Phosphoramidate compounds and uses thereof

Abstract

Provided herein are novel compounds (eg, of Formula I, II, or III), pharmaceutical compositions, and methods of use, for example, for the treatment of cancer. [Formula 1] TIFF2025534444000397.tif56161

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to International Patent Application No. PCT / CN2022 / 124090, filed October 9, 2022, the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] In various embodiments, the present disclosure generally relates to novel compounds, compositions containing these compounds, methods of making these compounds, and methods of using these compounds, for example, to treat or prevent various diseases or disorders described herein. [Background technology]

[0003] Aldo-keto reductase family 1 member C3 (AKR1C3) is a member of the aldo-keto reductase (AKR) superfamily, which catalyzes the conversion of aldehydes and ketones to their corresponding alcohols using NADH and / or NADPH as cofactors. AKR1C3 is known to be overexpressed in various cancers, such as prostate cancer and non-small cell lung cancer. AKR1C3 is also a biomarker for NRF2 activation. Abnormal activation of the NRF2 pathway (e.g., activation by NRF2 gain-of-function gene alterations or KEAP1 or CUL3 loss-of-function gene alterations) can lead to increased expression of its target genes, including AKR1C3. Abnormal activation of the NRF2 pathway is associated with various cancers and poor prognosis. Novel compounds that can selectively target or exploit abnormal activation of the NRF2 and / or AKR1C3 pathways are needed. Summary of the Invention

[0004] In various embodiments, the present disclosure is based in part on the discovery of novel compounds that can selectively inhibit the growth of cancer cells that have aberrant AKR1C3 activity and / or AKR1C3 overexpression. As described in the Examples section herein, the exemplary compounds tested herein generally exhibit lower IC 50 value (in the absence of an AKR1C3 inhibitor), and the low IC 50 The AKR1C3 level inhibits the proliferation of cancer cells. Therefore, it is expected that the novel compounds herein can selectively target those cancers characterized by abnormal AKR1C3 activity and / or overexpression of AKR1C3 levels (e.g., cancers due to abnormal activation of the NRF2 pathway) and have better safety profiles.

[0005] Some embodiments of the present disclosure relate to compounds of Formula I, II, or III, or pharmaceutically acceptable salts thereof: [ka] wherein these variables are defined herein. In some embodiments, the compound having formula I can be any of the sub-formulas described herein, for example, formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-B- and the like. The compounds may be characterized as having a structure according to any one of: I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B-E1, I-11-B-E2, I-13-A, I-13-B, I-13-B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, or IV-8. In some embodiments, a compound having Formula II may be characterized as having a structure according to any one of the subformulas described herein, e.g., II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1, as defined herein. In some embodiments, a compound having Formula III may be characterized as having a structure according to any one of the subformulas described herein, e.g., III-1, III-2, III-3, or III-4. In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof according to any one of those set forth in Tables A1 to A18. In some embodiments, the present disclosure provides a compound according to Examples 1-569 or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure and, optionally, a pharmaceutically acceptable excipient. Pharmaceutical compositions can generally be prepared for oral administration.

[0007] In some embodiments, the present disclosure provides a method of treating or preventing cancer (e.g., cancer with aberrant AKR1C3 activity and / or AKR1C3 overexpression) in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of one or more compounds of the present disclosure or pharmaceutical compositions herein. In some embodiments, the method comprises administering to the subject an effective amount of a compound having Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I- 7-B, I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B-E1, I-11-B-E2, I-13-A, I-13-B, I-1 3-B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, or IV-8), a compound having Formula II (e.g., II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1), a compound having Formula III (e.g., III-1, III-2, III-3, or III-4), any one of Examples 1 to 569, or any one of the specific compounds disclosed in Tables A1 to A18 herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, to the subject.

[0008] In some embodiments, the present disclosure further provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to a subject an effective amount of a compound of the present disclosure (e.g., a compound having Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B- E1, I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B- E1, I-11-B-E2, I-13-A, I-13-B, I-13-B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3 , IV-4, IV-5, IV-6, IV-7, or IV-8), a compound having Formula II (e.g., II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1), a compound having Formula III (e.g., III-1, III-2, III-3, or III-4), any one of Examples 1-569, or any one of the specific compounds disclosed in Tables A1-A18 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is characterized by having aberrant AKR1C3 activity and / or AKR1C3 overexpression. In some embodiments, the cancer is characterized by having an NRF2 / KEAP1 pathway mutation that causes aberrant NRF2 activation.

[0009] The administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the administration is oral. In some embodiments, the administration is parenteral injection, such as intravenous injection.

[0010] The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present disclosure can be administered as the sole active ingredient or as multiple active ingredients. In some embodiments, the methods herein further include administering to the subject another therapeutic agent, for example, another anti-cancer agent described herein.

[0011] It should be understood that both the foregoing summary of the invention and the following specific embodiments are exemplary and explanatory only and are not restrictive of the invention herein. DETAILED DESCRIPTION OF THE INVENTION

[0012] In various embodiments, the present disclosure provides compounds and compositions that can be used to treat or prevent various diseases or disorders (eg, cancer) described herein.

[0013] compound Generally, the compounds disclosed herein are substrates of AKR1C3, which may be activated by AKR1C3, eg, to release a phosphoramidate.

[0014] Formula I In some embodiments, the present disclosure provides a compound having Formula I, or a pharmaceutically acceptable salt thereof: [ka] where: (1) R 1 is hydrogen (in another embodiment, deuterium), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 alkenyl group, or optionally substituted C 2-4 is an alkynyl group, R 2 , R 4 and R 5are each independently hydrogen, halogen (e.g., F), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4 Alkynyl group, optionally substituted C 1-4 an alkoxy group or an optionally substituted 3- to 5-membered ring, or (2) R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; and R 4 and R 5 is as defined in (1), or (3) R 1 and R 5 are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; and R 2 and R 4 is as defined in (1), or (4) R 4 and R 5 are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered ring; and R 1 and R 2 is as defined in (1) or (2), and where: X is O, S, or NR 10 , optionally substituted C 1-4 an alkylene group, or an optionally substituted C 1-4 heteroalkylene group, where R 10 is hydrogen, optionally substituted C 1-4 an alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; R 3 is hydrogen, optionally substituted C 1-4 an alkyl group or an optionally substituted 3- to 10-membered ring; R 6is hydrogen (in another embodiment, deuterium), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 alkenyl group, or optionally substituted C 2-4 is an alkynyl group, Integers n1 and n2 are each independently 0, 1, 2, 3, or 4; R a and R b Each occurrence of 1-4 alkyl group or optionally substituted C 1-4 is a heteroalkylene group, or R a Two examples of R b are joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, and R a and / or R b Any remaining examples of are as defined above.

[0015] In some embodiments, compounds having Formula I (including any applicable subformulas described herein) may contain one or more asymmetric centers and / or axial chirality and therefore may exist in multiple stereoisomeric forms (e.g., enantiomers and / or diastereomers). In some embodiments, compounds having Formula I may exist in the form of a single enantiomer and / or diastereomer (where applicable), or a stereoisomeric mixture (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some examples, where applicable, compounds having Formula I (including any applicable sub-formulas described herein) may exist as a resolved single enantiomer substantially free of the other enantiomer (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight by HPLC or SFC area or both), e.g., the compound may have an enantiomeric excess ("ee") of greater than 60% (e.g., 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater, etc.). In some examples, where applicable, compounds having Formula I (including any applicable sub-formulas described herein) may exist as a mixture of stereoisomers (in any ratio), e.g., a racemic mixture.

[0016] In some embodiments, compounds having Formula I (including any applicable subformulas described herein) may exist as isotopically labeled compounds, particularly deuterated analogs, where one or more hydrogen atoms of a compound having Formula I are replaced with deuterium atoms that are in abundance above their natural abundance, e.g., if the compound has a CH group, it is a CD analog.

[0017] It will be apparent to one skilled in the art that in some cases, compounds having Formula I may exist as a mixture of tautomers. The present disclosure is not limited to any particular tautomer. To the contrary, the present disclosure encompasses any and all such tautomers, whether or not explicitly depicted or referred to.

[0018] As shown herein, R 1 , R 2 , R 4 and R 5 Compounds with various cyclization functions in the formula (I) can be activated by AKR1C3 to release the phosphoramidate moiety in the formula (I).

[0019] For example, in some embodiments according to Formula I, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, where R 4 and R 5 is as defined herein, for example, in some embodiments, R 4 and R 5 are both hydrogen. As used herein, a "4-8-membered carbocyclic or heterocyclic ring" refers to a ring system that is not fully aromatic and has 4 to 8 ring members, and, in the case of a heterocyclic ring, contains one or more ring heteroatoms. It should be noted that, when substituted, a 4-8-membered carbocyclic or heterocyclic ring may be substituted at any one or more available positions, and unless otherwise specified for the one or more substituents, two or more substituents may optionally be linked to one or more intervening atoms to form one or more additional fused, bridged, or spiro ring structures. Carbocyclic or heterocyclic rings with different ring member names should be understood similarly.

[0020] In some embodiments according to Formula I, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted 5- to 7-membered carbocyclic ring. Generally, when substituted, the 5- to 7-membered carbocyclic ring is independently selected from C substituted with oxo, halogen, OH, NH, optionally F. 1-4 alkyl group, C having one or two heteroatoms and optionally substituted with F 1-4and a 3- to 6-membered ring. In one embodiment, two substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring. In one embodiment, "C having one or two heteroatoms" is 1-4 A "heteroalkyl group" has one oxygen atom, one nitrogen atom, one oxygen and one nitrogen atom, two oxygen atoms, or two nitrogen atoms. 1-4 Non-limiting examples of "heteroalkyl groups" include C 1-4 Alkoxy group, NH(C 1-4 alkyl), N(C 1-3 Alkyl)(C 1-3 alkyl), provided that the total number of carbon atoms is less than 4, such as -CH2-OC 1-3 Alkyl groups, -CH2-OH, -CH2-NH2, -CH2-NH(C 1-3 As used herein, a "3- to 6-membered ring" refers to any ring having 3 to 6 ring members, which may be a carbocycle, a heterocycle, an aryl group, or a heteroaryl group, wherein a ring carbon atom may be present as C=O, and wherein the ring nitrogen and sulfur atoms may be optionally oxidized, for example, in a pyrrolidone ring. Non-limiting examples of a "3- to 6-membered ring" include a cyclopropyl group, a cyclobutyl group, an azetidinyl group, an oxetanyl group, a 5-membered heteroaryl group, a phenyl group, a 6-membered heteroaryl group, a 5- or 6-membered heterocyclyl group, and the like. When a "3- to 6-membered ring" is referred to as being substituted, one or more substituents may be attached to any one or more available positions, and, unless otherwise specified for the one or more substituents, two or more substituents may further, optionally, be connected to one or more intervening atoms to form one or more additional fused, bridged, or spiro ring structures. Rings having different ring member names should be understood similarly.

[0021] In some particular embodiments according to Formula I, the compound may be characterized by having a structure according to Formula I-1, I-2, or I-3: [ka] where: the integer n3 is 0, 1, or 2; R c each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 is a heteroalkyl group, or R c are joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, and Other variables are as defined herein.

[0022] In some embodiments, n3 is 0. For example, in some embodiments, a compound having Formula I-1 may be characterized as having a structure according to Formula I-1-A or I-1-B. [ka]

[0023] As shown herein, one of the enantiomers according to Formula I-1 may have more effective antiproliferative activity. In some embodiments, the compound having Formula I-1 may be a single isomer and have 80% ee or more, e.g., 90% ee or more, 95% ee or more, 98% ee or more, or 99% ee or more, or the other enantiomer is not detectable by HPLC or SFC. For example, in some embodiments, the compound having Formula I-1-B may be a substantially pure enantiomer according to Formula I-1-B-E1. [ka] As used herein, "substantially pure enantiomer" refers to such an enantiomer, which has 80% ee or greater, e.g., 90% ee or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater, or wherein the other enantiomer is not detectable by HPLC or SFC.

[0024] In some embodiments, the compound having formula I-1-B may be a substantially pure enantiomer according to formula I-1-B-E2. [ka]

[0025] In some embodiments, n3 in Formula I-1, I-2, or I-3 can be 1 or 2. For example, in some embodiments, n3 is 1 or 2 and R c each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 In one embodiment, R is a heteroalkyl group. c are joined via one or more intervening atoms to form an optionally substituted 3- to 6-membered ring. c is joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, which is 1 and R 2 In one embodiment, two adjacent R c is joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, which is 1 and R 2 In one embodiment, two non-original and non-adjacent R c is joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, which is 1and R 2 forms a bridged ring system with the ring formed by

[0026] In some embodiments according to Formula I, R 1 and R 2 are linked together with the intervening atoms to form an optionally substituted 5- to 7-membered heterocycle, the 5- to 7-membered heterocycle having one or two ring heteroatoms independently selected from O, N, and S. In some embodiments, the 5- to 7-membered heterocycle has one ring heteroatom, which may be oxygen or nitrogen, particularly oxygen. Generally, when substituted, the 5- to 7-membered heterocycle may be independently selected from oxo, halogen, OH, NH, C optionally substituted with F, 1-4 alkyl group, C having one or two heteroatoms and optionally substituted with F 1-4 and a heteroalkyl group, and a 3- to 6-membered ring. In one embodiment, two substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring.

[0027] In some particular embodiments, compounds having Formula I may be characterized as having a structure according to Formula I-4, I-5, or I-6: [ka] where: The integer n4 is 0, 1, or 2; R d each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 is a heteroalkyl group, or R d are joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, and Other variables are as defined herein.

[0028] In some embodiments, n4 is 0. For example, in some embodiments, a compound having Formula I-5 may be characterized as having a structure according to Formula I-5-A or I-5-B. [ka]

[0029] In some embodiments, the compound having formula I-5 may be a single isomer and have 80% ee or greater, e.g., 90% ee or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater, or no other enantiomer is detectable by HPLC or SFC. For example, in some embodiments, the compound having formula I-5-B may be a substantially pure enantiomer according to formula I-5-B-E1. [ka]

[0030] For example, in some embodiments, the compound having formula I-5-B may be a substantially pure enantiomer according to formula I-5-B-E2. [ka]

[0031] In some embodiments, n4 in Formula I-4, I-5, or I-6 can be 1 or 2. For example, in some embodiments, n4 is 1 or 2 and R d each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 It is a heteroalkyl group.

[0032] In some embodiments, in Formula I, R 1 and R 5are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, with R 2 and R 4 is as defined herein, for example, R 2 and R 4 may both be hydrogen.

[0033] In some embodiments according to Formula I, R 1 and R 5 are joined together with the intervening atoms to form an optionally substituted 5- to 7-membered carbocyclic ring. Generally, when substituted, the 5- to 7-membered carbocyclic ring is independently selected from C substituted with oxo, halogen, OH, NH, optionally F. 1-4 alkyl group, C having one or two heteroatoms and optionally substituted with F 1-4 and a heteroalkyl group, and a 3- to 6-membered ring. In one embodiment, two substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring.

[0034] In some particular embodiments according to Formula I, the compound may be characterized as having a structure according to Formula I-7, I-8, or I-9: [ka] where: The integer n5 is 0, 1, or 2; R e each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 is a heteroalkyl group, or R e are joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, and Other variables are as defined herein.

[0035] In some embodiments, n5 is 0. For example, in some embodiments, a compound having Formula I-7 may be characterized as having a structure according to Formula I-7-A or I-7-B. [ka]

[0036] In some embodiments, the compound having formula I-7 may be a single isomer and have 80% ee or greater, e.g., 90% ee or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater, or no other enantiomer is detectable by HPLC or SFC. For example, in some embodiments, the compound having formula I-7-B may be a substantially pure enantiomer according to formula I-7-B-E1. [ka]

[0037] In some embodiments, the compound having formula I-7-B may be a substantially pure enantiomer according to formula I-7-B-E2. [ka]

[0038] In some embodiments, n5 in Formula I-7, I-8, or I-9 can be 1 or 2. For example, in some embodiments, n5 is 1 or 2 and R e each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 It is a heteroalkyl group.

[0039] In some embodiments according to Formula I, R 1 and R 5are linked together with the intervening atoms to form an optionally substituted 5- to 7-membered heterocycle, the 5- to 7-membered heterocycle having one or two ring heteroatoms independently selected from O, N, and S. In some embodiments, the 5- to 7-membered heterocycle has one ring heteroatom, which may be oxygen or nitrogen, particularly oxygen. Generally, when substituted, the 5- to 7-membered heterocycle may be independently selected from oxo, halogen, OH, NH, C optionally substituted with F, 1-4 alkyl group, C having one or two heteroatoms and optionally substituted with F 1-4 and a heteroalkyl group, and a 3- to 6-membered ring. In one embodiment, two substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring.

[0040] In some particular embodiments, compounds having formula I may be characterized as having a structure according to formula I-10, I-11, or I-12: [ka] where: The integer n6 is 0, 1, or 2, and R f each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 is a heteroalkyl group, or R f are joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, and Other variables are as defined herein.

[0041] In some embodiments, n6 is 0. For example, in some embodiments, compounds having Formula I-11 may be characterized as having a structure according to Formula I-11-A or I-11-B. [ka]

[0042] In some embodiments, the compound having formula I-11 may be a single isomer and have 80% ee or greater, e.g., 90% ee or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater, or no other enantiomer is detectable by HPLC or SFC. For example, in some embodiments, the compound having formula I-11-B may be a substantially pure enantiomer according to formula I-11-B-E1. [ka]

[0043] In some embodiments, the compound having formula I-11-B may be a substantially pure enantiomer according to formula I-11-B-E2. [ka]

[0044] In some embodiments, n6 in Formula I-10, I-11, or I-12 can be 1 or 2. For example, in some embodiments, n6 is 1 or 2 and R f each occurrence independently represents oxo, F, OH, NH, C optionally substituted with F 1-4 alkyl group or C having one or two heteroatoms and optionally substituted with F 1-4 It is a heteroalkyl group.

[0045] In some embodiments according to Formula I, R 4 and R 5 may be linked together with the intervening atoms to form an optionally substituted 4- to 8-membered ring.

[0046] In some embodiments according to Formula I, R 1 , R 2 , R 4 and R5 do not form any ring structure with each other. In such embodiments, R 1 is hydrogen, optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 alkenyl group, or optionally substituted C 2-4 is an alkynyl group, and R 2 , R 4 and R 5 are each independently hydrogen, halogen (e.g., F), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4 Alkynyl group, optionally substituted C 1-4 an alkoxy group, or an optionally substituted 3- to 5-membered ring. For example, in some embodiments, R 1 is hydrogen or C optionally substituted with F 1-4 It may be an alkyl group, such as a methyl group, CF3, etc., and R 2 , R 4 and R 5 Each of R may be hydrogen. 1 is deuterium.

[0047] Generally, the integers n1 and n2 in Formula I are each independently 0, 1, or 2. In some embodiments, at least one of n1 and n2 is not 0.

[0048] In some embodiments, the integers n1 and n2 in Formula I are both 0 or both 1. For example, in some embodiments, a compound having Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-2, I-3, I-4, I-5, I-6, I-5-A, I-5-B, I-5-B-E1, I-5-B-E2, I-7, I-8, I-9, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-10, I-11, I-12, I-11A, I-11-B, I-11-B-E1, I-11-B-E2, etc.) is characterized in that n1 and n2 are both 0.

[0049] In some embodiments, a compound having Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-2, I-3, I-4, I-5, I-6, I-5-A, I-5-B, I-5-B-E1, I-5-B-E2, I-7, I-8, I-9, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-10, I-11, I-12, I-11A, I-11-B, I-11-B-E1, I-11-B-E2, etc.) is characterized in that n1 and n2 are both 1. For example, in some embodiments, a compound having Formula I may be characterized in that it has a structure according to Formula I-13. [ka]

[0050] When n1 and n2 are both 1, R in Formula I (e.g., Formulas I-1, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-2, I-3, I-4, I-5, I-6, I-5-A, I-5-B, I-5-B-E1, I-5-B-E2, I-7, I-8, I-9, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-10, I-11, I-12, I-11A, I-11-B, I-11-B-E1, I-11-B-E2, I-13, etc.) a and R bIn some embodiments, n1 and n2 are both 1, and R in Formula I a and R b are the same, and they are C 1-4 It may be an alkyl group, for example a methyl group, an ethyl group, or an isopropyl group.

[0051] In some embodiments, n1 and n2 are both 1, and R in Formula I a and R b are both methyl groups. For example, in some embodiments, compounds having formula I-13 may be characterized as having a structure according to formula I-13-A or I-13-B. [ka]

[0052] In some embodiments, the compound having formula I-13 may be a single isomer and have 80% ee or greater, e.g., 90% ee or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater, or no other enantiomer is detectable by HPLC or SFC. For example, in some embodiments, the compound having formula I-13-B may be a substantially pure enantiomer according to formula I-13-B-E1. [ka]

[0053] In some embodiments, the compound having formula I-13-B may be a substantially pure enantiomer according to formula I-13-B-E2. [ka]

[0054] In some embodiments, the compound having formula I-13-B may be a substantially pure enantiomer according to formula I-13-B-E3. [ka]

[0055] In some embodiments, the compound having formula I-13-B may be a substantially pure enantiomer according to formula I-13-B-E4. [ka]

[0056] The groups R in Formula I 6 Generally, however, R in Formula I (e.g., any one of the sub-formulas applicable herein) 6 is hydrogen. In one embodiment, R 6 is deuterium. In one embodiment, R 6 is an optionally substituted C 1-4 In one embodiment, R 6 is CH3. In one embodiment, R 6 is CF3.

[0057] The groups R in Formula I 4 Generally, R in Formula I (e.g., any one of the sub-formulas applied herein) 4 is hydrogen.

[0058] R 2 R 1 When R in Formula I (e.g., any one of the subformulas as applied herein) does not form a ring with 2 is also generally hydrogen. 2 Other definitions of

[0059] R 5 R 1 or R 4 When R in Formula I (e.g., any one of the subformulas as applied herein) does not form a ring with 5 is also generally hydrogen.5 Other definitions of

[0060] X in Formula I (e.g., any one of the subformulas as applied herein) is typically O. In one embodiment, X is S. In one embodiment, X is NR 10 In one embodiment, X is NH.

[0061] In some embodiments, X in Formula I (e.g., any one of the subformulas as applied herein) is C 1-4 It may also be an alkylene group, for example CH2.

[0062] In some embodiments, X in Formula I (e.g., any one of the subformulas as applied herein) is C 1-4 Heteroalkylene groups, such as C, ... 1-4 It may also be a heteroalkylene group. For example, in some embodiments, X in Formula I (e.g., any one of the subformulas as applied herein) may be -O-CH-. In one embodiment, X is -CH-O-. Unless otherwise specified, the left attachment site of X is R 3 is.

[0063] R in Formula I (e.g., any one of the subformulas as applied herein) 3 is typically an optionally substituted 3- to 10-membered ring. For example, in some embodiments, R 3 is an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted bicyclic heteroaryl group (e.g., an 8- to 10-membered bicyclic heteroaryl group).

[0064] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 is a phenyl group.

[0065] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 are phenyl groups, which are each independently halogen, CN, OH, NH2, COOH, CONH2, G 1 , O.G. 1 , N.H.G. 1 , N.G. 1 G 1 , C(O)G 1 , COOG 1 ,CONHG 1 , CONG 1 G 1 , O.C.(O)G 1 , O.C.O.G. 1 , OCONHG 1 , OCONG 1 G 1 , N.H.G. 1 C(O)G 1 , N.H.G. 1 COOG 1 , N.H.G. 1 CONHG 1 , N.H.G. 1 CONG 1 G 1 , N.G. 1 G 1 C(O)G 1 , N.G. 1 G 1 COOG 1 , N.G. 1 G 1 CONHG 1 , N.G. 1 G 1 CONG 1 G 1 , SO2G 1 , SO2NHG 1 , or SO2NG 1 G 1 wherein G is substituted with 1 to 3 substituents selected from 1 Each occurrence of is independently an optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4an alkynyl group, or an optionally substituted 3- to 6-membered ring structure, such as a cyclopropyl group, a cyclobutyl group, a phenyl group, a pyridyl group, or an NG 1 G 1 The two Gs 1 may be linked to the nitrogen atom to form an optionally substituted 4- to 8-membered heterocycle. In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 are phenyl groups, which are each independently halogen, CN, OH, NH2, COOH, CONH2, G 1 , O.G. 1 , S.G. 1 , N.H.G. 1 , N.G. 1 G 1 , C(O)G 1 , COOG 1 ,CONHG 1 , CONG 1 G 1 , O.C.(O)G 1 , O.C.O.G. 1 , OCONHG 1 , OCONG 1 G 1 , NHC(O)G 1 , NHCOOG 1 ,NHCONHG 1 , N.H.C.O.N. 1 G 1 , N.G. 1 C(O)G 1 , N.G. 1 COOG 1 , N.G. 1 CONHG 1 , N.G. 1 CONG 1 G 1 , SO2G 1 , SO2NHG 1 , or SO2NG 1 G 1 wherein G is substituted with 1 to 3 substituents selected from 1 Each occurrence of is independently an optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4an alkynyl group, or an optionally substituted 3- to 6-membered ring structure, such as a cyclopropyl group, a cyclobutyl group, a phenyl group, a pyridyl group, or an NG 1 G 1 The two Gs 1 may be linked to the nitrogen atom to form an optionally substituted 4- to 8-membered heterocycle.

[0066] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 are phenyl groups, which are each independently F, Cl, CN, OH, NH2, COOH, CONH2, G 2 , O.G. 2 , N.H.G. 2 , N.G. 2 G 2 , C(O)G 2 , COOG 2 ,CONHG 2 , CONG 2 G 2 , SO2G 2 , SO2NHG 2 , or SO2NG 2 G 2 wherein G is substituted with 1 to 3 substituents selected from 2 Each occurrence of is independently 1-4 Alkyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocycle having 1 to 2 ring heteroatoms, a phenyl group, or a 5- or 6-membered heteroaryl group, each of which is optionally independently selected from F, Cl, OH, NH, C optionally substituted with 1 to 3 F. 1-4 alkyl group or C having 1 or 2 heteroatoms and optionally substituted with 1 to 3 F 1-4 substituted with 1 to 3 substituents selected from heteroalkyl groups, or NG 2 G 2 The two Gs 2 may be joined to the nitrogen atom to form an optionally substituted 4-8 membered heterocyclic ring having 0 or 1 additional ring heteroatom.

[0067] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 are phenyl groups, which are each independently (i) halogen or CN, in particular F or Cl; (ii) C optionally substituted with 1 to 3 F 1-4 alkyl groups, such as CF3; (iii) C optionally substituted with 1 to 3 F 1-4 Alkoxy groups, such as OCF3, (iv) SC optionally substituted with 1 to 3 F 1-4 Alkyl groups, such as -S-CH3, (v) SO2-C optionally substituted with 1 to 3 F 1-4 Alkyl groups, such as -SO2-CH3, (vi) a 3- or 4-membered ring, such as a cyclopropyl group or a cyclobutyl group; (vii) O-(3- to 4-membered ring), for example, an O-cyclopropyl group, an O-cyclobutyl group, or an O-oxetanyl group, (viii) CONH(C 1-4 alkyl), or CON(C 1-4 Alkyl)(C 1-4 alkyl), such as CONHCH3 or CON(CH3)2, (ix) CONH (3-4 membered ring), for example CONH (cyclopropyl) or CONH (cyclobutyl), (x) SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 alkyl), such as SO2NHCH3 or SO2N(CH3)2, (xi) SO2NH (3-4 membered ring), (xii) CO-(4- to 7-membered heterocyclyl), for example, the 4- to 7-membered heterocyclyl group is azetidine, pyrrolidine, piperazine, piperidine, etc., which is optionally substituted with 1 to 3 substituents, each independently being F or a methyl group; (xiii) CO—NH(5- or 6-membered heteroaryl), for example, CO—NH-pyridyl group; (xiv) a phenyl group, which is optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F, 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4 those substituted with one or two substituents selected from an alkoxy group and a 3- to 4-membered ring (e.g., a cyclopropyl group, a cyclobutyl group, etc.); (xv) 6-membered heteroaryl groups, such as pyridine, pyrimidine, pyridone, or pyrimidinone, which are optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F. 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4 those substituted with one or two substituents selected from an alkoxy group and a 3- to 4-membered ring (e.g., a cyclopropyl group, a cyclobutyl group, etc.); (xvi) 5-membered heteroaryl groups, such as pyrazine, oxadiazole, etc., which are optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F. 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4 those substituted with one or two substituents selected from alkoxy groups and 3- to 4-membered rings (e.g., cyclopropyl groups, cyclobutyl groups, etc.); (xvii) a 5- to 7-membered heterocyclic ring having 1 to 2 ring heteroatoms, such as a 5- or 6-membered lactam ring, which is optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F, 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4 It is substituted with 1 to 3 (for example, 1 or 2) substituents selected from alkoxy groups and those substituted with 1 or 2 substituents selected from 3- to 4-membered rings (for example, cyclopropyl groups, cyclobutyl groups, etc.).

[0068] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 represents a 6-membered heteroaryl group, such as a pyridyl group (e.g., [ka] ), which may optionally each independently be: (i) halogen or CN, in particular F or Cl; (ii) C optionally substituted with 1 to 3 F 1-4 alkyl groups, such as CF3; (iii) C optionally substituted with 1 to 3 F 1-4 Alkoxy groups, such as OCF3, (iv) SC optionally substituted with 1 to 3 F 1-4 Alkyl groups, such as -S-CH3, (v) SO2-C optionally substituted with 1 to 3 F 1-4 Alkyl groups, such as -SO2-CH3, (vi) a 3- or 4-membered ring, such as a cyclopropyl group or a cyclobutyl group; (vii) O-(3- to 4-membered ring), for example, an O-cyclopropyl group, an O-cyclobutyl group, or an O-oxetanyl group, (viii) CONH(C 1-4 alkyl), or CON(C 1-4 Alkyl)(C 1-4 alkyl), such as CONHCH3 or CON(CH3)2, (ix) CONH (3-4 membered ring), for example CONH (cyclopropyl) or CONH (cyclobutyl), (x) SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 alkyl), such as SO2NHCH3 or SO2N(CH3)2, (xi) SO2NH (3-4 membered ring), (xii) CO-(4- to 7-membered heterocyclyl), for example, the 4- to 7-membered heterocyclyl group is azetidine, pyrrolidine, piperazine, piperidine, etc., which is optionally substituted with 1 to 3 substituents, each independently being F or a methyl group; (xiii) CO—NH(5- or 6-membered heteroaryl), for example, CO—NH-pyridyl group; (xiv) a phenyl group, which is optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F, 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4 those substituted with one or two substituents selected from an alkoxy group and a 3- to 4-membered ring (e.g., a cyclopropyl group, a cyclobutyl group, etc.); (xv) 6-membered heteroaryl groups, such as pyridine, pyrimidine, pyridone, or pyrimidinone, which are optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F. 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4 those substituted with one or two substituents selected from an alkoxy group and a 3- to 4-membered ring (e.g., a cyclopropyl group, a cyclobutyl group, etc.); (xvi) 5-membered heteroaryl groups, such as pyrazine, oxadiazole, etc., which are optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F. 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4 those substituted with one or two substituents selected from alkoxy groups and 3- to 4-membered rings (e.g., cyclopropyl groups, cyclobutyl groups, etc.); (xvii) a 5- to 7-membered heterocyclic ring having 1 to 2 ring heteroatoms, such as a 5- or 6-membered lactam ring, which is optionally independently substituted with halogen (e.g., F), CN, optionally 1 to 3 F, 1-4 alkyl group, optionally substituted with 1 to 3 F 1-4It is substituted with 1 to 3 (for example, 1 or 2) substituents selected from alkoxy groups and those substituted with 1 or 2 substituents selected from 3- to 4-membered rings (for example, cyclopropyl groups, cyclobutyl groups, etc.).

[0069] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 may be a phenyl group or a pyridyl group, each of which is independently selected from (1) F, Cl, Br, or CN, (2) C optionally substituted with 1 to 3 F, 1-4 Alkyl groups, such as methyl, ethyl, CF3, (3) C optionally substituted with 1 to 3 F 1-4 Alkoxy groups, such as methoxy, ethoxy, isopropoxy, OCF3, OCH2CF3, etc.; (4) C optionally substituted with 1 to 3 F; 1-4 Alkyl sulfones, such as CH3S-, (5) C optionally substituted with 1 to 3 F 1-4 Alkyl sulfones, such as CH3SO2-, (6) 3- to 6-membered rings, such as a cyclopropyl group, a cyclobutyl group, or an oxetanyl group, (7) (3- to 6-membered ring)-O, such as a cyclopropoxy group or a cyclobutoxy group, [ka] etc., (8) SO2N(C 1-4 Alkyl)(C 1-4 alkyl), such as SO2N(CH3)2, and the like.

[0070] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 is a monosubstituted phenyl or pyridyl group, for example [ka] where R S1 (1) F, Cl, Br, or CN; (2) C optionally substituted with 1 to 3 F; 1-4Alkyl groups, such as methyl, ethyl, CF3, (3) C optionally substituted with 1 to 3 F 1-4 Alkoxy groups, such as methoxy, ethoxy, isopropoxy, OCF3, OCH2CF3, etc.; (4) C optionally substituted with 1 to 3 F; 1-4 Alkyl sulfones, such as CH3S-, (5) C optionally substituted with 1 to 3 F 1-4 Alkyl sulfones, such as CH3SO2-, (6) 3- to 4-membered rings, such as a cyclopropyl group, a cyclobutyl group, or an oxetanyl group, (7) (3- to 4-membered ring)-O, such as a cyclopropoxy group or a cyclobutoxy group, [ka] etc., (8) SO2N(C 1-4 Alkyl)(C 1-4 alkyl), such as SO2N(CH3)2.

