some cases,some cases,some cases, Y is -O-. In some cases, R2is selected from -L-heterocycle, and -L-N(CH3)2, wherein the heterocycle portion of -L- heterocycle, is optionally substituted with one or more R6. In some cases, R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R6. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, =CH2, =CHF, =CF2, -C(O)-Ci-C3alkyl-N(R5)2, and -CH2O-CI-C6alkyl. In some cases, each R6is independently selected from halogen. . In some cases, at least one R6is independently selected from C1-C3 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 aminoalkyl, C1-6 alkoxy, Ci-6 hydroxyalkyl, C 1-6 haloalkyl. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is selected fromIn some cases, Y-R2isIn some cases, Y-R2is. In some cases, Y-R2isIn some cases,Y-R2is I . In some cases, R1Bis selected from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen; R1Ais selected from C1-6 alkyl, and 5- membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle or 4-membered heterocycle; and each R11is independently selected from -OR20, - C(O)N(R20)2, -N(R20)2, -C(O)R20, =0, -CN, and 5- to 6-membered heterocycle, wherein the 5- to6-membered heterocycle are each optionally substituted with one or more substituentsC(O)OR20, and Ci-6 haloalkyl. In some cases, R3is selected from hydrogen. In some cases, R3is selected from halogen. In some cases, R3is selected from -CN. In some cases, R3is selected from -NO2. In some cases, R3is selected from -C(O)R20. In some cases, R3is selected from -C(O)OR20. In some cases, R3is selected from Ci-6 haloalkyl. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl.

[0230] In some embodiments, for a compound or salt of Formula (II), R1Bis selected from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen; R1Ais selected from Ci-6 alkyl, and 5-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle; and each R11is independently selected from -OR20, -C(O)N(R20)2, -N(R20)2, -C(O)R20, =0, -CN, C2.6alkynyl, and 5- to 6-memberedheterocycle, wherein the 5- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from -NIL, and -Cuio haloalkyl. In some cases, R100orcases,some cases, B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OR20, -N(R20)2, -CN, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the optional substituents of B are independently selected at each occurrence from C1-C3 alkyl, -NH2,cases,some cases,some cases, Y is -O-. In some cases, R2is selected from -L-heterocycle, and -L-N(CH3)2, wherein the heterocycle portion of -L- heterocycle, is optionally substituted with one or more R6. In some cases, R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R6. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, =CH2, =CHF, =CF2, -C(O)-Ci-C3alkyl-N(R5)2, and -CH2O-CI-C6alkyl. In some cases, each R6is independently selected from halogen. . In some cases, at least one R6is independently selected from C1-C3 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 haloalkyl. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases,two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some7. In some cases, Y-R is, In some cases, Y-R2is. In some cases, Y-R2isIn some cases,In some cases, R1Bis selected from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen; R1Ais selected from Ci-6 alkyl, and 5- membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle or 4-membered heterocycle; and each R11is independently selected from -OR20, - C(O)N(R20)2, -N(R20)2, -C(O)R20, =0, -CN, and 5- to 6-membered heterocycle, wherein the 5- to6-membered heterocycle are each optionally substituted with one or more substituents independently selected from -NH2, -OH, and -C1-3 alkyl. In some cases, R100or. In some cases, R3is selected from hydrogen, halogen, -CN, -NO2, -C(O)R20, -C(O)OR20, and Ci-6 haloalkyl. In some cases, R3is selected from hydrogen. In some cases, R3is selected from halogen. In some cases, R3is selected from -CN. In some cases, R3is selected from -NCh. In some cases, R3is selected from -C(O)R20. In some cases, R3is selected from -C(O)OR20. In some cases, R3is selected from Ci-6 haloalkyl. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl.

[0231] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), a substituent is selected from a compound in Table 1.

[0232] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each R20is independently selected from hydrogen; and Ci-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci -10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen and C1-6 alkyl. In some cases, each R20is independently selected from C1-6 alkyl.

[0233] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C 1-10 haloalkyl, -O-Ci-10 alkyl, oxo, and =NH.

[0234] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen; and Ci-e alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, -N(CI.6alkyl)2, Ci -io alkyl, “C i- 10 haloalkyl, — O— C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen; and C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NH2, -N(Ci-6alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen; and C1-6 alkyl, C3-6 carbocycle. In some cases, each R21is independently selected from hydrogen and Ci -e alkyl.

[0235] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), wherein when two R11come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, only when R1Ais selected from a C1-6 alkyl.

[0236] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), when two R11come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, R1Ais not C3-C12 carbocycle or 4- to 12-membered heterocycle.

[0237] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A),some cases, Y-R2is:In some cases, Y-R2is:,

[0238] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula (LB), Formula (II), or Formula (I-C), does not contain an electrophile moiety.

[0239] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula(LB), Formula (II), or Formula (I-C), the compound or salt does not include an electrophilic substituent.

[0240] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula(LB), Formula (II), or Formula (I-C), the compound or salt does include an electrophilic moiety.

[0241] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula(I-B), Formula (II), or Formula (I-C), the compound or salt does not include an electrophilic moiety.

[0242] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula(I-B), Formula (II), or Formula (I-C), the compound or salt does not form a covalent bond with any of the KRAS G12D and / or other G12 mutants.

[0243] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula(I-B), Formula (II), or Formula (I-C), the compound or salt does form a covalent bond with any of the KRAS G12D and / or other G12 mutants.

[0244] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is not a covalent modifier of KRAS G12D and / or other G12 mutants.

[0245] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is a covalent modifier of KRAS G12D and / or other G12 mutants.

[0246] In some embodiments, a compound or salt of Formula (I), Formula (I- A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is capable of reacting with a cysteine.

[0247] In some embodiments, a compound or salt of Formula (I), Formula (I- A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is not a covalent inhibitor for KRAS G12D and / or other G12 mutants.

[0248] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0249] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I), are intended to include all Z-, E- and tautomeric forms as well.

[0250] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography andpolarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0251] The compounds or salts for Formula (I), Formula (I- A), Formula (I-B), orFormula (I-C), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0252] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non-limiting examples of tautomeric

[0253] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0254] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0255] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine- 125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,160,170,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0256] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0257] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0258] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0259] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates,hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0260] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0261] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0262] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0263] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0264] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0265] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus etal., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula e / c / / ., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0266] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).Pharmaceutical Formulations

[0267] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound or salt of Formula (I), Formula (LA), Formula (LB), Formula (II), or Formula (LC) (also referred to herein as “a pharmaceutical agent”).

[0268] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;Liberman, H A. and Lachman, L , Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0269] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0270] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer

[0271] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example,as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0272] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0273] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0274] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When twoor more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0275] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semisolid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0276] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0277] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.

[0278] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0279] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0280] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0281] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0282] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0283] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0284] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0285] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0286] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.

[0287] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-meltextrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross-linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.

[0288] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.

[0289] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.

[0290] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained- release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell.Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0291] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.Methods of Treatment

[0292] In an aspect, the present disclosure provides compounds that inhibit KRas G12 mutants. In some cases, the method may inhibit KRas G12 mutants activity in a cell. In somecases, inhibitng KRas G12 mutants activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical compositions containing a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C) and a pharmaceutically acceptable excipient. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12D and / or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and / or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and / or other G12 mutants. In some cases, a cell in which inhibition of KRas G12D and / or other G12 mutants activity is desired is contacted with an effective amount of a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutical composition of any one thereof to negatively modulate the activity of KRas G12D and / or other G12 mutants. In some cases, by negatively modulating the activity of KRas G12D and / or other G12 mutants, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and / or other G12 mutants activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and / or other G12 mutants. The ability of compounds to bind KRas G12D and / or other G12 mutants may be monitored in vitro using well known methods.

[0293] In some embodiments, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D and / or other G12 mutants activity of the amount of phosphorylated ERK.

[0294] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a pharmaceutically acceptable excipient are provided. The compositions and methods provided herein may be used for the treatment of a KRas G12D and / or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceuticallyacceptable salt thereof are provided. In some cases, the KRas G12D and / or other G12 mutants associated cancer is lung cancer. The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be coadministered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0295] Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in therapy.

[0296] Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the treatment of cancer.

[0297] Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the inhibition of KRas G12D and / or other G12 mutants.

[0298] Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the treatment of a KRas G12D and / or other G12 mutants associated disease or disorder.

[0299] Also provided herein is the use of a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0300] Also provided herein is a use of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, in the manufacture of a medicament for the inhibition of activity ofKRas G12D and / or other G12 mutants.

[0301] Also provided herein is the use of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, in the manufacture of a medicament for the treatment of a KRas G12D and / or other G12 mutants-associated disease or disorder.

[0302] In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation and / or other G12 mutants (e g., a KRas G12D and / or other G12 mutants- associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0303] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0304] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0305] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0306] In the case wherein the patient’ s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0307] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0308] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0309] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Nonlimiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[0310] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio betweenLDso and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0311] In certain embodiments, the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein.Bifunctional Compounds

[0312] In some embodiments, compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein. In some embodiments, another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPS) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19; 348 (6241): 1376-81), which can bind with both mutated KRas protein and E3 ligase, create interactions between those two proteins and induce KRas degradation.

[0313] Disclosed herein is a bifunctional compound composed of a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety, which may induce proteasome-mediated degradation of selected proteins. In some embodiments, the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art. In some embodiments, disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein. In some cases, the target proteinbinding moiety is derived from a compound of Formula (I), Formula (I-A), Formula (LB), Formula (II), or Formula (LC).Preparation of Compounds

[0314] The compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.

[0315] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein.EXAMPLES

[0316] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0317] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0318] The present disclosure provides processes for preparing compounds the compounds described herein (described in greater detail below).

[0319] Certain compounds of Tables herein can be prepared employing appropriate reagents in the schemes described herein.INTERMEDIATES

[0320] Intermediate 1. Synthesis of 2-aminospiro[6H-thieno[2,3-c]thiophene-4, 3'- azetidine]-3-carbonitrile; methanesulfonic acid

[0321] Step 1. Preparation of 01 -tert-butyl O3-methyl 3-bromoazetidine-l,3-dicarboxylate (Int-la). To a solution of [bis(trimethylsilyl)amino]lithium (2798.55 mg, 16.72 mmol) in THF (60mL) was added dropwise 01-tert-butyl O3-methyl azetidine- 1,3 -dicarboxylate (3 g, 13.94 mmol) in THF (30mL) at -70 °C under N2. The mixture was stirred at RT for 15 min, followed by the dropwise addition of a solution of carbon tetrabromide (6933.03 mg, 20.91 mmol) in THF (30 mL). The resulting mixture was stirred at RT for 16 h. The reaction mixture was quenched with aq. NH4CI, and wash with aq. NaHCCh, brine, concentrated. The residue was purified by column chromatography (0% - 25% EtOAc / PE) to afford 01-tert-butyl 03 -methyl 3- bromoazetidine-l,3-dicarboxylate (Int-la, 2.30 g, 7.82 mmol, 56.10 %yield) as a yellow oil. LCMS calculated for CioHi7BrN04 (M+H)+m / z = 295.0; found: 239.8 (M-tBu). ' H NMR (400 MHz, CDCI3) 5 = 4.65 (dd, J=10.3, 1.3 Hz, 2H), 4.30 (dd, J=10.3, 1.3 Hz, 2H), 3.85 (s, 3H), 1.45 (s, 9H).

[0322] Step 2. Preparation of 01-tert-butyl O3-methyl 3 -(3 -m ethoxy-3 -oxo- propyl)sulfanylazeti dine- 1,3 -dicarboxylate (Int-lb). To a solution of 01-tert-butyl O3-methyl 3- bromoazetidine-l,3-di carboxylate (Int-la, 1.5g, 5.1mmol) in DMF (16 mL) was added methyl 3- sulfanylpropanoate (1348.2 mg, 11.22 mmol) and K2CO3 (2819.27 mg, 20.4 mmol) at 20 °C under N2. The mixture was stirred at RT overnight. Then the reaction mixture was quenched with water, extracted with EtOAc, wash with water and brine, concentrated. The residue was purified by column chromatography (0% - 25% EtOAc in PE) to afford 01-tert-butyl O3-methyl 3-(3- methoxy-3-oxo-propyl)sulfanylazeti dine- 1,3 -dicarboxylate (Int-lb, 1.60 g, 4.80 mmol, 94.11% yield) as a colorless oil. LCMS calculated for C14H24NO6S (M+H)+m / z = 334.13; found: 233.9 (M-Boc).

[0323] Step 3. Preparation of 02-tert-butyl O7-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane- 2,7-dicarboxylate (Int-lc). To a solution of 01-tert-butyl O3-methyl 3-(3-methoxy-3-oxo- propyl)sulfanylazeti dine- 1,3 -dicarboxylate (Int-lb, 200 mg, 3.6 mmol) in THF (20 mL) was added t-BuONa (691.78 mg, 7.2 mmol) by portions at 0 °C under N2. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water and adjusted pH to 5-6 by acetic acid. The mixture was extracted with EtOAc, wash with brine and dried over Na SO4, concentrated.The residue was purified by flash chromatography (10% - 30% EtOAc / PE) to afford 02-tert- butyl 07-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2,7-dicarboxylate (Int-lc, 800 mg, 2.65 mmol, 73.75 %yield) as light red oil. LCMS calculated for C13H20NO5S (M+H)+m / z = 302.36; found: 246.1(M-ffiu). ’H NMR (400 MHz, CDCI3) 5 = 11.02 (s, 1H), 4.47 (d, .7=9,9 Hz, 2H), 4.03 (d, 9.8, 2H), 3.82 (s, 3H), 3.72 (s, 2H), 1.45 (s, 9H).

[0324] Step 4. Preparation of tert-butyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2-carboxylate (Int-ld). To a solution of 02-tert-butyl 07-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2,7- dicarboxylate (Int-lc, 800 mg, 2.65 mmol) in DMSO (12 mL) was added LiCl (225.06 mg, 5.31 mmol) and water (1.2 mL) at rt under N2. then the mixture was heated at 160 °C for 1.5 h, The reaction mixture was diluted with water, extracted with EtOAc, washed with brine dried Na2SO4 and concentrated. The residue was purified by column chromatography (0% - 30% EtOAc in PE) to afford tert-butyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2-carboxylate (Int-ld, 480 mg, 1.97 mmol, 74.31 %yield) as a colorless oil. LCMS calculated for CnHi8NO3S(M+H)+m / z = 244.32; found: 187.9 (M- / Bu).XH NMR (400 MHz, CDCI3) 8 = 4.27 (d, >9.1, 2H), 3.93 (d, >9.3, 2H), 2.97 (t, >7.1, 2H), 2.70 (t, >7.1, 2H), 1.44 (s, 9H).