[0071] In some more particular embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] may be selected from where: G 3 Each occurrence of is independently an optionally substituted C 1-4 an alkyl group or an optionally substituted 3- to 6-membered ring, such as a cyclopropyl group, a cyclobutyl group, an oxetanyl group (e.g. [ka] ) etc., or C 1-4 alkyl group or deuterated analogue of a 3- to 6-membered ring, and when substituted, the C 1-4 The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group, C having 1-2 heteroatoms and optionally substituted with F 1-4substituted with 1 to 3 substituents that are heteroalkyl groups or 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetanyl groups) optionally substituted with F; or Two Gs 3 are linked together with the nitrogen atom to which they are both attached to form a 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocycle having 0 or 1 additional ring heteroatom, wherein the 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocycle optionally each independently selected from oxo, F, C, 1-4 Alkyl group, OH, NH2, or C with 1-2 heteroatoms 1-4 substituted with 1 to 3 substituents which are heteroalkyl groups, and wherein: The integer n7 is 0, 1, or 2, and R h Each occurrence independently represents a halogen (e.g., F), CN, OH, C 1-4 Alkyl group, C 1-4 an alkoxy group or a 3- to 6-membered ring, 1-4 Alkyl group, C 1-4 The alkoxy group or the 3- to 6-membered ring may optionally each independently be selected from the group consisting of F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 It is substituted with 1 to 3 substituents which are heteroalkyl groups.

[0072] In one embodiment, the compound has a structure according to formula IV-1, IV-7, or IV-8, or a pharmaceutically acceptable salt thereof: [ka] where: R p are halogens, CN, OH, NH2, COOH, CONH2, G 3 , O.G. 3 , S.G. 3 , N.H.G. 3 , N.G. 3 G 3 , C(O)G 3 , COOG 3,CONHG 3 , CONG 3 G 3 , O.C.(O)G 3 , O.C.O.G. 3 , OCONHG 3 , OCONG 3 G 3 , NHC(O)G 3 , NHCOOG 3 ,NHCONHG 3 , N.H.C.O.N. 3 G 3 , N.G. 3 C(O)G 3 , N.G. 3 COOG 3 , N.G. 3 CONHG 3 , N.G. 3 CONG 3 G 3 , SO2G 3 , SO2NHG 3 , or SO2NG 3 G 3 and G 3 Each occurrence of is independently an optionally substituted C 1-4 an alkyl group or an optionally substituted 3- to 6-membered ring, such as a cyclopropyl group, a cyclobutyl group, an oxetanyl group (e.g. [ka] ) etc., or C 1-4 alkyl group or deuterated analogue of a 3- to 6-membered ring, and when substituted, the C 1-4 The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group, C having 1-2 heteroatoms and optionally substituted with F 1-4 substituted with 1 to 3 substituents that are heteroalkyl groups or 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetanyl groups) optionally substituted with F; or Two Gs 3are linked together with the nitrogen atom to which they are both attached to form a 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocycle having 0 or 1 additional ring heteroatom, wherein the 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocycle optionally each independently selected from oxo, F, C, 1-4 Alkyl group, OH, NH2, or C with 1-2 heteroatoms 1-4 substituted with 1 to 3 substituents that are heteroalkyl groups; R h’ is hydrogen or R h and R h Each occurrence independently represents a halogen (e.g., F), CN, OH, C 1-4 Alkyl group, C 1-4 an alkoxy group or a 3- to 6-membered ring, 1-4 Alkyl group, C 1-4 The alkoxy group or the 3- to 6-membered ring may optionally each independently be selected from the group consisting of F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 It is substituted with 1 to 3 substituents which are heteroalkyl groups.

[0073] In some embodiments, each G 3 are independently a methyl group, [ka] or two G 3 are linked together with the nitrogen atom to which they are both attached, [ka] In one embodiment, each G 3 is C 1-4 In one embodiment, each G 3 is C optionally substituted with F 1-4 For example, in some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, each G 3 is C 1-4 Deuterated analogs of alkyl groups, such as -CD3. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0074] In some embodiments, NHG 3 is NH-(cyclopropyl) or NH-(cyclobutyl). In some embodiments, NG 3 G 3 In G 3 An example of is a cyclopropyl group or a cyclobutyl group, and G 3 Another example of 1-4 For example, in some embodiments, R 3 teeth, [ka] may be.

[0075] In some embodiments, NHG 3 represents an NH-pyridyl group, e.g. [ka] is.

[0076] In some embodiments, NG 3 G 3 In this case, two G 3 are linked together with the nitrogen atom to which they are both attached to form a 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocyclic ring having 0 or 1 additional ring heteroatom, such as an azetidine, pyrrolidine, morpholine, piperidine, piperazine, azepane, or oxepane ring, wherein the 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocyclic ring is optionally substituted with 1 to 3 substituents (as defined herein, e.g., F, methyl, etc.). For example, in some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] may be.

[0077] The integer n7 may be 0, i.e., R 3 The phenyl group in R is not further substituted (even h’ corresponds to hydrogen).

[0078] In some embodiments, the integer n7 may be 1, and R h is halogen (e.g., F), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4It may be an alkoxy group or a 3- to 6-membered ring, and the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 Substituted with 1 to 2 substituents that are heteroalkyl groups. For example, in some embodiments, R h may be a halogen (eg, F).

[0079] In some more particular embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] may be selected from where: integers n8 and n9 are independently 0, 1, or 2; HET optionally contains 1 to 2 R j is a 5- or 6-membered heterocyclyl or heteroaryl group substituted with R i , R j and R k Each occurrence of each independently represents a halogen (e.g., F), CN, OH, C 1-4 Alkyl group, C 1-4 an alkoxy group or a 3- to 6-membered ring, 1-4 Alkyl group, C 1-4 The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F or OH. 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 It is substituted with 1 to 3 substituents which are heteroalkyl groups.

[0080] In one embodiment, the compound has a structure according to formula IV-2, IV-3, IV-4, IV-5, IV-4-1, or IV-5-1, or a pharmaceutically acceptable salt thereof: [ka] where R i’ is hydrogen or R i is.

[0081] In some embodiments, the integer n8 is 0 (also R i’ In some embodiments, the integer n8 is 1 and R i is halogen (e.g., F), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4 an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 Substituted with 1 to 2 substituents that are heteroalkyl groups. For example, in some embodiments, n8 is 1 and R i is a halogen (e.g., F).

[0082] In some embodiments, the integer n9 is 0. In some embodiments, the integer n9 is 1 and R k is a halogen (e.g., F or Cl), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4 an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 and n is 1 and R is substituted with 1 to 2 substituents that are heteroalkyl groups. For example, in some embodiments, n is 1 and R k is a C optionally substituted with halogen (e.g., F or Cl) or F 1-4 In some embodiments, [ka] teeth, [ka] For example, in some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0083] HET is typically a 5- or 6-membered heteroaryl group. For example, in some embodiments, HET is a 6-membered heteroaryl group having one or two ring nitrogen atoms, such as a pyridyl group (e.g., a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group) or a pyrimidinyl group. In some embodiments, a 6-membered heteroaryl group having one or two ring nitrogen atoms may optionally be joined by one R j and R is substituted with j is halogen (e.g., F), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4 an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 In some embodiments, HET is optionally substituted with 1 to 2 substituents that are heteroalkyl groups. j Pyridyl groups substituted with, for example, [ka] etc.) or pyrimidinyl groups (e.g., [ka] ), where R j each occurrence independently represents F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 In some embodiments, HET is a heteroalkyl group. In some embodiments, HET is optionally a heteroalkyl group. j Pyrazinyl groups substituted with (e.g. [ka] ), where R j each occurrence independently represents F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 For example, in some embodiments, R j is F, CF, etc. In some embodiments, HET is [ka] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0084] In some embodiments, HET optionally contains one R j pyridones substituted with (e.g., [ka] ), or pyrimidinones (e.g. [ka] ) and the R j is halogen (e.g., F), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4 an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 and substituted with 1 to 2 substituents that are heteroalkyl groups. For example, in some embodiments, HET is [ka] For example, in some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) may be 3 teeth, [ka] may be.

[0085] In some embodiments, HET is a 5-membered heteroaryl group having 1 to 3 ring heteroatoms, such as pyrazole, oxadiazole, etc. In some embodiments, the 5-membered heteroaryl group having 1 to 3 ring heteroatoms optionally contains one R j and R is substituted with j is halogen (e.g., F), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4 an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 In some embodiments, HET is optionally substituted with 1 to 2 substituents that are heteroalkyl groups. jpyrazoles or oxadiazoles substituted with, for example, [ka] etc.), where R j each occurrence independently represents F, OH, C optionally substituted with F, 1-4 alkyl group, C having 1-2 heteroatoms and optionally substituted with F 1-4 A heteroalkyl group, or a 3-4 membered ring, such as a cyclopropyl group or a cyclobutyl group. In some embodiments, HET optionally contains 1-2 R j substituted triazoles (e.g. [ka] ), tetrazole (e.g. [ka] ), thiadiazoles (e.g. [ka] ), thiazoles (e.g. [ka] ), oxazole (e.g. [ka] ), or imidazole (e.g. [ka] ), where R j each occurrence independently represents F, OH, C optionally substituted with F, 1-4 alkyl group, C having 1-2 heteroatoms and optionally substituted with F 1-4 A heteroalkyl group, or a 3- to 4-membered ring, such as a cyclopropyl group or a cyclobutyl group. For example, in some embodiments, R jis F, CH, CF, a cyclopropyl group, etc. For example, in some embodiments, HET is [ka] In some embodiments, HET may be [ka] For example, in some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0086] In some embodiments, HET is a 5- or 6-membered heterocyclyl group having 1 or 2 ring heteroatoms, such as [ka] In some embodiments, a 5- or 6-membered heterocyclyl group having one or two ring heteroatoms optionally contains one or two R j and R is substituted with j is halogen (e.g., F), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4 an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 and substituted with 1 to 2 substituents that are heteroalkyl groups. For example, in some embodiments, HET is [ka] For example, in some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) may be 3 teeth, [ka] may be.

[0087] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] may be.

[0088] In some more particular embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] where The integer n10 is 0, 1, or 2; R 7 and R 8 are linked together with the intervening atoms to form a 4- to 8-membered ring, and the 4- to 8-membered ring optionally contains 1 to 3 R n is replaced by R m Each occurrence independently represents a halogen (e.g., F), CN, OH, C 1-4 Alkyl group, C 1-4 an alkoxy group or a 3- to 6-membered ring, 1-4 Alkyl group, C 1-4 The alkoxy group or the 3- to 6-membered ring may optionally each independently be selected from the group consisting of F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 substituted with 1 to 3 substituents that are heteroalkyl groups; Rn Each occurrence independently represents oxo (where valence allows), halogen (e.g., F), CN, OH, C 1-4 Alkyl group, C 1-4 an alkoxy group or a 3- to 6-membered ring, 1-4 Alkyl group, C 1-4 The alkoxy group or the 3- to 6-membered ring may optionally each independently be selected from the group consisting of F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 It is substituted with 1 to 3 substituents which are heteroalkyl groups.

[0089] In one embodiment, the compound has a structure according to formula IV-6, or a pharmaceutically acceptable salt thereof: [ka] where R m’ is hydrogen or R m is.

[0090] R 7 and R 8 The ring formed by the atoms intervening therewith is not particularly limited. Generally, the ring formed is (1) a heterocyclic ring having one or two ring heteroatoms (e.g., one nitrogen, two nitrogens, or one nitrogen and one oxygen), or (2) a heteroaryl ring having one to three ring heteroatoms independently selected from O, N, and S. The ring formed may optionally contain one to three R as defined herein. n If substituted, R n may be attached at any applicable available position.

[0091] In some embodiments, R 7 and R 8 and the intervening atoms form a 5- or 6-membered heteroaryl ring having 1 to 3 ring heteroatoms, which optionally contain 1 to 2 R as defined herein. nFor example, in some embodiments, R 3 teeth, [ka] may be.

[0092] In some embodiments, R 7 and R 8 are joined together with intervening atoms to form a 4- to 7-membered heterocyclyl ring having 1 or 2 ring heteroatoms (e.g., one nitrogen, two nitrogens, two oxygens, or one nitrogen and one oxygen), which optionally contains 1 to 2 R as defined herein. n For example, in some embodiments, R 3 teeth, [ka] may be.

[0093] For example, in some more particular embodiments, R 3 teeth, [ka] may be where: R m and n10 are as defined herein, and G 4 Each occurrence of is independently an optionally substituted C 1-4 alkyl groups, or optionally substituted 3- to 6-membered rings, such as cyclopropyl, cyclobutyl, oxetanyl groups (e.g. [ka] ) etc. When replaced, C 1-4 The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4In some embodiments, G is substituted with 1 to 3 substituents that are heteroalkyl groups. 4 is a methyl group, or two G 4 When present, both are methyl groups. 4 is a cyclopropyl group, or two G 4 If there is G 4 One example of is a cyclopropyl group, and G 4 Another example of is as defined herein.

[0094] The integer n10 is generally 0 (which is m’ corresponds to hydrogen).

[0095] In some embodiments, n10 is 1 and R m is halogen (e.g., F), CN, C optionally substituted with F 1-4 alkyl group, C optionally substituted with F 1-4 an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group or C having 1-2 heteroatoms and optionally substituted with F 1-4 It is substituted with 1 to 2 substituents which are heteroalkyl groups.

[0096] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 is as defined herein [ka] for example, [ka] may be.

[0097] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3is as defined herein [ka] for example, [ka] may be.

[0098] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 is as defined herein [ka] for example, [ka] may be.

[0099] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 is as defined herein [ka] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) may be 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] may be.

[0100] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0101] In some embodiments, R in Formula I (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0102] In some embodiments, the present disclosure further provides the following non-limiting illustrative examples A1-A14 according to Formula I: Example A1 A compound having the formula I, I-1, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-2, I-3, I-4, I-5, I-6, I-5-A, I-5-B, I-5-B-E1, I-5-B-E2, I-7, I-8, I-9, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-10, I-11, I-12, I-11A, I-11-B, I-11-B-E1, I-11-B-E2, I-13, I-13-B-E1, I-13-B-E2, I-13-B-E3, or I-13-B-E4, or a pharmaceutically acceptable salt thereof, A compound or a pharmaceutically acceptable salt thereof, wherein the variables in each formula include any combination of any of the variables defined herein. Example A2 If applicable, R 1 is hydrogen or C optionally substituted with F 1-4 The compound according to Example A1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group. Example A3 If applicable, R 1is a methyl group or CF3, or a pharmaceutically acceptable salt thereof. Example A4 If applicable, R 2 The compound according to any one of Examples A1 to A3, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Example A5 If applicable, R 4 The compound according to any one of Examples A1 to A4, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Example A6 If applicable, R 5 The compound according to any one of Examples A1 to A5, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Example A7 If applicable, R 6 The compound according to any one of Examples A1 to A6, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Example A8 A compound according to any one of Examples A1 to A7, or a pharmaceutically acceptable salt thereof, wherein, where applicable, n1 and n2 are both 0. Example A9 Where applicable, n1 and n2 are both 1 and R a and R b and R are each a methyl group, or a pharmaceutically acceptable salt thereof. Example A10 The compound according to any one of Examples A1 to A9, wherein X is O, or a pharmaceutically acceptable salt thereof. Example A11 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof. Example A12 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof. Example A13 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof. Example A14 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof.

[0103] Formula II In some embodiments, the present disclosure provides a compound having Formula II, or a pharmaceutically acceptable salt thereof: [ka] where: X is O, S, or NR 10 , optionally substituted C 1-4 an alkylene group, or an optionally substituted C 1-4 heteroalkylene group, where R 10 is hydrogen, optionally substituted C 1-4 an alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; Y and Z each independently represent O, S, N, or NR 11 or CR 12 and, valence permitting, the proviso is that the five-membered ring containing Y and Z is aromatic, where: (i) R 11 is hydrogen, optionally substituted C 1-4 alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; R 12 is hydrogen, halogen, CN, optionally substituted C 1-4 alkyl groups, optionally substituted C 1-4 a heteroalkyl group or an optionally substituted 3- to 6-membered ring, or (ii) Where applicable, R 11 or R 12 is R 1and, together with the intervening atoms, join to form an optionally substituted 4- to 8-membered ring (in one embodiment, an optionally substituted 5- to 8-membered ring), R 1 is as defined in (ii) or hydrogen (in another embodiment, deuterium), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 alkenyl group, or optionally substituted C 2-4 is an alkynyl group, R 2 and R 4 are each independently hydrogen, halogen (e.g., F), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4 Alkynyl group, optionally substituted C 1-4 an alkoxy group or an optionally substituted 3- to 5-membered ring; R 3 is hydrogen, optionally substituted C 1-4 an alkyl group or an optionally substituted 3- to 10-membered ring; R 6 is hydrogen (in another embodiment, deuterium), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 alkenyl group, or optionally substituted C 2-4 is an alkynyl group, Integers n1 and n2 are each independently 0, 1, 2, 3, or 4; and R a and R b Each occurrence of 1-4 alkyl group or optionally substituted C 1-4 is a heteroalkylene group, or R a Two examples of R b are joined together with the intervening atoms to form an optionally substituted 3- to 6-membered ring, and R a and / or R bAny remaining examples of are as defined above.

[0104] In some embodiments, compounds having Formula II (including any applicable subformulas described herein) may contain one or more asymmetric centers and / or axial chirality and therefore may exist in multiple stereoisomeric forms (e.g., enantiomers and / or diastereomers). In some embodiments, compounds having Formula II may exist in the form of a single enantiomer and / or diastereomer (if applicable), or a stereoisomeric mixture (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some examples, where applicable, compounds having Formula II (including any applicable sub-formulas described herein) may exist as a single enantiomer substantially free of the other enantiomer (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or an undetectable amount by weight by HPLC or SFC area or both), e.g., the compound may have an enantiomeric excess ("ee") of greater than 60% (e.g., 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater, etc.). In some examples, where applicable, compounds having Formula II (including any applicable sub-formulas described herein) may exist as a mixture of stereoisomers (in any ratio), e.g., a racemic mixture.

[0105] In some embodiments, compounds having Formula II (including any applicable subformulas described herein) may exist as isotopically labeled compounds, particularly deuterated analogs, where one or more hydrogen atoms of a compound having Formula II are replaced with deuterium atoms that are in abundance above their natural abundance, e.g., if the compound has a CH3 group, it is a CD3 analog.

[0106] It will be apparent to one skilled in the art that in some cases, compounds having Formula II may exist as a mixture of tautomers. The present disclosure is not limited to any particular tautomer. To the contrary, the present disclosure encompasses any and all such tautomers, whether or not explicitly depicted or referred to.

[0107] Y and Z in formula II are not particularly limited as long as the five-membered ring containing Y and Z is aromatic, for example, furan, thiophene, pyrrole, imidazole, or the like.

[0108] In some embodiments, the five-membered ring containing Y and Z in Formula II is a furan ring. For example, in some embodiments, a compound having Formula II may be characterized by having a structure according to Formula II-1. [ka]

[0109] In one embodiment, the compound has a structure according to formula V-1, or a pharmaceutically acceptable salt thereof: [ka] where: R p are halogens, CN, OH, NH2, COOH, CONH2, G 3 , O.G. 3 , S.G. 3 , N.H.G. 3 , N.G. 3 G 3 , C(O)G 3 , COOG 3 ,CONHG 3 , CONG 3 G 3 , O.C.(O)G 3 , O.C.O.G. 3 , OCONHG 3 , OCONG 3 G 3 , NHC(O)G 3 , NHCOOG 3 ,NHCONHG 3, N.H.C.O.N. 3 G 3 , N.G. 3 C(O)G 3 , N.G. 3 COOG 3 , N.G. 3 CONHG 3 , N.G. 3 CONG 3 G 3 , SO2G 3 , SO2NHG 3 , or SO2NG 3 G 3 and G 3 Each occurrence of is independently an optionally substituted C 1-4 an alkyl group or an optionally substituted 3- to 6-membered ring, such as a cyclopropyl group, a cyclobutyl group, an oxetanyl group (e.g. [ka] ) etc., or C 1-4 alkyl group or deuterated analogue of a 3- to 6-membered ring, and when substituted, the C 1-4 The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, 1-4 alkyl group, C having 1-2 heteroatoms and optionally substituted with F 1-4 substituted with 1 to 3 substituents that are heteroalkyl groups or 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetanyl groups) optionally substituted with F; or Two Gs 3 are linked together with the nitrogen atom to which they are both attached to form a 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocycle having 0 or 1 additional ring heteroatom, wherein the 4- to 7-membered (in another embodiment, 4- to 8-membered) heterocycle optionally each independently selected from oxo, F, C, 1-4 Alkyl group, OH, NH2, or C with 1-2 heteroatoms 1-4 It is substituted with 1 to 3 substituents which are heteroalkyl groups.

[0110] In some embodiments, R in Formula II (e.g., II-1) 1 is hydrogen or C optionally substituted with F 1-4 It may be an alkyl group, such as a methyl group, CF3, etc. In one embodiment, R 1 is deuterium.

[0111] The variable R of Formula II or a sub-formula thereof (e.g., Formula II-1) 3 , R 6 , X, R a , R b , n1, and n2 and any other variables (e.g., R 1 , R 2 , R 4 , G 3 , R h etc.) may be any applicable variable defined herein for Formula I or any subformula thereof.

[0112] For example, generally, the integers n1 and n2 in Formula II are each independently 0, 1, or 2. In some embodiments, at least one of n1 and n2 is not 0. In some embodiments, the integers n1 and n2 in Formula II are both 0. In some embodiments, the integers n1 and n2 in Formula II are both 1. For example, in some embodiments, a compound having Formula II may be characterized by having a structure according to Formula II-2. [ka]

[0113] When n1 and n2 are both 1, R in Formula II (e.g., Formula II-1 or II-2) a and R b In some embodiments, n1 and n2 are both 1, and R in Formula II is a and R b is the same as C 1-4 It may be an alkyl group, for example a methyl group, an ethyl group, or an isopropyl group.

[0114] Generally, R in Formula II (e.g., any one of the subformulas applicable herein) 6 is hydrogen. In one embodiment, R 6 is deuterium. In one embodiment, R 6 is an optionally substituted C 1-4 In one embodiment, R 6 is CH3. In one embodiment, R 6 is CF3. For example, in some embodiments, a compound having formula II may be characterized as having a structure according to formula II-3 or II-4. [ka]

[0115] In some embodiments, the compound having Formula II may be characterized as having a structure according to Formula II-3-A or II-4-A. [ka]

[0116] In some embodiments, the compound having Formula II may be characterized as having a structure according to Formula II-3-B or II-4-B. [ka]

[0117] In some embodiments, the compound having formula II-3-A may be a substantially pure enantiomer according to formula II-3-A-E1. [ka]

[0118] In some embodiments, the compound having formula II-3-A may be a substantially pure enantiomer according to formula II-3-A-E2. [ka]

[0119] In some embodiments, the compound having formula II-4-A may be a substantially pure enantiomer according to formula II-4-A-E1. [ka]

[0120] In some embodiments, the compound having formula II-4-A may be a substantially pure enantiomer according to formula II-4-A-E2. [ka]

[0121] In some embodiments, the compound having formula II-4-A may be a substantially pure enantiomer according to formula II-4-A-E3. [ka]

[0122] In some embodiments, the compound having formula II-4-A may be a substantially pure enantiomer according to formula II-4-A-E4. [ka]

[0123] In some embodiments, the compound having formula II-4-B may be a substantially pure enantiomer according to formula II-4-B-E1. [ka]

[0124] In some embodiments, the compound having formula II-4-B may be a substantially pure enantiomer according to formula II-4-B-E2. [ka]

[0125] Generally, R in Formula II (e.g., any one of the subformulas applicable herein) 4 is hydrogen.

[0126] R in Formula II (e.g., any one of the subformulas as applied herein) 2 is generally hydrogen.

[0127] X in Formula II (e.g., any one of the subformulas as applied herein) is typically O. In one embodiment, X is S. In one embodiment, X is NR 10 In one embodiment, X is NH.

[0128] In some embodiments, X in Formula II (e.g., any one of the subformulas as applied herein) is C 1-4 It may also be an alkylene group, for example CH2.

[0129] In some embodiments, X in Formula II (e.g., any one of the subformulas as applied herein) is C 1-4 Heteroalkylene groups may also be used, for example, those having one or two heteroatoms, which are independently O, S, and N. For example, in some embodiments, X in Formula II (e.g., any one of the subformulas as applied herein) may be -O-CH-. In one embodiment, X is -CH-O-. Unless otherwise specified, the left attachment site of X is R 3 is.

[0130] R in Formula II (e.g., any one of the subformulas as applied herein) 3 may be any of the definitions associated with formula I and its subformulas.

[0131] For example, in some embodiments, R in Formula II and subformulas thereof 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0132] In some embodiments, R in Formula II and subformulas thereof 3 teeth, [ka] may be.

[0133] In some embodiments, R in Formula II (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] may be.

[0134] In some embodiments, R in Formula II (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] may be.

[0135] In some embodiments, the present disclosure further provides the following non-limiting illustrative examples B1-B14 according to Formula II. Example B1 A compound having the formula II, II-1, II-2, II-3, II-4, II-3-A, II-3-B, II-4-A, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or a pharmaceutically acceptable salt thereof, wherein the variables of each formula include any combination of any of the variables defined herein. Example B2 R 1 is hydrogen or C optionally substituted with F 1-4 The compound according to Example B1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group. Example B3 R 1 is hydrogen; or a pharmaceutically acceptable salt thereof. Example B4 Where applicable, R 1 is a methyl group, or a pharmaceutically acceptable salt thereof. Example B5 R 2 The compound according to any one of Examples B1 to B4, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Example B6 R 4 The compound according to any one of Examples B1 to B5, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Example B7 R 6 The compound according to any one of Examples B1 to B6, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. Example B8 A compound according to any one of Examples B1 to B7, or a pharmaceutically acceptable salt thereof, wherein, where applicable, n1 and n2 are both 0. Example B9 Where applicable, n1 and n2 are both 1 and Ra and R b and R are each a methyl group, or a pharmaceutically acceptable salt thereof. Example B10 The compound according to any one of Examples B1 to B9, wherein X is O, or a pharmaceutically acceptable salt thereof. Example B11 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof. Example B12 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof. Example B13 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof. Example B14 R 3 teeth, [ka] or a pharmaceutically acceptable salt thereof.

[0136] Formula III In some embodiments, the present disclosure provides a compound having Formula III or a pharmaceutically acceptable salt thereof: [ka] (1) R 1 is hydrogen (in another embodiment, deuterium), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4alkenyl group, or optionally substituted C 2-4 is an alkynyl group, and R 2 , R 4 and R 5 are each independently hydrogen, halogen (e.g., F), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4 Alkynyl group, optionally substituted C 1-4 an alkoxy group or an optionally substituted 3- to 5-membered ring, or (2) R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; and R 4 and R 5 is as defined in (1), or (3) R 1 and R 5 are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; and R 2 and R 4 is as defined in (1), or (4) R 4 and R 5 are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered ring; and R 1 and R 2 is as defined in (1) or (2), and where: X is O, S, or NR 10 , optionally substituted C 1-4 an alkylene group, or an optionally substituted C 1-4 heteroalkylene group, where R 10 is hydrogen, optionally substituted C 1-4 an alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; AR represents an optionally substituted arylene group or an optionally substituted heteroarylene group; R 3 is hydrogen, optionally substituted C 1-4 an alkyl group or an optionally substituted 3- to 10-membered ring; R 1’ is hydrogen (in another embodiment, deuterium), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 alkenyl group, or optionally substituted C 2-4 is an alkynyl group, R 6 and R 6’ are each independently hydrogen (in another embodiment, deuterium), optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 alkenyl group, or optionally substituted C 2-4 is an alkynyl group, Integers n1 and n2 are each independently 0, 1, 2, 3, or 4; and R a and R b Each occurrence of 1-4 alkyl group or optionally substituted C 1-4 is a heteroalkylene group, or R a Two examples of R b are joined together with the intervening atoms to form an optionally substituted 3- to 6-membered ring, and R a and / or R b Any remaining examples of are as defined above.

[0137] In some embodiments, compounds having Formula III (including any applicable subformulas described herein) may contain one or more asymmetric centers and / or axial chirality and therefore may exist in multiple stereoisomeric forms (e.g., enantiomers and / or diastereomers). In some embodiments, compounds having Formula III may exist in the form of a single enantiomer and / or diastereomer (if applicable), or a stereoisomeric mixture (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some examples, where applicable, compounds having Formula III (including any applicable sub-formulas described herein) may exist as a single enantiomer substantially free of the other enantiomer (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or an undetectable amount by weight by HPLC or SFC area or both), e.g., the compound may have an enantiomeric excess ("ee") of greater than 60% (e.g., 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater, etc.). In some examples, where applicable, compounds having Formula III (including any applicable sub-formulas described herein) may exist as a mixture of stereoisomers (in any ratio), e.g., a racemic mixture.

[0138] In some embodiments, compounds having Formula III (including any applicable subformulas described herein) may exist as isotopically labeled compounds, particularly deuterated analogs, where one or more hydrogen atoms of a compound having Formula III are replaced with deuterium atoms that are in abundance above their natural abundance, e.g., if the compound has a CH3 group, it is a CD3 analog.

[0139] It will be apparent to one skilled in the art that in some cases, compounds having Formula III may exist as a mixture of tautomers. The present disclosure is not limited to any particular tautomer. To the contrary, the present disclosure encompasses any and all such tautomers, whether or not expressly depicted or referred to.

[0140] The variable R of formula III or any sub-formula thereof 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, R a , R b , n1, and n2, and any other variables, may be those representative variables defined herein for Formula I or any subformula thereof. 1’ and R 6’ are each R as defined herein for Formula I or any subformula thereof. 1 and R 6 In Formula III, R 1 and R 1’ Similarly, R in Formula III 6 and R 6’ may be the same or different.

[0141] In some embodiments, A represents an optionally substituted phenylene group. For example, A can be a phenylene group, which can optionally be independently selected from the group consisting of halogen, CN, OH, NH, optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4 Alkynyl group, optionally substituted C 1-4 In some embodiments, AR is substituted with 1 to 4 substituents selected from a heteroalkyl group or an optionally substituted 3- to 6-membered ring structure (e.g., a cyclopropyl group, etc.). In some embodiments, AR is a tetrafluorophenylene group, [ka] may be.

[0142] In some embodiments, A R represents an optionally substituted 5- or 6-membered heteroarylene group. In some embodiments, A R may represent an optionally substituted bicyclic arylene group or heteroarylene group.

[0143] In some embodiments, the compound having Formula III may be characterized as having a structure according to Formula III-1, III-2, III-3, or III-4: [ka] where: n11 is 0, 1, 2, 3, or 4; R o is independently selected from halogen (e.g., F), CN, OH, NH, optionally substituted C 1-4 alkyl groups, optionally substituted C 2-4 Alkenyl group, optionally substituted C 2-4 Alkynyl group, optionally substituted C 1-4 a heteroalkyl group or an optionally substituted 3- to 6-membered ring structure, such as a cyclopropyl group, and Other variables are as defined herein.

[0144] In some embodiments, the integers n1 and n2 in Formula III are both 1, and R in Formula III (e.g., III-1, III-2, or III-3) a and R b is the same as C 1-4 It may be an alkyl group, for example a methyl group, an ethyl group, or an isopropyl group.

[0145] Generally, R in Formula III (e.g., any one of the subformulas applicable herein) 6 and R 6’ are hydrogen. In one embodiment, R 6 is deuterium. In one embodiment, R 6’ is deuterium.

[0146] In some embodiments, R in Formula III (e.g., any one of the subformulas as applied herein) 1 and R 1’ are independently hydrogen or methyl groups, e.g., both hydrogen or both methyl groups. In one embodiment, R 1 is deuterium. In one embodiment, R 1’ is deuterium.

[0147] In some embodiments, R in Formula III (e.g., any one of the subformulas as applied herein) 4 and R 5 are both hydrogen.

[0148] In some embodiments, R in Formula III (e.g., any one of the subformulas as applied herein) 2 is hydrogen.

[0149] X in Formula III (e.g., any one of the subformulas as applied herein) is typically O. In one embodiment, X is S. In one embodiment, X is NR 10 In one embodiment, X is NH.

[0150] In some embodiments, X in Formula III (e.g., any one of the subformulas as applied herein) is C 1-4 It may also be an alkylene group, for example CH2.

[0151] In some embodiments, X in Formula III (e.g., any one of the subformulas as applied herein) is C 1-4Heteroalkylene groups may also be used, for example, those having one or two heteroatoms, which are independently O, S, and N. For example, in some embodiments, X in Formula III (e.g., any one of the subformulas as applied herein) may be -O-CH-. In one embodiment, X is -CH-O-. Unless otherwise specified, the left attachment site of X is R 3 is.

[0152] R in Formula III (e.g., any one of the subformulas as applied herein) 3 may be any of the definitions associated with formula I and its subformulas.

[0153] For example, in some embodiments, R in Formula III and subformulas thereof 3 teeth, [ka] may be.

[0154] In some embodiments, R in Formula III and subformulas thereof 3 teeth, [ka] may be.

[0155] In some embodiments, R in Formula III (e.g., any one of the subformulas as applied herein) 3 teeth, [ka] may be.

[0156] In one embodiment of any applicable formula according to this specification, R 6 The carbon connected to R has the S-configuration. 6The carbon connected to has the R-configuration. In one embodiment of any applicable formula according to this specification, R 6’ The carbon connected to R has the S-configuration. 6’ The carbon linked to has the R-configuration.

[0157] In some embodiments, the present disclosure provides a compound selected from any one of the following shown in Tables A1 to A10, or a pharmaceutically acceptable salt thereof. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] TIFF2025534444000138.tif225161TIFF2025534444000139.tif202161TIFF2025534444000140.tif230161 TIFF2025534444000141.tif211161TIFF2025534444000142.tif223161TIFF2025534444000143.tif136161 [Table 6] [Table 7] TIFF2025534444000146.tif205161TIFF2025534444000147.tif237161TIFF2025534444000148.tif184161 [Table 8] [Table 9] TIFF2025534444000151.tif67161

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 17

[0158] The compounds of Tables A1 through A18 can exist in multiple stereoisomeric forms, e.g., single isomers, single enantiomers and / or diastereomers (where applicable), or stereoisomeric mixtures (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some examples, where applicable, the compounds shown in Tables A1 through A18 may exist as a single enantiomer substantially free of the other enantiomer (e.g., having less than 20%, less than 10%, less than 5%, less than 1%, or an undetectable amount by weight by HPLC or SFC area or both), e.g., having an enantiomeric excess of 60% or greater, e.g., 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, or 99% ee or greater. In some examples, where applicable, the compounds shown in Tables A1 through A18 may exist as a mixture of stereoisomers (in any ratio), e.g., a racemic mixture.