[0325] Step 5. Preparation of tert-butyl 2-amino-3-cyano-spiro[6H-thieno[2,3-c]thiophene- 4,3'-azetidine]-l'-carboxylate (Int-le). A solution of tert-butyl 8-oxo-5-thia-2- azaspiro[3.4]octane-2-carboxylate (480 mg, 1.97 mmol), Sulfur (94.93 mg, 2.96 mmol), ammonium acetate (228.08 mg, 2.96mmol) in Ethanol (7 mL) was added to propanedinitrile (195.48 mg, 2.96 mmol) at RT. Then the mixture was stirred at 60 °C for 1.5 h, then diluted with water and extracted with EtOAc. The combined extracts were dried, filtered, and concentrated. The crude product was purified by chromatography (20-30% EtOAc in PE) to afford tert-butyl 2- amino-3-cyano-spiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-T-carboxylate (Int-le, 250 mg, 0.773 mmol, 39.18 %yield) as yellow solid, the chromatographic column was washed with MeOH, and concentrated, the residue was wash with IP A, and filtered to afford an additional tertbutyl 2-amino-3-cyano-spiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-T-carboxylate, (Int-le, 360 mg, 1.11 mmol, 56.42 %yield) as yellow solid. LCMS calculated for C14H18N3O2S2 (M+H)+m / z =324.08; found: 268.0 (M-ZBu), 224.0 (M-Boc).

[0326] Step 6. Preparation of 2-aminospiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-3- carbonitrile;methanesulfonic acid (Intermediate 1). A solution of tert-butyl 2-amino-3-cyano- spiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-T-carboxylate (Int-le, 250 mg, 0.77 mmol) in IPA (2.5 mL) was added methanesulfonic acid (0.1 mL, 1.54 mmol) at RT. The mixture was heated at 60 °C for 8 h. The reaction was cooled down and was filtered. The solid was wash with IPA (2 mLx3) and was dried over in vacuum to afford 2-aminospiro[6H-thieno[2,3- c]thiophene-4,3'-azetidine]-3-carbonitrile;methanesulfonic acid (Intermediate 1, 210 mg, 0.657mmol, 85 % yield) as grey solid. LCMS calculated for C9H10N3S2 (M+H)+m / z =224.31; found:224.2.

[0327] Intermediate 2. Synthesis of 3-[l-(methylamino)ethyl]pyridin-2-amineIntermediate 2

[0328] To a stirred solution of l-(2-amino-3-pyridyl)ethanone (1985.56 mg, 14.58 mmol) in THF (30mL). Methylamine in CH3OH (3019.79 mg, 29.17 mmol) was added at 0°C followed by the drop wise addition of titanium(IV)isopropoxide (12.95 mL, 43.75 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, added Methanol (45mL), and cooled to 0°C. NaBH4 (1079.19 mg, 29.17 mmol) was added and was stirred for 3h at room temperature. The reaction was quenched with ice, filtered and solids were washed thoroughly with methanol. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by automated flash chromatography using 20% MeOH in DCM to obtain 3-[l-(methylamino)ethyl]pyridin-2-amine (Intermediate 2, 1500 mg, 9.92 mmol, 68.021% yield) as white solid. LCMS calculated for CsHuNs (M+H)+m / z =152.12; found: 152.2.

[0329] Chiral Synthesis of intermediate 2A. (R)-3-(l-(methylamino)ethyl)pyridin-2-amine.

[0330] Step 1. Synthesis of 2-(bis(4-methoxybenzyl)amino)nicotinaldehyde (Int-2b)

[0331] The mixture of 2-chloropyridine-3-carbaldehyde (23.0 g, 162.48 mmol), l-(4- methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (50171.72 mg, 194.97mmol) and Potassium carbonate (44843.18 mg, 324.95 mmol) in 1,4-Dioxane (320 mL) / Water (210 mL) was heated to 110 °C for 6 days. The reaction mixture was cooled to rt and extracted with EtOAc (100 mL x 3). The organic layer was washed with saturated brine (50 ml), dried (MgSCL) and concentrated in vacuo to dryness. The crude product was then purified by using FC (eluting 9- 20% EtOAc in PE). The desired fractions were concentrated to dryness in vacuo to afford 2- [bis[(4-methoxyphenyl)methyl]amino]pyridine-3-carbaldehyde (47.90 g, 132 mmol, 81.34 % yield) as yellow oil. LCMS calculated for C22H23N2O3 (M+H)+m / z =363.4; found: 363.3.

[0332] Step 2. Synthesis of (S,E)-N-((2-(bis(4-methoxybenzyl)amino)pyridin-3- yl)methylene)-2-methylpropane-2-sulfinamide (Int-2c). To the solution of (S)-2-methylpropane-2-sulfinamide (32037.3 mg, 264.33 mmol) and 2-[bis[(4-methoxyphenyl)methyl]amino]pyridine-3-carbaldehyde (47.9 g, 132.17 mmol) in THF (300 mL) was added Titanium(IV) ethanolate (60297.27 mg, 264.33 mmol) at rt under N2. The mixture was stirred at 20 °C overnight. TLC showed the reaction was completed. Ice water, celite and MgSC was added to the reaction, fdtered and purified using FC (eluant with EtOAc in PE 0 to 30%) to give the product (S,E)-N- ((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide, 61.00 g, 131 mmol, 99.13 % yield as a yellow oil. LCMS calculated for C26H32N3O3S (M+H)+m / z =466.6; found: 466.2.

[0333] Step 3. Synthesis of (S)-N-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3- yl)ethyl)-2-methylpropane-2-sulfinamide (Int-2d). To the mixture of (S,E)-N-((2-(bis(4- methoxybenzyl)amino)pyridin-3-yl)methylene)-2-methylpropane-2-sulfmamide (61.0 g, 131.01 mmol) in DCM (500 mL) was added Bromo(methyl)magnesium in THF (87.34 mL, 3M 262.02 mmol) at -70 °C dropwise under N2. The mixture was stirred at -40 °C for 4 h and then allowed to warm to rt and stirred for 16 h. It was quenched by the addition of NH4CI solution and extracted with EtOAc. The organic layer was washed with saturated brine followed by the drying over Na2SO4. The solvent was removed in vacuo and the residue was purified using FC (eluant with EtOAc in PE 0 to 60%) to give the product (S)-N-[(lR)-l-[2-[bis[(4- methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-2-methyl-propane-2-sulfinamide, 45.70 g, 92.4 mmol, 70.54 % yield. LCMS calculated for C27H36N3O3S (M+H)+ m / z =482.2; found: 482.2.

[0334] Step 4. Synthesis of (S)-N-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3- yl)ethyl)-N,2-dimethylpropane-2-sulfmamide (Int-2e). To the mixture of (S)-N-[(lR)-l-[2- [bis[(4-methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-2-methyl-propane-2-sulfmamide (46.92 g, 94.88 mmol) in DMF (500 mL) was added NaH (60%, 7590.57 mg, 189.76mmol) at 0 °C under N2. The mixture was stirred at the same temperature for 1 h and then Mel (11.82 mL, 189.76 mmol) was added. The whole mixture was stirred at 0 °C for 1 h. The reaction was quenched by the addition of H2O and then extracted with EtOAc (300 mL*3). The organic layer was washed with H2O, followed by saturated brine. It was then dried over Na2SO4 and concentrated in vacuo to give the crude product. It was purified using FC (eluant with EtOAc in PE 0 to 60%) to give the product (S)-N-[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-N,2-dimethyl-propane-2-sulfmamide (43.80 g, 88.4 mmol, 93.13 % yield) as a color-less oil. LCMS calculated for C28H38N3O3S (M+H)+m / z =496.68; found: 496.2.

[0335] Step 5. Synthesis of (R)-3-(l-(methylamino)ethyl)pyridin-2-amine (Intermediate 2A)

[0336] To the mixture of (S)-N-[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-N,2-dimethyl-propane-2-sulfinamide (43.8 g, 88.36 mmol) in TFA (120 mL, 1568.15 mmol) was added Trifluoromethanesulfonic acid (1800.92 mg, 12.0 mmol) at rt underN2. The mixture was stirred at 35 °C for 24 h. TFA was removed in vacuo, aq Na2CO?> was added to the mixture to adjust the pH to 9-10. It was extracted with DCM / MeOH (10 / 1, 200 mL *3). The combined extracts were dried over Na2SC>4 and concentrated in vacuo to give the crude product. It was purified using FC (eluant with MeOH in DCM 0 to 10%, 0.1 % NH4OH) to give the product 3-[(lR)-l-(methylamino)ethyl]pyridin-2-amine (11.10 g, 73.4 mmol, 83.07 % yield) as a red solid. LCMS calculated for C8H14N3 (M+H)+m / z =152.12; found: 152.0. The absolute stereochemistry was determined by single crystal X-ray structure of Int-9a mono HC1 salt.

[0337] Intermediate 3. Synthesis of 3-(l-aminoethyl)pyridin-2-amine

[0338] Step 1. Preparation of l-(2-amino-3-pyridyl)ethanone oxime (Int-3a). To a solution of l-(2-amino-3-pyridyl)ethanone (1000 mg, 7.34 mmol) in pyridine (18mL) was added hydroxylamine hydrochloride (765.59 mg, 11.02 mmol). The mixture was stirred at 80 °C for 2 h. Then reaction mixture was concentrated under reduced pressure to give the crude of l-(2- amino-3-pyridyl)ethanone oxime (1110 mg, 7.34 mmol, 99.97% yield) as a yellow solid for next step without further purification. LCMS calculated for C7H10N3O (M+H)+m / z =152.2; found: 152.2.

[0339] Step 2. Preparation of 3-(l-aminoethyl)pyridin-2-amine (Intermediate 3) . To a mixture of l-(2-amino-3-pyridyl)ethanone oxime (996 mg, 6.59 mmol) and zinc (1723.05 mg, 26.35 mmol) at RT was slowly added cone, hydrochloric acid (16.8 mL, 201.6 mmol) with vigorous stirring. The mixture was heated at 90 °C overnight. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (20 mL), then basified with 2N NaOH at room temperature to pH = 9-10, and then extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by Prep-HPLC on a C 18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / ACN at flow rate: 40 mL / min to afford 3-(l-aminoethyl)pyridin-2-amine (276 mg, 2.01 mmol, 30.54% yield) as a white solid. LCMS calculated for C7H12N3 (M+H)+m / z = 138.1, found: 138.2.

[0340] Intermediate 4. Synthesis of 8-aminospiro[9-thiatricyclo[4.3.0.02,4]nona-l(6),7- diene-5,3'-azetidine]-7-carbonitrile;methanesulfonic acid & 2-aminospiro[6,7-dihydro-5H- benzothiophene-4,3'-azetidine]-3-carbonitrile;methanesulfonic acid

[0341] Step 1. Synthesis of 01 -tert-butyl O3-methyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-l- hydroxy-propyl]azetidine-l,3-dicarboxylate (Int-4a). LDA (99.55mL, 199.1 Immol) was diluted by THF (500mL) at -78 °C under argon before a solution of 01 -tert-butyl O3-methyl azetidine- 1,3-dicarboxylate (21.43g, 99.55mmol) in THF (30mL) was added dropwise over Ih. The mixture was stirred at -78 °C for 1.5h after HMPA (242.49mL, 1393.76mmol) was added. A solution of 3-[tert-butyl(dimethyl)silyl]oxypropanal (12.5g, 66.37mmol) in THF (30mL) was added to the reaction mixture before the reaction was stirred at -78 °C for another Ih. The mixture was quenched with sat. NH4CI (500 mL) aq. at -78 °C, extracted with EtOAc (500 mL x 3), dried over Na?SO4, filtered, and concentrated to afford the crude product. The crude product was purified by flash chromatography (eluted with EtOAc in petroleum ether from 0% to 20%) to afford 01 -tert-butyl O3-methyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-l-hydroxy- propyl]azetidine-l,3-dicarboxylate (15 g,37.166mmol, 55.999% yield) was obtained as yellow oil. LCMS calculated for CiglfxNOeSi (M+H)+m / z = 404.5, found 404.5.

[0342] Step 2. Synthesis of 3-[l-benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-propyl]-l-tert- butoxycarbonyl-azetidine-3-carboxylic acid (Int-4b). To a solution of 01 -tert-butyl O3-methyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-l-hydroxy-propyl]azetidine-l,3-dicarboxylate (20 g, 49.56 mmol) in THF (600 mL) was added NaH (2.38 g, 59.47 mmol) at 0 °C under Argon. The mixture was stirred at 0 °C for 30 min. Then Benzyl Bromide (7.07 mL, 59.47 mmol) in THF (5 mL) and KI (4.11 g, 24.78 mmol) was added. The resulting mixture was stirred at r.t. for 12 h. The mixture was quenched with AcOH (40 mL) and sat. NH4CI aq. (500 mL), extracted with EtOAc (500 mL*2). The combined organic layer was dried overNa2SO4, filtered, and concentrated to afford the crude product. The crude product was purified by flash chromatography (eluted with EtOAc in PE from 0% to 50%) to give 3-[l-benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-propyl]- l-tert-butoxycarbonyl-azetidine-3 -carboxylic acid (12500 mg, 26.06 mmol, 52.58% yield) as yellow oil. LCMS calculated for C25H4iNOeSiNa (M+Na)+(m / z) = 502.5, found: 502.5.

[0343] Step 3. Synthesis of tert-butyl 9-benzyloxy-5-oxo-6-oxa-2-azaspiro[3.5]nonane-2- carboxylate (Int-4c). To a solution of 3-[l-benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-propyl]-l- tert-butoxycarbonyl-azetidine-3-carboxylic acid (20 g, 41.69 mmol) in THF (600 mL) was added PPTS (5.24 g, 20.85 mmol) at r.t. under Ar. The resulting mixture was stirred at 70 °C for 16 h. Upon cocomplete, the mixture was cooled down to r.t., and quenched with H2O (600 mL), extracted with EtOAc (500 mLx3). The combined organic layer was washed with brine (300 mL), dried over Na2SC>4, fdtered, and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (eluted with EtOAc in PE from 0% to 50%) to give tert-butyl 9-benzyloxy-5-oxo-6-oxa-2-azaspiro[3.5]nonane-2-carboxylate (13 g, 37.42 mmol, 89.75% yield) as yellow oil. LCMS calculated for C19H26NO5 (M+H)+m / z = 348.2, found: 348.2.