[0159] In some embodiments, to the extent applicable, the classes of compounds described herein further exclude any specific single compounds known prior to the present disclosure. In some embodiments, to the extent applicable, any subclass or type of compound that entirely belonged to a class of compounds described herein prior to the present disclosure may also be excluded from this class of compounds herein.

[0160] In view of this disclosure, one of ordinary skill in the art can readily synthesize the compounds of the present disclosure. Exemplary syntheses are also provided in the Examples section.

[0161] As will be apparent to those skilled in the art, conventional protecting groups are necessary to protect some functional groups from undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis," 4th Edition, PGM Wuts; TW Greene, John Wiley, 2007, and the references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Other reagents can be prepared by procedures or obvious modifications thereof described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Vols. 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7th Edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH Publishers, 1999), as well as any available updated versions up to the present filing.

[0162] Pharmaceutical Composition Some embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0163] The pharmaceutical composition may optionally include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-C, I-7-D, I-7-E, I-7-E, I-7-F, I-7-G, I-7-H, I-7-I ... , I-7-B, I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B-E1, I-11-B-E2, I-13-A, I-13-B, I-13-B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7 , or IV-8), a compound having Formula II (e.g., II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1), a compound having Formula III (e.g., III-1, III-2, III-3, or III-4), any one of Examples 1-569, or any one of the specific compounds disclosed in Tables A1-A18 herein, or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting examples of suitable excipients include encapsulating materials or additives such as antioxidants, adhesives, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof.Further reference is made to Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Baltimore, MD, Williams & Wilkins, 2005, incorporated herein by reference), which disclosed various excipients for preparing pharmaceutical compositions and known techniques for manufacturing pharmaceutical compositions.

[0164] Pharmaceutical compositions may include any one or more compounds of the present disclosure. For example, in some embodiments, pharmaceutical compositions may include a compound of Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-C, I-7-D, I-7-E, I-7-E, I-7-F, I-7-H, I-7-I ... B, I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B-E1, I-11-B-E2, I-13-A, I-13-B, I-13 -B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, or or IV-8), a compound having Formula II (e.g., II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1), a compound having Formula III (e.g., III-1, III-2, III-3, or III-4), any one of Examples 1-569, or any one of the specific compounds disclosed in Tables A1-A18 herein, or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. In any example described herein, the pharmaceutical composition may include a therapeutically effective amount of a compound (e.g., used to treat a cancer described herein), the compound being selected from any one of Examples 1-569, or any one of the specific compounds disclosed in Tables A1-A18 herein, or a pharmaceutically acceptable salt thereof.

[0165] The pharmaceutical compositions herein can be formulated for delivery via any known route of delivery, including, but not limited to, oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal or parenteral administration.

[0166] In some embodiments, pharmaceutical compositions can be prepared for oral administration. Oral formulations can be present in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of active compound, and can be present as powders or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion. Excipients for preparing oral administration compositions are known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, and the like. oil), potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts, sodium dodecyl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0167] In some embodiments, the pharmaceutical composition is prepared for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for preparing parenteral formulations are known in the art. Non-limiting examples of suitable excipients include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0168] The compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, such as another anti-cancer therapeutic agent, e.g., any therapeutic agent approved on the market, e.g., approved by the U.S. Food and Drug Administration or other similar governmental agency.

[0169] When used in combination with one or more additional therapeutic agents, the compounds of the present disclosure or pharmaceutical compositions herein can be administered to a subject simultaneously with such other therapeutic agents in any order, or sequentially. In some embodiments, a pharmaceutical composition can contain one or more compounds of the present disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition containing one or more compounds of the present disclosure can be included in a kit, which further includes a separate pharmaceutical composition containing one or more additional therapeutic agents.

[0170] Pharmaceutical compositions may contain varying amounts of the compounds of the present disclosure, depending on various factors, such as the compound's expected use and its efficacy and selectivity. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount that effectively treats a disease or disorder described herein, such as a cancer described herein, and may depend on the recipient of the treatment, the disorder, symptom, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the efficacy of the compound, its clearance rate, and whether another drug is administered concomitantly.

[0171] Treatment / Usage The compounds of the present disclosure have multiple uses. For example, the compounds of the present disclosure can be used as therapeutic active agents to treat and / or prevent cancer, such as cancers characterized by aberrant AKR1C3 activity and / or AKR1C3 overexpression, such as cancers with NRF2 / KEAP1 mutations.

[0172] In some embodiments, the disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of one or more compounds of the disclosure (e.g., compounds of Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-I, I-1-I, I-1-I, I-1-J ... -1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B-E1, I-11-B-E2, I-13-A, I-13-B, I-13-B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV The present invention includes administering to the subject a compound having Formula II (e.g., II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1), a compound having Formula III (e.g., III-1, III-2, III-3, or III-4), any one of Examples 1-569, or any one of the specific compounds disclosed in Tables A1-A18 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition herein. Generally, the cancer is characterized by aberrant AKR1C3 activity and / or AKR1C3 overexpression. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is melanoma. In one embodiment, the cancer is prostate cancer, e.g., castration-resistant prostate cancer.

[0173] In some embodiments, the present disclosure provides a method of treating or preventing cancer with an NRF2 / KEAP1 mutation in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I-1-I, I-1-I-J, I-1-I-K, I-1-J ... I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B-E1, I-11-B-E2 , I-13-A, I-13-B, I-13-B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, or or IV-8), a compound having Formula II (e.g., II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A-E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1), a compound having Formula III (e.g., III-1, III-2, III-3, or III-4), any one of Examples 1-569, or any one of the specific compounds disclosed in Tables A1-A18 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition herein, wherein the NRF2 / KAEP1 mutation causes aberrant NRF2 activity, e.g., causing overexpression of AKR1C3. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is melanoma. In one embodiment, the cancer is prostate cancer, e.g., castration-resistant prostate cancer.

[0174] The type of cancer suitable for treatment with the methods herein is not particularly limited. For example, in some embodiments, the cancer may be cancer of the adrenal gland, bone, brain, breast, bronchus, colon and / or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nervous tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid, as well as acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, glioblastoma multiforme, hairy cell tumor, ganglioneuroma, proliferative corneal nerve tumor, pancreatic islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, The cancer is selected from the group consisting of lymphoma, malignant carcinoid, malignant melanoma, malignant hypercalcemia, Marfan tumor, medullary carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, osteogenic and other sarcomas, ovarian tumor, pheochromocytoma, polycythemia vera, primary brain tumor, small cell lung tumor, ulcerative and papillary squamous cell carcinoma, hyperplasia, seminoma, soft tissue sarcoma, retinoblastoma, rhabdomyosarcoma, small cell renal tumor, localized skin lesion, reticulum cell sarcoma, and Wilms' tumor. In some embodiments, the cancer is liver cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, or prostate cancer. In any embodiment described herein, the cancer may be characterized by abnormal AKR1C3 activity / AKR1C3 overexpression, which may be due to, for example, an NRF2 / KEAP1 mutation. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is melanoma. In one embodiment, the cancer is prostate cancer, for example, castration-resistant prostate cancer.

[0175] In some embodiments, the method includes first determining the AKR1C3 reductase level in the cancer, for example, by using an AKR1C3 antibody, and administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable composition according to the present specification if the AKR1C3 level is above a predetermined value, for example, if the AKR1C3 level is higher than the AKR1C3 level in control healthy cells.

[0176] In some embodiments, the method includes, prior to administration, determining intratumoral AKR1C3 reductase levels in a sample isolated from a cancer subject, and selecting the subject for treatment if the AKR1C3 level is above a predetermined level, for example, if the AKR1C3 level is higher than the AKR1C3 level in control healthy cells.

[0177] AKR1C3 levels can be measured by common methods well known to those skilled in the art. In some embodiments, the present specification provides a kit, which includes a method for isolating a sample from a patient and determining the AKR1C3 reductase level in cancer tumors in the sample using an AKR1C3 antibody, and a method for determining whether to administer a compound disclosed herein or a composition disclosed herein. In light of the present disclosure, it will be clear to those skilled in the art how to determine a therapeutically effective amount of a compound or composition disclosed herein and the appropriate administration method based on other methods known to them.

[0178] The administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the administration is oral. In some embodiments, the administration is parenteral injection, such as intravenous injection.

[0179] The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present disclosure can be administered as the sole active ingredient or as multiple active ingredients. In some embodiments according to the methods described herein, one or more compounds of the present disclosure can be administered together with another therapeutic agent, and can be administered simultaneously or sequentially in any order to a subject in need thereof. The other therapeutic agent can generally be another anti-cancer therapeutic agent, for example, any therapeutic agent approved on the market, such as a therapeutic agent approved by the U.S. Food and Drug Administration or other similar government agency.

[0180] The administration regimen includes possible variations and adjustments in the dosage of the methods described herein, which may depend on the recipient of treatment, the disorder, condition or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether other drugs are administered concomitantly.

[0181] definition It is to be understood that all parts and combinations thereof maintain proper valence.

[0182] It should further be understood that a particular embodiment of a variable portion herein may be the same as or different from another specific embodiment having the same identifier.

[0183] Suitable groups for use as variables in compounds having Formula I, II, or III, or subformulas thereof, are independently selected. Non-limiting useful groups for variables in compounds having Formula I, II, or III, or subformulas thereof (where applicable), include any applicable groups, alone or in any combination, shown in the examples or in the specific compounds described in Tables A1 through A18 herein. The variable R 3 In some embodiments, a compound having Formula I, II, or III may be prepared by adding any R shown in the examples or in the specific compounds described in Tables A1-A18 herein, without considering other variables shown in the specific compound. 3 R by group 3 In some embodiments, compounds having Formula I, II, or III may include any R group shown in the examples or in the specific compounds described in Tables A1-A18 herein. 3 R by group 3 may include combinations of groups with at least one other variable (e.g., X) in the examples or specific compounds described in Tables A1-A18 herein, where R 3 and at least one other variable may be from the same compound or a different compound. Any such combination is contemplated and is within the scope of the present disclosure.

[0184] The described embodiments of the present disclosure may be combined. Such combinations are contemplated and are within the scope of the present disclosure. For example, Formula I (e.g., Formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-B-E1, I- 7-B-E2, I-11-A, I-11-B, I-11-B-E1, I-11-B-E2, I-13-A, I-13-B, I-13-B-E1, I-13 -B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, or IV-8) R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , n1, n2, and any one or more definitions of X are R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , n1, n2, and X may be combined with any one or more other definitions (where applicable), and it is expected that compounds produced by such combinations will fall within the scope of the present disclosure.

[0185] symbol [ka] is displayed perpendicular to the bond or crossing it in some other way, e.g. [ka] indicates the point at which the indicated moiety is attached to the remainder of the molecule. It should be noted that, as will be understood by those of skill in the art, one or more groups that are directly linked may be denoted by the symbol ⁢ ... [ka] may be displayed outside of

[0186] Below, certain functional groups and chemical terminology definitions are explained in more detail. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th Edition, inside cover, and certain functional groups are generally defined as set forth therein. It should be noted that general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way to the exemplary list of substituents set forth herein.

[0187] The compounds described herein may contain one or more asymmetric centers and therefore may exist in multiple stereoisomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may exist in the form of a single enantiomer, diastereomer, or geometric isomer, or in the form of a stereoisomeric mixture (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and chiral salt formation and crystallization, or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, Indiana, 1972). The present disclosure also includes the compounds described herein as single isomers, substantially free of other isomers, and alternatively, as mixtures of various isomers, including racemic mixtures.Where stereochemistry is specifically depicted, unless the context contradicts otherwise, it should be understood that for that particular chiral center or axial chirality, the compound may exist predominantly as the depicted stereoisomer, with less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of one or more other stereoisomers, e.g., by weight by HPLC or SFC area or both, and that for that particular chiral center or axial chirality, the compound may have an enantiomeric excess ("ee") of greater than 60% (e.g., 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater, etc.). The presence and / or amount of stereoisomers can be determined by one of ordinary skill in the art based on this disclosure, including using chiral HPLC or chiral SFC. As will be understood by those of skill in the art, the inclusion of an "*" in a chemical structure herein, unless the context dictates otherwise, indicates that the corresponding chiral center is enantiomerically pure or enriched in any configuration, or is enantiomerically pure or enriched in the depicted configuration, e.g., less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of one or more other stereoisomers by weight, e.g., by HPLC or SFC area or both. It should be understood that, unless the stereochemistry is specifically depicted and an "*" is not used in a chemical structure, unless the context dictates otherwise, such structure includes the corresponding compound in any stereoisomeric form, including a single isomer substantially free of other isomers, and mixtures of various isomers, including racemic mixtures. For example, it will be understood by those of skill in the art that Formula I includes the corresponding compound in any stereoisomeric form and mixtures of various isomers.

[0188] Unless the context contradicts otherwise, when the stereochemistry of a chiral center in a compound prepared in the examples is explicitly shown (e.g., with a widget bond and / or a dash bond), whether without further designation or designated as "R" (or "(R)") or "S" (or "(S)"), this means that either the two enantiomers of that chiral center are separated and the absolute stereochemistry is known, or only one enantiomer is obtained and the absolute stereochemistry is known. Unless the context contradicts otherwise, when the stereochemistry of a chiral center in a compound prepared in the examples is not explicitly shown (e.g., with a direct bond) but "*" is used to represent the chiral center, this means that the compound itself is separated as a single stereoisomer and is enantiomerically pure or enriched, but the absolute stereochemistry has not been determined. Unless the context contradicts otherwise, when the stereochemistry of a chiral center in a compound prepared in an example is not explicitly indicated (e.g., with a direct bond) and no "*" is used to indicate a chiral center, this means that the compound is a racemic mixture at that chiral center.

[0189] When a numerical range is recited, it is intended to encompass all values ​​and subranges within that range. For example, "C 1-6 ” is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 is intended to encompass:

[0190] As used herein, the term "one or more compounds of the disclosure" refers to compounds of Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-1-A, I-1-B, I-1-B-E1, I-1-B-E2, I-5-B-E1, I-5-B-E2, I-7-A, I-7-B, I-7-B-E1, I-7-B-E2, I-11-A, I-11-B, I-11-B-E1 , I-11-B-E2, I-13-A, I-13-B, I-13-B-E1, I-13-B-E2, I-13-B-E3, I-13-B-E4, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, or IV-8), formula II (e.g. II-1, II-2, II-3, II-4, II-3-A, II-4-A, II-3-B, II-4-B, II-3-A-E1, II-3-A-E2, II-4-A-E1, II-4-A- E2, II-4-A-E3, II-4-A-E4, II-4-B-E1, II-4-B-E2, or V-1), Formula III (e.g., III-1, III-2, III-3, or III-4), any one of Examples 1-569, or any one of the specific compounds disclosed in Tables A1-A18 herein, one or more isotopically labeled compounds thereof (e.g., deuterated analogs, where one or more hydrogen atoms are replaced with deuterium atoms that are in abundance greater than their natural abundance, e.g., CD3 analogs when the compound has a CH3 group), possible regioisomers thereof, possible geometric isomers, possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), possible tautomers thereof, possible conformational isomers thereof, pharmaceutically acceptable esters thereof, and / or possible pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts, or base addition salts such as Na salts). For clarity, the compounds of Examples 1-569 refer to compounds labeled with the integer in the Example portion only, e.g., 1, 2, etc., up to 569. See, e.g., Examples 1-51 and the Table of Characteristics herein. Exemplary syntheses and characterizations of Examples 1-569 are provided in the Examples section. Detailed exemplary procedures are provided in the illustrated examples, e.g., 1-51.Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, where one or more compounds are associated with water or a solvent, respectively. In some examples, the compound of the present disclosure may be any compound set forth in Examples A1 to A14 or B1 to B14.

[0191] The compounds of the present disclosure may exist in isotopically labeled or isotopically enriched forms containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine are 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl, and 125 Compounds containing other isotopes of these and / or other atoms are within the scope of this invention, including but not limited to I.

[0192] As used herein, the phrase "administration of" a compound, "administering" a compound or other variant refers to providing the compound or a prodrug of the compound to an individual in need of treatment.

[0193] As used herein, the term "alkyl group," used alone or as part of another group, refers to a straight or branched chain aliphatic saturated hydrocarbon. In some embodiments, an alkyl group has 1 to 12 carbon atoms (i.e., C 1-12 The alkyl group may contain a specified number of carbon atoms. In one embodiment, the alkyl group is a straight-chain C 1-10 In another embodiment, the alkyl group is a branched C 3-10 In another embodiment, the alkyl group is a straight chain C 1-6In another embodiment, the alkyl group is a branched C 3-6 In another embodiment, the alkyl group is a straight chain C 1-4 It is an alkyl group. For example, C 1-4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl groups. As used herein, the term "alkylene group," used alone or as part of another group, refers to a divalent group derived from an alkyl group. For example, non-limiting straight-chain alkylene groups include -CH-CH-CH-CH-, -CH-CH-CH-, -CH-CH-, and the like.

[0194] As used herein, the term "alkenyl group," used alone or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one, two, or three, carbon-carbon double bonds. In one embodiment, the alkenyl group is 2-6 In another embodiment, the alkenyl group is C 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl groups.

[0195] As used herein, the term "alkynyl group," used alone or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., 1 to 3, carbon-carbon triple bonds. In one embodiment, an alkynyl group has one carbon-carbon triple bond. In one embodiment, an alkynyl group is a C 2-6 In another embodiment, the alkynyl group is C 2-4 Alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0196] As used herein, the term "alkoxy group" used alone or as part of another group refers to a group of the formula OR a1 where R a1 is an alkyl group.

[0197] As used herein, the term "cycloalkoxy group" used alone or as part of another group refers to a group of the formula OR a1 where R a1 is a cycloalkyl group.

[0198] As used herein, the term "haloalkyl group," used alone or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a C 1-10 In one embodiment, the haloalkyl group is C 1-6 In one embodiment, the haloalkyl group is C 1-4 It is a haloalkyl group.

[0199] As used herein, the term "heteroalkyl group," alone or in combination with other terms, refers to, unless otherwise specified, a stable straight- or branched-chain alkyl group, e.g., having 2 to 14 carbons in the chain, e.g., 2 to 10 carbons, in which one or more carbons have been replaced with a heteroatom selected from S, O, P, and N, and in which the nitrogen, phosphine, and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms S, O, P, and N may be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When a heteroalkyl group is referred to as substituted, one or more substituents can replace one or more carbon atoms and / or one or more hydrogen atoms bonded to one or more heteroatoms of the heteroalkyl group. In some embodiments, a heteroalkyl group is selected from the group consisting of C 1-4 C is a heteroalkyl group, and refers to a heteroalkyl group having 1 to 4 carbon atoms as defined herein. 1-4Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups such as, for example, -CH2-CH2-N(CH3)-CH3; C3 heteroalkyl groups such as, for example, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3; C2 heteroalkyl groups such as, for example, -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3; and C1 heteroalkyl groups such as, for example, -CH2-OH, -CH2-NH2, -O-CH3. Similarly, the term "heteroalkylene group," by itself or as part of another substituent, refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH-CH-O-CH-CH- and -O-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can occupy one or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Also, for alkylene groups and heteroalkylene linking groups, the direction of the written formula of the linking group does not imply any orientation of the linking group. "Heteroalkyl groups" are mentioned, and specific heteroalkyl groups, such as -NR'R ’’ It should be understood that the terms heteroalkyl group and -NR'R" are neither redundant nor mutually exclusive. Conversely, specific heteroalkyl groups are recited for clarity. Thus, the term "heteroalkyl group" should not be construed herein to exclude specific heteroalkyl groups, such as -NR'R".

[0200] A "carbocyclic group" or "carbocyclic" used alone or as part of another group refers to a ring containing at least three carbon atoms, e.g., 3 to 10 ring carbon atoms ("C 3-10"Carbocyclylene" refers to a group of non-aromatic cyclic hydrocarbon groups having a ring structure ("monocyclic carbocyclic group") and having zero heteroatoms in the non-aromatic ring system. Carbocyclic groups can be monocyclic ("monocyclic carbocyclic group") or contain fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic carbocyclic group"), and can be saturated or partially unsaturated. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene group," used alone or as part of another group, refers to a divalent radical derived from a carbocyclic group, as defined herein.

[0201] In some embodiments, a "carbocyclic group" is fully saturated and is also referred to as a cycloalkyl group. In some embodiments, a cycloalkyl group can have from 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the cycloalkyl group is monocyclic. As used herein, a "cycloalkylene group," used alone or as part of another group, refers to a cycloalkyl group, e.g., [ka] It refers to a divalent group derived from, for example,

[0202] A "heterocyclyl group" or "heterocyclic" used alone or as part of another group refers to a group of three or more (e.g., 3 to 14) membered non-aromatic ring systems having ring carbon atoms and at least one ring heteroatom (e.g., 1 to 4 ring heteroatoms), where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, if valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl groups") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl groups"), and may be saturated or partially unsaturated. Bicyclic systems of heterocyclyl groups may contain one or more heteroatoms in one or both rings, and the point of attachment may be at any ring. As used herein, a "heterocyclylene group," used alone or as part of another group, refers to a divalent radical derived from a heterocyclyl group, as defined herein. The heterocyclyl or heteroalkylene group can be optionally attached to the remainder of the molecule through a carbon or nitrogen atom.

[0203] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups having two heteroatoms include, but are not limited to, dioxolanyl, oxathiofuryl, dithiofuryl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl groups. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thioalkyl groups. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxane groups. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl groups. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiacycloheptyl groups. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azacyclooctyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, dihydroindolyl, isoindolinyl, dihydrobenzofuryl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolyl, and the like.

[0204] An "aryl group," used alone or as part of another group, refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., sharing 6, 10, or 14 pi electrons in a cyclic array) containing 6 to 14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, the aryl group has six ring carbon atoms (a "C aryl group," e.g., a phenyl group). In some embodiments, the aryl group has ten ring carbon atoms (a "C 10 Aryl groups, such as naphthyl groups, e.g., 1-naphthyl and 2-naphthyl groups. In some embodiments, the aryl group has fourteen ring carbon atoms ("C 14 As used herein, the term "arylene group" used alone or as part of another group refers to a divalent radical derived from an aryl group, as defined herein.

[0205] An "aralkyl group," used alone or as part of another group, refers to an alkyl group substituted with one or more aryl groups, in one embodiment, one aryl group. Examples of aralkyl groups include benzyl, phenethyl, and the like. When an aralkyl group is referred to as being optionally substituted, either the alkyl or aryl portion of the aralkyl group may be optionally substituted.

[0206] A "heteroaryl group," used alone or as part of another group, refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., sharing 6 or 10 π-electrons in a cyclic array) containing ring carbon atoms and at least one, and in one embodiment, 1 to 4, ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 14-membered heteroaryl group"). In heteroaryl groups containing one or more nitrogen atoms, the attachment site may be at a carbon atom or a nitrogen atom, if valence permits. Bicyclic systems of heteroaryl groups may contain one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups, where one ring (e.g., indolyl, quinolyl, etc.) does not contain a heteroatom, the attachment site may be at either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene group," used alone or as part of another group, refers to a divalent radical derived from an aryl group, as defined herein.

[0207] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuryl, benzoisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolyl, quinoxalyl, phthalazinyl, and quinazolyl groups.

[0208] A "heteroaralkyl group," used alone or as part of another group, refers to an alkyl group substituted with one or more heteroaryl groups, and in one embodiment, one heteroaryl group. When a heteroaralkyl group is referred to as being optionally substituted, either the alkyl group portion or the heteroaryl group portion of the heteroaralkyl group can be optionally substituted.

[0209] "Optionally substituted" groups, such as optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted carbocyclic groups, optionally substituted heterocyclyl groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, refer to the corresponding groups whether unsubstituted or substituted. Generally, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent (e.g., a substituent that, upon substitution, results in a stable compound; e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction)). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituents can be the same or different at each position. Unless otherwise specified, when the number of substituents on a "substituted" group is not specified, it means that the group is substituted with one or more substituents, valence permitting. For example, unless otherwise specified, C optionally substituted with F 1-4 The alkyl group may be a C optionally substituted with one or more F. 1-4" refers to an alkyl group, including, for example, CF3. Generally, when substituted, optionally substituted groups herein may be substituted with 1 to 5 substituents. The substituents may be carbon atom, nitrogen atom, oxygen atom, or sulfur atom substituents, each of which, if applicable, may be optionally isotopically labeled, e.g., deuterated. Two of the optional substituents may be linked to form a ring structure, such as an optionally substituted cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl ring. Substitution may occur at any available carbon, oxygen, or nitrogen atom and may form a spirocyclic ring. Generally, substitutions herein do not result in OO, ON, SS, SN (excluding SO2-N bonds), heteroatom-halogen, or -C(O)-S bonds or three or more consecutive heteroatoms, except for O-SO2-O, O-SO2-N, and N-SO2-N, except where several such bonds or linkages may be tolerated in a stable aromatic system.

[0210] In a broad sense, the permissible substituents herein include both cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. For appropriate organic compounds, the permissible substituents can be one or more and the same or different. For purposes of this disclosure, heteroatoms (e.g., nitrogen) can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatom. The substituents may include any of the substituents described herein, for example, a halogen, a hydroxy group, a carbonyl group (e.g., a carboxyl group, an alkoxycarbonyl group, a formyl group, or an acyl group), a thiocarbonyl group (e.g., a thioester, a thioacetate, or a thioformate ester), an alkoxy group, a cycloalkoxy group, a phosphoryl group, a phosphate ester, a phosphonate ester, a phosphonite ester, an amino group, an amidine, an imine, a cyano group, a nitro group, an azide group, a mercapto group, an alkylthio group, a sulfate ester, a sulfonate ester, a sulfamoyl group, a sulfonamide group, a sulfonyl group, a heterocyclyl group, an aralkyl group, an aryl group, or a heteroaryl group, each of which may be optionally substituted, where applicable.

[0211] Exemplary substituents are alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, -alkylene-aryl groups, -arylene-alkyl groups, -alkylene-heteroaryl groups, -alkenylene-heteroaryl groups, -alkynylene-heteroaryl groups, -OH, hydroxyalkyl groups, haloalkyl groups, -O-alkyl groups, -O-haloalkyl groups, -alkylene-O-alkyl groups, -O-aryl groups, -O-alkylene-aryl groups, acyl groups, -C(O)-aryl groups, halo, -NO, -CN, -SF, -C(O)OH, -C(O)O-alkyl groups, -C(O)O-aryl groups, -C(O)O-alkylene-aryl groups, -S(O)-alkyl groups, -S(O)-alkyl groups, -S(O)-aryl groups, -S(O)-aryl groups, -S(O)-heteroaryl groups, -S(O)-heteroaryl groups. , -S-alkyl groups, -S-aryl groups, -S-heteroaryl groups, -S-alkylene-aryl groups, -S-alkylene-heteroaryl groups, -S(O)-alkylene-aryl groups, -S(O)-alkylene-heteroaryl groups, cycloalkyl groups, heterocycloalkyl groups, -OC(O)-alkyl groups, -OC(O)-aryl groups, -OC(O)-cycloalkyl groups, -C(=N-CN)-NH, -C(=NH)-NH, -C(=NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y1)(Y2), -C(O)N(Y1)(Y2), and -S(O)N(Y1)(Y2), where Y1 and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl groups, aryl groups, cycloalkyl groups, and -alkylene-aryl groups.

[0212] Some examples of suitable substituents are (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10) cycloalkyl groups, halogen (F, Cl, Br, or I), halogenated (C1-C8) alkyl groups (such as, but not limited to, -CF3), -O-(C1-C8) alkyl groups, -OH, -S-(C1-C8) alkyl groups, -SH, -NH(C1-C8) alkyl groups, -N((C1-C8) alkyl) groups, -NH, -C(O)NH, -C(O)NH(C1-C8) alkyl groups, -C(O)N((C1-C8) alkyl) groups, -NHC(O)H, -NHC(O) (C1-C8) alkyl groups, -NHC(O)(C3-C8)cycloalkyl group, -N((C1-C8)alkyl)C(O)H, -N((C1-C8)alkyl)C(O)(C1-C8)alkyl group, -NHC(O)NH2, -NHC(O)NH(C1-C8)alkyl group, -N((C1-C8)alkyl)C(O)NH2 group, -NHC(O)N((C1-C8)alkyl)2 group, -N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 group, -N((C1-C8)alkyl)C(O)NH((C1-C8)alkyl), -C(O)H, -C(O)(C 1-C8) alkyl group, -CN, -NO2, -S(O)(C1-C8) alkyl group, -S(O)2(C1-C8) alkyl group, -S(O)2N((C1-C8) alkyl)2 group, -S(O)2NH(C1-C8) alkyl group, -S(O)2NH(C3-C8) cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1-C8) alkyl group, -N((C1-C8) alkyl)S(O)2(C1-C8) alkyl group, -(C1-C8) alkyl-O-(C1-C8) alkyl group, -O-(C1-C8) alkyl-O-( C1-C8)alkyl groups, -C(O)OH, -C(O)O(C1-C8)alkyl groups, NHOH, NHO(C1-C8)alkyl groups, -O-halogenated(C1-C8)alkyl groups (such as, but not limited to, -OCF3), -S(O)2-halogenated(C1-C8)alkyl groups (such as, but not limited to, -S(O)2CF3), -S-halogenated(C1-C8)alkyl groups (such as, but not limited to, -SCF3), -(C1-C6)heterocycles (such as, for example, pyrrolidine, tetrahydrofuran, pyran, or mol Examples of alkyl groups include, but are not limited to, -(C1-C6)heteroaryl groups (such as, but not limited to, tetrazole, imidazole, furan, pyrazine, or pyrazole), -phenyl groups, -NHC(O)O-(C1-C6)alkyl groups, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl groups, -C(=NH)-(C1-C6)alkyl groups, -C(=NOH)-(C1-C6)alkyl groups, or -C(=NO-(C1-C6)alkyl)-(C1-C6)alkyl groups.

[0213] Exemplary carbon atom substituents are deuterium, halogen, -CN, -NO2, -N3, hydroxy groups, alkoxy groups, cycloalkoxy groups, aryloxy groups, amino groups, monoalkylamino groups, dialkylamino groups, amides, sulfonamides, thiols, acyl groups, carboxylic acids, esters, sulfones, sulfoxides, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, C 3-10 carbocyclic group, C 6-10 These include, but are not limited to, aryl groups, 3- to 10-membered heterocyclyl groups, 5- to 10-membered heteroaryl groups, etc. For example, exemplary carbon atom substituents are F, Cl, —CN, —SOH, —SOH, —OH, —OC 1-6 Alkyl group, -NH2, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), -SH, -SC 1-6 Alkyl group, -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl group, -SO2OC 1-6 Alkyl group, -OSO2C 1-6 Alkyl group, -SOC 1-6 Alkyl group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6Alkenyl group, C 2-6 Alkynyl group, C 3-10 carbocyclic group, C 6-10 It may include an aryl group, a 3- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or two geminal substituents may be linked to form =O.

[0214] Where valence allows, nitrogen atoms may be substituted or unsubstituted and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, acyl groups, esters, sulfones, sulfoxides, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Carbocyclic groups, 3- to 14-membered heterocyclyl groups, C 6-14or two substituents attached to a nitrogen atom may be linked to form a 3- to 14-membered heterocyclyl group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also called an amino protecting group). Nitrogen protecting groups are well known in the art and include those nitrogen protecting groups described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those that form urethanes, such as benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), Troc, 9-fluorenemethoxycarbonyl (Fmoc), etc.; those that form amides, such as acetyl, benzoyl, etc.; those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those that form sulfonamides, such as toluenesulfonyl, nitrobenzenesulfonyl, etc.; and others, such as p-methoxyphenyl.

[0215] Exemplary oxygen atom substituents are acyl groups, esters, sulfonate esters, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Carbocyclic groups, 3- to 14-membered heterocyclyl groups, C 6-14

[0023] Examples of suitable oxygen protecting groups include, but are not limited to, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and 5- to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxy protecting group). Oxygen protecting groups are well known in the art and include those oxygen protecting groups described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl groups, e.g., 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and the like; those that form silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), and the like; those that form acetals or ketals, such as tetrahydropyranyl (THP); those that form ester systems, such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, and the like; and those that form carbonates or sulfonates, such as methanesulfonate (or mesylate), benzylsulfonate, toluenesulfonate (Ts), and the like.

[0216] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that is separable from preparation and whose structure and properties can be maintained or remain substantially unchanged for a period of time sufficient to permit use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0217] In some examples, an "optionally substituted" alkyl group, alkylene group, heteroalkyl group, heteroalkylene group, alkenyl group, alkynyl group, carbocycle, carbocyclylene group, cycloalkyl group, cycloalkylene group, alkoxy group, cycloalkoxy group, heterocyclyl group, or heterocyclylene group herein is each independently unsubstituted or independently substituted with deuterium, F, Cl, -OH, a protected hydroxy group, oxo (where applicable), NH, a protected amino group, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 alkyl), C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 and cycloalkoxy groups, phenyl groups, 5- or 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl groups containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl groups is optionally substituted independently with deuterium, F, —OH, oxo (where applicable), C, or HCl. 1-4 Alkyl groups, fluorine-substituted C 1-4 Alkyl groups (e.g., CF3), C 1-4Alkoxy and fluorine-substituted C 1-4 In some embodiments, the "optionally substituted" aryl, arylene, heteroaryl, or heteroarylene groups herein are each independently unsubstituted or independently substituted with deuterium, F, Cl, -OH, -CN, NH, a protected amino group, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 alkyl), -S(=O)(C 1-4 alkyl), -SO2(C 1-4 alkyl), C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 and cycloalkoxy groups, phenyl groups, 5- or 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl groups containing 1 or 2 heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl groups is optionally substituted independently with deuterium, F, —OH, oxo (where applicable), C 1-4 Alkyl groups, fluorine-substituted C 1-4 Alkyl group, C 1-4 Alkoxy and fluorine-substituted C 1-4 It is substituted with 1, 2, or 3 substituents selected from alkoxy groups.

[0218] "Halo" or "halogen" refers to fluorine (fluorine or fluoro, -F), chlorine (chlorine or chloro, -Cl), bromine (bromine or bromo, -Br), or iodine (iodine or iodo, -I).

[0219] The term "pharmaceutically acceptable salt" refers to a salt that may be adapted, within the scope of sound medical judgment, for contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0220] The terms "tautomer" or "tautomeric" refer to two or more interconvertible compounds resulting from tautomerism. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerism is known to those skilled in the art. Exemplary tautomerisms include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(different)enamine tautomerism.

[0221] As used herein, the term "subject" (alternatively referred to herein as "patient") refers to an animal, in one embodiment, a mammal, and, in another embodiment, a human, who has been the object of treatment, observation or experiment.

[0222] As used herein, terms such as "treat," "treating," "treatment," and the like refer to the elimination, reduction, or amelioration of a disease or condition and / or its associated symptoms. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition, or its associated symptoms. As used herein, in a subject not suffering from, but at risk of, or susceptible to recurrence of, the disease or condition, the terms "treat," "treating," "treatment," and the like, can include "prophylactic treatment," which refers to reducing the likelihood of recurrence of a disease or condition or the recurrence of a previously managed disease or condition. The terms "treatment" and cognate terms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0223] The term "effective amount" refers to the amount of a compound or combination of compounds described herein sufficient to achieve the expected application (including, but not limited to, disease prevention or treatment). A therapeutically effective amount can vary based on the expected administration (in vitro or in vivo), or the subject and disease condition being treated (e.g., the subject's weight, age, and sex), the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a specific response in target cells and / or tissues. The specific dose will vary based on the particular compound selected, the subsequent administration regimen (whether or not the compound is combined with other compounds), the time of administration, the tissue to which it is administered, and the physical delivery system with which the compound is associated.

[0224] As used herein, the singular forms "a" and "an" and "the" include plural referents unless expressly stated or clearly indicated otherwise from the context.

[0225] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include A and B, A or B, A alone, and B alone. Similarly, the term "and / or" as used in phrases such as "A, B and / or C" is intended to cover each of the following embodiments: A, B and C, A, B or C, A or C, A or B, B or C, A and C, A and B, B and C, A alone, B alone, and C alone.

[0226] Titles and subtitles are used for convenience and / or formal compliance only, do not limit the subject technology, and are not related to interpretation of the description of the subject technology. In various embodiments, features described under one title or one subtitle disclosed in this subject matter may be combined with features described under other titles or subtitles. However, not all features under a single title or a single subtitle may be used together in an embodiment.

[0227] example The various starting materials, intermediates, and compounds of the Examples herein can be isolated and purified, where appropriate, using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds may be performed by conventional methods, such as melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Abbreviations used in the Examples section should be understood to have their ordinary meaning in the art, unless otherwise specified or clearly contrary to the context. The Examples are illustrative only and do not limit the invention sought to be protected in any manner.

[0228] Illustrative examples for carrying out the steps of synthesizing the products described herein are described in more detail below. Some examples discussed herein can be prepared by separation from the corresponding racemic mixture. As will be understood by those skilled in the art, prior to a chiral separation step, e.g., by supercritical fluid chromatography (SFC), the compounds described in the Examples section exist in the form of racemic and / or stereoisomeric mixtures, and the relative stereochemistry is represented in the chemical structure diagrams by bold type rather than a wedge-shaped bond. It should be understood that the enantiomeric excess ("ee") reported for these examples is representative of the illustrative procedures herein only and is not limiting, and one skilled in the art will understand, in light of the present disclosure, that such enantiomers having different ees, e.g., higher ees, can be obtained. [Table 19] TIFF2025534444000184.tif135161

[0229] Analytical Instrumentation and Purification NMR instrument details: Varian 400MHz, probe-1: Auto XID, probe-2: ATB.

[0230] LCMS instrument details: Shimadzu LCMS-2010EV system coupled to an SPD-M20A PDA and ELS detector. Softa model no. 400. Synthesis of 3-hydroxy-N,N-dimethylbenzamide (Int. 1) [ka] 3-Acetoxybenzoic acid

[0231] To a solution of 3-hydroxybenzoic acid (10.0 g, 0.14 mol, 1.0 eq.) in pyridine (100 mL) was added acetic anhydride (50 mL), and the mixture was stirred under nitrogen gas at 125 °C for 2 hr. After completion, the reaction mixture was cooled in an ice bath and carefully neutralized with aqueous NaHCO (30 mL, saturated), followed by acidification with 12 N HCl until the pH was adjusted to pH = 2. The suspension was filtered, and the filter cake was washed with HO (100 mL) and dried under vacuum to give 3-acetoxybenzoic acid (12.0 g, 66.7 mmol, 92%) as a brown solid. LC-MS (ESI): m / z 181 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.59-8.55 (m,1H),7.86-7.81 (m,1H),7.68-7.64 (m,1H),7.55 (t,J=7.9Hz,1H),7.41-7.37 (m,1H),2.29 (s,3H).

[0232] Acetic acid 3-(dimethylaminoformyl)phenyl ester At 0 °C under nitrogen gas, oxalyl chloride (14.3 mL, 166.5 mmol, 5.0 eq.) was added dropwise to a stirred suspension of 3-acetoxybenzoic acid (6.0 g, 33.3 mmol, 1.0 eq.) in DCM (60 mL). After stirring at 0 °C for 4 h, a solution of dimethylamine (33.3 mL, 66.6 mmol, 2 M in THF, 2.0 eq.) was added dropwise below 0 °C, and the mixture was stirred for an additional 20 h. Upon completion, the resulting mixture was poured into ice-water HCl (20 mL, 1 M) and extracted with DCM (50 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give acetic acid 3-(dimethylaminoformyl)phenyl ester (6.4 g, 31.0 mmol, 99%) as a yellow solid. LC-MS (ESI): m / z 208[M+H] + .

[0233] 3-Hydroxy-N,N-dimethylbenzamide Under nitrogen gas, K2CO3 (4.5 g, 32.6 mmol, 1.05 eq.) was added to a solution of acetic acid 3-(dimethylaminoformyl)phenyl ester (6.4 g, 31.0 mmol, 1.0 eq.) in MeOH (70 mL). The reaction mixture was stirred at room temperature for 18 h. The suspension was filtered, and the filter cake was washed with MeOH (20 mL). The combined filtrate was concentrated to give a colorless oil, 3-hydroxy-N,N-dimethylbenzamide (5.3 g, 32.1 mmol, 98%), which was used directly in the next step without purification. LC-MS (ESI): m / z 166 [M+H] + . Synthesis of 2-cyclopropyl-6-hydroxyisoindolin-1-one (Int. 2, upper fragment) [ka] 2-Cyclopropyl-6-methoxyisoindolin-1-one

[0234] To a solution of 2-(bromomethyl)-5-methoxybenzoic acid methyl ester (300 mg, 1.16 mmol, 1.0 eq.) and cyclopropylamine (72.72 mg, 1.27 mmol, 1.1 eq.) in MeOH (5 mL) was added dipotassium carbonate (400.07 mg, 2.90 mmol, 2.5 eq.) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a white solid, 2-cyclopropyl-6-methoxyisoindolin-1-one (200 mg, 0.98 mmol, 85%). LC-MS (ESI): m / z 204.2 [M+H] + .

[0235] 2-Cyclopropyl-6-hydroxyisoindolin-1-one To a solution of 2-cyclopropyl-6-methoxyisoindolin-1-one (100 mg, 0.49 mmol) in DCM (5 mL) at −20° C., tribromoborane (0.07 mL, 0.74 mmol, 1.5 eq.) in DCM (1 mL) was added dropwise. The reaction mixture was stirred at −20° C. for 2 hours under a nitrogen atmosphere. Upon completion, the reaction mixture was poured into ice water (5 mL) at 0° C. and extracted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give a white solid, 2-cyclopropyl-6-hydroxyisoindolin-1-one (60 mg, 0.32 mmol, 64%). LC-MS (ESI): m / z 190.1 [M+H] + . Synthesis of 6-hydroxy-2-methylisoindolin-1-one (Int.3) [ka] 6-Methoxy-2-methylisoindolin-1-one

[0236] To a solution of 6-methoxyisoindolin-1-one (200 mg, 1.23 mmol, 1.0 eq.) in DMF (5 mL) at 25 °C, CS2CO3 (798.68 mg, 2.45 mmol, 2.0 eq.) and methyl iodide (0.15 mL, 2.40 mmol, 2.0 eq.) were added. The reaction mixture was heated to 40 °C and stirred under a nitrogen atmosphere for 2 h. Upon completion, the reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 6-methoxy-2-methylisoindolin-1-one (180 mg, 1.02 mmol, 83%) as a white solid. LC-MS (ESI): m / z = 178 [M+H] + .

[0237] 6-Hydroxy-2-methylisoindolin-1-one Tribromoborane (0.19 mL, 2.03 mmol, 2.0 eq.) was added dropwise to a solution of 6-methoxy-2-methylisoindolin-1-one (180 mg, 1.02 mmol, 1.0 eq.) in DCM (5 mL) at −20° C. The reaction mixture was stirred at −20° C. for 2 hours under a nitrogen atmosphere. After completion, the reaction mixture was poured into ice water (5 mL) at 0° C. and extracted with DCM (5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a yellow solid, 6-hydroxy-2-methylisoindolin-1-one (160 mg, 0.981 mmol, 97%), which was used directly in the next step without purification. LC-MS (ESI): m / z 164 [M+H] + . Synthesis of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (Int.4) [ka] 3-(3-bromo-2-fluorophenyl)propionic acid

[0238] At 0 °C, HCOOH (40.6 g, 882 mmol, 3.00 equiv.) was added dropwise to EtN (38.7 g, 382 mmol, 1.30 equiv.). The mixture was stirred at room temperature for 15 min. To the above mixture at room temperature, DMF (500 mL), 3-bromo-2-fluorobenzaldehyde (59.7 g, 294 mmol, 1.00 equiv.), and Meldrum's acid (42.4 g, 294 mmol, 1.00 equiv.) were added. The resulting mixture was stirred at 100 °C for an additional 12 h. The mixture was cooled to room temperature and poured into concentrated HCl / ice water (1 / 10 v / v) (3.0 L). The precipitated solid was collected by filtration and washed with water (3 × 300 mL). The solid was dried under reduced pressure. This gave an off-white solid, 3-(3-bromo-2-fluorophenyl)propionic acid (64.5 g, crude). LC-MS (ESI): m / z 244.80, 246.80 [MH] -

[0239] 3-(3-bromo-2-fluorophenyl)propionyl chloride To a stirred solution of 3-(3-bromo-2-fluorophenyl)propionic acid (80.0 g, 324 mmol, 1.00 equiv.) and DMF (0.50 mL, 6.48 mmol, 0.02 equiv.) in DCM (500 mL) at 0 °C, SOCl (116 g, 972 mmol, 3.00 equiv.) was added dropwise. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure to give 3-(3-bromo-2-fluorophenyl)propionyl chloride (82.0 g, crude) as a yellow oil.

[0240] 5-Bromo-4-fluoro-2,3-dihydroinden-1-one To a stirred solution of 3-(3-bromo-2-fluorophenyl)propionyl chloride (82.0 g, 308.8 mmol, 1.00 equiv.) in DCM (500.0 mL) at 0 °C, AlCl (61.8 g, 463.3 mmol, 1.50 equiv.) was added portionwise. The resulting mixture was stirred at 0 °C for 15 min, then warmed to room temperature and continued stirring for 3 h under a nitrogen gas atmosphere. The resulting mixture was poured into ice water (1000 mL). The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 100 mL). The filtrate was extracted with CHCl (3 × 400 mL). The combined organic layers were washed with brine (2 × 500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE / EA (6 / 1) (400 mL) to give a pale yellow solid, 5-bromo-4-fluoro-2,3-dihydroinden-1-one (65.3 g, crude). 1 H NMR (400MHz,DMSO-d6) δ 7.81-7.71 (m,1H),7.42 (d,J=8.1Hz,1H),3.20-3.07 (m,2H),2.80-2.64 (m,2H).

[0241] N-(4-fluoro-1-oxo-2,3-dihydroinden-5-yl)acetamide A mixture of 5-bromo-4-fluoro-2,3-dihydroinden-1-one (5.0 g, 21.8 mmol, 1.00 equiv.), acetamide (2.6 g, 43.7 mmol, 2.00 equiv.), Pd(OAc) (250 mg, 1.09 mmol, 0.05 equiv.), XantPhos (630 mg, 1.09 mmol, 0.05 equiv.), and CsCO (14.2 g, 43.7 mmol, 2.00 equiv.) in dioxane (50.0 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with CHCl (100 mL). The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give a yellow solid, N-(4-fluoro-1-oxo-2,3-dihydroinden-5-yl)acetamide (1.07 g, 23.7%). LC-MS (ESI): m / z=205.85 [MH] -

[0242] 5-amino-4-fluoro-2,3-dihydroinden-1-one A mixture of N-(4-fluoro-1-oxo-2,3-dihydroinden-5-yl)acetamide (1.10 g, 5.16 mmol, 1.00 equiv) and KCO (1.40 g, 10.3 mmol, 2.00 equiv) in MeOH (10.0 mL) was stirred at 60 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This produced a yellow solid, 5-amino-4-fluoro-2,3-dihydroinden-1-one (780 mg, crude). LC-MS (ESI): m / z 166.20 [M+H] +

[0243] 4-Fluoro-5-nitro-2,3-dihydroinden-1-one At 0 °C, m-CPBA (15.0 g, 86.9 mmol, 3.12 equiv.) was added portionwise to a stirred solution of 5-amino-4-fluoro-2,3-dihydroinden-1-one (4.60 g, 27.9 mmol, 1.00 equiv.) (crude) in DCM (60.0 mL). The resulting mixture was stirred at room temperature for 1 h. At 0 °C, the reaction was quenched with saturated NaHCO (aq.). The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 4-fluoro-5-nitro-2,3-dihydroinden-1-one (1.1 g, 20.2%) as a yellow solid. 1 H NMR (400MHz,DMSO-d6) δ 8.21 (dd,J=8.2,6.4Hz,1H),7.71 (d,J=8.2Hz,1H),3.32-3.21 (m,2H),2.92-2.81 (m,2H).

[0244] 4-Fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol At 0 °C, to a stirred solution of 4-fluoro-5-nitro-2,3-dihydroinden-1-one (1.10 g, 5.64 mmol, 1.00 equiv) in MeOH (12.0 mL) was added NaBH (640 mg, 16.9 mmol, 3.00 equiv) in portions. The resulting mixture was stirred at room temperature for 1 h. At 0 °C, the reaction was quenched with saturated NH Cl (aq.). The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CHCl (3 × 80 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give a yellow solid, 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (910 mg, 81.9%). Synthesis of 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (Int.5) [ka] 3-(3-bromo-4-fluorophenyl)propionic acid

[0245] A mixture of TEA (32.5 g, 322 mmol, 1.3 eq.) and HCOOH (34.2 g, 744 mmol, 3.0 eq.) was stirred at room temperature for 15 min, and DMF (1.5 L) was added. To the solution was added 3-bromo-4-fluorobenzaldehyde (50 g, 248 mmol, 1.0 eq.) and 2,2-dimethyl-1,3-dioxane-4,6-dione (35.7 g, 248 mmol, 1.0 eq.). The reaction solution was stirred at 100 °C overnight. Upon completion, the reaction solution was poured into concentrated HCl / ice water (1 L) and the suspension was filtered to give a white solid, 3-(3-bromo-2-fluorophenyl)propionic acid (57 g, 231 mol, 93%), which was used directly in the next step without purification. LC-MS (ESI): m / z 247 [M+H] + .

[0246] 3-(3-bromo-4-fluorophenyl)propionyl chloride To a solution of 3-(3-bromo-2-fluorophenyl)propionic acid (57 g, 231 mmol, 1.0 eq.) in DCM (500 mL) was added SOCl (50 mL, 693 mmol, 3.0 eq.), followed by DMF (169 mg, 2.31 mmol, 0.01 eq.). The solution was stirred at room temperature for 12 hours. Upon completion, the reaction solution was concentrated under reduced pressure to give crude 3-(3-bromo-2-fluorophenyl)propionyl chloride (58 g, quantitative) as a yellow oil, which was used directly in the next step without purification. LC-MS (ESI): m / z 265 [M+H] + .

[0247] 5-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-one At 0 °C, a solution of 3-(3-bromo-2-fluorophenyl)propionyl chloride (58 g, 220 mmol, 1.0 eq.) in DCM (500 mL) was added to a solution of AlCl (43.9 g, 330 mmol, 1.5 eq.) in DCM (500 mL). The solution was stirred at 0 °C for 15 min, then warmed to room temperature and stirred for 3 h. After completion, the solution was poured into ice water (500 mL), and the resulting suspension was filtered. The filtrate was extracted with DCM (500 mL × 2). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a white solid, 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (19.5 g, 85.5 mmol, 39%). LC-MS (ESI): m / z 229[M+H] + .

[0248] N-(6-fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide To a solution of 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (1.00 g, 4.39 mmol, 1.0 eq.) in dioxane (30 mL) was added acetamide (518 mg, 8.77 mmol, 2.0 eq.), CS2CO3 (2.86 g, 8.77 mmol, 2.0 eq.), Pd2(dba)3 (403 mg, 0.44 mmol, 0.1 eq.), and Xantphos (510 mg, 0.88 mmol, 0.2 eq.). Under a nitrogen atmosphere, the solution was stirred at 110 °C for 12 h. After completion, the reaction solution was cooled to room temperature and extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, N-(6-fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide (850 mg, 4.10 mmol, 94%). LC-MS (ESI): m / z 208 [M+H] + .

[0249] 5-amino-6-fluoro-2,3-dihydro-1H-inden-1-one To a solution of N-(6-fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide (6.00 g, 29.0 mmol, 1.0 eq.) in MeOH (60 mL) was added KCO (60 mL, saturated, aqueous). The reaction solution was stirred at 55 °C for 16 hours. After completion, the reaction solution was diluted with HO (60 mL) and extracted with EtOAc (60 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 5-amino-6-fluoro-2,3-dihydro-1H-inden-1-one (4.3 g, 25.9 mmol, 89%). LC-MS (ESI): m / z 166 [M+H] + .

[0250] 6-Fluoro-5-nitro-2,3-dihydro-1H-inden-1-one To a solution of 5-amino-6-fluoro-2,3-dihydro-1H-inden-1-one (8.9 g, 53.9 mmol, 1.0 eq.) and NaHCO (23.5 g, 270 mmol, 5.0 eq.) in a mixture of DCM (450 mL) and HO (20 mL) was added m-CPBA (55.0 g, 85 wt%, 270 mmol, 5.0 eq.) in portions. After the addition, the reaction mixture was stirred at 30 °C for 2 h. After completion, the reaction mixture was cooled in an ice bath and carefully neutralized with NaHCO (aq.) until the pH was adjusted to pH = 8. The resulting mixture was extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow oil, 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-one (4.2 g, 21.5 mmol, 40%). LC-MS (ESI): m / z 196 [M+H] + .

[0251] 6-Fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol To a solution of 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-one (45 mg, 0.23 mmol, 1.0 eq.) in MeOH (5 mL) was added NaBH (13 mg, 0.35 mmol, 1.5 eq.). The reaction solution was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give an oil, 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (35 mg, 0.18 mmol, 78%). LC-MS (ESI): m / z 198 [M+H] + . Synthesis of di(aziridin-1-yl)phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (Int.6) [ka] (2-Bromoethyl)({[(2-bromoethyl)amino][(6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl)oxy]phosphoryl})amine

[0252] To a solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (400 mg, 2.03 mmol, 1.0 eq.) in THF (5 mL) was added LiHMDS (2.23 mL, 1 M in THF, 2.23 mmol, 1.1 eq.) dropwise at −65°C under N2, and the resulting solution was stirred at −65°C for 20 min under N2. POCl3 (621 mg, 4.06 mmol, 2.0 eq.) was added, and the resulting mixture was stirred at −65°C for 20 min. 2-Bromoethylamine hydrobromide (2497 mg, 12.2 mmol, 6.0 eq.) and TEA (2.46 g, 24.4 mmol, 12.0 eq.) were added to the above mixture. The resulting mixture was warmed to room temperature and stirred for 1 h. After completion, the reaction mixture was quenched with NH4Cl solution (50 mL, saturated, aqueous) and extracted with EtOAc (50 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow oil, P,P-bis[(2-bromoethyl)amino]phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-indenyl ester (200 mg, 0.41 mmol, 20%). LC-MS (ESI): m / z 488 [M+H] + .

[0253] Di(aziridin-1-yl)phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of P,P-bis[(2-bromoethyl)amino]phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-indenyl ester (200 mg, 0.41 mmol, 1.0 eq.) in THF (5 mL) was added AgO (951 mg, 4.10 mmol, 10.0 eq.) and DIEA (529 mg, 4.10 mmol, 10.0 eq.). The resulting solution was stirred at 70 °C for 18 hours under N. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a solid, di(aziridin-1-yl)phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (84 mg, 0.26 mmol, 63%). LC-MS (ESI): m / z 328[M+H] + . Example 1. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-1-(3-((4-methoxy-2-oxopyridin-1(2H)-yl)methyl)-4-nitrophenyl)ethyl ester (2) and di(aziridin-1-yl)phosphinic acid (S)-1-(3-(((4-methoxypyridin-2-yl)oxy)methyl)-4-nitrophenyl)ethyl ester (3) (General Procedure 1) [ka] (5-Bromo-2-nitrophenyl)methanol

[0254] At room temperature under nitrogen gas, BH3.THF (41 mL, 1 N, 41 mmol, 2.0 eq.) was added to a solution of 5-bromo-2-nitrobenzoic acid (5.0 g, 20.3 mmol, 1.0 eq.) in THF (20 mL). The solution was heated at 70 °C for 3 h. After completion, the reaction mixture was cooled to 0 °C and quenched with 2 N HCl solution (20 mL, aq.). The mixture was extracted with EtOAc (50 mL × 2). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow solid, (5-bromo-2-nitrophenyl)methanol (4.0 g, 17.2 mmol, 85%). 1H NMR (400MHz, CDCl3) δ 8.01-7.98 (m,2H),7.60 (dd,J=8.7,2.2Hz,1H),5.02 (s,2H).

[0255] ((5-bromo-2-nitrobenzyl)oxy)(tert-butyl)diphenylsilane To a solution of (5-bromo-2-nitrophenyl)methanol (4.0 g, 4.0 g, 17.2 mmol, 1.0 eq.) in DMF (40 mL) at room temperature, imidazole (1.41 g, 20.7 mmol, 1.2 eq.) and TBDPSCl (4.46 g, 17.2 mmol, 1.0 eq.) were added. After the addition, the reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give ((5-bromo-2-nitrobenzyl)oxy)(tert-butyl)diphenylsilane (7.2 g, 15.3 mmol, 89%) as a yellow oil. 1 H NMR (400MHz,CDCl3) δ 8.31-8.18 (m,1H),7.96 (d,J=8.7Hz,1H),7.69-7.63 (m,4H),7.56 (dd,J=8.7,2.2Hz,1H),7.45-7.36 (m,6H),5.12 (s,2H),1.14 (s,9H).

[0256] tert-butyl((5-(1-ethoxyvinyl)-2-nitrobenzyl)oxy)diphenylsilane To a solution of ((5-bromo-2-nitrobenzyl)oxy)(tert-butyl)diphenylsilane (7.2 g, 15.3 mmol, 1.0 eq.) in dioxane (110 mL) was added tributyl(1-ethoxyvinyl)stannane (5.2 mL, 15.3 mmol, 1.0 eq.) and (PPh3)2PdCl2 (0.32 g, 0.46 mmol, 0.03 eq.). The mixture was evaporated and backfilled with nitrogen gas three times. The mixture was stirred at 60 °C for 16 h. After completion, the reaction mixture was cooled to room temperature, quenched with KF solution (100 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to obtain a yellow solid, tert-butyl((5-(1-ethoxyvinyl)-2-nitrobenzyl)oxy)diphenylsilane (6.1 g, 13.2 mmol, 86%). 1 H NMR (400MHz,CDCl3) δ 8.51-8.39 (m,1H),8.07 (d,J=8.6Hz,1H),7.75-7.60 (m,5H),7.49-7.33 (m,6H),5.16 (s,2H),4.85 (d,J=3.0Hz,1H),4.40 (d,J=3.0Hz,1H),3.96 (q,J=7.0Hz,2H),1.45 (t,J=7.0Hz,3H),1.15 (s,9H).

[0257] 1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethan-1-one To a solution of tert-butyl((5-(1-ethoxyvinyl)-2-nitrobenzyl)oxy)diphenylsilane (6.1 g, 13.2 mmol, 1.0 eq.) in THF (40 mL) was added aqueous HCl (40 mL, 2 N), and the mixture was stirred under nitrogen gas atmosphere at 20 °C for 2 hr. After completion, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give a yellow oil, 1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethan-1-one (15.6 g, quantitative), which was used directly in the next step without purification. 1 H NMR (400MHz,CDCl3) δ 8.72-8.53 (m,1H),8.11 (d,J=8.5Hz,1H),8.00 (d,J=1.9Hz,1H),7.75-7.61 (m,4H),7.51-7.31 (m,6H),5.17 (s,2H),2.66 (s,3H),1.15 (s,9H).

[0258] (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethan-1-ol At 0°C under nitrogen gas, BH3.THF (15 mL, 1 N, 15.0 mmol, 1.1 eq.) was added to a solution of (S)-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolidine (1.50 g, 5.17 mmol, 0.3 eq.) in toluene (6 mL). The solution was stirred at 0°C for 30 min and cooled to -40°C. At -40°C, a solution of 1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethan-1-one (5.6 g, 12.9 mmol, 1.0 eq.) in THF (60 mL) was slowly added to the above mixture. After the addition, the reaction mixture was stirred at -40°C for 2 h. MeOH (20 mL) was added to the reaction mixture at −40° C., and the solution was stirred for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethan-1-ol (4.3 g, 9.87 mmol, 76%). 1 H NMR (400MHz,CDCl3) δ 8.07 (d,J=8.4Hz,2H),7.73-7.59 (m,4H),7.48-7.32 (m,7H),5.17 (s,2H),5.08-4.91 (m,1H),1.53 (d,J=6.5Hz,3H),1.14 (s,9H).

[0259] Di((2-bromoethyl)amino)phosphinic acid (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethyl ester At −40° C. under a nitrogen atmosphere, to a solution of (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethan-1-ol (3.5 g, 8.04 mmol, 1.0 eq.) in THF (20 mL) was added LiHMDS (12 mL, 12.0 mmol, 1 N in THF, 1.5 eq.), and the resulting mixture was stirred for 20 min. POCl (1.5 mL, 16.1 mmol, 2.0 eq.) was added to the mixture at −40° C., and the reaction solution was stirred for an additional 20 min. 2-Bromoethan-1-amine hydrobromide (1.88 g, 9.18 mmol, 1.1 eq.) and DIEA (10.6 mL, 64.3 mmol, 8.0 eq.) were then added. The resulting mixture was allowed to warm to room temperature and stirred for 1 hr. After completion, the reaction mixture was quenched with saturated NH4Cl solution (40 mL) and extracted with DCM (40 mL x 3). The organic layers were combined, washed with water (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow solid, di((2-bromoethyl)amino)phosphinic acid (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethyl ester (2.8 g, 3.85 mmol, 48%). 1 H NMR (400MHz,CDCl3) δ 8.14-8.04 (m,2H),7.68-7.63 (m,4H),7.47-7.34 (m,7H),5.63-5.60 (m,1H),5.18 (s,2H),3.52-3.48 (m,2H),3.41-3.34 (m,2H),3.27-3.05 (m,4H),1.64 (d,J=6.5Hz,3H),1.15 (s,9H).

[0260] Di(aziridin-1-yl)phosphinic acid (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethyl ester To a solution of di((2-bromoethyl)amino)phosphinic acid (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethyl ester (2.8 g, 3.85 mmol, 1.0 eq.) and DIEA (3.2 mL, 19.2 mmol, 5.0 eq.) in THF (20 mL) was added AgO (4.46 g, 19.2 mmol, 5.0 eq.). The mixture was stirred at 65 °C under N for 16 hr. After completion, the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oily substance, di(aziridin-1-yl)phosphinic acid (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethyl ester (1.1 g, 1.95 mmol, 51%). 1 H NMR (400MHz,CDCl3) δ 8.11-8.06 (m,2H),7.69-7.64 (m,4H),7.47-7.36 (m,7H),5.80-5.65 (m,1H),5.16 (s,2H),2.27-1.98 (m,8H),1.65 (d,J=6.5Hz,3H),1.14 (s,9H). 31 P NMR (162MHz, CDCl3) δ 30.01(s). LC-MS (ESI): m / z 588.3[M+Na] + .

[0261] Di(aziridin-1-yl)phosphinic acid (S)-1-(3-(hydroxymethyl)-4-nitrophenyl)ethyl ester To a solution of di(aziridin-1-yl)phosphinic acid (S)-1-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-nitrophenyl)ethyl ester (1.1 g, 1.95 mmol, 1.0 eq.) in THF (3 mL) was added TBAF (2.9 mL, 2.91 mmol, 1.5 eq., 1 M), and the resulting mixture was stirred at room temperature under N for 30 min. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid (S)-1-(3-(hydroxymethyl)-4-nitrophenyl)ethyl ester (340 mg, 1.04 mmol, 53%) as a yellow oil. 1 H NMR (400MHz,CDCl3) δ 8.12 (d,J=8.4Hz,1H),7.79 (s,1H),7.50-7.48 (m,1H),5.74-5.67 (m,1H),5.00 (s,2H),2.25-2.01 (m,8H),1.64 (d,J=6.6Hz,3H). 31 P NMR (162MHz, CDCl3) δ 30.27(s). LC-MS (ESI): m / z 328.1[M+H] + .

[0262] Di(aziridin-1-yl)phosphinic acid (S)-1-(3-((4-methoxy-2-oxopyridin-1(2H)-yl)methyl)-4-nitrophenyl)ethyl ester and di(aziridin-1-yl)phosphinic acid (S)-1-(3-(((4-methoxypyridin-2-yl)oxy)methyl)-4-nitrophenyl)ethyl ester At 0 °C, to a solution of 4-methoxypyridin-2(1H)-one (50 mg, 0.40 mmol, 1.5 eq.), PPh (210 mg, 0.80 mmol, 3.0 eq.), and di(aziridin-1-yl)phosphinic acid (S)-1-(3-(hydroxymethyl)-4-nitrophenyl)ethyl ester (87.2 mg, 0.27 mmol, 1.0 eq.) in THF (12 mL) was added DIAD (0.13 mL, 0.67 mmol, 2.5 eq.). The resulting mixture was warmed to room temperature and stirred under N for 1 h. After completion, the reaction solution was concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give di(aziridin-1-yl)phosphinic acid (S)-1-(3-((4-methoxy-2-oxopyridin-1(2H)-yl)methyl)-4-nitrophenyl)ethyl ester (35 mg, 0.08 mmol, 30%) as a white solid and di(aziridin-1-yl)phosphinic acid (S)-1-(3-(((4-methoxypyridin-2-yl)oxy)methyl)-4-nitrophenyl)ethyl ester (1.2 mg) as a yellow oil.

[0263] Isomer 1(2), 35 mg, 0.08 mmol, 30%, 1 H NMR (400MHz,CDCl3) δ 8.12 (d,J=8.5Hz,1H),7.49 (dd,J=8.5,1.7Hz,1H),7.18 (d,J=7.6Hz,1H),7.08 (s,1H),6.01-5.94 (m,2H),5.65-5.55 (m,1H),5.46 (d,J=1.9Hz,2H),2.21-1.98 (m,8H),1.56 (d,J=6.5Hz,3H). 31 P NMR (162MHz, CDCl3) δ 29.89(s). LC-MS (ESI): m / z 435.2[M+H] + .

[0264] Isomer 2(3), 1.2mg, 1H NMR (400MHz,CDCl3) δ 8.19-8.08 (m,1H),7.97-7.87 (m,1H),7.76-7.67 (m,1H),7.54-7.41 (m,1H),6.57-6.44 (m,1H),6.41-6.27 (m,1H),5.87-5.73 (m,2H),5.72-5.47 (m,1H),3.85 (s,3H),2.23-1.90 (m,8H),1.60 (d,J=6.4Hz,3H). 31 P NMR (162MHz, CDCl3) δ 30.24 (s). LC-MS (ESI): m / z 435.2[M+H] + . Example 2. Synthesis of bis((S)-2-methylaziridin-1-yl)phosphinic acid 4-((3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzyl)oxy)-2,3,5,6-tetrafluorobenzyl ester (12) (General Procedure 5) [ka] 2,3,5,6-Tetrafluoro-4-hydroxybenzaldehyde

[0265] A solution of 2,3,4,5,6-pentafluorobenzaldehyde (10.0 g, 51.0 mmol, 1.0 eq.), (diethoxymethoxy)ethane (11.0 mL, 66.3 mmol, 1.3 eq.), and 12 N HCl (0.15 mL) in EtOH (30 mL) was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure to give a colorless oil, 1-(diethoxymethyl)-2,3,4,5,6-pentafluorobenzene (11.2 g, 41.4 mmol, 75%). The residue was dissolved in t-BuOH (150 mL), KOH (9.3 g, 165.8 mmol, 4.0 eq.) was added at room temperature, and the reaction mixture was stirred at 85 °C for 4 h. After completion, the reaction mixture was cooled in an ice bath and carefully neutralized with HCl (12 N) until the pH was adjusted to pH = 3. The resulting mixture was extracted with EtOAc (100 mL × 2), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give 2,3,5,6-tetrafluoro-4-hydroxybenzaldehyde (5.1 g, 26.3 mmol, 57%) as a white solid. LCMS (ESI): m / z 193 [MH] - .

[0266] 3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzoic acid methyl ester Under nitrogen gas, K2CO3 (534 mg, 3.86 mmol, 1.1 eq.) was added to a solution of 3-hydroxy-N,N-dimethylbenzamide (580 mg, 3.51 mmol, 1.0 eq.) and 3-fluoro-4-nitrobenzoic acid methyl ester (699 mg, 3.51 mmol, 1.0 eq.) in DMF (5 mL), and the reaction mixture was stirred at 80 °C for 18 h. After completion, the reaction mixture was diluted with HO (25 mL) and extracted with EtOAc (25 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzoic acid methyl ester (1.1 g, 3.19 mmol, 91%) as a white solid. LCMS (ESI): m / z 345[M+H] + .