[0344] Step 4. Synthesis of tert-butyl 3-(l-benzyloxy-3-hydroxy-propyl)-3-formyl-azetidine- 1-carboxylate (Int-4d). To a solution of tert-butyl 9-benzyloxy-5-oxo-6-oxa-2- azaspiro[3.5]nonane-2-carboxylate (23 g, 66.2 mmol) in DCM (800 mL) was added DIBAL-H in hexane (99.31 mL, 99.31 mmol) at -78 °C under Ar. The resulting mixture was stirred at -78 °C for 3 h. Upon completion, the mixture was warmed to r.t., and quenched with sat. NH4CI aq. (1 L), extracted with EtOAc (800 mL><2). The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford tert-butyl 3-(l-benzyloxy-3-hydroxy-propyl)-3-formyl- azetidine-1 -carboxylate (20 g, 57.24 mmol) as yellow oil. The crude product was used directly for the next step. LCMS calculated for C19H28NO5 (M+H)+m / z = 350.3, found: 350.3.

[0345] Step 5. Synthesis of tert-butyl 3-(l-benzyloxy-3-hydroxy-propyl)-3-vinyl-azetidine-l- carboxylate (Int-4e). To a solution of Methyltriphenylphosphonium Bromide (40.89 g, 114.47 mmol) in THF (600 mL) was added t-BuOK in THF (114.47 mL, 114.47 mmol) at 0 °C under Ar. The resulting mixture was stirred at r.t. for 0.5 h. Then tert-butyl 3-(l-benzyloxy-3-hydroxy- propyl)-3-formyl-azetidine-l -carboxylate (20 g, 57.24 mmol) was added. The mixture was stirred for another 1 h. Upon completion, the mixture was quenched with sat. NH4CI aq. (1000 mL), extracted with EtOAc (800 mLx2). The combined organic layer was dried over Na2SO4, fdtered, and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 50%) to give tert-butyl 3-(l- benzyloxy-3-hydroxy-propyl)-3-vinyl-azetidine-l-carboxylate (9.8 g, 28.20 mmol, 49.27% yield) as yellow oil. LCMS calculated for C20H30NO4 (M+H)+m / z = 348.3, found: 348.3.

[0346] Step 6. Synthesis of tert-butyl 3-(l-benzyloxy-3-oxo-propyl)-3-vinyl-azetidine-l- carboxylate (Int-4f). To a solution of tert-butyl 3-(l-benzyloxy-3-hydroxy-propyl)-3-vinyl- azetidine-1 -carboxylate (11 g, 31.66 mmol) in DCM (350 mL) was added DMP (26.86 g, 63.32 mmol). The resulting mixture was stirred at r.t. for 6 h. Then, the reaction mixture was dilutedwith CH2CI2 (500 mL) and added 1.3 M NaOH (200 mL). After the mixture was stirred for 10 min, the organic layer was separated, and washed with water (200 mL) and brine (200 mL), dried over Na2SC>4 and concentrated. The crude product was purified by flash chromatography (Mobile phase A: 0.1% NH4HCO3 in H2O, mobile phase B: ACN; Gradient from 5 to 95%) to give tertbutyl 3-(l-benzyloxy-3-oxo-propyl)-3-vinyl-azetidine-l-carboxylate (6.4 g, 18.52 mmol, 58.52% yield) as yellow oil. LCMS calculated for C20H28NO4 (M+H)+m / z = 346.4, found: 346.4.

[0347] Step 7. Synthesis of tert-butyl 3-[(3E)-l-benzyloxy-3-(p- tolylsulfonylhydrazono)propyl]-3-vinyl-azetidine-l-carboxylate (Int-4g). To a solution of tertbutyl 3-(l-benzyloxy-3-oxo-propyl)-3-vinyl-azetidine-l-carboxylate (2 g, 5.79 mmol) in THF (60 mL) was added TsNHNEE (1.62 g, 8.68 mmol). The resulting mixture was stirred at -20 °C for 0.2 h. The mixture was quenched with H2O (50 mL), extracted with EtOAc (50 mL><3). The combined organic layer was washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 50%) to give tert-butyl 3-[(3E)-l-benzyloxy-3-(p- tolylsulfonylhydrazono)propyl]-3-vinyl-azetidine-l-carboxylate (2.3 g, 4.48 mmol, 77.34% yield) as yellow oil. LCMS calculated for C27H36N3O5S (M+H)+m / z = 514.2, found: 514.2.

[0348] Step 8. Synthesis of tert-butyl 3'-benzyloxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]- 1-carboxylate (Int-4h). To a solution of tert-butyl 3-[(3E)-l-benzyloxy-3-(p- tolylsulfonylhydrazono)propyl]-3-vinyl-azetidine-l-carboxylate (2 g, 3.89 mmol) and MeONa (420 mg, 7.79 mmol) in DMF (60 mL) was added Pd2(dba)3 (1.07 g, 1.17 mmol) under Ar. The resulting mixture was stirred at 80 °C for 12 h. Upon completion, the mixture was cooled down to r.t., and quenched with H2O (100 mL), extracted with EtOAc (100 mL*3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 20%) to give tert-butyl 3'-benzyloxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]- 1-carboxylate (600 mg, 1.82 mmol, 46.77% yield) as yellow solid. LCMS calculated for C20H28NO3 (M+H)+m / z =330.1; found: 230.1 (M-Boc).

[0349] Step 9. Synthesis of tert-butyl 3'-hydroxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l- carboxylate & tert-butyl 5-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (Int-4i and by-product). To a solution of tert-butyl 3'-benzyloxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l-carboxylate (300 mg, 0.91 mmol) in Methanol (10 mL) was added Pd / C (150 mg, 1.41 mmol). The resulting mixture was stirred at 75 °C under atmosphere of H2 (3 MPa) for 12 h. Upon completion, the mixture was cooled down to r.t.. The mixture was filtered over celite and concentrated to give a crude mixture of tert-butyl 3'-hydroxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l-carboxylate and tert-butyl 5-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (280 mg, 1.17 mmol) as yellowoil. The crude product was used directly for the next step. LCMS calculated for C13H22NO3 (M+H)+m / z =239.2; found: 184.1 (M-tBu).

[0350] Step 10. Synthesis of tert-butyl 3'-oxospiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l- carboxylate & tert-butyl 5-oxo-2-azaspiro[3.5]nonane-2-carboxylate (Int-4j and by-product). To a solution of tert-butyl 3'-hydroxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l-carboxylate and tert-butyl 5-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (280 mg, 1.17 mmol) and in DCM (3 m ) was added DMP (744.35 mg, 1.75 mmol). The resulting mixture was stirred at r.t. for 2 h. The reaction mixture was diluted with CH2CI2 (10 mL) and the resulting mixture was added to 1.3 M NaOH (10 mL). After the mixture was stirred for 10 min, the organic layer was separated, washed with water (10 mL) and brine (10 mL). The organic layer was then dried over Na2SC>4 and concentrated. The crude product was purified by flash chromatography (Mobile phase A: 0.1% NH4HCO3 in H2O, mobile phase B: ACN; Gradient from 5 to 95%) to give a mixture of tert-butyl 3'-oxospiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l-carboxylate and tert-butyl 5-oxo-2- azaspiro[3.5]nonane-2-carboxylate (70 mg, 0.2950 mmol, 25.213% yield) as yellow oil. LCMS calculated for C13H20NO3 (M+H)+m / z =237.1; found: 182.0 (M-tBu).

[0351] Step 11. Synthesis of tert-butyl 8-amino-7-cyano-spiro[9-thiatricyclo[4.3.0.02,4]nona- l(6),7-diene-5,3'-azetidine]-l'-carboxylate and tert-butyl 2-amino-3-cyano-spiro[6,7-dihydro-5H- benzothiophene-4,3'-azetidine]-l'-carboxylate (Int-4k and by-product). To a solution of tertbutyl 3'-oxospiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l-carboxylate and tert-butyl 5-oxo-2- azaspiro[3.5]nonane-2-carboxylate (80 mg, 0.34 mmol), S (21.62 mg, 0.67 mmol) and Malononitrile (44.54 mg, 0.67 mmol) in Ethanol (3 mL) was added Ammonium acetate (51.92 mg, 0.67 mmol) under Ar. The resulting mixture was stirred at 60 °C for 12 h. Upon completion, the mixture was cooled down to r.t.. The mixture was quenched with H2O (10 mL), extracted with EtOAc (10 mL><3), The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered, and concentrated to afford the crude product. The crude product was purified by flash chromatography (Mobile phase A: 0.1% NH4HCO3 in H2O, mobile phase B: ACN; Gradient from 5 to 95%. ) to give a mixture of tert-butyl 8-amino-7-cyano-spiro[9- thiatricyclo[4.3.0.02,4]nona-l(6),7-diene-5,3'-azetidine]-l'-carboxylate and tert-butyl 2-amino-3- cyano-spiro[6,7-dihydro-5H-benzothiophene-4,3'-azetidine]-l'-carboxylate (60 mg, 0.0851 mmol, 25.232% yield) as yellow oil. LCMS calculated for C16H20N3O2S (M-H)' m / z = 316.1, found: 316.1.

[0352] Step 12. Synthesis of 8-aminospiro[9-thiatricyclo[4.3.0.02, 4]nona-l(6),7-diene-5, 3'- azetidine]-7-carbonitrile;methanesulfonic acid & 2-aminospiro[6,7-dihydro-5H-benzothiophene- 4,3'-azetidine]-3-carbonitrile;methanesulfonic acid (Intermediate 4 and by-product). To a solution of tert-butyl 8-amino-7-cyano-spiro[9-thiatricyclo[4.3.0.02,4]nona-l(6),7-diene-5,3'-azetidine]-l'-carboxylate and tert-butyl 2-amino-3-cyano-spiro[6,7-dihydro-5H-benzothiophene- 4,3'-azetidine]-l'-carboxylate (50 mg, 0.16 mmol) in IPA (ImL) was added Methanesulfonic acid (45.42 mg, 0.47 mmol). The reaction mixture was stirred at 60 °C for 3 h. Upon completion, the mixture was cooled down to r.t.. The mixture was concentrated to afford a crude mixture of 8- aminospiro[9-thiatricyclo[4.3.0.02,4]nona-l(6),7-diene-5,3'-azetidine]-7- carbonitrile;methanesulfonic acid & 2-aminospiro[6,7-dihydro-5H-benzothiophene-4,3'- azetidine]-3-carbonitrile;methanesulfonic acid (59 mg, 0.1883 mmol) as yellow oil. The crude product was used directly for the next step. LCMS calculated for C11H12N3S (M+H)+ m / z = 218.1, found: 218.1.

[0353] Intermediate 5. Synthesis of 2-amino-5-methyl-spiro[6H-thieno[2,3-c]pyrrole-4,3'- azetidine]-3-carbonitrile.

[0354] Step 1. Synthesis of 1 -(tert-butyl) 3-methyl 3 -azidoazetidine- 1,3 -dicarboxylate (Int- 5a). The mixture of 1 -(tert-butyl) 3-methyl 3-bromoazetidine-l,3-dicarboxylate (2.00 g, 6.80 mmol) and azidosodium (1.33 g, 20.4 mmol) in anhydrous DMSO (20.0 mL) was stirred at 50 °C for 18 h under N2. The reaction mixture was cooled to r.t and diluted with EtOAc (200 mL). It was washed with saturated aqueous NaHCOa (150 mL) followed by saturated brine (2* 150 mL), dried (Na2SO4) and concentrated in vacuo to dryness to afford 1 -(tert-butyl) 3-methyl 3- azidoazeti dine- 1,3 -dicarboxylate (1.67g, 6.52 mmol, 95.8% yield) as a yellow oil. LCMS calculated for C10H17N4O4 (M+H)+m / z = 256.1; found: 201.1 (M- / Bu).

[0355] Step 2. Synthesis of 1 -(tert-butyl) 3-methyl 3 -aminoazetidine- 1,3 -dicarboxylate (Int- 5b). The mixture of 1 -(tert-butyl) 3-methyl 3-azidoazetidine-l,3-dicarboxylate (1.66 g, 6.48 mmol) and 10% Pd / C (55% wt, 300 mg) in Ethanol (20.0 mL) was stirred at r.t under H2 atmosphere overnight. The mixture was filtrated through Celite and the filtrate was concentrated in vacuo o get 1 -(tert-butyl) 3-methyl 3-aminoazetidine-l,3-dicarboxylate (1.43 g, 6.21 mmol, 95.9% yield) as a colorless. LCMS calculated for C10H18N2O4 (M+H)+ m / z = 231.1; found: 231.1.

[0356] Step 3. Synthesis of 1 -(tert-butyl) 3-methyl 3-((3-methoxy-3- oxopropyl)amino)azetidine-l,3-dicarboxylate (Int-5c). The mixture of 1 -(tert-butyl) 3-methyl 3-aminoazetidine-l,3-dicarboxylate (1.30 g, 5.65 mmol), Methyl Acrylate (3.58 mL, 39.5 mmol), EtsN (2.36 mL, 16.9 mmol) and CuO (0.09 g, 1.13 mmol) in MeOH (10 mL) was stirred at 85 °C for 8 h under N2. It was cooled to r.t and filtered. The filtrate was concentrated in vacuo to give the residue. It was purified using FCC (silica gel, eluting with EtOAc in pet.ether 0 to 50%) to afford 1 -(tert-butyl) 3-methyl 3-((3-methoxy-3-oxopropyl)amino)azetidine-l,3-dicarboxylate (1.48 g, 4.68 mmol, 82.9% yield) as a light yellow oil. LCMS calculated for C14H25N2O6 (M+H)+m / z = 317.2; found: 317.2.

[0357] Step 4. Synthesis of 5-benzyl 2-(tert-butyl) 7-methyl 8-oxo-2,5-diazaspiro[3.4]octane- 2,5,7-tricarboxylate (Int-5d). To a solution of 1 -(tert-butyl) 3-methyl 3-((3-methoxy-3- oxopropyl)amino)azetidine-l,3-dicarboxylate (5.50 g, 17.4 mmol) in THF (80 mL) was added t- BuONa (3.34 g, 34.8 mmol) in five batches at 0 °C under N2. Then the mixture was stirred at same temperature for 2 h. Upon SM was consumed, Benzyl Chloroformate (4.96 mL, 34.8 mmol), DIEA (7.57 mL, 43.5 mmol) and DMAP (0.53 g, 4.35 mmol) was added and the whole mixture was stirred at r.t overnight. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layer was washed with water (100 mL) followed by saturated brine (100 mL), dried (Na2SO4) and concentrated in vacuo to give the residue. It was purified using FCC (silica gel, eluting with EtOAc in 0 to 50%) to afford 5-benzyl 2-(tert-butyl) 7-methyl 8-oxo-2,5-diazaspiro[3.4]octane-2,5,7-tricarboxylate (7.20 g, 12.9 mmol, 74.2% yield) as a light red oil. LCMS calculated for C21H27N2O7 (M+H)+m / z = 419.2; found (M- Boc): 319.2.