[0267] 3-(5-(hydroxymethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide Under nitrogen gas, NaBH (969 mg, 25.5 mmol, 8.0 eq.) was added portionwise to a solution of 3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzoic acid methyl ester (1.1 g, 3.2 mmol, 1.0 eq.) in THF (20 mL), and the reaction mixture was stirred at 60 °C for 18 h. After completion, the reaction mixture was quenched by the addition of saturated aqueous NH Cl (20 mL) and extracted with EtOAc (40 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by Biotage C column chromatography to give 3-(5-(hydroxymethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide (1.0 g, 3.2 mmol, 98%) as a white solid. LC-MS (ESI) m / z 317[M+H] + . 1H NMR (400MHz,CDCl3) δ 7.95 (d,J=8.4Hz,1H),7.41 (t,J=7.9Hz,1H),7.21-7.15 (m,2H),7.13-7.10 (m,1H),7.08-7.06 (m,1H),7.03-7.02(m,1H),,4.64 (s,2H),3.07 (s,3H),2.97 (s,3H).

[0268] 3-(5-(chloromethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide At 0 °C under nitrogen gas, SOCl (0.4 mL, 5.7 mmol, 2.0 eq.) was added dropwise to a solution of 3-(5-(hydroxymethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide (900 mg, 2.8 mmol, 1.0 eq.) in DCM (15 mL). After the addition, the mixture was stirred at room temperature for 1 h. TEA (0.4 mL, 2.8 mmol, 1.0 eq.) was then added, and the reaction mixture was stirred at room temperature for an additional 30 min. After completion, the reaction mixture was cooled in an ice bath and quenched with NaHCO solution (aq.). The resulting mixture was extracted with DCM (30 mL x 2), and the combined organic layers were washed with water (10 mL x 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give crude 3-(5-(chloromethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide (820 mg, quantitative) as a yellow solid, which was used directly in the next step without purification. LCMS (ESI): m / z 335 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 7.97 (d,J=8.4Hz,1H),7.44 (t,J=7.9Hz,1H),7.27 (d,J=1.8Hz,1H),7.25-7.22 (m,1H),7.12-7.09 (m,1H),7.08-7.06 (m,2H),4.51 (s,2H),3.09 (s,3H),2.97 (s,3H).

[0269] 3-(5-(chloromethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide A solution of 3-(5-(chloromethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide (820 mg, 2.45 mmol, 1.0 eq.), 2,3,5,6-tetrafluoro-4-hydroxybenzaldehyde (1.4 g, 7.3 mmol, 3.0 eq.), and DIEA (1.2 mL, 7.3 mmol, 3.0 eq.) in DMF (15 mL) was stirred at 60° C. for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 3-(5-(chloromethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide (150 mg, 0.29 mmol, 12%) as a yellow solid. 1 H NMR (400MHz,CDCl3) δ 10.22 (s,1H),8.01 (d,J=8.4Hz,1H),7.45-7.40 (m,1H),7.30 (dd,J=8.4,1.7Hz,1H),7.26-7.24 (m,1H),7.10 (m,3H),5.37 (s,2H),3.10 (s,3H),2.98 (s,3H).

[0270] N,N-Dimethyl-3-(2-nitro-5-((2,3,5,6-tetrafluoro-4-(hydroxymethyl)phenoxy)methyl)phenoxy)benzamide At 0° C., NaBH (34 mg, 0.61 mmol, 2.0 eq.) was added portionwise to a solution of 3-(5-(chloromethyl)-2-nitrophenoxy)-N,N-dimethylbenzamide (150 mg, 0.30 mmol, 1.0 eq.) in THF (5 mL), and the reaction mixture was stirred at 0° C. for 1 hr. After completion, the reaction mixture was quenched by the addition of water (10 mL) and extracted with DCM (20 mL × 3). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a white solid, N,N-dimethyl-3-(2-nitro-5-((2,3,5,6-tetrafluoro-4-(hydroxymethyl)phenoxy)methyl)phenoxy)benzamide (120 mg, 0.24 mmol, 80%). LCMS (ESI): m / z 495[M+H] + .

[0271] Di((R)-1-bromopropan-2-ylamino)phosphinic acid 4-((3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzyl)oxy)-2,3,5,6-tetrafluorobenzyl ester At −78° C. under nitrogen gas, LiHMDS (0.64 mL, 0.64 mmol, 1.5 eq.) was added to a solution of N,N-dimethyl-3-(2-nitro-5-((2,3,5,6-tetrafluoro-4-(hydroxymethyl)phenoxy)methyl)phenoxy)benzamide (210 mg, 0.43 mmol, 1.0 eq.) in THF (10 mL). After the addition, the mixture was stirred at this temperature for 20 min. Then, POCl (130.26 mg, 0.85 mmol, 2.0 eq.) was added, and the mixture was stirred at −78° C. for 20 min. Then, (S)-1-bromopropan-2-amine hydrobromide (557.93 mg, 2.55 mmol, 5.9 eq.) and DIEA (0.562 mL, 3.40 mmol, 5.9 eq.) were added to the mixture. After the addition, the reaction mixture was heated to room temperature and stirred for 1 hour. Upon completion, the reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with DCM (80 mL). The organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di((R)-1-bromopropan-2-ylamino)phosphinic acid 4-((3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzyl)oxy)-2,3,5,6-tetrafluorobenzyl ester (45 mg, 55 μmol, 13%). LCMS (ESI): m / z 813.0 [M+H] + .

[0272] Bis((S)-2-methylaziridin-1-yl)phosphinic acid 4-((3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzyl)oxy)-2,3,5,6-tetrafluorobenzyl ester To a solution of di((R)-1-bromopropan-2-ylamino)phosphinic acid 4-((3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzyl)oxy)-2,3,5,6-tetrafluorobenzyl ester (45 mg, 55 μmol, 1.0 eq.) and DIEA (35.71 mg, 0.28 mmol, 5.0 eq.) in THF (5 mL) was added AgO (64.03 mg, 0.28 mmol, 5.0 eq.) and the reaction mixture was stirred at 65° C. for 16 hr. After completion, the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Biotage® C18 column chromatography to give a colorless oily substance, bis((S)-2-methylaziridin-1-yl)phosphinic acid 4-((3-(3-(dimethylaminoformyl)phenoxy)-4-nitrobenzyl)oxy)-2,3,5,6-tetrafluorobenzyl ester (22.2 mg, 34 μmol, 62%). 1 H NMR (400MHz,CDCl3) δ 8.01 (d,J=8.4Hz,1H),7.48-7.44 (m,1H),7.34-7.31 (m,1H),7.28-7.25 (m,1H),7.15-7.09 (m,3H),5.25 (s,2H),5.21 (d,J=5.8Hz,2H),3.11 (s,3H),3.00 (s,3H),2.64-2.52 (m,2H),2.43-2.33 (m,2H),1.96-1.85 (m,2H),1.30-1.28 (m,6H). 31 P NMR (162MHz,CDCl3) δ 29.22 (s) 19 F NMR (376MHz, CDCl3) δ -143.13-143.20 (m), -156.15--156.24 (m). LCMS (ESI): m / z 653.2[M+H] + . Example 3. Synthesis of di(aziridin-1-yl)phosphinic acid 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-yl ester (16) (General Procedure 8, 6,5 Core 2 - Method A) [ka] 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-one

[0273] At 0°C, phenoxysodium (19.6 mg, 0.17 mmol, 1.1 eq.) was added to a solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-one (30 mg, 0.15 mmol, 1.0 eq.) in THF (3 mL). The solution was warmed to room temperature and stirred for 3 hours. After completion, the solution was concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-one (28 mg, 0.10 mmol, 68%) as a yellow solid. 1 H NMR (400MHz,CDCl3) δ 7.91 (d,J=8.2Hz,1H),7.71 (d,J=8.2Hz,1H),7.38-7.30 (m,2H),7.16-7.09 (m,1H),6.97-6.89 (m,2H),2.85 (dd,J=7.2,4.6Hz,2H),2.75-2.67 (m,2H).

[0274] 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-ol To a solution of 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-one (100 mg, 0.37 mmol, 1.0 eq.) in MeOH (5 mL) was added NaBH (33.8 mg, 1.86 mmol, 5.0 eq.). The reaction solution was stirred at room temperature for 1 hour. Upon completion, the solution was concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-ol (88 mg, 0.32 mmol, 87%) as a green oil.

[0275] Di((2-bromoethyl)amino)phosphinic acid 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-yl ester At −40°C under a nitrogen atmosphere, LiHMDS (0.15 mL, 1N in THF, 0.15 mmol, 1.0 eq.) was added to a solution of 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-ol (40 mg, 0.15 mmol, 1.0 eq.) in THF (10 mL) and the resulting mixture was stirred for 20 min. POCl (0.03 mL, 0.30 mmol, 2.0 eq.) was added to the mixture at −40°C, and the reaction mixture was stirred for an additional 20 min. 2-Bromoethan-1-amine hydrobromide (109.5 mg, 0.89 mmol, 6.0 eq.) and DIEA (0.194 mL, 1.18 mmol, 8.0 eq.) were then added to the mixture and stirred for 10 min at −40°C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di((2-bromoethyl)amino)phosphinic acid 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-yl ester (30 mg, 0.055 mmol, 37%). LCMS (ESI): m / z 584 [M+Na] + . 1 H NMR (400MHz,CDCl3) δ 7.89 (d,J=8.3Hz,1H),7.55 (d,J=8.4Hz,1H),7.35-7.28 (m,2H),7.11-7.06 (m,1H),6.88 (d,J=8.7Hz,2H),5.92-5.84 (m,1H),3.54-3.29 (m,9H),3.14-2.97 (m,1H),2.89-2.77 (m,1H),2.65-2.46 (m,2H),2.24-2.11 (m,1H).

[0276] Di(aziridin-1-yl)phosphinic acid 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-yl ester (30 mg, 0.055 mmol, 1.0 eq.) in THF (10 mL) was added AgO (63.52 mg, 0.27 mmol, 4.9 eq.) and DIEA (0.018 mL, 0.11 mmol, 2.0 eq.). The solution was stirred at 70 °C for 12 hours under a nitrogen atmosphere. Upon completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give di(aziridin-1-yl)phosphinic acid 5-nitro-4-phenoxy-2,3-dihydro-1H-inden-1-yl ester (12 mg, 0.031 mmol, 56%) as a yellow oil. 1 H NMR (400MHz,CDCl3) δ 7.88 (d,J=8.2Hz,1H),7.50 (d,J=8.2Hz,1H),7.35-7.28 (m,2H),7.08 (t,J=7.4Hz,1H),6.87 (d,J=7.8Hz,2H),6.06-5.94 (m,1H),2.95-2.76 (m,1H),2.66-2.45 (m,2H),2.34-2.13 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.97 (s). LC-MS (ESI): m / z 402.2[M+H] + . Example 4. Di(aziridin-1-yl)phosphinic acid (S)-4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (17 and 18) (General Procedure 8, 6,5 Core 2 - Method B) [ka] 4-((1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy)-N,N-dimethylbenzamide

[0277] To a solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (180 mg, 0.91 mmol, 1.0 eq.) and 4-hydroxy-N,N-dimethylbenzamide (226 mg, 1.37 mmol, 1.5 eq.) in ACN (10 mL) was added CsCO (592 mg, 1.82 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a gray solid, 4-((1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy)-N,N-dimethylbenzamide (120 mg, 0.35 mmol, 18%). LC-MS (ESI): m / z 343 [M+H] + .

[0278] Di((2-bromoethyl)amino)phosphinic acid 4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 4-((1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy)-N,N-dimethylbenzamide (150 mg, 0.44 mmol, 1.0 eq.) in THF (30 mL) at −60° C. under N2, LiHMDS (0.88 mL, 1 M in THF, 0.88 mmol, 2.0 eq.) was added dropwise, and the resulting solution was stirred for 20 min at −60° C. under N2. POCl3 (0.082 mL, 0.89 mmol, 2.0 eq.) in THF (10 mL) was added rapidly, and the resulting mixture was stirred at −60° C. for 15 min. 2-Bromoethylamine hydrobromide (628 mg, 3.07 mmol, 7.0 eq.) and TEA (0.73 mL, 5.26 mmol, 12.0 eq.) were added, and the mixture was stirred at −60° C. for 10 min. The resulting mixture was warmed to room temperature and stirred for 0.5 hr. After completion, the reaction mixture was quenched with NH4Cl solution (5 mL, saturated, aqueous) and extracted with EtOAc (10 mL × 2). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di((2-bromoethyl)amino)phosphinic acid 4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (70 mg, 110 μmol, 25%) as a yellow oil. LC-MS (ESI): m / z 633.1[M+H] + .

[0279] Di(aziridin-1-yl)phosphinic acid (S)-4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (70 mg, 0.11 mmol, 1.0 eq.) in THF (10 mL) was added AgO (256 mg, 1.10 mmol, 10.0 eq.) and DIEA (0.18 mL, 1.10 mmol, 10.0 eq.). The resulting solution was stirred at 70 °C for 18 h under N. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 4-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (40 mg, 85 μmol, 77%) in the form of a solid stereoisomeric mixture, which was further separated by chiral SFC to give:

[0280] Isomer 1(17), retention time: 3.963min, >99% ee. LC-MS (ESI): m / z 473.2[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.91 (d,J=8.2Hz,1H),7.54 (d,J=8.2Hz,1H),7.40 (d,J=8.6Hz,2H),6.88 (d,J=8.7Hz,2H),6.06-5.94 (m,1H),3.09 (s,3H),3.03 (s,3H),2.91-2.78 (m,1H),2.67-2.49 (m,2H),2.35-2.13 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.99 (s).

[0281] Isomer 2(18), retention time: 6.352min, >99% ee. LC-MS (ESI): m / z 473.2[M+H] + ; 1H NMR (400MHz,CDCl3) δ 7.91 (d,J=8.2Hz,1H),7.54 (d,J=8.2Hz,1H),7.40 (d,J=8.7Hz,2H),6.88 (d,J=8.7Hz,2H),6.09-5.93 (m,1H),3.09 (s,3H),3.03 (s,3H),2.90-2.79 (m,1H),2.67-2.51 (m,2H),2.36-2.09 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.99 (s).

[0282] Analytical method: Column: ChiralPak AD, 250 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, ethanol (0.05% DEA); Gradient: B 40% within 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 35°C.

[0283] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralPak AD, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2, and B, ETOH + 0.1% NH3H2O, Gradient: B 35%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 10 min, Elution time: 2.0 H. Example 5. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (19 and 20) [ka] 4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-ol

[0284] To a solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (200 mg, 1.02 mmol, 1.0 eq.) and [1,1'-biphenyl]-4-ol (262 mg, 1.53 mmol, 1.5 eq.) in ACN (10 mL) was added CsCO (665 mg, 2.04 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a solid, 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-ol (150 mg, 0.43 mmol, 42%). LC-MS (ESI): m / z 348 [M+H] + .

[0285] Di((2-bromoethyl)amino)phosphinic acid 4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 5-nitro-4-(4-phenylphenoxy)-2,3-dihydro-1H-inden-1-ol (40 mg, 0.12 mmol, 1.0 eq.) in THF (15 mL) was added LiHMDS (0.23 mL, 1 M in THF, 0.23 mmol, 2.0 eq.) dropwise at −60° C. under N , and the resulting solution was stirred at −60° C. for 20 min under N . POCl (153 mg, 0.23 mmol, 2.0 eq.) in THF (5 mL) was added, and the resulting mixture was stirred at −60° C. for 15 min. 2-Bromoethylamine hydrobromide (423 mg, 2.07 mmol, 6.0 eq.) and TEA (412 mg, 4.08 mmol, 12.0 eq.) were added, and the mixture was stirred at −60° C. for 10 min. The resulting mixture was warmed to room temperature and stirred for 0.5 hours. After completion, the reaction mixture was quenched with NH4Cl solution (5 mL, saturated, aqueous) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di((2-bromoethyl)amino)phosphinic acid 4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (20 mg, 31 μmol, 27%). LC-MS (ESI): m / z 638 [M+H] + .

[0286] Di(aziridin-1-yl)phosphinic acid 4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (20 mg, 31 μmol, 1.0 eq.) in THF (10 mL) was added AgO (73 mg, 0.31 mmol, 10.0 eq.) and DIEA (40 mg, 0.31 mmol, 10.0 eq.). The resulting solution was stirred at 70 °C for 18 h under N. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 4-([1,1′-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (3.0 mg, 6.0 μmol, 20%) as a white solid in the form of a mixture of stereoisomers. 1 H NMR (400MHz,CDCl3) δ 7.91 (d,J=8.2Hz,1H),7.60-7.51 (m,5H),7.45-7.41 (m,2H),7.35-7.31 (m,1H),6.95-6.93 (m,2H),6.07-5.96 (m,1H),2.96-2.85 (m,1H),2.70-2.51 (m,2H),2.33-2.12 (m,9H). 31 P NMR (162MHz, CDCl3) δ 30.02 (s). LC-MS (ESI): m / z 500.2[M+Na] + .

[0287] Di(aziridin-1-yl)phosphinic acid (S)-4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 4-([1,1′-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (80 mg, 0.17 mmol) was further separated by chiral SFC to give:

[0288] Isomerate 1 (19), 20.1 mg, 42 μmol, 25%, retention time: 4.803 min, >99% ee. LC-MS (ESI): m / z 500.2 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ 7.90 (d,J=8.0Hz,1H),7.62-7.47 (m,5H),7.47-7.38 (m,2H),7.37-7.29 (m,1H),6.94 (d,J=7.7Hz,2H),6.10-5.94 (m,1H),2.97-2.84 (m,1H),2.73-2.51 (m,2H),2.37-2.12 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.99 (s).

[0289] Isomerate 2 (20), 30.7 mg, 64 μmol, 38%, retention time: 5.694 min, 99% ee. LC-MS (ESI): m / z 500.2 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ 7.90 (d,J=8.0Hz,1H),7.59-7.47 (m,5H),7.46-7.37 (m,2H),7.36-7.28 (m,1H),6.94 (d,J=7.9Hz,2H),6.09-5.93 (m,1H),3.01-2.80 (m,1H),2.77-2.49 (m,2H),2.39-2.03 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.99 (s).

[0290] Analysis method: カラム: ChiralPak IH, 100×4.6mm ID, 5μm, mobile phase: A, CO2, and びB, エタノール (0.05% DEA), blending: within 8 minutes, 20% B, flow rate: 2.5mL / min, カラム temperature: 40°C.

[0291] SFC method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralPak IH, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2, and B, MEOH + 0.1% NH3H2O, Gradient: B 25%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 254 nm, Cycle time: 6 min, Elution time: 2 h. Example 6. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (27 and 28) [ka] 4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-ol

[0292] To a solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (150 mg, 0.76 mmol, 1.0 eq.) and 2,4'-difluoro-[1,1'-biphenyl]-4-ol (235 mg, 1.14 mmol, 1.5 eq.) in ACN (5 mL) was added CsCO (496 mg, 1.52 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 2 h. After completion, the reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (20 mL × 3). The organic layers were combined, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-ol (170 mg, 0.44 mmol, 58%). LC-MS (ESI): m / z 384 [M+H] + .

[0293] Di((2-bromoethyl)amino)phosphinic acid 4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-ol (70 mg, 0.18 mmol, 1.0 eq.) in THF (10 mL) at −78 °C under N2, LiHMDS (0.22 mL, 1 M in THF, 0.22 mmol, 1.2 eq.) was added dropwise, and the resulting solution was stirred at −78 °C for 15 min. POCl3 (55 mg, 0.37 mmol, 2.0 eq.) in THF (5 mL) was added, and the resulting mixture was stirred at −78 °C for 15 min. 2-Bromoethylamine hydrobromide (221 mg, 1.08 mmol, 6.0 eq.) and TEA (218 mg, 2.16 mmol, 12.0 eq.) were added. The resulting mixture was warmed to room temperature and stirred for 1 hour. After completion, the reaction mixture was quenched with NH4Cl solution (5 mL, saturated, aqueous) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di((2-bromoethyl)amino)phosphinic acid 4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (50 mg, 74 μmol, 41%). LC-MS (ESI): m / z 696 [M+Na] + .

[0294] Di(aziridin-1-yl)phosphinic acid 4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (100 mg, 0.15 mmol, 1.0 eq.) in THF (5 mL) was added AgO (206 mg, 0.89 mmol, 6.0 eq.) and DIEA (115 mg, 0.89 mmol, 6.0 eq.). The resulting solution was stirred at 70 °C for 18 h under N. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 4-((2,4′-difluoro-[1,1′-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (30 mg, 58 μmol, 39%) in the form of a stereoisomeric mixture as a white solid. 1 H NMR (400MHz,CDCl3) δ 7.94 (d,J=8.2Hz,1H),7.57 (d,J=8.2Hz,1H),7.51-7.43 (m,2H),7.32 (t,J=8.6Hz,1H),7.17-7.06 (m,2H),6.75-6.66 (m,2H),6.07-5.99 (m,1H),3.00-2.90 (m,1H),2.76-2.56 (m,2H),2.31-2.16 (m,9H). 31 P NMR (162MHz, CDCl3) δ 30.02 (s). 19 F NMR (376MHz, CDCl3) δ -114.53 (s), -114.69 (s). LC-MS (ESI): m / z 536.1[M+Na] + .

[0295] Di(aziridin-1-yl)phosphinic acid (S)-4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 4-((2,4′-difluoro-[1,1′-biphenyl]-4-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (50 mg, 97.5 μmol) was further separated by chiral SFC to give:

[0296] Isomer 1(27), 16.4mg, 32μmol, 33%, retention time: 2.872min, 99% ee. LC-MS (ESI): m / z=536.1[M+Na] + ; 1 H NMR (400MHz,CDCl3) δ 7.93 (d,J=8.2Hz,1H),7.56 (d,J=8.2Hz,1H),7.49-7.43 (m,2H),7.32 (t,J=8.6Hz,1H),7.11 (t,J=8.7Hz,2H),6.76-6.65 (m,2H),6.07-5.99 (m,1H),3.01-2.90 (m,1H),2.75-2.56 (m,2H),2.36-2.13 (m,9H). 31 P NMR (162MHz, CDCl3) δ 30.02 (s). 19 F NMR (376MHz, CDCl3) δ -114.52 (s), -114.69 (s).

[0297] Isomer 2 (28), 18.4 mg, 35 μmol, 37%, retention time: 4.362 min, 99% ee. LC-MS (ESI): m / z 536.1[M+Na] + ; 1H NMR (400MHz,CDCl3) δ 7.93 (d,J=8.2Hz,1H),7.56 (d,J=8.2Hz,1H),7.50-7.42 (m,2H),7.32 (t,J=8.6Hz,1H),7.15-7.08 (m,2H),6.75-6.66 (m,2H),6.06-5.99 (m,1H),3.00-2.90 (m,1H),2.75-2.56 (m,2H),2.34-2.14 (m,9H). 31 P NMR (162MHz, CDCl3) δ 30.02 (s). 19 F NMR (376MHz, CDCl3) δ -114.52 (s), -114.69 (s).

[0298] Analytical method: Column: ChiralPak C-IG, 100 × 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 40% B within 8 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C.

[0299] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralPak C-IG, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2 and B, MEOH + 0.1% NH3H2O, Gradient: B 40%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 20 min, Elution time: 2 H. Example 7. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-4-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (30 and 31) [ka] Di(aziridin-1-yl)phosphinic acid 4-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester

[0300] To a solution of di(aziridin-1-yl)phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (20 mg, 61.2 μmol, 1.0 eq.) and [1,1′-biphenyl]-3-ol (15.6 mg, 91.8 μmol, 1.5 eq.) in MeCN (5 mL) was added CsCO (39.9 mg, 122.4 μmol, 2.0 eq.). The reaction mixture was stirred at 60° C. for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 4-([1,1′-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (4.7 mg, 9.85 μmol, 16%) as a white solid in the form of a mixture of stereoisomers. 1 H NMR (400MHz,CDCl3) δ 7.90 (d,J=8.2Hz,1H),7.56-7.50 (m,3H),7.46-7.39 (m,2H),7.39-7.29 (m,3H),7.12-7.09 (m,1H),6.85-6.80 (m,1H),6.04-5.96 (m,1H),2.95-2.85 (m,1H),2.69-2.49 (m,2H),2.28-2.18 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.90 (s). LC-MS (ESI): m / z 500.2[M+Na] + .

[0301] Di(aziridin-1-yl)phosphinic acid (S)-4-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 4-([1,1′-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (75 mg, 0.16 mmol) was purified by chiral SFC to give:

[0302] Isomer 1(30), 33.9mg, 71μmol, 45%, retention time: 2.148min, >99% ee. LC-MS (ESI): m / z 478.2[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.82 (d,J=8.2Hz,1H),7.49-7.41 (m,3H),7.39-7.32 (m,2H),7.31-7.21 (m,3H),7.05-7.01 (m,1H),6.79-6.72 (m,1H),5.97-5.88 (m,1H),2.88-2.76 (m,1H),2.61-2.43 (m,2H),2.21-2.08 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.90 (s).

[0303] Isomer 2(31), 34.9mg, 73μmol, 47%, retention time: 2.544min, 99% ee. LC-MS (ESI): m / z 478.2[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.82 (d,J=8.2Hz,1H),7.49-7.41 (m,3H),7.39-7.32 (m,2H),7.30-7.21 (m,3H),7.07-7.01 (m,1H),6.78-6.72 (m,1H),5.95-5.88 (m,1H),2.87-2.77 (m,1H),2.62-2.42 (m,2H),2.22-2.08 (m,8H). 31 P NMR (162MHz, CDCl3) δ 29.90 (s).

[0304] Analytical method: Column: ChiralPak IB, 100 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 30% B within 8 min; Flow rate: 2.5 mL / min; Column temperature: 40°C.

[0305] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralPak IB, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2 and B, MEOH + 0.1% NH3H2O, Gradient: B 27%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 15 min, Elution time: 2.0 H. Example 8. Synthesis of di(aziridin-1-yl)phosphinic acid (R)-4-(3-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-(3-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (32 and 33) [ka]

[0306] 3-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-N,N-dimethylbenzamide A mixture of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (910 mg, 4.62 mmol, 1.00 equiv.), 3-hydroxy-N,N-dimethylbenzamide (840 mg, 5.09 mmol, 1.10 equiv.), and CsCO (3.00 g, 9.23 mmol, 2.00 equiv.) in MeCN (10.0 mL) was stirred at 60 °C for 2 h. The mixture was allowed to cool to room temperature. At room temperature, the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give a yellow solid, 3-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-N,N-dimethylbenzamide (960 mg, 60.8%). LC-MS (ESI): m / z 343.20 [M+H] +

[0307] Di((2-bromoethyl)amino)phosphinic acid 4-[3-(dimethylaminoformyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a stirred solution of 3-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-N,N-dimethylbenzamide (830 mg, 2.42 mmol, 1.00 equiv.) in THF (170 mL) was added LiHMDS (6.10 mL, 6.06 mmol, 2.50 equiv., 1.0 mol / L in THF) dropwise at −50° C. under a nitrogen atmosphere. The resulting mixture was stirred at −50° C. under a nitrogen atmosphere for 20 min. To the above mixture was added POCl (929 mg, 6.06 mmol, 2.50 equiv.) dropwise at −50° C. The resulting mixture was stirred for an additional 20 min at −50° C. To the above mixture was added 2-bromoethan-1-amine hydrobromide (3.0 g, 14.5 mmol, 6.00 equiv.) and DIEA (2.5 g, 19.4 mmol, 8.00 equiv.) at −50° C. The resulting mixture was stirred at −50° C. for an additional 30 min and then at room temperature under a nitrogen atmosphere for 1 h. At room temperature, the reaction was quenched with water. The resulting mixture was extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give a yellow solid, di((2-bromoethyl)amino)phosphinic acid 4-[3-(dimethylaminoformyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (929 mg, 60.4%). LC-MS (ESI): m / z 633.10, 635.10, 637.05 [M+H] +

[0308] Bis(aziridin-1-yl)phosphinic acid 4-[3-(dimethylaminoformyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester A mixture of di((2-bromoethyl)amino)phosphinic acid 4-[3-(dimethylaminoformyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (500 mg, 0.79 mmol, 1.00 equiv.), AgO (895 mg, 3.86 mmol, 4.9 equiv.), and DIEA (204 mg, 1.58 mmol, 2.00 equiv.) in THF (166 mL) was stirred at 70 °C under a nitrogen atmosphere for 7 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 50 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 30*100 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 30% B to 35% B, 35% B within 7 min, wavelength: 254 / 220 nm) to give an off-white oily substance, bis(aziridin-1-yl)phosphinic acid 4-[3-(dimethylaminoformyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (237 mg, 63.6%). LC-MS (ESI): m / z 473.25 [M+H] +

[0309] Di(aziridin-1-yl)phosphinic acid (R)-4-(3-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-(3-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester The compound bis(aziridin-1-yl)phosphinic acid 4-[3-(dimethylaminoformyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (237 mg) was separated by preparative chiral HPLC under the following conditions: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH) - HPLC; Mobile Phase B: IPA - HPLC; Flow Rate: 40 mL / min; Gradient: 50% B to 50% B within 34 min; Wavelength: 200 / 220 nm; RT1 (min): 21.5; RT2 (min): 27.5; Sample Solvent: MeOH:DCM = 1:1; Injection Volume: 0.4 mL; Run Number: 14.

[0310] Isomer 1(32), 40.7mg, 17.2%, ee>99.0%, LC-MS (ESI): m / z 473.25[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.04 (d,J=8.2Hz,1H),7.55 (d,J=8.2Hz,1H),7.43 (t,J=7.9Hz,1H),7.13 (dt,J=7.6,1.2Hz,1H),7.01 (ddd,J=8.3,2.7,1.0Hz,1H),6.91-6.82 (m,1H),5.94 (q,J=6.7Hz,1H),2.94 (s,3H),2.85 (s,3H),2.79-2.66 (m,1H),2.61-2.52 (m,2H),2.20-2.01 (m,9H). 31 P NMR (162MHz, DMSO-d6) δ 30.10 (d,J=2.8Hz).

[0311] Isomer 2(33), 49.1mg, 20.7, ee>99.0%, LC-MS (ESI): m / z 473.25[M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.04 (d,J=8.2Hz,1H),7.55 (d,J=8.2Hz,1H),7.43 (t,J=7.9Hz,1H),7.13 (dt,J=7.6,1.3Hz,1H),7.01 (dd,J=7.9,2.7Hz,1H),6.91-6.85 (m,1H),5.94 (q,J=6.5Hz,1H),2.94 (s,3H),2.85 (s,3H),2.78-2.66 (m,1H),2.62-2.52 (m,2H),2.26-1.98 (m,9H). 31 P NMR (162MHz,DMSO-d6) δ 30.10. Example 9: Synthesis of di(aziridin-1-yl)phosphinic acid (R)-4-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (38 and 39) [ka] 2-Cyclopropyl-6-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-3H-isoindol-1-one

[0312] To a stirred solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (500 mg, 2.54 mmol, 1.00 equiv.) and 2-cyclopropyl-6-hydroxy-3H-isoindol-1-one (528 mg, 2.79 mmol, 1.10 equiv.) in MeCN (15.0 mL) was added CsCO (1.65 g, 5.07 mmol, 2.00 equiv.). The resulting mixture was stirred at 60 °C for 1 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give a brown solid, 2-cyclopropyl-6-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-3H-isoindol-1-one (340 mg, 36.5%). LC-MS (ESI): m / z 367.15 [M+H] +

[0313] Di((2-bromoethyl)amino)phosphinic acid 4-[(2-cyclopropyl-3-oxo-1H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a stirred solution of 2-cyclopropyl-6-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-3H-isoindol-1-one (500 mg, 1.36 mmol, 1.00 equiv.) in THF (65.0 mL) at −50° C. under a nitrogen atmosphere, LiHMDS (2.05 mL, 2.05 mmol, 1.0 M in THF, 1.50 equiv.) was added dropwise. The mixture was stirred at −50° C. for an additional 20 min. To the above mixture, POCl (314 mg, 2.05 mmol, 1.50 equiv.) was added dropwise. The resulting mixture was stirred at −50° C. for an additional 20 min. To the above mixture were then added 2-bromoethanamine hydrobromide (1.68 g, 8.19 mmol, 6.00 equiv.) and DIEA (1.41 g, 10.9 mmol, 8.00 equiv.). The resulting mixture was stirred at room temperature for an additional 2 h. At room temperature, the reaction was quenched by the addition of water (30 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase high-performance chromatography using the following conditions: column, C18 silica gel, mobile phase A: water (0.1% NH3 . HO), mobile phase B: MeCN, 10% to 90% gradient within 30 min, detector, UV 254 nm. Di((2-bromoethyl)amino)phosphinic acid 4-[(2-cyclopropyl-3-oxo-1H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (690 mg, 76.8%) was obtained as a brown oil. LC-MS (ESI): m / z 657.00, 659.00, 660.95 [M+H] +

[0314] Bis(aziridin-1-yl)phosphinic acid 4-[(2-cyclopropyl-3-oxo-1H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester At room temperature under a nitrogen atmosphere, DIEA (638 mg, 4.94 mmol, 5.00 equiv.) was added to a stirred solution of di((2-bromoethyl)amino)phosphinic acid 4-[(2-cyclopropyl-3-oxo-1H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (650 mg, 0.99 mmol, 1.00 equiv.) and AgO (1.14 g, 4.93 mmol, 5.00 equiv.) in THF (10.0 mL). The resulting mixture was stirred at 70 °C for 2 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified under the following conditions: column: XB C18, mobile phase A: water (10 mmol / L NH . The residue was purified by preparative HPLC using a 200 mL / min gradient (15% B to 55% B within 40 min, 254 / 220 nm wavelength) of bis(aziridin-1-yl)phosphinic acid 4-[(2-cyclopropyl-3-oxo-1H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (357 mg, 72.8%) as a white solid. LC-MS (ESI): m / z 497.25 [M+H] +

[0315] Di(aziridin-1-yl)phosphinic acid (R)-4-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester The compound bis(aziridin-1-yl)phosphinic acid 4-[(2-cyclopropyl-3-oxo-1H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester was separated by chiral HPLC under the following conditions: CHIRALPAK IE, 3*25 cm, 5 μm, mobile phase A: HEX: MtBE = 1:1 (1:1 (0.5% 2 M NH3-MEOH)), mobile phase B: MeOH - HPLC, flow rate: 40 mL / min, gradient: 30% B to 30% B within 22 min, wavelength: 212 / 260 nm, RT1 (min): 16.7, RT2 (min): 19.2, sample solvent: MeOH: DCM = 1:1 - HPLC, injection volume: 0.6 mL, run number: 11.

[0316] Isomer 1(38), 107.4mg, 22.25%, ee>99%, LC-MS (ESI): m / z 497.25[M+H] + 1 H NMR (300MHz,DMSO-d6) δ 8.06 (d,J=8.2Hz,1H),7.68-7.48 (m,2H),7.26 (dd,J=8.3,2.5Hz,1H),6.95 (d,J=2.5Hz,1H),5.96 (q,J=6.5,6.0Hz,1H),4.37 (s,2H),3.02-2.84 (m,1H),2.83-2.62 (m,1H),2.61-2.51 (m,2H),2.29-1.88 (m,9H),0.93-0.68 (m,4H). 31 P NMR (121MHz, DMSO-d6) δ 30.09.

[0317] Isomer 2(39), 88.6mg, 18.36%, ee>99%, LC-MS (ESI): m / z 497.25[M+H] + 1H NMR (300MHz,DMSO-d6) δ 8.06 (d,J=8.2Hz,1H),7.64-7.52 (m,2H),7.27 (dd,J=8.3,2.5Hz,1H),6.95 (d,J=2.4Hz,1H),6.03-5.90 (m,1H),4.37 (s,2H),3.00-2.85 (m,1H),2.81-2.65 (m,1H),2.61-2.52 (m,2H),2.23-1.97 (m,9H),0.93-0.71 (m,4H). 31 P NMR (121MHz, DMSO-d6) δ 30.09. Example 10. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (40 and 41) [ka] 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-ol

[0318] To a solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (200 mg, 1.02 mmol, 1.0 eq.) and 4-(pyridin-2-yl)phenol (262 mg, 1.53 mmol, 1.5 eq.) in ACN (10 mL) was added CsCO (665 mg, 2.04 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a gray solid, 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-ol (3, 150 mg, 0.43 mmol, 42%). LC-MS (ESI): m / z 349 [M+H] + .

[0319] Di((2-bromoethyl)amino)phosphinic acid 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester To a solution of 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-ol (120 mg, 0.34 mmol, 1.0 eq.) in THF (15 mL) was added LiHMDS (0.68 mL, 1 M, THF, 0.68 mmol, 2.0 eq.) dropwise at −60° C. under N2, and the resulting solution was stirred at −60° C. for 20 min under N2. POCl3 (104 mg, 0.68 mmol, 2.0 eq.) in THF (5 mL) was added, and the resulting mixture was stirred at −60° C. for 15 min. 2-Bromoethylamine hydrobromide (423 mg, 2.07 mmol, 6.0 eq.) and TEA (412 mg, 4.08 mmol, 12.0 eq.) were added, and the mixture was stirred at −60° C. for 10 min. The resulting mixture was warmed to room temperature and stirred for 0.5 hours. After completion, the reaction mixture was quenched with NH4Cl solution (5 mL, saturated, aqueous) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di((2-bromoethyl)amino)phosphinic acid 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (170 mg, 0.27 mmol, 77%). LC-MS (ESI): m / z 639 [M+H] + .

[0320] Di(aziridin-1-yl)phosphinic acid 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (210 mg, 0.33 mmol, 1.0 eq.) in THF (10 mL) was added AgO (766 mg, 3.30 mmol, 10.0 eq.) and DIEA (426 mg, 3.30 mmol, 10.0 eq.). The resulting solution was stirred at 70 °C for 18 h under N. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (126 mg, 0.26 mmol, 80%) as a yellow oil in the form of a stereoisomer mixture. 1 H NMR (400MHz,CDCl3) δ 8.79-8.59 (m,1H),8.00-7.87 (m,3H),7.83-7.62 (m,2H),7.59-7.50 (m,1H),7.25-7.16 (m,1H),7.05-6.86 (m,2H),6.15-5.74 (m,1H),2.98-2.82 (m,1H),2.73-2.48 (m,2H),2.37-2.09 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.92 (s). LC-MS (ESI): m / z 479.1[M+H] + .

[0321] Di(aziridin-1-yl)phosphinic acid (S)-5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 5-nitro-4-(4-(pyridin-2-yl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (126 mg, 0.26 mmol) was further separated by chiral SFC to give:

[0322] Isomer 1(40), 50 mg, 0.11 mmol, 32%, retention time: 1.941 min, >99% ee. LC-MS (ESI): m / z 479.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 8.58 (d,J=4.6Hz,1H),7.92-7.79 (m,3H),7.71-7.56 (m,2H),7.45 (d,J=8.2Hz,1H),7.16-7.10 (m,1H),6.93-6.85 (m,2H),6.00-5.85 (m,1H),2.91-2.69 (m,1H),2.61-2.41 (m,2H),2.21-2.10 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.90 (s).

[0323] Isomer 2(41), 50mg, 0.11mmol, 32%, retention time: 2.317min, 95% ee. LC-MS (ESI): m / z 479.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 8.67 (d,J=4.6Hz,1H),7.99-7.86 (m,3H),7.78-7.71 (m,1H),7.71-7.64 (m,1H),7.54 (d,J=8.2Hz,1H),7.26-7.19 (m,1H),7.05-6.91 (m,2H),6.10-5.89 (m,1H),2.95-2.83 (m,1H),2.70-2.49 (m,2H),2.32-2.18 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.91 (s).

[0324] Analytical method: Column: ChiralPak IH, 100 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 30% B within 8 min; Flow rate: 2.5 mL / min; Column temperature: 40°C.

[0325] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralPak AD, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2 and B, MEOH + 0.1% NH3H2O, Gradient: B 30%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 10 min, Elution time: 2 H. Example 11. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-4-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (42 and 43) [ka] 5-Methoxy-2-methyl-3H-isoindol-1-one

[0326] To a stirred solution of 2-(bromomethyl)-4-methoxybenzoic acid methyl ester (3.00 g, 11.6 mmol, 1.00 equiv) and CHNHHCl (1.56 g, 23.2 mmol, 2.00 equiv) in MeOH (30.0 mL) was added EtN (3.52 g, 34.7 mmol, 3.00 equiv). The resulting mixture was stirred at 60 °C for 1 h. At room temperature, the resulting mixture was quenched with water and extracted with CHCl (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 5-methoxy-2-methyl-3H-isoindol-1-one (1.15 g, 56.0%) as a white solid. LC-MS (ESI): m / z 178.10[M+H] +

[0327] 5-Hydroxy-2-methyl-3H-isoindol-1-one At 0 °C under a nitrogen atmosphere, BBr (24.0 mL, 24.0 mmol, 3.00 equiv., 1.0 mol / L in DCM) was added dropwise to a stirred solution of 5-methoxy-2-methyl-3H-isoindol-1-one (1.42 g, 8.01 mmol, 1.00 equiv.) in THF (150 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. At 0 °C, the reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give 5-hydroxy-2-methyl-3H-isoindol-1-one (1.02 g, 78.0%) as a white solid. LC-MS (ESI): m / z 164.10[M+H] +

[0328] 5-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-2-methyl-3H-isoindol-1-one A mixture of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (700 mg, 3.55 mmol, 1.00 equiv.), CsCO (2.31 g, 7.10 mmol, 2.00 equiv.), and 5-hydroxy-2-methyl-3H-isoindol-1-one (579 mg, 3.55 mmol, 1.00 equiv.) in ACN (15.0 mL) was stirred at 60 °C overnight. The mixture was allowed to cool to room temperature. At room temperature, the reaction was quenched with water. The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give a light brown solid, 5-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-2-methyl-3H-isoindol-1-one (413 mg, 34.2%). LC-MS (ESI): m / z 341.15 [M+H] +

[0329] Di((2-bromoethyl)amino)phosphinic acid 4-[(2-methyl-1-oxo-3H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a stirred solution of 5-[(1-hydroxy-5-nitro-2,3-dihydro-1H-inden-4-yl)oxy]-2-methyl-3H-isoindol-1-one (395 mg, 1.16 mmol, 1.00 equiv.) in THF (20.0 mL) was added LiHMDS (2.90 mL, 2.90 mmol, 2.50 equiv., 1.0 mol / L in THF) dropwise at −60° C. under a nitrogen atmosphere. The resulting mixture was stirred at −60° C. under a nitrogen atmosphere for 20 min. To the above mixture was added POCl (445 mg, 2.90 mmol, 2.50 equiv.) dropwise at −60° C. The resulting mixture was stirred at −60° C. for an additional 30 min. To the above mixture was added 2-bromoethan-1-amine hydrobromide (1.43 g, 6.97 mmol, 6.00 equiv.) and DIEA (1.20 g, 9.29 mmol, 8.00 equiv.) in portions at −60° C. The resulting mixture was stirred at −60° C. for an additional 20 min and then at room temperature under a nitrogen atmosphere for 1 h. At room temperature, the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give a yellow solid, di((2-bromoethyl)amino)phosphinic acid 4-[(2-methyl-1-oxo-3H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (397 mg, 54.1%). LC-MS (ESI): m / z 631.05, 633.05, 635.05 [M+H] +

[0330] Bis(aziridin-1-yl)phosphinic acid 4-[(2-methyl-1-oxo-3H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester A mixture of di((2-bromoethyl)amino)phosphinic acid 4-[(2-methyl-1-oxo-3H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (377 mg, 0.60 mmol, 1.00 equiv.), DIEA (154 mg, 1.19 mmol, 2.00 equiv.), and AgO (677 mg, 2.92 mmol, 4.90 equiv.) in THF (128 mL) was stirred at 70 °C under a nitrogen atmosphere overnight. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep C18 OBD column, 50*250 mm, 10 μm, mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN, flow rate: 100 mL / min, gradient: 10% B to 40% B, 40% B within 30 min, wavelength: 254 / 220 nm) to obtain a pale yellow oily substance, bis(aziridin-1-yl)phosphinic acid 4-[(2-methyl-1-oxo-3H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (159 mg, 53.4%). LC-MS (ESI): m / z 471.15 [M+H] +

[0331] Di(aziridin-1-yl)phosphinic acid (R)-4-((2-methyl-1-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-((2-methyl-1-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Bis(aziridin-1-yl)phosphinic acid 4-[(2-methyl-1-oxo-3H-isoindol-5-yl)oxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (159 mg, 0.337 mmol, 1.00 equiv.) was separated by preparative chiral HPLC using a CHIRALPAK IC column (2*25 cm, 5 μm), mobile phase A: MtBE (10 mM NH3-MeOH), mobile phase B: MeOH, flow rate: 20 mL / min, gradient: 50% B to 50% B within 13 min, wavelength: 208 / 248 nm, RT1 (min): 7.98, RT2 (min): 10.4, sample solvent: MeOH:DCM = 1:2, injection volume: 0.8 mL, run number: 5.

[0332] Isomer 1(42), 48.5mg, 30.6%, ee>99%, LC-MS (ESI): m / z 471.15[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.08 (d,J=8.2Hz,1H),7.64 (d,J=8.3Hz,1H),7.58 (dd,J=8.2,0.8Hz,1H),7.12 (d,J=2.2Hz,1H),7.02 (dd,J=8.3,2.4Hz,1H),5.95 (q,J=6.6Hz,1H),4.40 (s,2H),3.04 (s,3H),2.80-2.44 (m,3H),2.22-1.98 (m,9H).

[0333] Isomer 2(43), 49.0mg, 30.9%, ee>99%, LC-MS (ESI): m / z 471.15[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.08 (d,J=8.2Hz,1H),7.64 (d,J=8.3Hz,1H),7.58 (d,J=8.2Hz,1H),7.12 (d,J=2.3Hz,1H),7.02 (dd,J=8.3,2.3Hz,1H),5.95 (q,J=6.5Hz,1H),4.40 (s,2H),3.04 (s,3H),2.79-2.43 (m,3H),2.28-1.98 (m,9H). Example 12. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-4-(4-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-(4-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (58 and 59) [ka] 4-(1-methyl-1H-pyrazol-4-yl)phenol

[0334] To a mixture of 4-iodophenol (3.6 g, 16.3 mmol, 1.0 eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.1 g, 24.5 mmol, 1.5 eq.), and NaCO (5.2 g, 48.9 mmol, 3.0 eq.) in DME (100 mL) and HO (10 mL) was added Pd(PPh) (1.88 g, 1.63 mmol, 0.1 eq.) at room temperature under N. The resulting solution was stirred at 90 °C for 16 h under N. After completion, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 4-(1-methyl-1H-pyrazol-4-yl)phenol (1.2 g, 6.90 mmol, 42%). LCMS (ESI): m / z 175 [M+H] + .

[0335] Di(aziridin-1-yl)phosphinic acid 4-(4-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 4-(1-methyl-1H-pyrazol-4-yl)phenol (73 mg, 0.42 mmol, 1.5 eq.) and di(aziridin-1-yl)phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (90 mg, 0.28 mmol, 1.0 eq.) in MeCN (5 mL) was added CsCO (273 mg, 0.84 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 4-(4-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (85 mg, 0.18 mmol, 64%) in the form of a stereoisomeric mixture as a gray oil. 1 H NMR (400MHz,CDCl3) δ 7.88 (d,J=8.2Hz,1H),7.69 (s,1H),7.54 (s,1H),7.50 (d,J=8.2Hz,1H),7.40-7.36 (m,2H),6.90-6.84 (m,2H),6.06-5.94 (m,1H),3.94 (s,3H),2.94-2.83 (m,1H),2.67-2.50 (m,2H),2.33-2.17 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.99 (s). LC-MS (ESI): m / z 482.2[M+H] + .

[0336] Di(aziridin-1-yl)phosphinic acid (S)-4-(4-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-(4-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 4-(4-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (70 mg, 0.15 mmol) was further separated by chiral SFC to give:

[0337] Isomer 1(58), 21mg, 30%, retention time: 2.395min, >99% ee. LC-MS (ESI): m / z 482.2[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.88 (d,J=8.2Hz,1H),7.69 (s,1H),7.55 (s,1H),7.50 (d,J=8.2Hz,1H),7.41-7.35 (m,2H),6.90-6.84 (m,2H),6.05-5.95 (m,1H),3.93 (s,3H),2.93-2.82 (m,1H),2.66-2.50 (m,2H),2.29-2.18 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.97 (s).

[0338] Isomer 2 (59), 21mg, 30%, retention time: 3.070min, >99% ee. LC-MS (ESI): m / z 482.2[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.88 (d,J=8.2Hz,1H),7.69 (s,1H),7.55 (s,1H),7.50 (d,J=8.2Hz,1H),7.41-7.36 (m,2H),6.90-6.83 (m,2H),6.05-5.96 (m,1H),3.93 (s,3H),2.92-2.82 (m,1H),2.65-2.51 (m,2H),2.32-2.17 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.99 (s).

[0339] Analytical method: Column: ChiralPak IB, 100 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 30% B within 8 min; Flow rate: 2.5 mL / min; Column temperature: 40°C.

[0340] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralPak IB, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2 and B, MEOH + 0.1% NH3H2O, Gradient: B 40%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 254 nm, Cycle time: 15 min, Elution time: 2 H. Example 13. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-4-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (64 and 65) [ka] 5-((tert-butyldimethylsilyl)oxy)-3-methylbenzo[d]oxazol-2(3H)-one

[0341] To a stirred suspension of 5-((tert-butyldimethylsilyl)oxy)benzo[d]oxazol-2(3H)-one (2.2 g, 8.29 mmol, 1.0 eq.) and CsCO (5.4 g, 16.6 mmol, 2.0 eq.) in DMF (10 mL) was added CHCl (0.77 mL, 12.4 mmol, 1.5 eq.) at room temperature. The mixture was stirred at room temperature for 2 h. After completion, the resulting mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 5-((tert-butyldimethylsilyl)oxy)-3-methylbenzo[d]oxazol-2(3H)-one (2 g, 7.16 mmol, 86%). LC-MS (ESI): m / z 280.2[M+H] + .

[0342] 5-Hydroxy-3-methylbenzo[d]oxazol-2(3H)-one To a stirred suspension of 5-((tert-butyldimethylsilyl)oxy)-3-methylbenzo[d]oxazol-2(3H)-one (2.0 g, 7.16 mmol, 1.0 eq.) in THF (25 mL) was added TBAF (11 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. After completion, the resulting mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 5-hydroxy-3-methylbenzo[d]oxazol-2(3H)-one (860 mg, 5.21 mmol, 73%). LCMS (ESI): m / z 166.1 [M+H] + .

[0343] Di(aziridin-1-yl)phosphinic acid 4-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 5-hydroxy-3-methylbenzo[d]oxazol-2(3H)-one (80 mg, 0.48 mmol, 1.5 eq.) and di(aziridin-1-yl)phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (105 mg, 0.32 mmol, 1.0 eq.) in MeCN (5 mL) was added CsCO (208 mg, 0.64 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 4-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (40 mg, 85 μmol, 17%) in the form of a stereoisomeric mixture as a yellow solid. 1 H NMR (400MHz,CDCl3) δ 7.92-7.87 (m,1H),7.57-7.51 (m,1H),7.10-7.05 (m,1H),6.63-6.60 (m,1H),6.51 (dd,J=8.7,2.5Hz,1H),6.04-5.98 (m,1H),3.37 (s,3H),2.94-2.80 (m,1H),2.66-2.53 (m,2H),2.31-2.15 (m,9H). 31 P NMR (162MHz, CDCl3) δ 30.12 (s). LC-MS (ESI): m / z 473.1[M+H] + .

[0344] Di(aziridin-1-yl)phosphinic acid (S)-4-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 4-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (40 mg, 85 μmol) was further separated by chiral SFC to give:

[0345] Isomer 1(64), 3.6mg, 9%, retention time: 4.259min, >99% ee. LC-MS (ESI): m / z 473.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.90 (d,J=8.2Hz,1H),7.54 (d,J=8.3Hz,1H),7.08 (d,J=8.7Hz,1H),6.62 (t,J=3.4Hz,1H),6.52 (dd,J=8.7,2.5Hz,1H),6.05-5.97 (m,1H),3.37 (s,3H),2.93-2.82 (m,1H),2.66-2.50 (m,2H),2.30-2.14 (m,9H). 31 P NMR (162MHz, CDCl3) δ 30.13 (s).

[0346] Isomer 2(65), 4.0mg, 9%, retention time: 5.464min, >99% ee. LC-MS (ESI): m / z 473.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.93-7.87 (m,1H),7.56-7.49 (m,1H),7.11- 7.04 (m,1H),6.66-6.59 (m,1H),6.55-6.48 (m,1H),6.04-5.98 (m,1H),3.40-3.32 (m,3H),2.93-2.82 (m,1H),2.66-2.51 (m,2H),2.33-2.14 (m,9H). 31 P NMR (162MHz, CDCl3) δ 30.13 (s).

[0347] Analytical method: Column: ChiralPak C-IG, 100 × 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 40% B within 8 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C.

[0348] SFC method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralPak C-IG, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2, and B, MEOH + 0.1% NH3H2O, Gradient: B 50%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 9 min, Elution time: 2 h. Example 14. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-5-nitro-4-(3-(piperidine-1-carbonyl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-5-nitro-4-(3-(piperidine-1-carbonyl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (68 and 69) [ka] (3-Hydroxyphenyl)(piperidin-1-yl)methanone

[0349] To a solution of 3-hydroxybenzoic acid (500 mg, 3.62 mmol, 1.0 eq.) and piperidine (462 mg, 5.43 mmol, 1.5 eq.) in DMF (10 mL) was added HOBt (734 mg, 5.43 mmol, 1.0 eq.) and EDCI (1.04 g, 5.43 mmol, 1.5 eq.). The mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The residue was triturated with EtOAc and filtered to give (3-hydroxyphenyl)(piperidin-1-yl)methanone (500 mg, 2.44 mmol, 67%) as a white solid. LC-MS (ESI): m / z 206 [M+H]+ .

[0350] Di(aziridin-1-yl)phosphinic acid 5-nitro-4-(3-(piperidine-1-carbonyl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester To a solution of di(aziridin-1-yl)phosphinic acid (3-hydroxyphenyl)(piperidin-1-yl)methanone (100 mg, 0.49 mmol, 1.5 eq.) and 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (106 mg, 0.33 mmol, 1.0 eq.) in MeCN (5 mL) was added CsCO (215 mg, 0.66 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 5-nitro-4-(3-(piperidine-1-carbonyl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (86 mg, 17 μmol, 35%) as an oily stereoisomer mixture. 1 H NMR (400MHz,CDCl3) δ 7.89 (d,J=8.2Hz,1H),7.53 (d,J=8.2Hz,1H),7.34 (t,J=7.9Hz,1H),7.09 (d,J=7.6Hz,1H),6.93 (dd,J=8.2,2.1Hz,1H),6.84 (s,1H),6.04-5.96 (m,1H),3.74-3.58 (m,2H),3.38-3.24 (m,2H),2.93-2.83 (m,1H),2.68-2.51 (m,2H),2.32-2.08 (m,9H),1.73-1.64 (m,4H),1.53-1.43 (m,2H). 31 P NMR (162MHz, CDCl3) δ 29.88 (s). LC-MS (ESI): m / z 513.2[M+H] + .

[0351] Di(aziridin-1-yl)phosphinic acid (S)-5-nitro-4-(3-(piperidine-1-carbonyl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-5-nitro-4-(3-(piperidine-1-carbonyl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 5-nitro-4-(3-(piperidine-1-carbonyl)phenoxy)-2,3-dihydro-1H-inden-1-yl ester (86 mg, 17 μmol) was further separated by chiral SFC to give:

[0352] Isomer 1(68), 25mg, 29%, retention time: 2.513min, >99% ee. LC-MS (ESI): m / z 513.4[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.87 (d,J=8.2Hz,1H),7.51 (d,J=8.2Hz,1H),7.32 (t,J=7.9Hz,1H),7.10-7.05 (m,1H),6.95-6.88 (m,1H),6.84-6.80 (m,1H),6.02-5.95 (m,1H),3.72-3.57 (m,2H),3.35-3.20 (m,2H),2.91-2.79 (m,1H),2.65-2.48 (m,2H),2.26- 2.16 (m,9H),1.70-1.56 (m,4H),1.53-1.41 (m,2H). 31 P NMR (162MHz, CDCl3) δ 29.86 (s).

[0353] Isomer 2(69), 25mg, 29%, retention time: 2.746min, >99% ee. LC-MS (ESI): m / z 513.4[M+H] + ; 1H NMR (400MHz,CDCl3) δ 7.89 (d,J=8.2Hz,1H),7.53 (d,J=8.2Hz,1H),7.34 (t,J=7.9Hz,1H),7.12-7.07 (m,1H),6.96-6.91 (m,1H),6.86- 6.82 (m,1H),6.04-5.97 (m,1H),3.76-3.57 (m,2H),3.41-3.24 (m,2H),2.94-2.81 (m,1H),2.69-2.50 (m,2H),2.32-2.13 (m,9H),1.71-1.58 (m,4H),1.55- 1.44 (m,2H). 31 P NMR (162MHz, CDCl3) δ 29.87 (s).

[0354] Analytical method: Column: ChiralPak IB, 100 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 20% B within 8 min; Flow rate: 2.5 mL / min; Column temperature: 40°C.

[0355] SFC method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralPak IB, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2, and B, MEOH + 0.1% NH3H2O, Gradient: B 15%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 7 min, Elution time: 3 h. Example 15. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-4-(3-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-(3-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (76 and 77) [ka] 3-(1-methyl-1H-pyrazol-4-yl)phenol

[0356] To a mixture of 3-bromophenol (100 mg, 0.58 mmol, 1.0 eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (144 mg, 0.69 mmol, 1.2 eq.), and CsCO (565 mg, 1.73 mmol, 3.0 eq.) in DMF (8 mL) was added Pd(PPh) (33.4 mg, 29 μmol, 0.05 eq.) at room temperature under N. The resulting solution was stirred at 100 °C for 5 h under N. After completion, the reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high performance column chromatography to obtain a yellow solid, 3-(1-methyl-1H-pyrazol-4-yl)phenol (75 mg, 0.43 mmol, 74%). 1 H NMR (400MHz,CDCl3) δ 7.76 (s,1H),7.61 (s,1H),7.25-7.21 (m,1H),7.09-7.05 (m,1H),6.99-6.96 (m,1H),6.74-6.68 (m,1H),3.96 (s,3H).

[0357] Di(aziridin-1-yl)phosphinic acid 4-(3-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 3-(1-methyl-1H-pyrazol-4-yl)phenol (40.2 mg, 0.23 mmol, 1.5 eq.) and di(aziridin-1-yl)phosphinic acid 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (50 mg, 0.15 mmol, 1.0 eq.) in MeCN (5 mL) was added CsCO (100 mg, 0.31 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 4-(3-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (47 mg, 98 μmol, 64%) in the form of a stereoisomeric mixture as a gray oil. 1 H NMR (400MHz,CDCl3) δ 7.89 (d,J=8.2Hz,1H),7.70 (s,1H),7.57 (s,1H),7.51 (d,J=8.2Hz,1H),7.30-7.15 (m,2H),7.05-7.00 (m,1H),6.65 (dd,J=8.1,2.4Hz,1H), 6.04-5.97 (m,1H),3.93 (s,3H),2.94-2.84 (m,1H),2.68-2.49 (m,2H),2.34-2.16 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.97 (s). LC-MS (ESI): m / z482.2[M+H] + .

[0358] Di(aziridin-1-yl)phosphinic acid (S)-4-(3-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-4-(3-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 4-(3-(1-methyl-1H-pyrazol-4-yl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (55 mg, 0.11 mmol) was further separated by chiral SFC to give:

[0359] Isomer 1(76), 26.1mg, 47%, retention time: 4.999min, >99% ee. LC-MS (ESI): m / z 482.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.89 (d,J=8.2Hz,1H),7.70 (s,1H),7.57 (s,1H),7.51 (d,J=8.2Hz,1H),7.26-7.24 (m,1H),7.20-7.16 (m,1H),7.08-6.95 (m,1H),6.71-6.60 (m,1H),6.04-5.95 (m,1H),3.93 (s,3H),2.93-2.84 (m,1H),2.68-2.47 (m,2H),2.28-2.13 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.98 (s).

[0360] Isomer 2(77), 26.8mg, 49%, retention time: 8.646min, >99% ee. LC-MS (ESI): m / z 482.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.89 (d,J=8.2Hz,1H),7.70 (s,1H),7.57 (s,1H),7.51 (d,J=8.2Hz,1H),7.29-7.26 (m,1H),7.19-7.16 (m,1H),7.04-7.01 (m,1H),6.68-6.62 (m,1H),6.04-5.96 (m,1H),3.93 (s,3H),2.94-2.84 (m,1H),2.67-2.50 (m,2H),2.31-2.15 (m,9H). 31 P NMR (162MHz, CDCl3) δ 29.98 (s).

[0361] Analytical method: Column: ChiralPak AD, 250 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 50% within 8 min; Flow rate: 1.8 mL / min; Back pressure: 100 bar; Column temperature: 35°C.

[0362] SFC method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralPak AD, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2, and B, MEOH + 0.1% NH3H2O, Gradient: B 50%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 5.3 min, Elution time: 2 h. Example 16: Synthesis of di(aziridin-1-yl)phosphinic acid (R)-4-(3-(morpholine-4-carbonyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-(3-(morpholine-4-carbonyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (125 and 126) [ka] 3-(morpholine-4-carbonyl)phenol

[0363] To a stirred solution of 3-hydroxybenzoic acid (10.0 g, 72.4 mmol, 1.00 equiv.) and morpholine (6.94 g, 79.6 mmol, 1.10 equiv.) in DCM (200 mL) at room temperature, EDCI (15.3 g, 79.6 mmol, 1.10 equiv.), DIEA (18.7 g, 145 mmol, 2.00 equiv.), and DMAP (630 mg, 7.24 mmol, 0.10 equiv.) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give 3-(morpholine-4-carbonyl)phenol (10.0 g, 66.7%) as a pale yellow oil. LC-MS (ESI): m / z 208.25 [M+H] + .

[0364] 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-ol To a stirred solution of 4-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (500 mg, 2.54 mmol, 1.00 equiv.) in CHCN (10 mL) at room temperature, 3-(morpholine-4-carbonyl)phenol (631 mg, 3.04 mmol, 1.20 equiv.) and CsCO (1.65 g, 5.07 mmol, 2.00 equiv.) were added. The resulting mixture was stirred at 60 °C for 2 h. It was then filtered through a short pad of diatomaceous earth. The pad was washed with EtOAc (3 × 10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give a white solid, 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-ol (750 mg, 76.9%). LC-MS (ESI): m / z 385.20 [M+H] +

[0365] Di((2-bromoethyl)amino)phosphinic acid 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a stirred solution of 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-ol (700 mg, 1.82 mmol, 1.00 equiv.) in THF (125 mL) at −78 °C under a nitrogen atmosphere, LiHMDS (4.55 mL, 4.55 mmol, 2.5 equiv., 1.0 M in THF) was added dropwise. The resulting mixture was stirred at −78 °C for 30 min. POCl (698 mg, 4.56 mmol, 2.50 equiv.) was added dropwise to the above mixture and stirred at −78 °C for an additional 30 min. To the above mixture was added 2-bromoethan-1-amine hydrobromide (2.24 g, 10.9 mmol, 6.00 equiv.) and DIEA (1.88 g, 14.6 mmol, 8.00 equiv.) at -78 °C. The resulting mixture was stirred at -78 °C for 30 min. The mixture was then warmed to room temperature and stirred for an additional 2 h under a nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase high-performance chromatography [using the following conditions: column, C18, mobile phase A: water (0.1% NH3 . HO), mobile phase B: MeCN, 10% to 80% gradient within 30 min, detector, UV 254 nm] to give a yellow solid, di((2-bromoethyl)amino)phosphinic acid 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (490 mg, 39.8%). LC-MS (ESI): m / z 674.80, 677.05, 679.05 [M+H] +

[0366] Bis(aziridin-1-yl)phosphinic acid 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a stirred solution of di((2-bromoethyl)amino)phosphinic acid 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (440 mg, 0.650 mmol, 1.00 equiv.) in THF (10.0 mL) at room temperature was added AgO (754 mg, 3.26 mmol, 5.00 equiv.) and DIEA (420 mg, 3.26 mmol, 5.00 equiv.). The resulting mixture was stirred at 60 °C for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through a short pad of diatomaceous earth. The pad was washed with EtOAc (10 mL × 3). The combined filtrate was diluted with water (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (10 mL × 3) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: Ultimate XB-C18, 50 x 250 mm, 10 μm; mobile phase A: water (0.05% NH . HO), mobile phase B: CHCN, flow rate: 100 mL / min, gradient: 25% B to 60% B within 930 min, wavelength: 254 / 220 nm)] to give a yellow oil, bis(aziridin-1-yl)phosphinic acid 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (120 mg, 35.9%). LC-MS (ESI): m / z 515.20 [M+H] +

[0367] Di(aziridin-1-yl)phosphinic acid (R)-4-(3-(morpholine-4-carbonyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-4-(3-(morpholine-4-carbonyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester The compound bis(aziridin-1-yl)phosphinic acid 4-[3-(morpholine-4-carbonyl)phenoxy]-5-nitro-2,3-dihydro-1H-inden-1-yl ester (110 mg, 0.21 mmol, 1.00 equiv.) was separated by preparative chiral HPLC under the following conditions: [Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile Phase A: Hex:MtBE = 1:1 (0.5% 2M NH3-MEOH); Mobile Phase B: MeOH; Flow Rate: 20 mL / min; Gradient: 20% B to 20% B within 14 min; Wavelength: 222 / 230 nm; RT1 (min): 9.67; RT2 (min): 10.86; Sample Solvent: MeOH:DCM = 1:1; Injection Volume: 0.4 mL; Run Number: 21].

[0368] Isomer 1 (125), 30.0 mg, 27.3%, ee>97%. LC-MS (ESI): m / z 515.15[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.89 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.11 (dt, J = 7.5, 1.2 Hz, 1H), 6.95 (dd, J = 8.2, 2.6 Hz, 1H), 6.87 (dd, J = 2.7, 1.4 Hz, 1H), 6.06-5.94 (m, 1H), 4.01-3.24 (m, 8H), 2.98-2.78 (m, 1H), 2.77-2.50 (m, 2H), 2.41-2.13 (m, 9H). 31 P NMR (162 MHz, chloroform-d) δ 23.29.

[0369] Isomer 2(126), 32.8mg, 29.8%, ee>98%. LC-MS (ESI): m / z 515.20[M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.89 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.11 (dt, J = 7.5, 1.2 Hz, 1H), 6.95 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.90-6.84 (m, 1H), 6.06-5.96 (m, 1H), 4.00-3.21 (m, 8H), 2.95-2.82 (m, 1H), 2.70-2.51 (m, 2H), 2.32-2.15 (m, 9H). 31 P NMR (162 MHz, chloroform-d) δ 23.29. Example 17. Synthesis of bis(aziridin-1-yl)phosphinic acid 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl ester (127) (General Procedure 6, 6,6 Core 1 - Method A) [ka] 4-Bromo-2-fluoro-3-methoxyaniline

[0370] To a solution of 2-fluoro-3-methoxyaniline (2.8 g, 19.83 mmol, 1.0 eq.) in DMF (50 mL) was added NBS (3.5 g, 19.84 mmol, 1.0 eq.), and the mixture was stirred under nitrogen gas at 20 °C for 4 hours. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4-bromo-2-fluoro-3-methoxyaniline (4.3 g, 19.54 mmol, 99%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.06 (dd, J=8.7, 2.1Hz, 1H), 6.43-6.42 (m, 1H), 3.94 (s, 3H).

[0371] 1-Bromo-3-fluoro-2-methoxy-4-nitrobenzene To a solution of 4-bromo-2-fluoro-3-methoxyaniline (3.2 g, 14.54 mmol, 1.0 eq.) in ACN (50 mL) was added KCO (2.0 g, 14.54 mmol, 1.0 eq.) and HO (49.5 mL, 1454.28 mmol, 30 wt%, 10.0 eq.). The mixture was stirred under nitrogen gas at 20 °C for 16 h. After completion, the mixture was quenched with saturated aqueous NaSO solution (100 mL) and extracted with EtOAc (100 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give 1-bromo-3-fluoro-2-methoxy-4-nitrobenzene (2.4 g, 9.60 mmol, 66%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.68 (dd,J=9.0,7.0Hz,1H),7.48 (dd,J=9.0,2.1Hz,1H),4.04 (s,3H).