[0358] Step 5. Synthesis of 5-benzyl 2-(tert-butyl) 8-oxo-2,5-diazaspiro[3.4]octane-2,5- dicarboxylate (Int-5e). The mixture of 5-benzyl 2-(tert-butyl) 7-methyl 8-oxo-2,5- diazaspiro[3.4]octane-2,5,7-tricarboxylate (7.20 g, 12.9 mmol) and LiCl (1.09 g, 25.8 mmol) in DMSO (115 mL) and Water (11.5 mL) was stirred at 160 °C for 1.5 h under N2. It was cooled to r.t and diluted with water (500 mL). It was extracted with EtOAc (200 mL*2). The combined extracts were wash with water (200 mL*3) followed by saturated brine (100 mL), dried (Na2SO4) and concentrated in vacuo to give the residue. It was purified using FCC (silica gel, eluting with EtOAc in PE 0 to 50) to afford 5-benzyl 2-(tert-butyl) 8-oxo-2,5-diazaspiro[3.4]octane-2,5- dicarboxylate (2.74 g, 7.60 mmol, 58.9% yield) as a colorless oil. LCMS calculated for Ci9H25N2O5(M+H)+m / z = 361.2; found: 261.1 ((M-Boc)).

[0359] Step 6. Synthesis of tert-butyl 8-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate (Int-5f). The mixture of 5-benzyl 2-(tert-butyl) 8-oxo-2,5-diazaspiro[3.4]octane-2,5-dicarboxylate (2.00 g, 5.55 mmol) and 10% Pd / C (55% wt, 250 mg) in Methanol (40 mL) was stirred at room temperature overnight under H2. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to afford crude of tert-butyl 8-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate(1.20 g, 5.30 mmol, 95.6% yield) as a yellow solid. LCMS calculated for C11H19N2O3 (M+H)+m / z = 227.1; found: 127.0 ((M-#oc)) / 17L0((M-tBu)).

[0360] Step 7. Synthesis of tert-butyl 5-methyl-8-oxo-2,5-diazaspiro[3.4]octane-2- carboxylate (Int-5g). The mixture of tert-butyl 8-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate (60.0 mg, 0.27 mmol), Methyl Iodide (0.05 mL, 0.80 mmol) and DIEA (0.12 mL, 0.66 mmol) in THF (2 mL) was stirred at 60 °C for 16 h under N2. The mixture was cooled to r.t and diluted with water (10 mL), extracted with EtOAc (10 m). The extracts were washed with saturated brine (10 mL), dried (ISfeSCU) and concentrated in vacuo to give the residue. It was purified using (silica gel, eluting with MeOH in DCM 0 to 3%) to afford tert-butyl 5-methyl-8-oxo-2,5- diazaspiro[3.4]octane-2-carboxylate (35.0 mg, 0.146 mmol, 54.9% yield) as a yellow oil. LCMS calculated for C12H21N2O3 (M+H)+m / z =241.2; found: 141.2 (M-Boc) / 185.2(M-tBu).

[0361] Step 8. Synthesis of tert-butyl 2-amino-3-cyano-5-methyl-spiro[6H-thieno[2,3- c]pyrrole-4,3'-azetidine]-l'-carboxylate (Int-5h). The mixture of tert-butyl 5-methyl-8-oxo-2,5- diazaspiro[3.4]octane-2-carboxylate (158 mg, 0.66 mmol) Sulfur (31.6 mg, 0.99 mmol), ammonium acetate (76. 0 mg, 0.99 mmol) and malononitrile (65.1 mg, 0.99 mmol) in Ethanol (4 mL) was stirred at 55 °C for 1 h under N2. It was cooled to r.t and diluted with water, extracted with EtOAc (20 mL). The extracts was wash with saturated brine dried (Na2SO4) and concentrated under reduce pressure to give the residue. It was purified using FCC (silica gel, eluting with MeOH in DCM 0 to 3%) to afford tert-butyl 2-amino-3-cyano-5-methyl-spiro[6H- thieno[2,3-c]pyrrole-4,3'-azetidine]-l'-carboxylate (150 mg, 0.47 mmol, 71.2% yield) as brown solid. LCMS calculated for C15H21N4O2S (M+H)+m / z = 321.1; found: 221.1((M-Boc)) / 265.1((M- / Bu)).

[0362] Step 9. Synthesis of 2-amino-5-methyl-spiro[6H-thieno[2,3-c]pyrrole-4,3'-azetidine]- 3-carbonitrile (Intermediate 5). To the solution of tert-butyl 2-amino-3-cyano-5-methyl- spiro[6H-thieno[2,3-c]pyrrole-4,3'-azetidine]-l'-carboxylate (150 mg, 0.47 mmol) in IPA (1.5 mL) was added MsOH (0.09 mL, 1.40 mmol) at room temperature. Then the mixture was stirred at 60 °C for 8 h under N2. The solid was collected by filtration and wash with IPA (3*2 mL). It was dried in vacuo to afford 2-amino-5-methyl-spiro[6H-thieno[2,3-c]pyrrole-4,3'-azetidine]-3- carbonitrile;methanesulfonic acid (155 mg, 0.38 mmol, 80.2% yield) as grey solid. LCMS calculated for C10H13N4S (M+H)+m / z = 221.1; found: 221.0.

[0363] Intermediate 6. Synthesis of tert-butyl N-[4-[l-(ethylamino)ethyl]-l,2,5-thiadiazol-3- yl] carbamate

[0364] Step 1. Synthesis of 4-amino-N-methoxy-N-methyl-l,2,5-thiadiazole-3-carboxamide (Int-6a). To the solution of O-Dimethylhydroxylamine Hydrochloride (2.02g, 20.67mmol) and 4-amino-l,2,5-thiadiazole-3-carboxylic acid (2.5g, 17.22mmol) in DMF (25mL) was added HATU (6.4mL, 25.84mmol) and DIEA (11.13g, 86.12mmol) at 25°C. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (100 mL), and then extracted with EtOAc (100 mL x 3). The organic phase was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 10% to 60%) to obtained 4-amino-N-methoxy-N-methyl- 1,2,5- thiadiazole-3-carboxamide (2.60 g, 13.8 mmol, 80.20 % yield) as white solid. LCMS calcld for C5H9N4O2S (M+H)+m / z =189.2, found: 189.0.

[0365] Step 2. Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[4- [methoxy(methyl)carbamoyl]-l,2,5-thiadiazol-3-yl]carbamate (Int-6b). To a solution of 4- amino-N-methoxy-N-methyl-l,2,5-thiadiazole-3-carboxamide (2.6 g, 13.81 mmol) and (Boc)2O (6.03 g, 27.63 mmol) in MeCN (30 mL) was added DMAP (0.84 g, 6.91 mmol) at 25 °C. The mixture was stirred at 30 °C for 2 h. Upon completion, the reaction was cooled down to r.t. The mixture was diluted with water (100 mL), and then extracted with EtOAc (150 mL x 3). The organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 40%) to obtained tert-butyl N-tert-butoxycarbonyl-N-[4- [methoxy(methyl)carbamoyl]-l,2,5-thiadiazol-3-yl]carbamate (3.50 g, 9.01 mmol, 65.22 %yield ) as yellow solid. LCMS calculated for CisH24N4O6SNa (2M+Na)+m / z =799.2, found:799.2.

[0366] Step 3. Synthesis of tert-butyl N-(4-acetyl-l,2,5-thiadiazol-3-yl)carbamate (Int-6c). To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-[methoxy(methyl)carbamoyl]-l,2,5- thiadiazol-3-yl]carbamate (2 g, 5.15 mmol) in THF (20 mL) was added 3 M CH3MgBr in THF (5.15 mL, 15.45 mmol) at 0 °C. The mixture was warmed to 25°C for 16 h. The mixture was quenched with NH4CI aq. at 0 °C, the mixture was diluted with EtOAc (200 mL), washed with H2O (100 mL) and brine (100 mL), The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 20%) to obtained tert-butyl N-(4-acetyl-l,2,5-thiadiazol-3- yl)carbamate (1 2g, 4.9326 mmol, 95.801% yield) as crude yellow oil LCMS calculated for C9Hi3N3O3SNa (M+Na)+m / z = 266.2, found:266.1.

[0367] Step 4. Synthesis of tert-butyl N-[4-[l-(ethylamino)ethyl]-l,2,5-thiadiazol-3- yl]carbamate (Intermediate 6). To the solution of tert-butyl N-(4-acetyl-l,2,5-thiadiazol-3- yl)carbamate (500 mg, 2.06 mmol) and Ethylamine in THF (2.06 mL, 4.11 mmol) in Methanol (10 mL) was added Titanium tetraisopropanolate (1168.28 mg, 4.11 mmol) at 25 °C. The mixturewas stirred at 80 °C for 16 h. Upon completion, the reaction was cooled down to r.t. Then the mixture was added Sodium borohydride (155.5 mg, 4.11 mmol) at rt. The mixture was stirred at rt for 2 h. The mixture was added water (10 mL), then filtered and the filtrate was extracted with EtOAc (3 x 15 mL). The organic phases were washed with water (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc / PE=l / l) to obtained tert-butyl N-[4-[l-(ethylamino)ethyl]- l,2,5-thiadiazol-3-yl]carbamate (400 mg, 1.47 mmol, 71.46% yield) as white solid. LCMS calculated for C11H21N4O2S (M+H)+m / z =273.1, found: 273.1. ^ NMR (400 MHz, CDCh) 5: 10.73 (s, 1H), 4.34-4.29 (m, 1H), 2.71-2.63 (m, 1H), 2.51-2.42 (m, 1H), 1.54 (s, 9H), 1.45-1.44 (m, 3H), 1.16-1.12 (m, 3H).

[0368] Intermediate 7. Synthesis of 3-[l-(methylamino)ethyl]pyrazin-2-amine

[0369] Step 1. Synthesis of l-(3-chloropyrazin-2-yl)ethenone (Int-7a). The mixture of 1- Ethoxyvinyltri-N-Butyltin (4.07mL, 11.95mmol), 2,3-Dichloropyrazine (1.24mL, 11.95mmol) and Pd(PPh3)2C12 (419.31 mg, 0.6 mmol) in Toluene (20 mL) was purged with N2 and heated to 110 °C for 3 h. TLC showed the reaction was completed. It was cooled to rt and the solvent was removed in vacuo to give the crude intermediate. It was then diluted with MeCN (20mL) and HC1 (3 mL, 36 mmol) was added. The whole mixture was stirred for 16 h at rt. It was diluted with H2O (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with saturated brine followed by drying over Na2SC>4. It was concentrated in vacuo and purified using FC (eluant with EtOAc in PE 0 to 20%) to give the product l-(3- chloropyrazin-2-yl)ethanone, 1600 mg, 10.2 mmol, 85.53 %yield as a white solid LCMS calculated for CsHgC ) (M+H)+m / z =157.0; found: 157.1 and 159.1.

[0370] Step 2. Synthesis of l-(3-aminopyrazin-2-yl)ethenone (Int-7b). The mixture of l-(3- chloropyrazin-2-yl)ethanone (L4g, 8.94mmol), and NH3H2O (36 mL, 1927.06 mmol) in Ethanol (15 mL) was heated to 140 °C for 3 h. After completion the reaction mixture was concentrated in vacuo and the residue was purified using FC (eluant with EtOAc in PE 0 to 30%) to give the product l-(3-aminopyrazin- 2-yl)ethanone, 700 mg, 5.10 mmol, 57.08 %yield as a white solid. LCMS calculated for C6H8N3O (M+H)+ m / z =138.0; found: 138.3.

[0371] Step 3. Synthesis of 3-[l-(methylamino)ethyl]pyrazin-2-amine (Intermediate 7). To a stirred solution of l-(3-aminopyrazin-2-yl)ethanone (402.91 mg, 2.94 mmol) in THF (5mL). Methylamine in MeOH (608.35 mg, 5.88 mmol) was added at 0°C followed by the drop wise addition of titanium(IV)isopropoxide (2.61 mL, 8.81 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, added Methanol (5mL) and cooled to 0°C. NaBH4 (217.41mg, 5.88mmol) was added and was stirred for 3h at room temperature. The reaction was quenched with ice, filtered and solids were washed thoroughly with methanol. The filtrate was evaporated todryness under reduced pressure and the residue was purified by automated flash chromatography using 20% MeOH in DCM to obtain 3-[l-(methylamino)ethyl]pyrazin-2 -amine (68 mg,0.447mmol, 15.21% yield) as white solid. LCMS calculated for C7H13N4 (M+H)+ m / z =153.1; found: 153.2

[0372] Intermediate 8. Synthesis of 3-[l-(ethylamino)ethyl]pyrazin-2-amine

[0373] Intermediate 8 was prepared similarly to that of Intermediate 7. LCMS calculated forC8H15N4(M+H)+m / z = 167.1; found: 167.1

[0374] Intermediate 9. Synthesis of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-methyl-amino]-6-chloro-2-methylsulfonyl-pyrimidine-5-carbonitrile

[0375] Step 1. Synthesis of N,N-bis[(4-methoxyphenyl)methyl]-3-[(lR)-l- (methylamino)ethyl]pyridin-2-amine (Int-9a). To the solution of N-[(lR)-l-[2-[bis[(4- methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-N,2-dimethyl-propane-2-sulfinamide (Int-2e, 24. g, 46. mmol) in Methanol (200mL) was added HC1 in MeOH (34.5mL, 137.99mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was basified with saturated aqueous Na2CCh to pH=9, extracted with DCM (3 x 200mL), The combined organic layers was dried over Na2SO4, filtered, and concentrated to afford the crude product. The crude product was purified by flash chromatography (eluted with MeOH in DCM from 0% to 7%) to afford N,N-bis[(4- methoxyphenyl)methyl]-3-[(lR)-l-(methylamino)ethyl]pyridin-2-amine (16.80 g, 42.9 mmol, 93.29 %yield) was obtained as yellow oil. LCMS calculated for C24H3oN302 (M+H)+m / z = 392.2, found: 392.2. The absolute stereochemistry was determined by single crystal X-ray structure of its mono HC1 salt.

[0376] Step 2. Synthesis of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (Int-9b)

[0377] To the solution of N,N-bis[(4-methoxyphenyl)methyl]-3-[(lR)-l-(methylamino)ethyl]pyridin- 2-amine (1.78g, 4.54mmol) and 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (l.g, 4.54mmol) in DCM (20mL) was added DIEA (2.37mL, 13.63mmol) at 25 °C. The mixture was stirred at 25 °C for 4 h. The mixture was diluted with water (50 mL), and then extracted with DCM (80 mL x 3). The combined organic phases were washed with brine (80 mL), dried overNa2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to30%). The desired fractions were concentrated under vacuum to afford 4-[[(lR)-l-[2-[bis[(4- methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5- carbonitrile, 2.20 g, 3.83 mmol, 84.18 %yield was obtained as yellow solid. LCMS calculated for C30H32CIN6O2S (M+H)+m / z =575.1, found:575.1.

[0378] Step 3. Synthesis of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-methyl-amino]-6-chloro-2-methylsulfonyl-pyrimidine-5-carbonitrile (Intermediate 9). To the solution of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (3.1g, 5.39mmol) in THF (40mL) / Water (20mL) was added oxone (6.63g, 10.78mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with EtOAc (500 mb), and then extracted with water (200 m ). The organic phase was washed with brine (200 mb), dried over NazSC , filtered and concentrated. The crude product was used directly for the next step. 4- [[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-methyl-amino]-6-chloro-2- methylsulfonyl-pyrimidine-5-carbonitrile (3.20 g, 5.27 mmol) was obtained as yellow solid. LCMS calculated for C30H32CIN6O4S (M+H)+m / z =607.2, found:607.2.

[0379] Intermediate 10. Synthesis of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]- 3-pyridyl]ethyl]-ethyl-amino]-6-chl oro-2 -methylsulfonyl-pyrimidine-5-carbonitrile

[0380] Intermediate 10 was prepared similarly to that of Intermediate 9. LCMS calculated for C31H34CIN6O4S (M+H)+m / z = 621.21; found: 621.2. 'H NMR (400 MHz, CDCI3) 5 = 8.50 (d, .7=3.6 Hz, 1H), 7.75 (d, .7=7.4 Hz, 1H), 7.15 (dd, .7=7,7, 4.8 Hz, 1H), 6.92 (d, J=8.5 Hz, 4H), 6.69 (d, .7=8.6 Hz, 4H), 6.47 (s, 1H), 4.41 - 4.19 (m, 2H), 4.12 (dd, J=18.6, 10.4 Hz, 2H), 3.77 (d, .7=4.2 Hz, 6H), 3.49 (dd, .7=14.5, 7.4 Hz, 2H), 3.26 (s, 3H), 1.48 - 1.18 (m, 3H), 0.71 (s, 3H).

[0381] Intermediate 11. Synthesis of 3-[(lR)-l-(2,2-difluoroethylamino)ethyl]pyridin-2- amine.

[0382] Step 1. Synthesis of (R)-3-(l-((2,2-difluoroethyl)amino)ethyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine (Int-lla). The mixture of 3-[(lR)-l-aminoethyl]-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine (prepared similarly to that of Intermediate 2A, 1800 mg, 4.77 mmol), 1 , 1 -difluoro-2-iodo-ethane (915.27 mg, 4.77 mmol) and K2CO3(1.32 g, 9.54mmol) in MeCN (10 mL) was stirred at 90 °C under N2 for 16 h. The reaction was concentrated to dryness and the residue was diluted with EtOAc (30 mL) and washed with water (2 xlO mL) followed by saturated brine (10 mL). The organic layer was dried (MgSCU) and concentration to dryness. The residue was then purified using FCC (eluting with MeOH in DCM 0 to 2%). The desired fractions were concentrated to dryness to afford the product 3-[(lR)-l-(2,2- difluoroethylamino)ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (1.36 g, 3.08 mmol, 61.20 % yield) as yellow oil. LCMS: calculated for C25H30F2N3O2 (M+H)+m / z = 442.5; found:442.5.

[0383] Step 2. Synthesis of (R)-3-(l-((2,2-difluoroethyl)amino)ethyl)pyridin-2-amine (Intermediate 11). To the mixture of 3-[(lR)-l-(2,2-difluoroethylamino)ethyl]-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine (1.36 g, 3.08 mmol) in TFA (3.0 mL, 39.2 mmol) was added TfOH (0.3 mL, 3.39 mmol) at rt under N2. The mixture was stirred at 35 °C for 2h. TFA was removed in vacuo. The residue was basified using aq NaHCO? and Na2COs, and then extracted with EtOAc (2 x30 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the residue. It was purified using FCC (eluant with MeOH in DCM 0 to 5%). The desired fractions were concentrated to dryness to afford the product 3-[(lR)-l-(2,2- difluoroethylamino)ethyl]pyridin-2-amine (479 mg, 2.38 mmol, 77.28 % yield) as a yellow oil. LCMS: calculated for C9H14F2N3 (M+H)+m / z =202.2; found: 202.8.

[0384] Intermediate 12. 2-amino-5-ethyl-spiro[6H-thieno[2,3-c]pyrrole-4,3'-azetidine]-3- carbonitrileIntermediate 12

[0385] Intermediate 12 was prepared similarly to that of Intermediate 5. LCMS calculated for C11H15N4S (M+H)+m / z =235.35; found: 235.1.

[0386] Intermediate 13. 2-amino-5-cyclopropyl-spiro[6H-thieno[2,3-c]pyrrole-4,3'- azetidine]-3-carbonitrileIntermediate 13

[0387] Intermediate 13 was prepared similarly to that of Intermediate 5. LCMS calculated for C12H15N4S (M+H)+m / z =247.33; found: 247.2.

[0388] Intermediate 14. tert-butyl N-[4-[l-(methylamino)ethyl]-l,2,5-thiadiazol-3- yl] carbamateIntermediate 14

[0389] Intermediate 14 was prepared similarly to that of Intermediate 6. LCMS calculated for C10H19N4O2S (M+H)+m / z =259.1, found:259.1.

[0390] Example 1. 2-amino-l'-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 1)

[0391] Step 1. Preparation of 4-chloro-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfanyl-pyrimidine-5-carbonitrile (la). To a solution of 4,6-dichloro-2-methylsulfanyl- pyrimidine-5-carbonitrile (500 mg, 2.27 mmol) in THF (2mL) was added 1- (hydroxymethyl)cyclopropanecarbonitrile (220.65 mg, 2.27 mmol), followed by the addition of LiHMDS (2.95 mL, 2.95 mmol) under -78 °C. The reaction was stirred at -78 °C for 2h. The mixture was extracted with EtOAc, washed with brine. The organic layer was dried over Na2SC>4, concentrated and purified by flash column chromatography to afford 4-chloro-6-[(l- cyanocyclopropyl)methoxy]-2-methylsulfanyl-pyrimidine-5-carbonitrile (la, 480 mg, 1.71 mmol, 75.26% yield) as a white solid. LCMS calculated for C11H10CIN4OS (M+H)+m / z = 281.0; found: 281.0

[0392] Step 2. Preparation of 2-amino-T-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfanyl-pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3- carbonitrile (lb). To a solution of 4-chloro-6-[(l-cyanocyclopropyl)methoxy]-2-methylsulfanyl- pyrimidine-5-carbonitrile (la, 200 mg, 0.71 mmol) in DMSO (5mL) was added 2- aminospiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile;methanesulfonic acid (214.72 mg, 0.71 mmol) and DIEA (460.37 mg, 3.56 mmol), the mixture was stirred at 20 °C for 2h. The reaction mixture was extracted with EtOAc, washed with brine , dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, eluting with DCM / MeOH) and concentrated afford 2-amino-l'-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfanyl-pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (lb, 270 mg, 0.601 mmol, 84.30% yield) as a white solid. LCMS calculated for C21H20N7OS2 (M+H)+m / z =450.1; found:450.2

[0393] Step 3. Preparation of 2-amino-l'-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfinyl-pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3- carbonitrile (lc). To a solution of 2-amino-T-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfanyl-pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3- carbonitrile (lb, 270 mg, 0.6 mmol) in DCM (5mL) was added m-CPBA (259.11 mg, 1.5 mmol) at 0 °C, then the mixture was stirred at 0 °C for lOmin.The reaction mixture was extracted with EtOAc, washed with brine, dried over NajSCL, concentrated and purified by flash column chromatography (silica gel, eluting with DCM / MeOH) and concentrated afford 2-amino-l'-[5- cyano-6-[(l-cyanocyclopropyl)methoxy]-2-methylsulfinyl-pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (lc, 138 mg, 0.296 mmol, 49.35% yield) as a yellow solid. LCMS calculated for C21H20N7O2S2 (M+H)+m / z =466.1; found:466.0.

[0394] Step 4. Preparation of 2-amino-l'-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2- [[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 1). To a solution of 2- amino-T-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2-methylsulfinyl-pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (lc, 50 mg, 0.11 mmol) in THF (2 mL) was added [(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (17.1 mg, 0.11 mmol), then added LiHMDS (0.14 mL, 0.14 mmol) to the mixture at -78 °C. The reaction was stirred at -78 °C for 2h. LCMS showed the reaction was completed. Then the mixture was concentrated and purified by Prep-HPLC on a Cl 8 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / MeCN at flow rate : 35 mL / min to afford 2-amino-l'-[5-cyano-6- [(l-cyanocyclopropyl)methoxy]-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3- carbonitrile (Compound 1, 14 mg, 0.025 mmol, 23.30% yield) as a white solid. LCMS calculated for C28H30FN8O2S (M+H)+m / z =561.2; found: 561.0. *HNMR (400 MHz, CD3OD) 5 5.26 (d, J = 55.2 Hz, 1H), 4.23 - 4.56 (m, 6H), 4.15 (dd, J = 36.8 , 10.4 Hz, 2H), 3.23 (s, 2H), 3.12 - 3.17 (m, 1H), 2.94 - 3.04 (m, 1H), 2.65 - 2.81 (m, 4H), 1.94 - 2.25 (m, 6H), 1.36 - 1.41 (m, 2H), 1.20 - 1.26 (m, 2H).

[0395] Compound 2. 2-amino-T-[5-cyano-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-[(l -hydroxy cyclopropyl)methoxy]pyrimi din-4- yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile

[0396] Compound 2 was prepared similarly to that of Ex. 1. LCMS calculated for C27H31FN7O3S (M+H)+m / z =552.2; found: 552.0. ’H NMR (400 MHz, CD3OD) 5 5.25 (d, J = 54.4 Hz, 1H), 4.22 - 4.57 (m, 6H), 4.11 (m, 2H), 3.19 (s, 2H), 3.10 - 3.14 (m, 1H), 2.91 - 3.03 (m, 1H), 2.68 - 2.82 (m, 4H), 1.95 - 2.28 (m, 5H), 1.79 - 1.91 (m, 1H), 0.82 (m, 2H), 0.75 (m, 2H).

[0397] Compound 3. 2-amino-l'-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2-[[l- (morpholinomethyl)cyclopropyl]methoxy]pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile

[0398] Compound 3 was prepared similarly to that of Ex. 1. LCMS calculated for C29H33N8O3S (M+H)+m / z =573.2; found: 573.4. *HNMR (400 MHz, CD3OD) 54.74 (s, 2H), 4.48 (s, 3H), 4.28 (s, 3H), 3.66 (m, 4H), 2.68 - 2.83 (m, 4H), 2.42 (m, 6H), 1.39 (m, 2H), 1.24 (m, 2H), 0.64 (m, 2H), 0.46 (m, 2H).

[0399] Example 2. Synthesis of 2-amino-r-[5-cyano-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-(lH-pyrazol-5-ylmethylamino)pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 4)

[0400] Step 1. Preparation of 4-chloro-2-methylsulfanyl-6-(lH-pyrazol-5- ylmethylamino)pyrimidine-5-carbonitrile (4a). To a solution of 4,6-dichloro-2-methylsulfanyl- pyrimidine-5-carbonitrile (500 mg, 2.27 mmol)) and lH-pyrazol-5-ylmethanamine (220.65 mg, 2.27 mmol) in DCM (lOmL) was added DIEA (0.79 mL, 4.54 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 10% to 90%). 4-chloro-2-methylsulfanyl-6-(lH-pyrazol-5- ylmethylamino)pyrimidine-5-carbonitrile (4a, 421 mg, 1.50 mmol, 66.01% yield) was obtained as white solid. LCMS calculated for CioHioCINeS (M+H)+m / z = 281.74, found: 281.1.

[0401] Step 2. Preparation of tert-butyl 5-[[(6-chloro-5-cyano-2-methylsulfanyl- pyrimidin-4-yl)amino]methyl]pyrazole-l -carboxylate (4b). To a solution of 4-chloro-2- methylsulfanyl-6-(lH-pyrazol-5-ylmethylamino)pyrimidine-5-carbonitrile (4a, 200 mg, 0.71 mmol) and BOC2O (0.21 mL, 1.57 mmol) in MeCN (6mL) and DCM (4mL) were added DMAP (17.41mg, 0.14mmol) at 25 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated and extracted with EtOAC (80 mL) and H2O (20 ml), dried over JXfeSCU, concentrated and the crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 10% to 60%). Tert-butyl 5-[[(6-chloro-5-cyano-2- methylsulfanyl-pyrimidin-4-yl)amino]methyl]pyrazole-l-carboxylate (4b, 171 mg, 0.424 mmol, 59.54 %yield) was obtained as white solid. LCMS calculated for C15H18CIN6O2S (M+H)+m / z = 381.85, found: 381.4.

[0402] Step 3. Preparation of tert-butyl 5-[[(6-chloro-5-cyano-2-methylsulfmyl-pyrimidin- 4-yl)amino]methyl]pyrazole-l -carboxylate (4c). To a solution of tert-butyl 5-[[(6-chloro-5-cyano- 2-methylsulfanyl-pyrimidin-4-yl)amino]methyl]pyrazole-l-carboxylate (4b, 50 mg, 0.13 mmol) and Oxone (177.56 mg, 0.29 mmol)in THF (ImL) and Water (ImL) at 25 °C. The mixture was stirred at 50 °C for 1 h. The mixture was concentrated and extracted with EtOAC (80 mL) andwater (15 ml), dried over Na2SO4, concentrated. The crude product was used directly for the next step, tert-butyl 5-[[(6-chloro-5-cyano-2-methylsulfinyl-pyrimidin-4-yl)amino]methyl]pyrazole-l- carboxylate (4c, 66 mg, 0.166 mmol, 126.68 %yield) was obtained as white crude solid. LCMS calculated for CisHisCINeChS (M+H)+m / z = 397.85, found: 397.4.

[0403] Step 4. Preparation of tert-butyl 5-[[[6-chloro-5-cyano-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]amino]methyl]pyrazole-l- carboxylate (4d). To a solution of [(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (31.77 mg, 0.2 mmol) and NaH (9.98 mg, 0.25 mmol) in THF (1.5mL)was stirred for 30min. Then, tert-butyl 5-[[(6-chloro-5-cyano-2-methylsulfmyl-pyrimidin-4- yl)amino]methyl]pyrazole-l -carboxylate (4c, 66 mg, 0.17 mmol) in THF (2mL) was added at 0 °C. The mixture was stirred at 0 °C for 2 h.