[0372] 1-(1-ethoxyvinyl)-3-fluoro-2-methoxy-4-nitrobenzene To a solution of 1-bromo-3-fluoro-2-methoxy-4-nitrobenzene (2.4 g, 9.60 mmol, 1.0 eq.) in dioxane (60 mL) was added tributyl(1-ethoxyvinyl)stannane (3.5 g, 9.60 mmol, 1.0 eq.) and (PPh3)2PdCl2 (0.37 g, 0.48 mmol, 0.05 eq.). The mixture was evaporated and backfilled with N2 three times. The mixture was stirred at 60 °C under a nitrogen atmosphere for 24 h until the starting material was completely consumed. The reaction mixture was cooled to room temperature, quenched with KF solution (100 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high performance column chromatography to obtain a yellow solid, 1-(1-ethoxyvinyl)-3-fluoro-2-methoxy-4-nitrobenzene (1.8 g, 7.46 mmol, 78%). 1H NMR (400MHz,DMSO-d6) δ 7.87 (dd,J=8.9,7.1Hz,1H),7.44 (dd,J=8.9,1.9Hz,1H),4.75 (d,J=2.6Hz,1H),4.62 (d,J=2.6Hz,1H),3.93-3.88 (m,2H),3.87 (s,3H),1.32 (t,J=7.0Hz,3H).

[0373] 1-(3-fluoro-2-methoxy-4-nitrophenyl)ethan-1-one To a solution of 1-(1-ethoxyvinyl)-3-fluoro-2-methoxy-4-nitrobenzene (1.6 g, 6.63 mmol, 1.0 eq.) in THF (20 mL) was added aqueous HCl (20 mL, 2 N), and the mixture was stirred at 20 °C for 24 hours under a nitrogen atmosphere. After completion, the mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 1-(3-fluoro-2-methoxy-4-nitrophenyl)ethan-1-one (1.4 g, 6.57 mmol, 99%). 1 H NMR (400MHz, CDCl3) δ 7.73 (dd,J=8.7,6.3Hz,1H),7.51 (dd,J=8.7,2.0Hz,1H),4.12 (d,J=2.6Hz,3H),2.64 (s,3H).

[0374] 1-(3-fluoro-2-hydroxy-4-nitrophenyl)ethan-1-one To a solution of 1-(3-fluoro-2-methoxy-4-nitrophenyl)ethan-1-one (1.4 g, 6.57 mmol, 1.0 eq.) in DCM (20 mL) was added BBr (4.9 g, 19.7 mmol, 3.0 eq.), and the mixture was stirred at room temperature under nitrogen gas for 24 hours. After completion, the mixture was poured into water (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 1-(3-fluoro-2-hydroxy-4-nitrophenyl)ethan-1-one (400 mg, 2.01 mmol, 31%). 1 HNMR (400MHz, CDCl3) δ 12.47 (s,1H),7.66 (dd,J=8.9,2.0Hz,1H),7.48 (dd,J=8.9,6.1Hz,1H),2.72 (s,3H).

[0375] 1-(2-hydroxy-4-nitro-3-phenoxyphenyl)ethan-1-one At 0 °C, phenoxysodium (245 mg, 2.11 mmol, 1.05 eq.) was added to a solution of 1-(3-fluoro-2-hydroxy-4-nitrophenyl)ethan-1-one (400 mg, 2.01 mmol, 1.0 eq.) in THF (20 mL), and the mixture was warmed to room temperature for 2 hours until complete consumption of the starting material was detected by TLC (PE:EA = 4:1, Rf = 0.8). The mixture was concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give 1-(2-hydroxy-4-nitro-3-phenoxyphenyl)ethan-1-one (180 mg, 0.66 mmol, 33%) as a yellow solid. 1 H NMR (400MHz,CDCl3) δ 12.59 (s,1H),7.75 (d,J=8.8Hz,1H),7.39 (d,J=8.8Hz,1H),7.34-7.27 (m,2H),7.08 (t,J=7.4Hz,1H),6.92 (m,2H),2.72 (s,3H).

[0376] 7-Nitro-8-phenoxy-4H-chromen-4-one At 0 °C, NaH (158 mg, 3.95 mmol, 1.0 eq.) was added to a solution of 1-(2-hydroxy-4-nitro-3-phenoxyphenyl)ethan-1-one (180 mg, 0.66 mmol, 1.0 eq.) in ethyl formate (10 mL) and warmed to room temperature for 2 h until complete consumption of the starting material was detected by TLC (PE:EA = 5:1, Rf = 0.5). After completion, the reaction mixture was quenched with aqueous HCl (10 mL, 2 N) and extracted with DCM (10 mL × 3). The combined organic phases were washed with water (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 7-nitro-8-phenoxy-4H-chromen-4-one (60 mg, 0.21 mmol, 32%). 1 H NMR (400MHz,DMSO-d6) δ 8.32 (d,J=6.0Hz,1H),8.12 (s,2H),7.40-7.31 (m,2H),7.13 (t,J=7.4Hz,1H),7.04-6.96 (m,2H),6.50 (d,J=6.0Hz,1H).

[0377] 7-Nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-ol To a solution of 7-nitro-8-phenoxy-4H-chromen-4-one (60 mg, 0.21 mmol, 1.0 eq.) in THF / EtOH (5 mL / 5 mL) was added NaBH (42 mg, 1.06 mmol, 5.0 eq.), and the resulting mixture was stirred at room temperature under N for 4 h until the starting material was completely consumed. After completion, the reaction mixture was concentrated in vacuo to remove most of the solvent. The residue was poured into water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with water (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-ol (30 mg, 0.10 mmol, 49%). 1 H NMR (400MHz,CDCl3) δ 7.51 (d,J=8.5Hz,1H),7.35 (d,J=8.6Hz,1H),7.31-7.26 (m,2H),7.04 (t,J=7.4Hz,1H),6.89-6.83 (m,2H),4.89 (t,J=4.6Hz,1H),4.31-4.21 (m,2H),2.20-2.02 (m,2H).

[0378] Di((2-bromoethyl)amino)phosphinic acid 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl ester To a solution of 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-ol (30 mg, 0.10 mmol, 1.0 eq.) in THF (20 mL) was added LiHMDS (0.21 mL, 1 N in THF, 2.0 eq.) at −40 °C under a nitrogen atmosphere, and the resulting mixture was stirred for 20 min. POCl (32 mg, 0.21 mmol, 2.0 eq.) was added to the mixture at −40 °C, and the reaction mixture was stirred for an additional 20 min. 2-Bromoethan-1-amine hydrobromide (90 mg, 0.84 mmol, 8.4 eq.) and TEA (84.38 mg, 0.84 mmol, 8.4 eq.) were then added to the mixture, and the mixture was stirred at −40 °C for 10 min. The reaction mixture was heated to room temperature and stirred for 30 min. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oily substance, di((2-bromoethyl)amino)phosphinic acid 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl ester (13 mg, 20 μmol, 21%). 1 H NMR (400MHz,CDCl3) δ 7.60-7.41 (m,2H),7.34-7.26 (m,2H),7.05 (t,J=6.9Hz,1H),6.93-6.78 (m,2H),5.68-5.42 (m,1H),4.42-4.09 (m,2H),3.55-3.28 (m,8H),3.20-2.94 (m,2H),2.33-2.17 (m,2H).

[0379] Bis(aziridin-1-yl)phosphinic acid 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl ester (13 mg, 20 μmol, 1.0 eq.) in THF (10 mL) was added silver(I) oxide (52 mg, 0.22 mmol, 11.0 eq.), and the mixture was stirred at 65° C. under a nitrogen atmosphere for 30 h. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give bis(aziridin-1-yl)phosphinic acid 7-nitro-8-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl ester (8 mg, 19 μmol, 85%) as a yellow oil. 1 H NMR (400MHz,CDCl3) δ 7.55-7.46 (m,2H),7.32-7.27 (m,2H),7.05 (t,J=6.9Hz,1H),6.95-6.81 (m,2H),5.75-5.60 (m,1H),4.38-4.19 (m,2H),2.36-2.17 (m,10H). 31 P NMR (162MHz, CDCl3) δ 29.99 (s). LCMS (ESI): m / z 440.0[M+Na] + . Example 18. Synthesis of di(aziridin-1-yl)phosphinic acid (R)-8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester and di(aziridin-1-yl)phosphinic acid (S)-8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester (130 and 131) (General Procedure 6, 6,6 Core 1 - Method B) [ka] 1-(3-fluoro-2-hydroxy-4-nitrophenyl)ethan-1-one

[0380] A solution of 1-(3-fluoro-2-methoxy-4-nitrophenyl)ethan-1-one (5.8 g, 27.2 mmol, 1.0 eq.) in HBr (50 mL, 48 wt%) was stirred at 80° C. overnight. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow oil, 1-(3-fluoro-2-hydroxy-4-nitrophenyl)ethan-1-one (5 g, 25.1 mmol, 92%). LC-MS (ESI): m / z 200 [M+H] + .

[0381] 3-(Dimethylamino)-1-(3-fluoro-2-hydroxy-4-nitrophenyl)propan-2-en-1-one To a solution of 1-(3-fluoro-2-hydroxy-4-nitrophenyl)ethan-1-one (1 g, 5.02 mmol, 1.0 eq.) in dry dioxane (10 mL) was added DMF-DMA (0.81 mL, 6.03 mmol, 1.2 eq.). The reaction mixture was stirred at 100° C. for 10 min in a microwave. After completion, the reaction mixture was used directly in the next step without further purification. LC-MS (ESI): m / z 255 [M+H] + .

[0382] 8-Fluoro-7-nitro-4H-chromen-4-one T3P (3.00 g, 4.72 mmol, 50 wt% in EtOAc) was added to the above mixture. The reaction was stirred at 90 °C for 10 min in a microwave. After completion, the mixture was diluted with HO (10 mL) and extracted with EtOAc (6 mL × 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a brown solid, 8-fluoro-7-nitro-4H-chromen-4-one (400 mg, 1.91 mmol, 41%). LC-MS (ESI): m / z 210 [M+H] + .

[0383] N,N-Dimethyl-4-((7-nitro-4-oxo-4H-chromen-8-yl)oxy)benzamide To a solution of 8-fluoro-7-nitro-4H-chromen-4-one (120 mg, 0.57 mmol, 1.0 eq.) in DMF (3 mL) was added 4-hydroxy-N,N-dimethylbenzamide (95 mg, 0.57 mmol, 1.0 eq.) and KCO (159 mg, 1.15 mmol, 2.0 eq.). The reaction mixture was stirred at 40 °C for 1 h. After completion, the mixture was diluted with HO (10 mL) and extracted with EtOAc (6 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, N,N-dimethyl-4-((7-nitro-4-oxo-4H-chromen-8-yl)oxy)benzamide (160 mg, 0.45 mmol, 79%). LC-MS (ESI): m / z 355[M+H] + .

[0384] 4-((4-hydroxy-7-nitrochroman-8-yl)oxy)-N,N-dimethylbenzamide To a solution of N,N-dimethyl-4-((7-nitro-4-oxo-4H-chromen-8-yl)oxy)benzamide (170 mg, 0.48 mmol, 1.0 eq.) in a mixture of EtOH (1.5 mL) and THF (1.5 mL) was added NaBH (91.2 mg, 2.40 mmol, 5.0 eq.). The reaction mixture was stirred at room temperature for 1 hr. After completion, the mixture was quenched with NaHCO (10 mL, aqueous saturated) and extracted with EtOAc (6 mL × 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 4-((4-hydroxy-7-nitrochroman-8-yl)oxy)-N,N-dimethylbenzamide (120 mg, 0.34 mmol, 70%). LC-MS (ESI): m / z 359[M+H] + .

[0385] Di((2-bromoethyl)amino)phosphinic acid 8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester To a solution of 4-((4-hydroxy-7-nitrochroman-8-yl)oxy)-N,N-dimethylbenzamide (80 mg, 0.22 mmol, 1.0 eq.) in THF (20 mL) was added LiHMDS (0.44 mL, 1 M in THF, 0.44 mmol, 2.0 eq.) dropwise at −60°C under N2, and the resulting solution was stirred at −60°C for 20 min under N2. POCl3 (0.042 mL, 0.44 mmol, 2.0 eq.) in THF (0.5 mL) was added rapidly, and the resulting mixture was stirred at −60°C for 15 min. 2-Bromoethylamine hydrobromide (320 mg, 1.56 mmol, 7.0 eq.) and TEA (0.37 mL, 2.68 mmol, 12.0 eq.) were added, and the mixture was stirred at −60°C for 10 min. The resulting mixture was warmed to room temperature and stirred for 0.5 hr. After completion, the reaction mixture was quenched with NH4Cl solution (5 mL, saturated, aqueous) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di((2-bromoethyl)amino)phosphinic acid 8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester (60 mg, 92 μmol, 41%). LC-MS (ESI): m / z 690.2 [M+H+MeCN] + .

[0386] Di(aziridin-1-yl)phosphinic acid 8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester (60 mg, 92 μmol, 1.0 eq.) in THF (10 mL) was added AgO (214 mg, 0.92 mmol, 10.0 eq.) and DIEA (0.152 mL, 0.92 mmol, 10.0 eq.). The reaction solution was stirred under N at 70° C. for 18 hours. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester (35 mg, 72 μmol, 78%) as a white solid in the form of a stereoisomeric mixture. 1 H NMR (400MHz,CDCl3) δ 77.51 (s,2H),7.43-7.33 (m,2H),6.93-6.81 (m,2H),5.78- 5.55 (m,1H),4.40-4.13 (m,2H),3.08 (s,3H),3.04 (s,3H),2.41-2.06 (m,10H). 31 P NMR (162MHz, CDCl3) δ 30.01 (s). LC-MS (ESI): m / z 489.2[M+H] + .

[0387] Di(aziridin-1-yl)phosphinic acid (R)-8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester and di(aziridin-1-yl)phosphinic acid (S)-8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester Di(aziridin-1-yl)phosphinic acid 8-(4-(dimethylaminoformyl)phenoxy)-7-nitrochroman-4-yl ester (35 mg, 72 μmol, 1.0 eq.) was further separated by chiral SFC to give:

[0388] Isomerate 1 (130), 5 mg, 14%, retention time: 3.008 min, >99% ee. LC-MS (ESI): m / z 489.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 7.51 (s,2H),7.38 (d,J=8.6Hz,2H),6.87 (d,J=8.6Hz,2H),5.73-5.59 (m,1H),4.41-4.14 (m,2H),3.08 (s,3H),3.04 (s,3H),2.39-2.08 (m,10H). 31 P NMR (162MHz, CDCl3) δ 30.02 (s).

[0389] Isomerate 2 (131), 6 mg, 17%, retention time: 4.757 min, 99.4% ee. LC-MS (ESI): m / z 489.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 7.52 (d,J=8.0Hz,2H),7.42-7.34 (m,2H),6.93-6.80 (m,2H),5.73-5.58 (m,1H),4.38-4.14 (m,2H),3.08 (s,3H),3.04 (s,3H),2.34-2.15 (m,10H). 31 P NMR (162MHz, CDCl3) δ 30.02 (s).

[0390] Analysis method: カラム: ChiralPak AD, 250×4.6mm ID, 5um, mobile phase: A, CO2, and びB, メタノール (0.05%DEA), blending: within 8min, B 40%, flow rate: 2.0mL / min, back pressure: 100バール, pressure temperature: 35℃.

[0391] SFC method: Instrument: Waters Thall 80 fraction SFC, cartridge: ChiralPak AD, 250×21.2 mm ID, 5 μm, mobile phase: A, CO2, and B, MEOH + 0.1% NH3H2O, mixture: B 40%, flow rate: 40 mL / min, back pressure: 100 bar, cartridge temperature: 35°C, wavelength: 220 nm, filter time: 10 min, dissolution time: 1.5 h. Example 19. Synthesis of di(aziridin-1-yl)phosphinic acid (R)-8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester and di(aziridin-1-yl)phosphinic acid (S)-8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester (138 and 139) [ka] 2-Cyclopropyl-6-((7-nitro-4-oxo-4H-chromen-8-yl)oxy)isoindolin-1-one

[0392] To a solution of 8-fluoro-7-nitro-4H-chromen-4-one (200 mg, 0.96 mmol, 1.0 eq.) and 2-cyclopropyl-6-hydroxyisoindolin-1-one (271 mg, 1.43 mmol, 1.5 eq.) in DMF (3 mL) was added KCO (264 mg, 1.91 mmol, 2.0 eq.), and the reaction mixture was stirred at 40° C. for 1 hour under a nitrogen atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 2-cyclopropyl-6-((7-nitro-4-oxo-4H-chromen-8-yl)oxy)isoindolin-1-one (280 mg, 0.74 mmol, 77%) as a yellow oil. LC-MS (ESI): m / z 379 [M+H] + .

[0393] 2-Cyclopropyl-6-((4-hydroxy-7-nitrochroman-8-yl)oxy)isoindolin-1-one At 0 °C, NaBH (62 mg, 1.82 mmol, 3.0 eq.) was added to a solution of 2-cyclopropyl-6-((7-nitro-4-oxo-4H-chromen-8-yl)oxy)isoindolin-1-one (230 mg, 0.61 mmol, 1.0 eq.) in THF / HO (40 mL / 4 mL). The reaction mixture was warmed to 25 °C and stirred for 1 h. After completion, the reaction mixture was quenched by the addition of NH Cl (2 mL, aqueous saturated) and extracted with EtOAc (10 mL × 2). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na SO , and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, 2-cyclopropyl-6-((4-hydroxy-7-nitrochroman-8-yl)oxy)isoindolin-1-one (200 mg, 0.52 mmol, 86%). LC-MS (ESI): m / z 383[M+H] + .

[0394] Di((2-bromoethyl)amino)phosphinic acid 8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester To a solution of 2-cyclopropyl-6-((4-hydroxy-7-nitrochroman-8-yl)oxy)isoindolin-1-one (220 mg, 0.58 mmol, 1.0 eq.) in THF (6 mL) was added LiHMDS (1.2 mL, 1.16 mmol, 2.0 eq.) at −60° C. The mixture was stirred at −60° C. for 15 min. POCl (176 mg, 1.15 mmol, 2.0 eq.) was added, and the reaction mixture was stirred at −60° C. for 15 min. 2-Bromoethan-1-amine hydrobromide (707 mg, 3.45 mmol, 6.0 eq.) and TEA (699 mg, 6.90 mmol, 12.0 eq.) were added to the mixture, and the mixture was stirred at −60° C. for 30 min. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (10 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di((2-bromoethyl)amino)phosphinic acid 8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester (160 mg, 0.24 mmol, 41%). LC-MS (ESI): m / z 673 [M+H] + .

[0395] Di(aziridin-1-yl)phosphinic acid 8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester (160 mg, 0.24 mmol, 1.0 eq.) in THF (5 mL) was added DIEA (307 mg, 2.37 mmol, 10.0 eq.) and AgO (548 mg, 2.37 mmol, 10.0 eq.). The reaction mixture was stirred at 70° C. for 12 hours under a nitrogen atmosphere. After completion, the reaction mixture was cooled to 25° C. and filtered. The filter cake was washed with DCM (10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester (50 mg, 98 mmol, 41%) in the form of a stereoisomeric mixture as a yellow oil.

[0396] Di(aziridin-1-yl)phosphinic acid (R)-8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester and di(aziridin-1-yl)phosphinic acid (S)-8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester Di(aziridin-1-yl)phosphinic acid 8-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-7-nitrochroman-4-yl ester (10 mg, 20 μmol) was further separated by chiral SFC to give:

[0397] Isomer 1(138), 2.0mg, 20%, retention time: 4.724min, >99% ee. LC-MS (ESI): m / z 513.1[M+H] + ; 1H NMR (400MHz, CDCl3) δ 7.52 (s,2H),7.38-7.33 (m,1H),7.26-7.22 (m,1H),7.14-7.06 (m,1H),5.70-5.62 (m,1H),4.28 (s,3H),4.26-4.21 (m,1H),2.98-2.87 (m,1H),2.29-2.18 (m,10H),0.92-0.85 (m,4H). 31 P NMR (162MHz, CDCl3) δ 29.74 (s).

[0398] Isomerate 2 (139), 2.0 mg, 20%, retention time: 5.854 min, >99% ee. LC-MS (ESI): m / z 513.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 7.54-7.50 (m,2H),7.39-7.34 (m,1H),7.26-7.23 (m,1H),7.11-7.04 (m,1H),5.71-5.59 (m,1H),4.28 (s,3H),4.25-4.20 (m,1H),2.96-2.88 (m,1H),2.29-2.19 (m,10H),0.97-0.85 (m,4H). 31 P NMR (162MHz, CDCl3) δ 29.74 (s).

[0399] Analysis method: カラム: ChiralPak AD, 250×4.6mm ID, 5μm, mobile phase: A, CO2, and びB, メタノール (0.05%DEA), blending: within 8 minutes, B 40%, flow rate: 2.0mL / min, back pressure: 100バール, pressure temperature: 35℃.

[0400] SFC method: Instrument: Waters Thall 80 fraction SFC, cartridge: ChiralPak AD, 250×21.2 mm ID, 5 μm, mobile phase: A, CO2, and B, MEOH + 0.1% NH3H2O, mixture: B 32%, flow rate: 40 mL / min, back pressure: 100 bar, cartridge temperature: 35°C, wavelength: 220 nm, filter time: 15 min, dissolution time: 3 h. Example 20. Synthesis of di(aziridin-1-yl)phosphinic acid ((R)-6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid ((S)-6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (140 and 141) (General Procedure 9, 6,5 Core 4 - Method A) [ka] 4-((3-hydroxy-6-nitro-2,3-dihydro-1H-inden-5-yl)oxy)-N,N-dimethylbenzamide

[0401] To a solution of 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (140 mg, 0.71 mmol, 1.0 eq.) and 4-hydroxy-N,N-dimethylbenzamide (176 mg, 1.07 mmol, 1.5 eq.) in ACN (10 mL) was added CsCO (462 mg, 1.42 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a white solid, 4-((3-hydroxy-6-nitro-2,3-dihydro-1H-inden-5-yl)oxy)-N,N-dimethylbenzamide (135 mg, 0.39 mmol, 56%). LC-MS (ESI): m / z 343 [M+H] + .

[0402] Di((2-bromoethyl)amino)phosphinic acid 6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 4-((3-hydroxy-6-nitro-2,3-dihydro-1H-inden-5-yl)oxy)-N,N-dimethylbenzamide (130 mg, 0.38 mmol, 1.0 eq.) in THF (10 mL) at −60° C. under N2, LiHMDS (0.76 mL, 1 M in THF, 0.76 mmol, 2.0 eq.) was added dropwise and the resulting solution was stirred for 20 min at −60° C. under N2. POCl3 (116 mg, 0.76 mmol, 2.0 eq.) in THF (10 mL) was added rapidly and the resulting mixture was stirred at −60° C. for 15 min. 2-Bromoethylamine hydrobromide (540 mg, 2.66 mmol, 7.0 eq.) and TEA (461 mg, 4.56 mmol, 12.0 eq.) were added, and the mixture was stirred at −60° C. for 10 min. The resulting mixture was warmed to room temperature and stirred for 0.5 hr. Upon completion, the reaction mixture was quenched with NH4Cl solution (5 mL, saturated, aqueous) and extracted with EtOAc (10 mL × 2). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di((2-bromoethyl)amino)phosphinic acid 6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (55 mg, 87 μmol, 23%) as a yellow oil. LC-MS (ESI): m / z 633.1[M+H] + .

[0403] Di(aziridin-1-yl)phosphinic acid ((R)-6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid ((S)-6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (55 mg, 87 μmol, 1.0 eq.) in THF (5 mL) was added AgO (202 mg, 0.87 mmol, 10.0 eq.) and DIEA (112 mg, 0.87 mmol, 10.0 eq.). The resulting solution was stirred at 70° C. for 18 h under N. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 6-(4-(dimethylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (24 mg, 51 μmol, 59%) in the form of a solid stereoisomeric mixture, which was further separated by chiral SFC to give:

[0404] Isomer 1(140), 9.5mg, 40%, retention time: 4.437min, >99% ee. LC-MS (ESI): m / z 473.2[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.84 (s,1H),7.45-7.42 (m,2H),7.26 (s,1H),7.04-7.00 (m,2H),5.96-5.91 (m,1H),3.19-3.12 (m,1H),3.10-3.03 (m,6H),2.96-2.88 (m,1H),2.67-2.59 (m,1H),2.35-2.27 (m,1H),2.20-2.07 (m,8H). 31 P NMR (162MHz, CDCl3) δ 30.01 (s).

[0405] Isomer 2(141), 8.0mg, 33%, retention time: 3.907min, >99% ee. LC-MS (ESI): m / z 473.2[M+H] + ; 1H NMR (400MHz,CDCl3) δ 7.83 (s,1H),7.47-7.39 (m,2H),7.05-6.98 (m,2H),7.26 (s,1H),5.95-5.91 (m,1H),3.22-3.13 (m,1H),3.12-2.99 (m,6H),2.96-2.86 (m,1H),2.70-2.56 (m,1H),2.38 -2.25 (m,1H),2.22-2.04 (m,8H). 31 P NMR (162MHz, CDCl3) δ 30.01 (s).

[0406] Analytical method: Column: ChiralPak IA, 250 x 4.6 mm ID, 5 um; Mobile phase: A, CO2, and B, EtOH (0.05% DEA); Gradient: 40% within 10 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 35°C.

[0407] SFC method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralPak AD, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2, and B, ETOH + 0.1% NH3H2O, Gradient: B 30%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 5 min, Elution time: 2 h. Example 21. Synthesis of di(aziridin-1-yl)phosphinic acid (R)-6-(4-(methylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-6-(4-(methylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (150 and 151) (General Procedure 9, 6,5 Core 4 - Method B) [ka] Di((2-bromoethyl)amino)phosphinic acid 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester

[0408] To a solution of 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (50 mg, 0.25 mmol, 1.0 eq.) in THF (5 mL) was added LiHMDS (0.28 mL, 1 M in THF, 0.28 mmol, 1.1 eq.) dropwise at −65°C under N2, and the resulting solution was stirred at −65°C for 20 min under N2. POCl3 (78 mg, 0.51 mmol, 2.0 eq.) was added, and the resulting mixture was stirred at −65°C for 20 min. 2-Bromoethylamine hydrobromide (312 mg, 1.52 mmol, 6.0 eq.) and TEA (0.42 mL, 3.05 mmol, 12.0 eq.) were added to the above mixture. The resulting mixture was warmed to room temperature and stirred for 1 h. After completion, the reaction mixture was quenched with NH4Cl solution (10 mL, saturated, aqueous) and extracted with EtOAc (15 mL x 2). The organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow oil, di((2-bromoethyl)amino)phosphinic acid 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (32 mg, 65 μmol, 26%). LC-MS (ESI): m / z 488 [M+H] + .

[0409] Di(aziridin-1-yl)phosphinic acid 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (100 mg, 0.21 mmol, 1.0 eq.) in THF (5 mL) was added AgO (487 mg, 2.10 mmol, 10.0 eq.) and DIEA (271 mg, 2.10 mmol, 10.0 eq.). The resulting solution was stirred at 70 °C under N for 18 hours. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a solid, di(aziridin-1-yl)phosphinic acid 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (60 mg, 0.17 mmol, 59%). LC-MS (ESI): m / z 328[M+H] + .

[0410] Di(aziridin-1-yl)phosphinic acid (R)-6-(4-(methylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-6-(4-(methylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di(aziridin-1-yl)phosphinic acid 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-yl ester (80 mg, 0.24 mmol, 1.0 eq.) and 4-hydroxy-N-methylbenzamide (54 mg, 0.36 mmol, 1.5 eq.) in MeCN (10 mL) was added CsCO (157 mg, 0.48 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di(aziridin-1-yl)phosphinic acid 6-(4-(methylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (34 mg, 74 μmol, 31%) as a white solid in the form of a stereoisomeric mixture. Di(aziridin-1-yl)phosphinic acid 6-(4-(methylaminoformyl)phenoxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (30 mg, 66 μmol) was further separated by chiral SFC to give:

[0411] Isomer 1(151), 11.6mg, 25μmol, 38%, retention time: 3.275min, >99% ee. LC-MS (ESI): m / z 459.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.78 (s,1H),7.71-7.67 (m,2H),7.21 (s,1H),6.97-6.93 (m,2H),6.13-6.03 (m,1H),5.89-5.84 (m,1H),3.13-3.06 (m,1H),2.94 (d,J=4.8Hz,3H),2.89-2.82 (m,1H),2.61-2.52 (m,1H),2.28-2.20 (m,1H),2.14-2.12 (m,1H),2.10-1.97 (m,7H). 31 P NMR (162MHz, CDCl3) δ 29.98 (s).

[0412] Isomer 2(150), 16.8mg, 37μmol, 56%, retention time: 3.897min, 99% ee. LC-MS (ESI): m / z 459.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.78 (s,1H),7.72-7.66 (m,2H),7.21 (s,1H),6.98-6.91 (m,2H),6.14-6.04 (m,1H),5.89-5.84 (m,1H),3.15-3.04 (m,1H),2.94 (d,J=4.8Hz,3H),2.89-2.83 (m,1H),2.59-2.54 (m,1H),2.29-2.21 (m,1H),2.15-2.11 (m,1H),2.10-1.98 (m,7H). 31 P NMR (162MHz, CDCl3) δ 30.00 (s).

[0413] Analytical method: Column: ChiralPak AD, 250 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 40% within 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 35°C.

[0414] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralPak AD, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2 and B, MEOH + 0.1% NH3H2O, Gradient: B 30%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 15 min, Elution time: 2 H. Example 22. Synthesis of di(aziridin-1-yl)phosphinic acid (R)-6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (152 and 153) [ka] 6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-ol

[0415] To a solution of 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (750 mg, 3.80 mmol, 1.0 eq.) and [1,1'-biphenyl]-4-ol (842 mg, 4.95 mmol, 1.3 eq.) in ACN (5 mL) was added CsCO (2.48 g, 7.61 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow solid, 6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-ol (650 mg, 1.87 mmol, 49%). LC-MS (ESI): m / z 348 [M+H] + .

[0416] Di((2-bromoethyl)amino)phosphinic acid ([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-ol (650 mg, 1.87 mmol, 1.0 eq.) in THF (10 mL) at −65° C. under N2, LiHMDS (2.25 mL, 1 M in THF, 2.25 mmol, 1.2 eq.) was added dropwise, and the resulting solution was stirred for 20 min at −65° C. under N2. POCl3 (0.35 mL, 3.74 mmol, 2.0 eq.) in THF (10 mL) was added rapidly, and the resulting mixture was stirred at −65° C. for 15 min. 2-Bromoethylamine hydrobromide (2.69 g, 13.1 mmol, 7.0 eq.) and TEA (2.27 g, 22.4 mmol, 12.0 eq.) were added, and the mixture was stirred at −65° C. for 10 min. The resulting mixture was warmed to room temperature and stirred for 0.5 hr. Upon completion, the reaction mixture was quenched with NH4Cl solution (5 mL, saturated, aqueous) and extracted with EtOAc (10 mL × 2). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give di((2-bromoethyl)amino)phosphinic acid 6-([1,1′-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (465 mg, 0.73 mmol, 39%) as a yellow oil. LC-MS (ESI): m / z 638[M+H] + .

[0417] Di(aziridin-1-yl)phosphinic acid (R)-6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 6-([1,1'-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (465 mg, 0.73 mmol, 1.0 eq.) in THF (10 mL) was added AgO (843 mg, 3.64 mmol, 5.0 eq.) and DIEA (470 mg, 3.64 mmol, 5.0 eq.). The resulting solution was stirred at 65 °C for 18 h under N. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel high-performance column chromatography to give a yellow solid, di(aziridin-1-yl)phosphinic acid 6-([1,1′-biphenyl]-4-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester in the form of a stereoisomer mixture, which was further separated by chiral SFC to give the following:

[0418] Isomer 1(153), 109.8 mg, 0.23 mmol, 32%, retention time: 3.708 min, 95% ee. LC-MS (ESI): m / z 478.2[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.82 (s,1H),7.60-7.54 (m,4H),7.46-7.42 (m,2H),7.37-7.33 (m,1H),7.23 (s,1H),7.13-7.08 (m,2H),5.95-5.90 (m,1H),3.18-3.10 (m,1H),2.94-2.86 (m,1H),2.66-2.57 (m,1H),2.33-2.24 (m,1H),2.17-2.16 (m,1H),2.14-2.01 (m,7H). 31 P NMR (162MHz, CDCl3) δ 29.98 (s).

[0419] Isomer 2(152), 90.9mg, 0.19mmol, 26%, retention time: 4.126min, 98% ee. LC-MS (ESI): m / z 478.2[M+H] + ; 1H NMR (400MHz,CDCl3) δ 7.82 (s,1H),7.59-7.54 (m,4H),7.46-7.42 (m,2H),7.37-7.33 (m,1H),7.23 (s,1H),7.12-7.10 (m,2H),5.95-5.90 (m,1H),3.18-3.10 (m,1H),2.94-2.86 (m,1H),2.66-2.57 (m,1H),2.32-2.24 (m,1H),2.17-2.15 (m,1H),2.13-2.00 (m,7H). 31 P NMR (162MHz, CDCl3) δ 29.98 (s).

[0420] Analytical method: Column: ChiralCel OJ, 250 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: B 40% within 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 35°C.

[0421] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralCel OD, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2 and B, MEOH, Gradient: B 30%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35°C, Wavelength: 220 nm, Cycle time: 20 min, Elution time: 5 H. Example 23. Synthesis of di(aziridin-1-yl)phosphinic acid (S)-6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (168 and 169) [ka] 6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-ol

[0422] To a solution of 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (400 mg, 2.03 mmol, 1.0 eq.) and [1,1'-biphenyl]-3-ol (414 mg, 2.44 mmol, 1.4 eq.) in ACN (10 mL) was added CsCO (1.32 g, 4.06 mmol, 2.0 eq.). The reaction mixture was stirred at 60 °C for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow solid, 6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-ol (522 mg, 1.50 mmol, 74%). LCMS (ESI): m / z 348 [M+H] + .