[0404] The mixture was concentrated and extracted with...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein:R100is selected fromB is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15- membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R20)2, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, Ci-6 alkyl-N(R20)2, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle;R1Ais selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R11A;R1Bis selected from hydrogen, Ci-6 alkyl, C3-C6 carbocycle, 4- to 6-membered heterocycle, wherein the Ci-6 alkyl and C3-C6 carbocycle, and 4- to 6-membered heterocycle, are each independently optionally substituted with one or more R10;R1Cis selected from hydrogen, Ci-6 alkyl, C3-Ci2carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R12A;R1Dis selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R13, and wherein optionally two R13on the same atom of R1Dcome together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R13A;Y is selected from a bond, -O-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L-aryl, - L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Ci-Ce haloalkyl, -L- OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L- N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCI-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L- NR20C(O)-aryl, the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(0)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, Ci-6 alkyl-N(R20)2, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C 1-6 aminoalkyl, Ci-6 alkoxy, C 1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkyl-Ns, C1-C3 alkoxy, cyano, =CH2, =CHF, =CF2, =N0-Ci-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSCLF, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)-Ci-C3 alkyl-N(R5)2, -CH2OC(O)NCF3(R5), -CH2O-CI-C6alkyl, -C(O)N(R5)2, tert- butyldimethylsilyloxyCFL-, -N(R5)2, (C1-C3 alkoxy)Ci-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OCI-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -0C(0)NH(CI-C3 alkyl)0(Ci-C3 alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -O-Ci-Ce haloalkyl, -C1-C3 alkyl-O-Ci-C6haloalkyl, Ci-6alkyl-N(R20)2, -SF5, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -(CH2)o-iS-heterocycle , - (CH2)o-i-0-heterocycle, -(CH2)o-i-0-phenyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(CI-C3 alkyl)O(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; wherein the alkyl of -CH2O-Ci-C6 alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6 carbocycle; wherein the heterocycle of -CH2heterocycle is optionally substituted with oxo; and wherein the phenyl of -(CH2)o-i-0-phenyl is optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-6 haloalkyl, SFs, C1-6 alkyl-OR20, - OR20; wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)o-i-S-heterocycle are each optionally substituted with one or more substituents selected from Ci-6 alkyl, C 1-6 haloalkyl, Ci-6 alkyl-OR20, and -OR20; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, Ci-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl- N(R20)2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -N02, =0, =S, -CN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, and Ci-6 haloalkyl; each R10is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl -N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3- C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C 1-10 alkyl, oxo; each R11, R12, and R13is independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NR20(C=NH)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, benzyl, C3-Ci2carbocycle and 5- to 12-membered heterocycle, wherein the C3-Ci2carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -N02, -N(R21)2, -SR21, -C(O)N(R21)2, CMO alkyl, -C1-10 haloalkyl, -O-Ci-io alkyl, - C(O)R21, -S(O)2F, -S(O)2(R21), -P(O)(OR21)2, -OP(O)(OR21)2, -P(O)(R21)2, 5- to 6-membered heterocycle and oxo; each R11A, R12A, and R13Ais independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =NO(R20), -CN, -NHCN, Ci-6alkyl -N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20is independently selected from hydrogen; and Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, Cs-i2carbocycle, and 3- to 12- membered heterocycle; and each R21is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.

2. The compound or salt of claim 1, wherein Formula (I) is represented by Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt thereof.

3. The compound or salt of any one of claims 1 to 2, wherein R1Bis selected from hydrogen, optionally substituted Cue alkyl, and optionally substituted Cs-Ce carbocycle.

4. The compound or salt of any one of claims 1 to 3, wherein R1Bis hydrogen, Ci-6 alkyl, Cu 6 hydroxyalkyl, Ci-6 cyanoalkyl, and C3-C6 carbocycle.

5. The compound or salt of any one of claims 1 to 4, wherein R1Bis hydrogen, methyl, ethyl, and cyclopropyl.

6. The compound or salt of any one of claims 1 to 5, wherein R1Bis hydrogen.

7. The compound or salt of any one of claims 1 to 3, wherein R1Bis selected from an optionally substituted Ci-6 alkyl.

8. The compound or salt of claim 7, wherein R1Bis selected from methyl and ethyl.

9. The compound or salt of claims 7 or 8, wherein R1Bis methyl.

10. The compound or salt of any one of claims 1 to 3, wherein R1Bis selected from an optionally substituted C3-C6 carbocycle.

11. The compound or salt of claim 10, wherein R1Bis.

12. The compound or salt of claims 1 to 2, wherein R1Bis selected from hydrogen, Ci-6 alkyl, C3 carbocycle, 4- to 5-membered heterocycle, wherein the C1-6 alkyl, C3 carbocycle, and 4-to 5- membered heterocycle, are each optionally substituted with one or more R10, wherein each R10is independently selected from halogen, -OR20, -C(O)N(R20)2, -N(R20)2, -C(O)OR20, =0, -CN, C2-6 alkenyl, Ci-e haloalkyl, C3-C6 carbocycle, and 4-membered heterocycle.The compound or salt of claim 12, wherein R1Bis selected from15. The compound or salt of claim 12, wherein R1Bis selected from Ci-6 alkyl .

16. The compound or salt of claim 12, wherein R1Bis17. The compound or salt of claim 12, wherein R1Bis18. The compound or salt of any one of claims 1 to 17, wherein R1Ais selected from an optionally substituted C1.3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle.

19. The compound or salt of any one of claims 1 to 18, wherein R11is selected from halogen, -N(R20)2, C3 carbocycle, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N(R21)2, Ci-io alkyl, and -C1-10 haloalkyl.

20. The compound or salt of any one of claims 1 to 19, wherein each R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6- membered heterocycle.

21. The compound or salt of any one of claims 1 to 20, wherein R1Ais selected from22. The compound or salt of any one of claims 1 to 21, wherein R100orof R100is23. The compound or salt of any one of claims 1 to 11, wherein R1Ais selected from an optionally substituted Ci-6 alkyl.

24. The compound or salt of any one of claims 1 to 11 or 17, wherein R1Ais selected from an optionally substituted C1.3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle.

25. The compound or salt of any one of claims 1 to 11 or 17 to 18, wherein R1Ais selected from an optionally substituted C1-3 alkyl.

26. The compound or salt of any one of claims 1 to 11, or 17 to 19, wherein R1Ais selected27. The compound or salt of any one of claims 1 to 11, or 17 to 19, wherein R1Ais selectedR1128. The compound or salt of any one of claims 1 to 20, wherein R1Ais selected fromR1129. The compound or salt of any one of claims 1 to 20, wherein R1Ais selected fromR1130. The compound or salt of any one of claims 1 to 20, wherein R1Ais selected from31. The compound or salt of any one of claims 1 to 20, wherein R1Ais selected from32. The compound or salt of any one of claims 1 to 20, or 23 to 31, wherein R11is selected from an optionally substituted 5- to 12-membered heterocycle.

33. The compound or salt of any one of claims 1 to 20, or 23 to 32, wherein R11is selected from an optionally substituted 5- to 8-membered heterocycle.

34. The compound or salt of any one of claims 1 to 20, or 23 to 33, wherein R11is selected from an optionally substituted 5- to 6-membered heterocycle.

35. The compound or salt of any one of claims 1 to 20, or 23 to 34, wherein R11is selected from an optionally substituted 5- to 6-membered heteroaryl.

36. The compound or salt of any one of claims 1 to 20, or 23 to 35, wherein R11is selected37. The compound or salt of any one of claims 1 to 20, or 23 to 36, wherein R11is selectedeach of which is optionally substituted.

38. The compound or salt of any one of claims 1 to 20, or 23 to 37, wherein R11is selectedeach of which is optionally substituted.

39. The compound or salt of any one of claims 1 to 20, or 23 to 37, wherein R11is selected, which is optionally substituted.

40. The compound or salt of any one of claims 1 to 20, or 23 to 37, wherein R11is selected from, which is optionally substituted.

41. The compound or salt of any one of claims 1 to 20, or 23 to 40, wherein the optional one or more substituents of R11are each independently selected from halogen, -OH, -CN, -N(R21)2, -C(O)N(R21)2, CI-IO alkyl, and -C1-10 haloalkyl.

42. The compound or salt of any one of claims 1 to 20, or 23 to 41, wherein each R21is independently selected from hydrogen; and Ci-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.

43. The compound or salt of any one of claims 1 to 20, or 23 to 42, wherein the optional one or more substituents of R11is selected from halogen, Ci-6 haloalkyl, -NH2, -NH(C 1-6 alkyl), -N(Ci-0 alkyl.

44. The compound or salt of any one of claims 1 to 20, or 23 to 43, wherein the optional one or more substituents of R11is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-io alkyl.

45. The compound or salt of any one of claims 1 to 20, or 23 to 43, wherein the optional one or more substituents of R11is selected from -NH2, and C1-10 alkyl.

46. The compound or salt of any one of claims 1 to 20, or 23 to 43, wherein the optional one or more substituents of R11is selected from -NH2.

47. The compound or salt of any one of claims 1 to 20, or 23 to 43, wherein R11is selected48. The compound or salt of any one of claims 1 to 20, or 23 to 43, wherein R1Ais selected49. The compound or salt of any one of claims 1 to 20, or 23 to 43, wherein R1Ais selected50. The compound or salt of any one of claims 1 to 20, or 23 to 43, wherein R1Ais51. The compound or salt of any one of claims 1 to 17, wherein R100or is selected52. The compound or salt of any one of claims 1 to 17, wherein R100os selected53. The compound or salt of claims 1 or 2, wherein R100oris selected fromThe compound or salt of claims 1 or 2, wherein R100or is selected fromThe compound or salt of claims 1 or 2, wherein R100or is selected from56. The compound or salt of any one of claims 1 to 17, wherein R1Ais C4-C6 carbocycle, wherein the C4-C6 carbocycle is optionally with one or more R11.

57. The compound or salt of claims 1 or 56, wherein each R11is selected from -N(R20)2, and wherein each R20is selected from hydrogen and optionally substituted C1-6 alkyl.

58. The compound or salt of any one of claims 1 or 56 to 57, wherein R1Ais selected59. The compound or salt of any one of claims 1 to 16, wherein R1Ais selected from 4- to 12- membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R11.

60. The compound or salt of any one of claims 1 to 17, or 59, wherein R1Ais selected fromand each of which is optionally substituted.

61. The compound or salt of any one of claims 1 to 17, or 59 to 60, wherein each R11is independently selected from Ci-6 aminoalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, -C(O)R20, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(CI-6 alkyl)2, Ci-10 alkyl, -Ci-io haloalkyl, -O-Ci.10 alkyl, and oxo.

62. The compound or salt of any one of claims 1 to 17, or 59 to 61, wherein each R11is selected from halogen, -OH, -N(R20)2, -C(O)R20, -C(O)N(R20)2, Ci-6 aminoalkyl, C1-6 alkoxy, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl.

63. The compound or salt of any one of claims 1 to 17, or 59 to 62, wherein R1Ais selected65. The compound or salt of any one of claims 1 to 17, wherein R1Ais selected from an optionally substituted Ci-6 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form an optionally substituted C3-C6 carbocycle.

66. The compound or salt of any one of claims 1 to 17, or 65, wherein R11is selected from - OH, -CN, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NH2, -NH(C 1-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -Cnio haloalkyl, and -O-Ci-io alkyl; and wherein two R11on the same atom of R1Acome together to form an unsubstituted C3 carbocycle.

67. The compound or salt of any one of claims 1 to 17, or 65 to 66, wherein R1Ais selected68. The compound or salt of any one of claims 1 to 17, or 65 to 67, wherein R1Ais selected fromR1 BR1AN69. The compound or salt of claims 1 or 2, wherein R100oris selected from70. The compound or salt of any one of claims 1 to 17, wherein R1Ais selected from an C1-5 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C4 carbocycle.

71. The compound or salt of any one of claims 1 to 17, or 70, wherein R1Ais selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R11, and wherein optionally two R11on the same atom of R1Acome together to form a C3-C4 carbocycle.

72. The compound or salt of any one of claims 1 to 17, or 70 to 71, wherein R11is selected from halogen, -OR20, -N(R20)2, -C(O)N(R20)2, -C(O)OR20, -CN, =0, -NH(C=NH)NH2, C2.6alkenyl, C3-C6 carbocycle, and 4- to 9-membered heterocycle, wherein the 4- to 9-membered heterocycle and C3-C6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -SR21, -S(O)2(R21), -S(O)2F, -C(O)R21, -P(O)(R21)2, -OH, -OCH3, -CN, oxo, -N(R21)2, -C(O)N(R21)2, CI-IO alkyl, 5- to 6-membered heterocycle, and -Ci-io haloalkyl; and wherein optionally two R11on the same atom of R1Acome together to form a C3- C4 carbocycle.

73. The compound or salt of any one of claims 1 to 17, or 70 to 72, wherein each R21is independently selected from hydrogen; and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.

74. The compound or salt of any one of claims 1 to 17, or 70 to 73, wherein R1Ais selected78. The compound or salt of any one of claims 1 to 17, or 70 to 74, wherein R100orThe compound or salt of any one of claims 1 to 17, or 70 to 74, wherein R100orRA80. The compound or salt of any one of claims 1 to 2, for R100or ,wherein R1Bis selected from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen; wherein R1Ais selected from Ci-6 alkyl, and 5-membered heterocycle, each of which is independently optionally substituted with one or more R11, and wherein optionally two R11on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle; and wherein each R11is independently selected from -OR20, -C(O)N(R20)2, -N(R20)2, - C(O)R20, =0, -CN, C2-6 alkynyl, and 5- to 6-membered heterocycle, wherein the 5- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from -NH2, and -C1-10 haloalkyl.

81. The compound or salt of any one of claims 1 to 2, or 80, wherein R100oris82. The compound or salt of any one of claims 1 to 2, or 80 to 81, wherein R100or83. The compound or salt of any one of claims 1 to 17, R1Bis selected from Ci-6 alkyl, and 4- to 5-membered heterocycle, wherein the Ci-6 alkyl, and 4-to 5-membered heterocycle, are each optionally substituted with one or more R10, wherein each R10is independently selected from halogen, -OR20, -C(O)N(R20)2, -N(R20)2, -C(O)OR20, =0, -CN, C2.6alkenyl, Ci-6haloalkyl, C3-C6carbocycle, and 4-membered heterocycle.ny one of claims 1 to 17, wherein R100ois selected86. The compound or salt of any one of claims 1 to 17, or 70 to 74, wherein R100oris selected fromThe compound or salt of any one of claims 1 to 17, or 70 to 74, wherein R100orR1VB^R1AN88. The compound or salt of claims 1 to 17, or 70 to 75, wherein R100or —I— , is selected from89. The compound or salt of any one of claims 1 to 17, wherein R1Ais selected from an optionally substituted Ci-6 alkyl.

90. The compound or salt of claim 89, wherein R1Ais selected from an optionally substituted Ci-3 alkyl, and wherein optionally two R11on the same atom of R1Acome together to form a C3 carbocycle.

91. The compound or salt of claim 90, wherein R1Ais selected from an optionally substituted Ci -3 alkyl.

92. The compound or salt of claim 90, wherein R1Ais selected from an optionally substituted Ci -2 alkyl.

93. The compound or salt of claim 90, wherein R1Ais selected from an optionally substituted Ci alkyl.

94. The compound or salt of claim 90, wherein R1Ais selected from an optionally substituted C2 alkyl.R1195. The compound or salt of any one of claims 89 to 91, wherein R1Ais selected fromR1196. The compound or salt of any one of claims 89 to 92, wherein R1Ais selected fromR1197. The compound or salt of any one of claims 89 to 93, wherein R1Ais selected from98. The compound or salt of any one of claims 89 to 92, wherein R1Ais selected from99. The compound or salt of any one of claims 89 to 98, wherein R11is selected from an optionally substituted 5- to 12-membered heterocycle.

100. The compound or salt of any one of claims 89 to 99, wherein R11is selected from an optionally substituted 5- to 8-membered heterocycle.

101. The compound or salt of any one of claims 89 to 100, wherein R11is selected from an optionally substituted 5- to 6-membered heterocycle.

102. The compound or salt of any one of claims 89 to 101, wherein R11is selected from an optionally substituted 5- to 6-membered heteroaryl.

103. The compound or salt of any one of claims 89 to 102, wherein R11is selected from,optionally substituted.

104. The compound or salt of any one of claims 89 to 103, wherein R11is selected from, each of which is optionally substituted.

105. The compound or salt of any one of claims 89 to 104, wherein R11is selected fromeach of which is optionally substituted.

106. The compound or salt of any one of claims 89 to 105, wherein the optional one or more substituents is independently selected from halogen, -OH, -CN, -N(R21)2, Ci-io alkyl, and -Ci-io haloalkyl.

107. The compound or salt of any one of claims 89 to 105, wherein each R21is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6- membered heterocycle.

108. The compound or salt of any one of claims 89 to 105, wherein the optional one or more substituents ofR11is selected from halogen, Ci-e haloalkyl, -NH2, -NH(CI-6 alkyl), -N(CI-60 alkyl.

109. The compound or salt of any one of claims 89 to 108, wherein the optional one or more substituents of R11is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and C1-10 alkyl.

110. The compound or salt of any one of claims 89 to 109, wherein the optional one or more substituents ofR11is selected from -NH2, and Ci-io alkyl.

111. The compound or salt of any one of claims 89 to 110, wherein the optional one or more substituents ofR11is selected from -NH2.

112. The compound or salt of any one of claims 89 to 111, wherein R11is selected from113. The compound or salt of any one of claims 89 to 112, wherein R1Ais selected from114. The compound or salt of any one of claims 89 to 113, wherein R1Ais selected from115. The compound or salt of any one of claims 1 to 17, or 89 to 114, wherein R1Ais116. The compound or salt of any one of claims 1 to 17, or 89 to 104, wherein R100or118. The compound or salt of any one of claims 1 to 13, or 89 to 104, wherein R100or119. The compound or salt of claim 118,120. The compound or salt of claim 119, wherein121. The compound or salt of any one of claims 89 to 102, wherein R11is selected from,, each of which is optionally substituted.

122. The compound or salt of any one of claims 89 to 102, or 121, wherein R11is selected,each of which is optionally substituted.

123. The compound or salt of any one of claims 89 to 102, or 121 to 122, wherein the optional one or more substituents independently selected from halogen, oxo, -OH, -OCH3, -CN, -N(R21)2, -C(O)N(R21)2, -P(O)(R21)2, -SCH3, CI-IO alkyl, and -Ci-iohaloalkyl.

124. The compound or salt of any one of claims 89 to 102, or 121 to 123, wherein the optional one or more substituents of R11is selected from halogen, oxo, -OH, -OCH3, Ci-g haloalkyl, -NH2,- y .

125. The compound or salt of any one of claims 89 to 102, or 121 to 124, wherein R11is126. The compound or salt of any one of claims 1 to 17, or 89 to 104, R100or129. The compound or salt of any one of claims 1 to 17, wherein R1Ais selected from 4- to 12- membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R11.

130. The compound or salt of any one of claims 1 to 17 or 129, wherein R1Ais selected from,1is independently selected from -OH, Ci-6 aminoalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, - C(O)R20, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(CI-6 alkyl)2, Ci-10 alkyl, -Ci-io haloalkyl, -O-Ci.10 alkyl, and oxo.

131. The compound or salt of claims 129 or 130, wherein each R11is selected from halogen, - OH, -N(R20)2, -C(O)R20, -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl.

133. The compound or salt of claim 1, wherein Formula (I) is represented by Formula (I-B):or a pharmaceutically acceptable salt thereof.

134. The compound or salt of claims 1 or 133, wherein R1Cis selected from an optionally substituted Ci-6 alkyl.

135. The compound or salt of claim 134, wherein R1Cis selected from an optionally substituted Ci-6 alkyl, and wherein optionally two R12on the same atom of R1Ccome together to form an optionally substituted C3-C6 carbocycle.

136. The compound or salt of claim 135, wherein R12is selected from -OH, -CN, and 5- to 6- membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -NH(Ci-g alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, and -O-Cnio alkyl; and wherein two R12on the same atom of R1Ccome together to form an unsubstituted C3 carbocycle.

138. The compound or salt of claim 1 or 133, wherein R100is selected from139. The compound or salt of any one of claims 133 to 135, wherein R1Cis selected from an optionally substituted C1-3 alkyl.

140. The compound or salt of claim 139, wherein R1Cis selected fromR12141. The compound or salt of claims 1 or 133, wherein R1Cis selected fromand142. The compound or salt of claim 141, wherein R12is selected from an optionally substituted 5- to 12-membered heterocycle.

143. The compound or salt of claim 142, wherein R12is selected from an optionally substituted 5- to 8-membered heterocycle.

144. The compound or salt of claim 143, wherein R12is selected from an optionally substituted 5- to 6-membered heterocycle.

145. The compound or salt of claim 144, wherein R12is selected from an optionally substituted 5- to 6-membered heteroaryl.

146. The compound or salt of claim 145, wherein R12is selected fromeach of which is optionally substituted.

147. The compound or salt of claim 146, wherein R12is selected fromeach of which is optionally substituted.

148. The compound or salt of claim 147, wherein R12is selected fromeach of which is optionally substituted.

149. The compound or salt of any one of claims 1, 133, or 141 to 148, wherein the optional one or more substituents of R12is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-10 alkyl.

150. The compound or salt of any one of claims 1, 133, or 141 to 149, wherein the optional one or more substituents of R12is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, andCi-io alkyl.

151. The compound or salt of any one of claims 1, 133, or 141 to 150, wherein the optional one or more substituents of R12is selected from -NH2, and C1-10 alkyl.

152. The compound or salt of any one of claims 1, 133, or 141 to 151, wherein the optional one or more substituents of R12is selected from -NH2.

153. The compound or salt of any one of claims 1, 133, or 141 to 151, wherein R12is selected155. The compound or salt of any one of claims 1, 133, or 141 to 154, wherein R1Cis selected156. The compound or salt of claim 155, wherein157. The compound or salt of claim 1, wherein R100is selected from158. The compound or salt of claims 1 or 133, wherein R1Cis selected from an optionally substituted 5- to 6-membered heterocycle.

159. The compound or salt of claim 158, wherein R1Cis selected from an optionally substituted 5-membered heterocycle having at least one oxygen atom.

160. The compound or salt of claims 158 or 159, wherein R1Cis selectedwhich is optionally substituted.

161. The compound or salt of claim 160, wherein each R12is selected from halogen, -OR20, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-ehaloalkyl, and Ci-6 alkyl.

162. The compound or salt of claim 161, wherein each R12is selected from -OH.The compound or salt of any one of claims 158 to 162, wherein R1Cis HO164. The compound or salt of claim 1, wherein R100is selected from165. The compound or salt of claims 1 or 133, wherein R1Cis selected from an optionally substituted Ci-6 alkyl.

166. The compound or salt of any one of claims 1, 133, or 165, wherein R1Cis selected from an optionally substituted C1-3 alkyl, and wherein optionally two R11on the same atom of R1Ccome together to form a C3 carbocycle.

167. The compound or salt of any one of claims 1, 133, or 165 to 166, wherein R1Cis selected from an optionally substituted C1-3 alkyl.

168. The compound or salt of any one of claims 1 , 133, or 165 to 167, wherein R1Cis selected169. The compound or salt of any one of claims 1, 133, or 165to 168, wherein R1Cis selected170. The compound or salt of any one of claims 1, 133, or 165 to 169, wherein R1Cis selected from171. The compound or salt of any one of claims 1, 133, or 165 to 169, wherein R1Cis selected from172. The compound or salt of any one of claims 1, 133, or 165 to 169, wherein R1Cis selected173. The compound or salt of any one of claims 1, 133, or 165 to 169, wherein R1Cis selected from174. The compound or salt of claims 1 or 133, wherein R1Cis selected from an Ci-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3 carbocycle.

175. The compound or salt of claims 1 or 133, wherein R1Cis selected from an C1-4 lkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C4 carbocycle.

176. The compound or salt of any one of claims 1, 133, 174 to 175, wherein R12is selected from halogen, -OR20, -N(R20)2, -C(O)N(R20)2, -C(O)OR20, -CN, =0, -NH(C NH)NH2, C2.6alkenyl, C3-C6 carbocycle, and 4- to 9-membered heterocycle, wherein the 4- to 9-membered heterocycle and C3-C6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -SR21, -S(O)2(R21), -S(O)2F, - C(O)R21, -P(O)(R21)2, -OH, -OCH3, -CN, oxo, -N(R21)2, -C(O)N(R21)2, CI-IO alkyl, 5- to 6- membered heterocycle, and -C1-10 haloalkyl; and wherein optionally two R12on the same atom of R1Ccome together to form a C3-C4 carbocycle.

177. The compound or salt of any one of claims 1, 133, 174 to 176, wherein each R21is independently selected from hydrogen; and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.

178. The compound or salt of any one of claims 1, 133, 174 to 177, wherein R1Cis selected179. The compound or salt of claims 1 or 133, , wherein R1Cis selected from C1-3 alkyl, and 5- to 6-membered heterocycle, each of which is independently optionally substituted with one or more R12, and wherein optionally two R12on the same atom of R1Ccome together to form aC3-C4 carbocycle or 4-membered heterocycle.

180. The compound or salt of any one of claims 1, 133, or 179, wherein each R12is independently selected from -OH, -CN, 5- to 6-membered heterocycle, wherein the 5- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, and C1-10 alkyl. R1 CO181. The compound or salt of claims 1 or 133, wherein R100or —J— is selected fromXR1CO182. The compound or salt of claims 1 or 133, wherein R100or — is selected from184. The compound or salt of claim 1, wherein Formula (I) is represented by Formula (I-C):Formula (I-C), or a pharmaceutically acceptable salt thereof185. The compound or salt of claim 1 or 184, wherein R1Dis selected from an optionally substituted Ci-6 alkyl.

186. The compound or salt of any one of claims 1, or 184 to 185, wherein R1Dis selected from187. The compound or salt of claim 186, wherein R13is selected from an optionally substituted 5- to 12-membered heterocycle.

188. The compound or salt of claim 187, wherein R13is selected from an optionally substituted 5- to 8-membered heterocycle.

189. The compound or salt of claim 188, wherein R13is selected from an optionally substituted 5- to 6-membered heterocycle.

190. The compound or salt of claim 189, wherein R13is selected from an optionally substituted 5- to 6-membered heteroaryl.

191. The compound or salt of claim 190, wherein R13is selected from, each of which is optionally substituted.

192. The compound or salt of claim 191, wherein R13is selected fromeach of which is optionally substituted.

193. The compound or salt of claim 192, wherein R13is selected fromeach of which is optionally substituted.

194. The compound or salt of any one of claims 1, or 184 to 193, wherein the optional one or more substituents of R12is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and C1-10 alkyl.

195. The compound or salt of any one of claims 1, or 184 to 194, wherein the optional one or more substituents of R12is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and C1-10 alkyl.

196. The compound or salt of any one of claims 1, or 184 to 195, wherein the optional one or more substituents of R12is selected from -NH2, and CMO alkyl.

197. The compound or salt of any one of claims 1, or 184 to 196, wherein the optional one or more substituents of R12is selected from -NH2.

198. The compound or salt of claim 197, wherein R13is selected from202. The compound or salt of claims 1 or 184, wherein R1Dis selected from an optionally substituted Ci-6 alkyl, and wherein optionally two R13on the same atom of R1Dcome together to form an optionally substituted C3-C6 carbocycle.

203. The compound or salt of claim 202, wherein R13is selected from -OH, -CN, and 5- to 6- membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, - H2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, Ci-io alkyl, -Ci-io haloalkyl, and -O-CMO alkyl; and wherein two R13on the same atom of R1Dcome together to form an unsubstituted C3 carbocycle.

204. The compound or salt of claim 203, wherein R1Dis selected from205. The compound or salt of claim 1, wherein R100is selected from206. The compound or salt of any one of claims 1 to 205, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle.

207. The compound or salt of any one of claims 1 to 206, wherein B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium.

208. The compound or salt of any one of claims 1 to 207, wherein B is an optionally substituted Cs-Cis fused carbocycle.

209. The compound or salt of any one of claims 1 to 208, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Ci5 fused carbocycle are each independently bicyclic or tricyclic.

210. The compound or salt of any one of claims 1 to 209, wherein the heterocycle or carbocycle of B is bicyclic.

211. The compound or salt of any one of claims 1 to 209, wherein the heterocycle or carbocycle of B is tricyclic.

212. The compound or salt of any one of claims 1 to 211, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted G-Cis fusedof which is optionally substituted with one or more substituents.

213. The compound or salt of any one of claims 1 to 212, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fusedeach of which is optionally substituted with one or more substituents.

214. The compound or salt of any one of claims 1 to 213, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, and C1-C3 alkyl.

215. The compound or salt of any one of claims 1 to 214, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted G-C15 fused216. The compound or salt of any one of claims 1 to 205, wherein B is selected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15 carbocycle.

217. The compound or salt of claim 216, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle.

218. The compound or salt of claim 217, wherein B is an optionally substituted 8- to 15- membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium.

219. The compound or salt of claim 218, wherein B is an optionally substituted unsaturated Cs-Cis fused carbocycle.

220. The compound or salt of any one of claims 216 to 219, wherein for B, the heterocycle and carbocycle are each independently bicyclic or tricyclic.

221. The compound or salt of claim 220, wherein for B, the heterocycle and carbocycle are each independently bicyclic.

222. The compound or salt of claim 220, wherein for B, the heterocycle and carbocycle are each independently tricyclic.

223. The compound or salt of any one of claims 216 to 222, wherein B is selected fromwhich is optionally substituted with one or more substituents.with one or more substituents.

225. The compound or salt of claim 224, wherein B is selected fromeach of which is optionally substituted with one or more substituents.

226. The compound or salt of any of claims 216 to 225, wherein for B, the one or more optional substituents are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.

228. The compound or salt of any of claims 216 to 225, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =0, -CN, - NHCN, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-g hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

229. The compound or salt of claim 228, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =0, - CN, C i-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl.

230. The compound or salt of claims 228 or 229, wherein B is selected from,231. The compound or salt of any one of claims 216 to 222, wherein B is an optionally substituted 7- to 12-membered fused heterocycle.

232. The compound or salt of any one of claims 216 to 222, wherein B is an optionally substituted 7- to 11-membered fused heterocycle.

233. The compound or salt of claims 231 or 232, wherein B is an optionally substituted 8- to 10-membered fused heterocycle.

234. The compound or salt of claim 233, wherein B is an optionally substituted 8- to 9- membered fused heterocycle.

235. The compound or salt of claims 233 or 234, wherein the heterocycle is an unsaturated heterocycle.

236. The compound or salt of any one of claims 231 to 235, wherein B has at least one sulfur atom.

237. The compound or salt of any one of claims 231 to 236, wherein B has at least one sulfur atom and at least one nitrogen atom.

238. The compound or salt of any one of claims 231 to 236, wherein B has at least one sulfur atom and at least one oxygen atom.

239. The compound or salt of any one of claims 231 to 238, wherein B has at two sulfur atoms.

240. The compound or salt of any one of claims 231 to 239, wherein B is selected fromeach of which is optionally substituted.

242. The compound or salt of claim 241, wherein B is selected fromis optionally substituted.

243. The compound or salt of claim 242, wherein B is selected from, each of which is optionally substituted.

244. The compound or salt of any one of claims 231 to 243, wherein the one or more optional substituents of B, are independently selected at each occurrence from halogen, oxo, -NH2, Ci- C3alkyl, -B(OH)2, -OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =0, -CN, Ci-6alkoxy, Ci-6hydroxyalkyl, C3 carbocycle, and C2-6 alkynyl.

245. The compound or salt of claim 244, wherein the one or more optional substituents of B, are independently selected at each occurrence from C3 carbocycle, C1-C3 alkyl, halogen, =0, C1-C3 alkyl, -NH2, and -CN.

246. The compound or salt of any one of claims 231 to 245, wherein B is selected from247. The compound or salt of any one of claims 1 to 205, wherein B is selected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle.

248. The compound or salt of claim 247, wherein the heterocycle of B has at least one sulfur atom.

249. The compound or salt of claim 247 or 248, wherein the heterocycle of B has one or sulfur atoms.

250. The compound or salt of claim 249, wherein the heterocycle of B has at least one nitrogen atom.

251. The compound or salt of any one of claims 247 to 250, wherein B is selected from252. The compound or salt of any one of claims 247 to 251, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, - B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =0, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, Ci 6 hydroxyalkyl, C1-6 cyanoalkyl, Ci-ehaloalkyl, C2-6 alkenyl, and C2-e alkynyl.

253. The compound or salt of any one of claims 247 to 252, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, - OH, -NH2, =0, and -CN.

254. The compound or salt of claim 253, wherein B is selected from255. The compound or salt of any one of claims 1 to 205, wherein B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom.

256. The compound or salt of claim 255, wherein B is selected from,each of which is optionally substituted.

257. The compound or salt of claims 255 or 256, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OR20, - C(O)N(R20)2, -N(R20)2, =0, -CN, -NHCN, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-ehydroxyalkyl, Ci- 6 cyanoalkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

258. The compound or salt of claim 257, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH , and -CN.

259. The compound or salt of any one of claims 1, or 255 to 258, wherein B is substituted.

260. The compound or salt of any one of claims 255 to 259, wherein B is substituted with at least one -NH2.

261. The compound or salt of any one of claims 255 to 260, wherein B is selected from262. The compound or salt of any one of claims 255 to 261, wherein B is substituted with at least one -NH2 at least one -CN.

263. The compound or salt of claim 262, wherein B is selected from264. The compound or salt of any one of claims 1 to 205, wherein265. The compound or salt of any one of claims 1 to 205, wherein266. The compound or salt of any one of claims 1 to 265, wherein R3is selected from hydrogen, -NO2, halogen, -CN, -C(O)R20, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C1-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-ghaloalkyl, and Ci-6 alkyl.

267. The compound or salt of claim 266, wherein R3is selected from hydrogen, -CF3, fluorine, -CN, -C(O)H, -NO2, Ci hydroxyalkyl, and Ci-6 alkyl.

268. The compound or salt of claims 266 or 267, wherein R3is selected from hydrogen, fluorine, and -CN.

269. The compound or salt of claim 268, wherein R3is selected from fluorine.

270. The compound or salt of claim 268, wherein R3is selected from hydrogen.

271. The compound or salt of claim 268, wherein R3is selected from -CN.

272. The compound or salt of any one of claims 1 to 271, wherein Y is -O-.

273. The compound or salt of any one of claims 1 to 272, wherein L is selected from C1-C4 alkylene.

274. The compound or salt of claim 273, wherein L is selected from unsubstituted C1-C4 alkylene.

275. The compound or salt of claim 273, wherein each L is independently selected from a Ci- C4 alkylene optionally substituted; and wherein optionally two substituents on the samecarbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-ehydroxyalkyl, Ci-s haloalkyl.

276. The compound or salt of claim 275, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and Ci-ehaloalkyl.

277. The compound or salt of any one of claims 1 to 276, wherein L is selected from279. The compound or salt of claim 275 or 276, wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle 3- to 5-membered heterocycle.

280. The compound or salt of claim 279, wherein each L is independently selected from a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen.

281. The compound or salt of claim 280, wherein each L is independently selected from282. The compound or salt of claim 281, wherein each L is independently selected from283. The compound or salt of claim 281, wherein each L is independently selected from a Ci- C4 alkylene optionally substituted with one or more substituents independently selected from halogen and C1-C4 alkyl.

284. The compound or salt of claim 283, wherein L is selected from285. The compound or salt of claim 273, wherein each L is independently selected from an unsubstituted C1-C4 alkylene.

286. The compound or salt of any one of claims 1 to 285, wherein R2is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R20)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

287. The compound or salt of claim 286, wherein R2is -L-heterocycle, wherein the heterocycle portion of R2is an optionally substituted heterocycle, and wherein the heterocycle portion of -L-heterocycle has at least one heteroatom selected from nitrogen, oxygen, silicon, and sulfur.

288. The compound or salt of claim 286 or 287, wherein R2is -L-heterocycle, optionally substituted with one or more R6.

289. The compound or salt of any one of claims 1 to 288, wherein Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

290. The compound or salt of any one of claims 1 to 289, wherein the heterocycle portion of R2is a heterocycle optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 aminoalkyl.

291. The compound or salt of claim 290, wherein the heterocycle portion of R2is a heterocycle optionally substituted with one or more substituents selected from C1-C3 alkyl and halogen.

292. The compound or salt of any one of claims 1 to 291, wherein Y-R2is selected from293. The compound or salt of any one of claims 1 to 291, wherein Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

294. The compound or salt of claim 293, wherein R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl.

295. The compound or salt of claim 294, wherein R6of R2is independently selected at each occurrence from C1-C3 alkyl and halogen.

296. The compound or salt of claim 295, wherein Y-R2is selected from297. The compound or salt of any one of claims 1 to 288, wherein Y-R2is selected fromoptionally substituted with one or more R6.

298. The compound or salt of claim 297, wherein Y-R2299. The compound or salt of claim 297, whereinwherein the heterocycle is optionally substituted.

300. The compound or salt of claims 297 or 299, wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-C3 alkyl, -alkyl, -CH2OC(O)heterocycle, - CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.

301. The compound or salt of any one of claims 1 to 271 or 299 to 300, wherein Y-R2is302. The compound or salt of any one of claims 1 to 286, wherein R2is -L-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7.

303. The compound or salt of claim 302, wherein each R7is independently selected from halogen, and C1-C4 haloalkyl;304. The compound or salt of any one of claims 1 to 286, wherein Y-R2is selected from305. T The compound or salt of any one of claims 1 to 286, wherein R2is -L-aryl, optionally substituted with one or more R7.

306. The compound or salt of claim 305, wherein Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R7.

307. The compound or salt of claim 305, wherein Y-R2is selected from308. The compound or salt of any one of claims 1 to 286, wherein R2is -L-heteroaryl, optionally substituted with one or more R7.

309. The compound or salt of claim 308, wherein Y-R2is selected fromand, wherein the heteroaryl portion is optionally substituted with one or moreR7.

310. The compound or salt of claims 308 or 309, wherein Y-R2is selected from311. The compound or salt of any one of claims 1 to 286, wherein R2is312. The compound or salt of claim 311, wherein Y-R2is selected from313. The compound or salt of any one of claims 1 to 272, wherein R2is heterocycle, optionally substituted with one or more R6.

314. The compound or salt of claim 313, wherein315. The compound or salt of claim 313, wherein Y-R2is.

316. The compound or salt of any one of claims 1 to 285, wherein R2is selected from heterocycle, -L-heterocycle, and -L-cycloalkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of -L-cycloalkyl, are each optionally substituted with one or more R6; -L-aryl, and -L-heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; and - L-N(R20)2.

317. The compound or salt of claim 316, wherein the heterocycle of R2is selected fromsubstituted with one or more R6; wherein the aryl and heteroaryl of R2is selected fromwherein the aryl and the heteroaryl are each optionally substituted with one or more318. The compound or salt of claim 317, wherein the heterocycle of R2is selected from, wherein the heterocycle is optionally substituted with one or more R6; wherein the aryl and heteroaryl of R2is selected fromwherein the aryl and the heteroaryl are eachAN- optionally substituted with one or more R7; and I ,.

319. The compound or salt of any one of claims 316 to 318, wherein each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, (C1-C3 alkoxy)Ci-C3 alkyl-, - N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, =CF2, OXO, =NO-CI-C3alkyl, -C(O)-Ci-C3alkyl- N(R5)2, -CH2OC(O)heterocycle, -CH2heterocycle, -S(O)2(R20), -CH2OC(O)N(R5)2, and -O-Ci- C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from C1-C3 alkyl, halogen and C1-C3 haloalkyl.

320. The compound or salt of any one of claims 316 to 319, wherein the heterocycle of R2, the aryl and heteroaryl of R2, and -N(R20)2 of R2is selected from is selected from21. The compound or salt of any one of claims 1 to 285, wherein Y-R2is selected from, wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6;wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more322. The compound or salt of any one of claims 316 to 321, wherein each R6is independently selected from halogen, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkyl, oxo, C1-C3 alkoxy, =CH2, hydroxy, =N0-CI-C3 alkyl, -CH2OC(O)N(R5)2, -CTfcheterocycle, - CH2OC(O)heterocycle, -NR20S(O)2R20, -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and each R7is independently selected from halogen, C1-C3 haloalkyl, and C1-C3 alkyl.

323. The compound or salt of any one of claims 1 to 285, or 316 to 322, wherein Y-R2is selected24. The compound or salt of any one of claims 1 to 285, wherein Y-R2is selected from325. The compound or salt of any one of claims 1 to 285, wherein Y is -O- and R2is selected from L-5-membered heteroaryl, wherein L is selected from an optionally substituted C1-C4 alkylene, and wherein the heteroaryl is optionally substituted with one or more R7, wherein each R7is preferably selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl.

326. The compound or salt of any one of claims 325, wherein Y-R2is selected from327. The compound or salt of claims 1 to 326, wherein each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, oxo, C1-C3 alkoxy, C1-C3 hydroxyalkyl, (Ci- C3alkoxy)Ci-C3alkyl-, =CH2, -OC(O)N(R5)2, =NO-CI-C3alkyl, -N(R5)S(O)2(R5), - CH2OC(O)N(R5)2, -CH2OC(O)heterocycle, -(CH2)o-iS-heterocycle, -(CH2)o-i-0-heterocycle, and -O-C1-C3 alkyl;wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)o-i-S-heterocycle are each optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, Ci-e alkyl-OR20, and -OR20.F328. The compound or salt of claim 327, wherein each R6is independently selected from332. The compound or salt of any one of claims 1 to 329, wherein Y-R2is selected from333. The compound or salt of any one of claims 1 to 2, or 206 to 332, wherein R100or334. A compound represented by Formula (II), or a pharmaceutically acceptable salt of any one thereof.

335. A compound selected from Table 1, or a pharmaceutically acceptable salt of any one thereof.

336. A pharmaceutical composition comprising the compound of any one of claims 1 to 335 and a pharmaceutically acceptable excipient.

337. A method of treating a disease or disorder, using a compound or salt of any one of claims 1 to 335 or a pharmaceutical composition of claim 336.

338. A method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of any one of claims 1 to 335 or a pharmaceutical composition of claim 336.

339. A method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of any one of claims 1 to 335 or a pharmaceutical composition of claim 336.

340. A method of inhibiting KRas G12D and / or other G12 alleles, using a compound or salt of any one of claims 1 to 335 or a pharmaceutical composition of claim 336.

341. A method of inhibiting KRas G12D and / or other alleles, using a compound or salt of any one of claims 1 to 335 or a pharmaceutical composition of claim 336.

342. The method of claim 337, wherein the disease or disorder is a KRas G12D mutant- associated cancer.

343. The method of claim 337, wherein the disease or disorder is a KRas G12V mutant- associated cancer.

344. The method of any one of claims 337 to 343, wherein the disease or disorder is a cancer selected from:Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; andAdrenal glands: neuroblastoma.

345. The method of claim 344, wherein the disease or disorder is a cancer, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer; or wherein the cancer is a tumor cancer.

346. Use of a compound of any one of claims 1-330 thereof in the preparation of a target protein degrading compound by using chemical modification of compound of any one of claims 1-335.

347. A bifunctional compound composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, wherein the target protein-binding moiety is derived from the compound of any of claims 1-335.

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