[0423] Di((2-bromoethyl)amino)phosphinic acid 6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of 6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-ol (200 mg, 0.58 mmol, 1.0 eq.) in THF (30 mL) at −78 °C under N2, LiHMDS (0.69 mL, 1 M in THF, 0.69 mmol, 1.2 eq.) was added, and the resulting solution was stirred at −78 °C for 15 min under N2. POCl3 (0.11 mL, 1.15 mmol, 2.0 eq.) was added, and the resulting mixture was stirred at −78 °C for 15 min. 2-Bromoethylamine hydrobromide (708 mg, 3.46 mmol, 6.0 eq.) and TEA (0.96 mL, 6.91 mmol, 12.0 eq.) were added. The mixture was warmed to room temperature and stirred for 1 h. After completion, the reaction mixture was quenched with NH4Cl solution (10 mL, saturated, aqueous) and extracted with EtOAc (20 mL x 2). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a white solid, di((2-bromoethyl)amino)phosphinic acid 6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (150 mg, 0.24 mmol, 41%). LCMS (ESI): m / z 638 [M+H] + .

[0424] Di(aziridin-1-yl)phosphinic acid 6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester To a solution of di((2-bromoethyl)amino)phosphinic acid 6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (150 mg, 0.24 mmol, 1.0 eq.) in THF (30 mL) was added AgO (544 mg, 2.35 mmol, 10.0 eq.) and DIEA (0.39 mL, 2.35 mmol, 10.0 eq.). The resulting solution was stirred under N at 70 °C overnight. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give a yellow oil, di(aziridin-1-yl)phosphinic acid 6-([1,1′-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (100 mg, 0.21 mmol, 89%). 1 H NMR (400MHz,CDCl3) δ 7.81 (s,1H),7.58-7.53 (m,2H),7.46-7.39 (m,4H),7.38-7.33 (m,1H),7.28-7.26 (m,1H),7.21 (s,1H),7.04-7.01 (m,1H),5.94-5.87 (m,1H),3.17-3.09 (m,1H),2.94- 2.84 (m,1H),2.65-2.55 (m,1H),2.29-2.23 (m,1H),2.14-1.96 (m,8H). 31 P NMR (162MHz, CDCl3) δ 29.88 (s). LC-MS (ESI): m / z 478[M+H] + .

[0425] Di(aziridin-1-yl)phosphinic acid (S)-6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (R)-6-([1,1'-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester Di(aziridin-1-yl)phosphinic acid 6-([1,1′-biphenyl]-3-yloxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (200 mg, 0.42 mmol) was purified by chiral SFC to give:

[0426] Isomer 1(169), 86.96 mg, 0.18 mmol, 43%, retention time: 1.618 min, >99% ee. LC-MS (ESI): m / z 478.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.78 (s,1H),7.52 (d,J=7.4Hz,2H),7.44-7.36 (m,4H),7.34-7.28 (m,1H),7.25 (s,1H),7.19 (s,1H),7.02-6.97 (m,1H),5.91- 5.84 (m,1H),3.15-3.05 (m,1H),2.92-2.81 (m,1H),2.62-2.52 (m,1H),2.29-2.20 (m,1H),2.10-1.91 (m,8H). 31 P NMR (162MHz, CDCl3) δ 29.86 (s).

[0427] Isomer 2(168), 102.02mg, 0.21mmol, 50%, retention time: 1.950min, 96% ee. LC-MS (ESI): m / z 478.1[M+H] + ; 1 H NMR (400MHz,CDCl3) δ 7.81 (s,1H),7.55 (d,J=7.4Hz,2H),7.46-7.39 (m,4H),7.37-7.31 (m,1H),7.27 (s,1H),7.22 (s,1H),7.05-7.00 (m,1H),5.94-5.85 (m,1H),3.18-3.08 (m,1H),2.94-2.83 (m,1H),2.66-2.54 (m,1H),2.32-2.23 (m,1H),2.13-1.96 (m,8H). 31 P NMR (162MHz, CDCl3) δ 29.86 (s).

[0428] Analytical method: Column: ChiralPak IH, 100 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 40% B within 8 min; Flow rate: 2.5 mL / min; Column temperature: 40°C.

[0429] SFC method: Instrument: Waters Thar 80 Preparative SFC, Column: ChiralPak IH, 250 x 21.2 mm ID, 5 μm, Mobile phase: A, CO2 and B, MEOH + 0.1% NH3H2O, Gradient: B 35%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 10 min, Elution time: 2 H. Example 24. Synthesis of di(aziridin-1-yl)phosphinic acid (R)-6-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester and di(aziridin-1-yl)phosphinic acid (S)-6-((2-cyclopropyl-3-oxoisoindolin-5-yl)oxy)-5-nitro-2,3-dihydro-1H-inden-1-yl ester (170 and 171) [ka] 2-Cyclopropyl-6-((3-hydroxy-6-nitro-2,3-dihydro-1H-inden-5-yl)oxy)isoindolin-1-one

[0430] To a solution of 6-fluoro-5-nitro-2,3-dihydro-1H-inden-1-ol (130 mg, 0.66 mmol, 1.0 eq.) and 2-cyclopropyl-6-...

Claims

1. A compound having formula I or a pharmaceutically acceptable salt thereof: 【Chemical 1】 where: (2) R １ and R ２ are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; and R ４ and R ５ is as defined in (1), or (3) R １ and R ５ are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; and R ２ and R ４ is as defined in (1), or (4) R ４ and R ５ are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered ring; or R １ and R ２ is as defined in (1) or (2), or (1) R １ is hydrogen, deuterium, optionally substituted C １－４ alkyl group, optionally substituted C ２－４ alkenyl group, or optionally substituted C ２－４ is an alkynyl group, and R ２ , R ４ and R ５ are each independently hydrogen, halogen (e.g., F), optionally substituted C １－４ alkyl group, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ Alkynyl group, optionally substituted C １－４ an alkoxy group or an optionally substituted 3- to 5-membered ring; and where: X is O, S, NR １０ , optionally substituted C １－４ an alkylene group, or an optionally substituted C １－４ heteroalkylene group, where R １０ is hydrogen, optionally substituted C １－４ an alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; R ３ is hydrogen, optionally substituted C １－４ an alkyl group or an optionally substituted 3- to 10-membered ring; R ６ is hydrogen, deuterium, optionally substituted C １－４ alkyl group, optionally substituted C ２－４ alkenyl group, or optionally substituted C ２－４ is an alkynyl group, Integers n1 and n2 are each independently 0, 1, 2, 3, or 4; R ａ and R ｂ Each occurrence of １－４ alkyl group or optionally substituted C １－４ is a heteroalkylene group, or R ａ Two examples of R ｂ are joined to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, and R ａ and / or R ｂ or a pharmaceutically acceptable salt thereof, wherein any remaining examples are as defined above.

2. R １ and R ２ are joined together with the intervening atoms to form an optionally substituted 5- to 7-membered carbocyclic ring, which, when substituted, may independently be oxo, halogen, OH, NH ２ , C optionally substituted with F １－４ alkyl group, C having one or two heteroatoms and optionally substituted with F １－４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with 1 to 3 substituents selected from a heteroalkyl group and a 3- to 6-membered ring, and two of the substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring.

3. having a structure according to formula I-1, I-2, I-3, I-1-B-E1, or I-1-B-E2; 【Chemistry 2】 where: The integer n3 is 0, 1, or 2; and R ｃ Each occurrence of represents independently oxo, F, OH, NH ２ , C optionally substituted with F １－４ an alkyl group or a C having one or two heteroatoms and optionally substituted with F; １－４ is a heteroalkyl group, or R ｃ are linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, or a pharmaceutically acceptable salt thereof.

4. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein n3 is 0.

5. R １ and R ２ are joined together with the intervening atoms to form an optionally substituted 5- to 7-membered heterocycle having one or two ring heteroatoms independently selected from O, N, and S, and when substituted, the 5- to 7-membered heterocycle may be independently selected from oxo, halogen, OH, NH ２ , C optionally substituted with F １－４ alkyl group, C having one or two heteroatoms and optionally substituted with F １－４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with 1 to 3 substituents selected from a heteroalkyl group and a 3- to 6-membered ring, and two of the substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring.

6. having a structure according to formula I-4, I-5, or I-6; 【Chemistry 3】 where: The integer n4 is 0, 1, or 2; and R ｄ Each occurrence of represents independently oxo, F, OH, NH ２ , C optionally substituted with F １－４ an alkyl group or a C having one or two heteroatoms and optionally substituted with F; １－４ is a heteroalkyl group, or R ｄ are linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, or a pharmaceutically acceptable salt thereof.

7. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein n4 is 0.

8. R １ and R ５ are joined together with the intervening atoms to form an optionally substituted 5- to 7-membered carbocyclic ring, which, when substituted, may independently be oxo, halogen, OH, NH ２ , C optionally substituted with F １－４ alkyl group, C having one or two heteroatoms and optionally substituted with F １－４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with 1 to 3 substituents selected from a heteroalkyl group and a 3- to 6-membered ring, and two of the substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring.

9. having a structure according to formula I-7, I-8, or I-9; 【Chemistry 4】 where: The integer n5 is 0, 1, or 2; and R ｅ Each occurrence of represents independently oxo, F, OH, NH ２ , C optionally substituted with F １－４ an alkyl group or a C having one or two heteroatoms and optionally substituted with F; １－４ is a heteroalkyl group, or R ｅ are linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, or a pharmaceutically acceptable salt thereof.

10. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein n5 is 0.

11. R １ and R ５ are joined together with the intervening atoms to form an optionally substituted 5- to 7-membered heterocycle having one or two ring heteroatoms independently selected from O, N, and S, and when substituted, the 5- to 7-membered heterocycle may be independently selected from oxo, halogen, OH, NH ２ , C optionally substituted with F １－４ alkyl group, C having one or two heteroatoms and optionally substituted with F １－４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with 1 to 3 substituents selected from a heteroalkyl group and a 3- to 6-membered ring, and two of the substituents are optionally linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring.

12. having a structure according to formula I-10, I-11, or I-12; 【Chemistry 5】 where: The integer n6 is 0, 1, or 2; R ｆ Each occurrence of represents independently oxo, F, OH, NH ２ , C optionally substituted with F １－４ an alkyl group or a C having one or two heteroatoms and optionally substituted with F; １－４ is a heteroalkyl group, or R ｆ are linked to one or more intervening atoms to form an optionally substituted 3- to 6-membered ring, or a pharmaceutically acceptable salt thereof.

13. 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein n6 is 0.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein n1 and n2 are both 0.

15. The compound is 【Chemistry 6】 14. The compound of any one of claims 1 to 13, characterized in that it has a structure according to: or a pharmaceutically acceptable salt thereof.

16. R ６ is hydrogen, deuterium, CH ３ or CF ３ 16. The compound according to any one of claims 1 to 15, wherein:

17. R ４ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

18. If applicable, R ５ The compound according to any one of claims 1 to 7 and 14 to 17, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

19. Where applicable, R ２ 19. The compound of any one of claims 1 and 8 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. If applicable, R １ is hydrogen, deuterium, or C optionally substituted with F １－４ Alkyl groups, such as methyl groups, CF ３ The compound according to any one of claims 1 and 14 to 19, or a pharmaceutically acceptable salt thereof,

21. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein X is O.

22. R ３ is an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted bicyclic heteroaryl group (e.g., an 8- to 10-membered bicyclic heteroaryl group), or a pharmaceutically acceptable salt thereof.

23. R ３ are phenyl groups, which are each independently halogen, CN, OH, NH ２ , COOH, CONH ２ , G １ , O.G. １ , S.G. １ , NHG １ ,NG １ G １ , C(O)G １ , COOG １ , CONHG １ ,CONG １ G １ , O.C.(O.)G １ , OCOOG １ , OCONHG １ , OCONG １ G １ , NHC(O)G １ , NHCOOG １ , NHCONHG １ , NHCONG １ G １ ,NG １ C(O)G １ ,NG １ COOG １ ,NG １ CONHG １ ,NG １ CONG １ G １ , S.O. ２ G １ , S.O. ２ NHG １ , or SO ２ NG １ G １ and wherein G is substituted with 1 to 3 substituents selected from １ Each occurrence of is independently an optionally substituted C １－４ alkyl group, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ an alkynyl group, or an optionally substituted 3- to 6-membered ring structure such as a cyclopropyl group, a cyclobutyl group, a phenyl group, a pyridyl group, or an NG １ G １ The two Gs １ is optionally linked to a nitrogen atom to form an optionally substituted 4-8 membered heterocycle, or a pharmaceutically acceptable salt thereof.

24. R ３ are phenyl groups, which are each independently F, Cl, CN, OH, NH ２ , COOH, CONH ２ , G ２ , O.G. ２ , NHG ２ ,NG ２ G ２ , C(O)G ２ , COOG ２ , CONHG ２ ,CONG ２ G ２ , S.O. ２ G ２ , S.O. ２ NHG ２ , or SO ２ NG ２ G ２ and wherein G is substituted with 1 to 3 substituents selected from ２ Each occurrence of is independently １－４ Alkyl group, C ３－６ a cycloalkyl group, a 3- to 6-membered heterocycle having 1 to 2 ring heteroatoms, a phenyl group, or a 5- or 6-membered heteroaryl group, each of which is optionally and independently selected from F, Cl, OH, NH ２ , C optionally substituted with 1 to 3 F １－４ alkyl group or C having 1 or 2 heteroatoms and optionally substituted with 1 to 3 F １－４ substituted with 1 to 3 substituents selected from heteroalkyl groups, or NG ２ G ２ The two Gs ２ is optionally linked to the nitrogen atom to form an optionally substituted 4-8 membered heterocyclic ring having 0 or 1 additional ring heteroatoms, or a pharmaceutically acceptable salt thereof.

25. R ３ teeth, 【Chemistry 7】 and where: G ３ Each occurrence of is independently an optionally substituted C １－４ alkyl groups or optionally substituted 3- to 6-membered rings, such as cyclopropyl, cyclobutyl, oxetanyl groups (e.g. 【Chemistry 8】 ) etc., or C １－４ alkyl group or deuterated analogue of a 3- to 6-membered ring, and when substituted, the C １－４ The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, １－４ alkyl group, C having 1-2 heteroatoms and optionally substituted with F １－４ substituted with 1 to 3 substituents that are heteroalkyl groups or 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetanyl groups) optionally substituted with F; or Two Gs ３ are joined together with the nitrogen atom to which they are both attached to form a 4- to 8-membered heterocycle having 0 or 1 additional ring heteroatom, wherein the 4- to 8-membered heterocycle is optionally each independently selected from oxo, F, C, １－４ Alkyl groups, OH, NH ２ or C having 1 to 2 heteroatoms １－４ substituted with 1 to 3 substituents which are heteroalkyl groups, and wherein: the integer n7 is 0, 1, or 2; R ｈ Each occurrence of represents independently a halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

26. having a structure according to formula IV-1, IV-7, or IV-8; 【Chemistry 9】 where: R ｐ is halogen, CN, OH, NH ２ , COOH, CONH ２ , G ３ , OG ３ , SG ３ , NHG ３ , NG ３ G ３ , C(O)G ３ , COOG ３ , CONHG ３ , CONG ３ G ３ , OC(O)G ３ , OCOOG ３ , OCONHG ３ , OCONG ３ G ３ , NHCOG ３ , NHCOOG ３ , NHCONHG ３ , NHCONG ３ G ３ , NG ３ C(O)G ３ , NG ３ COOG ３ , NG ３ CONHG ３ , NG ３ CONG ３ G ３ , SO ２ G ３ , SO ２ NHG ３ , or SO ２ NG ３ G ３ and G ３ Each occurrence of is independently an optionally substituted C １－４ alkyl groups or optionally substituted 3- to 6-membered rings, such as cyclopropyl, cyclobutyl, oxetanyl groups (e.g. 【Chemistry 10】 ) etc., or C １－４ alkyl group or deuterated analogue of a 3- to 6-membered ring, and when substituted, the C １－４ The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, １－４ alkyl group, C having 1-2 heteroatoms and optionally substituted with F １－４ substituted with 1 to 3 substituents that are heteroalkyl groups or 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetanyl groups) optionally substituted with F; or Two Gs ３ are joined together with the nitrogen atom to which they are both attached to form a 4- to 8-membered heterocycle having 0 or 1 additional ring heteroatom, wherein the 4- to 8-membered heterocycle is optionally each independently selected from oxo, F, C, １－４ Alkyl groups, OH, NH ２ or C having 1 to 2 heteroatoms １－４ substituted with 1 to 3 substituents which are heteroalkyl groups; R ｈ’ is hydrogen or R ｈ and R ｈ Each occurrence of represents independently a halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, which is substituted with 1 to 3 substituents which are heteroalkyl groups.

27. Each G ３ are independently a methyl group, 【Chemistry 11】 or two G ３ are linked together with the nitrogen atom to which they are both attached, 【Chemistry 12】 27. The compound of claim 25 or 26, or a pharmaceutically acceptable salt thereof, which forms:

28. n7 is 0, or R ｈ’ The compound according to any one of claims 25 to 27, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

29. n7 is 1 and R ｈ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 28. The compound of any one of claims 25 to 27, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

30. R ３ teeth, 【Chemistry 13】 and where: Integers n8 and n9 are independently 0, 1, or 2; HET optionally contains 1 to 2 R ｊ is a 5- or 6-membered heteroaryl group substituted with R ｉ , R ｊ and R ｋ Each occurrence of is independently selected from halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F or OH. １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

31. having a structure according to formula IV-2, IV-3, IV-4, or IV-5; 【Chemistry 14】 Here, R ｉ’ is hydrogen or R ｉ 31. The compound of claim 30, wherein:

32. n8 is 0, or R ｉ’ 32. The compound of claim 30 or 31, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

33. n8 is 1 and R ｉ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 32. The compound of claim 30 or 31, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

34. The compound according to any one of claims 30 to 33, or a pharmaceutically acceptable salt thereof, wherein n9 is 0.

35. n9 is 1, and R ｋ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 34. The compound of any one of claims 30 to 33, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

36. HET is a group consisting of (1) optionally 1 to 2 R ｊ pyridyl groups substituted with, for example, 【Chemistry 15】 and the like), pyrimidinyl groups (e.g., 【Chemistry 16】 ), pyrazinyl groups (e.g. 【Chemistry 17】 ), pyridonyl groups (e.g., 【Chemistry 18】 ), or a pyrimidinone group (e.g. 【Chemistry 19】 ), where R ｊ each occurrence independently represents F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ or (2) optionally one to two R ｊ pyrazoles, oxadiazoles, thiadiazoles, triazoles, tetrazoles, thiazoles, oxazoles, or imidazoles substituted with 【Chemistry 20】 etc.), where R ｊ each occurrence independently represents F, OH, C optionally substituted with F, １－４ alkyl group, C having 1-2 heteroatoms and optionally substituted with F １－４ 36. The compound according to any one of claims 30 to 35, or a pharmaceutically acceptable salt thereof, which is a heteroalkyl group or a 3- to 4-membered ring, such as a cyclopropyl group or a cyclobutyl group.

37. R ３ teeth, 【Chemical 21】 where: The integer n10 is 0, 1, or 2; R ７ and R ８ are joined together with the intervening atoms to form a 4- to 8-membered ring, which optionally contains 1 to 3 R ｎ is replaced by R ｍ Each occurrence of represents independently a halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ substituted with 1 to 3 substituents which are heteroalkyl groups; and R ｎ Each occurrence independently represents oxo (where valence allows), halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

38. 【Catalog 22】 The structure is Here, R ｍ’ is hydrogen or R ｍ 38. The compound of claim 37, wherein:

39. R ７ and R ８ are joined together with the intervening atoms to form a 5- or 6-membered heteroaryl ring having 1 to 3 ring heteroatoms, which optionally contains 1 to 2 R ｎ where R ｎ 39. The compound of claim 37 or 38, or a pharmaceutically acceptable salt thereof, wherein:

40. R ７ and R ８ are joined together with the intervening atoms to form a 4- to 7-membered heterocyclyl ring having 1 or 2 ring heteroatoms, which optionally contains 1 to 2 R ｎ where R ｎ 39. The compound of claim 37 or 38, or a pharmaceutically acceptable salt thereof, wherein:

41. R ３ teeth, 【Chemical 23】 and where: G ４ Each occurrence of is independently an optionally substituted C １－４ an alkyl group, or an optionally substituted 3- to 6-membered ring, such as a cyclopropyl group, and when substituted, the C １－４ The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 39. The compound of claim 37 or 38, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

42. n10 is 0, or R ｍ’ The compound according to any one of claims 37 to 41, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

43. n10 is 1, and R ｍ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 42. The compound of any one of claims 37 to 41, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

44. A compound having formula II or a pharmaceutically acceptable salt thereof: 【Chemistry 24】 where: X is O, S, NR １０ , optionally substituted C １－４ an alkylene group, or an optionally substituted C １－４ heteroalkylene group, where R １０ is hydrogen, optionally substituted C １－４ an alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; Y and Z are each independently O, S, or NR １１ or CR １２ and, valence permitting, the proviso is that the five-membered ring containing Y and Z is aromatic, wherein: (i) R １１ is hydrogen, optionally substituted C １－４ alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; R １２ is hydrogen, halogen, CN, optionally substituted C １－４ alkyl group, optionally substituted C １－４ a heteroalkyl group or an optionally substituted 3- to 6-membered ring; or (ii) Where applicable, R １１ or R １２ is R １ and, together with the intervening atoms, join to form an optionally substituted 5- to 8-membered ring; R １ is as defined in (ii) or is hydrogen, deuterium, optionally substituted C １－４ alkyl group, optionally substituted C ２－４ alkenyl group, or optionally substituted C ２－４ is an alkynyl group, R ２ and R ４ are each independently hydrogen, halogen (e.g., F), optionally substituted C １－４ alkyl group, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ Alkynyl group, optionally substituted C １－４ an alkoxy group or an optionally substituted 3- to 5-membered ring; R ３ is hydrogen, optionally substituted C １－４ an alkyl group or an optionally substituted 3- to 10-membered ring; R ６ is hydrogen, deuterium, optionally substituted C １－４ alkyl group, optionally substituted C ２－４ alkenyl group, or optionally substituted C ２－４ is an alkynyl group, Integers n1 and n2 are each independently 0, 1, 2, 3, or 4; and R ａ and R ｂ Each occurrence of １－４ alkyl group or optionally substituted C １－４ is a heteroalkylene group, or R ａ Two examples of R ｂ Two examples of R are joined together with the intervening atoms to form an optionally substituted 3- to 6-membered ring, and R ａ and / or R ｂ or a pharmaceutically acceptable salt thereof, wherein any remaining examples are as defined above.

45. 【Catalog 25】 45. The compound of claim 44, having a structure according to:

46. 46. ​​The compound of claim 44 or 45, or a pharmaceutically acceptable salt thereof, wherein n1 and n2 are both 0.

47. The compound is 【Chemical 26】 46. ​​The compound of claim 44 or 45, characterized in that it has the structure: or a pharmaceutically acceptable salt thereof.

48. R ６ is hydrogen, deuterium, CH ３ or CF ３ 48. The compound according to any one of claims 44 to 47, or a pharmaceutically acceptable salt thereof, wherein:

49. R ４ The compound according to any one of claims 44 to 48, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

50. Where applicable, R ２ 50. The compound of any one of claims 44 to 49, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

51. Where applicable, R １ is hydrogen, deuterium, or C optionally substituted with F １－４ Alkyl groups, such as methyl groups, CF ３ The compound according to any one of claims 44 to 50, or a pharmaceutically acceptable salt thereof.

52. 52. The compound of any one of claims 44 to 51, or a pharmaceutically acceptable salt thereof, wherein X is O.

53. R ３ is an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted bicyclic heteroaryl group (e.g., an 8- to 10-membered bicyclic heteroaryl group), or a pharmaceutically acceptable salt thereof.

54. R ３ are phenyl groups, which are each independently halogen, CN, OH, NH ２ , COOH, CONH ２ , G １ , O.G. １ , S.G. １ , NHG １ ,NG １ G １ , C(O)G １ , COOG １ , CONHG １ , CONG １ G １ , O.C.(O.)G １ , OCOOG １ , OCONHG １ , OCONG １ G １ , NHC(O)G １ , NHCOOG １ , NHCONHG １ , NHCONG １ G １ ,NG １ C(O)G １ ,NG １ COOG １ ,NG １ CONHG １ ,NG １ CONG １ G １ , S.O. ２ G １ , S.O. ２ NHG １ , or SO ２ NG １ G １ and wherein G is substituted with 1 to 3 substituents selected from １ Each occurrence of is independently an optionally substituted C １－４ alkyl group, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ an alkynyl group, or an optionally substituted 3- to 6-membered ring structure such as a cyclopropyl group, a cyclobutyl group, a phenyl group, a pyridyl group, or an NG １ G １ The two Gs １ is optionally linked to a nitrogen atom to form an optionally substituted 4-8 membered heterocycle, or a pharmaceutically acceptable salt thereof.

55. R ３ are phenyl groups, which are each independently F, Cl, CN, OH, NH ２ , COOH, CONH ２ , G ２ , O.G. ２ , NHG ２ ,NG ２ G ２ , C(O)G ２ , COOG ２ , CONHG ２ , CONG ２ G ２ , S.O. ２ G ２ , S.O. ２ NHG ２ , or SO ２ NG ２ G ２ and wherein G is substituted with 1 to 3 substituents selected from ２ Each occurrence of is independently １－４ Alkyl group, C ３－６ a cycloalkyl group, a 3- to 6-membered heterocycle having 1 to 2 ring heteroatoms, a phenyl group, or a 5- or 6-membered heteroaryl group, each of which is optionally and independently selected from F, Cl, OH, NH ２ , C optionally substituted with 1 to 3 F １－４ alkyl group or C having 1 or 2 heteroatoms and optionally substituted with 1 to 3 F １－４ substituted with 1 to 3 substituents selected from heteroalkyl groups, or NG ２ G ２ The two Gs ２ is optionally linked to the nitrogen atom to form an optionally substituted 4-8 membered heterocyclic ring having 0 or 1 additional ring heteroatoms, or a pharmaceutically acceptable salt thereof.

56. R ３ teeth, 【Chemical 27】 and where: G ３ Each occurrence of is independently an optionally substituted C １－４ alkyl groups or optionally substituted 3- to 6-membered rings, such as cyclopropyl, cyclobutyl, oxetanyl groups (e.g. 【Chemical 28】 ) etc., or C １－４ alkyl group or deuterated analogue of a 3- to 6-membered ring, and when substituted, the C １－４ The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, １－４ alkyl group, C having 1-2 heteroatoms and optionally substituted with F １－４ substituted with 1 to 3 substituents that are heteroalkyl groups or 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetanyl groups) optionally substituted with F; or Two Gs ３ are joined together with the nitrogen atom to which they are both attached to form a 4- to 8-membered heterocycle having 0 or 1 additional ring heteroatom, wherein the 4- to 8-membered heterocycle is optionally each independently selected from oxo, F, C, １－４ Alkyl groups, OH, NH ２ or C having 1 to 2 heteroatoms １－４ substituted with 1 to 3 substituents which are heteroalkyl groups, and wherein: The integer n7 is 0, 1, or 2; R ｈ Each occurrence of represents independently a halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 53. The compound of any one of claims 44 to 52, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

57. having a structure according to formula V-1, 【Chemical 29】 where: R ｐ is halogen, CN, OH, NH ２ , COOH, CONH ２ , G ３ , OG ３ , SG ３ , NHG ３ , NG ３ G ３ , C(O)G ３ , COOG ３ , CONHG ３ , CONG ３ G ３ , OC(O)G ３ , OCOOG ３ , OCONHG ３ , OCONG ３ G ３ , NHCOG ３ , NHCOOG ３ , NHCONHG ３ , NHCONG ３ G ３ , NG ３ C(O)G ３ , NG ３ COOG ３ , NG ３ CONHG ３ , NG ３ CONG ３ G ３ , SO ２ G ３ , SO ２ NHG ３ , or SO ２ NG ３ G ３ and G ３ Each occurrence of is independently an optionally substituted C １－４ alkyl groups or optionally substituted 3- to 6-membered rings, such as cyclopropyl, cyclobutyl, oxetanyl groups (e.g. 【Chemistry 30】 ) etc., or C １－４ alkyl group or deuterated analogue of a 3- to 6-membered ring, and when substituted, the C １－４ The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, １－４ alkyl group, C having 1-2 heteroatoms and optionally substituted with F １－４ substituted with 1 to 3 substituents that are heteroalkyl groups or 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetanyl groups) optionally substituted with F; or Two Gs ３ are joined together with the nitrogen atom to which they are both attached to form a 4- to 7-membered heterocycle having 0 or 1 additional ring heteroatom, wherein the 4- to 7-membered heterocycle is optionally each independently selected from oxo, F, C, １－４ Alkyl groups, OH, NH ２ or C having 1 to 2 heteroatoms １－４ 53. The compound of any one of claims 44 to 52, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

58. G ３ are independently a methyl group, 【Chemical 31】 or two G ３ are linked together with the nitrogen atom to which they are both attached, 【Chemical Formula 32】 58. The compound of claim 56 or 57, or a pharmaceutically acceptable salt thereof, which forms:

59. 59. The compound of claim 56 or 58, or a pharmaceutically acceptable salt thereof, wherein n7 is 0.

60. n7 is 1 and R ｈ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 59. The compound of claim 56 or 58, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

61. R ３ teeth, 【Chemical 33】 and where: Integers n8 and n9 are independently 0, 1, or 2; HET optionally contains 1 to 2 R ｊ is a 5- or 6-membered heteroaryl group substituted with R ｉ , R ｊ and R ｋ Each occurrence of is independently selected from halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 53. The compound of any one of claims 44 to 52, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

62. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein n8 is 0.

63. n8 is 1 and R ｉ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

64. 64. The compound according to any one of claims 61 to 63, or a pharmaceutically acceptable salt thereof, wherein n9 is 0.

65. n9 is 1, and R ｋ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 64. The compound of any one of claims 61 to 63, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

66. HET is a group consisting of (1) optionally 1 to 2 R ｊ pyridyl groups substituted with, for example, 【Chemical Formula 34】 and the like), pyrimidinyl groups (e.g., 【Chemical 35】 ), pyrazinyl groups (e.g. 【Chemical 36】 ), pyridonyl groups (e.g., 【Chemical 37】 ), or a pyrimidinone group (e.g. 【Chemical 38】 ), where R ｊ each occurrence independently represents F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ or (2) optionally one to two R ｊ pyrazoles, oxadiazoles, thiadiazoles, triazoles, tetrazoles, thiazoles, oxazoles, or imidazoles substituted with 【Chemical Formula 39】 etc.), where R ｊ each occurrence independently represents F, OH, C optionally substituted with F, １－４ alkyl group, C having 1-2 heteroatoms and optionally substituted with F １－４ 66. The compound of any one of claims 61 to 65, or a pharmaceutically acceptable salt thereof, which is a heteroalkyl group or a 3- to 4-membered ring, such as a cyclopropyl group or a cyclobutyl group.

67. R ３ teeth, 【Chemistry 40】 where: The integer n10 is 0, 1, or 2; and R ７ and R ８ are joined together with the intervening atoms to form a 4- to 8-membered ring, which optionally contains 1 to 3 R ｎ is replaced by R ｍ Each occurrence of represents independently a halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ substituted with 1 to 3 substituents which are heteroalkyl groups; and R ｎ Each occurrence independently represents oxo (where valence allows), halogen (e.g., F), CN, OH, C １－４ Alkyl group, C １－４ an alkoxy group or a 3- to 6-membered ring, １－４ Alkyl group, C １－４ The alkoxy group or the 3- to 6-membered ring may optionally each independently be F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 53. The compound of any one of claims 44 to 52, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

68. R ７ and R ８ are joined together with the intervening atoms to form a 5- or 6-membered heteroaryl ring having 1 to 3 ring heteroatoms, which optionally contains 1 to 2 R ｎ where R ｎ 68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein:

69. R ７ and R ８ are joined together with the intervening atoms to form a 4- to 7-membered heterocyclyl ring having 1 or 2 ring heteroatoms, which optionally contains 1 to 2 R ｎ where R ｎ 68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein:

70. R ３ teeth, 【Chemistry 41】 【change】 and where: G ４ Each occurrence of is independently an optionally substituted C １－４ an alkyl group, or an optionally substituted 3- to 6-membered ring, such as a cyclopropyl group, and when substituted, the C １－４ The alkyl group or the 3- to 6-membered ring is independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents which are heteroalkyl groups.

71. 71. The compound according to any one of claims 67 to 70, or a pharmaceutically acceptable salt thereof, wherein n10 is 0.

72. n10 is 1, and R ｍ is a halogen (e.g., F), CN, C optionally substituted with F １－４ alkyl group, optionally substituted with F １－４ an alkoxy group, or a 3- to 6-membered ring, each of which is optionally independently selected from F, OH, C optionally substituted with F, １－４ an alkyl group or a C having 1-2 heteroatoms and optionally substituted with F; １－４ 71. The compound of any one of claims 67 to 70, or a pharmaceutically acceptable salt thereof, substituted with 1 to 2 substituents which are heteroalkyl groups.

73. A compound having formula III or a pharmaceutically acceptable salt thereof: 【Chemistry 42】 (1) R １ is hydrogen, deuterium, optionally substituted C １－４ alkyl group, optionally substituted C ２－４ alkenyl group, or optionally substituted C ２－４ is an alkynyl group, R ２ , R ４ and R ５ are each independently hydrogen, halogen (e.g., F), optionally substituted C １－４ alkyl group, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ Alkynyl group, optionally substituted C １－４ an alkoxy group or an optionally substituted 3- to 5-membered ring; or (2) R １ and R ２ are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; and R ４ and R ５ is as defined in (1), or (3) R １ and R ５ are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; R ２ and R ４ is as defined in (1), or (4) R ４ and R ５ are joined together with the intervening atoms to form an optionally substituted 4- to 8-membered ring; and R １ and R ２ is as defined in (1) or (2), and where: X is O, S, NR １０ , optionally substituted C １－４ an alkylene group, or an optionally substituted C １－４ heteroalkylene group, where R １０ is hydrogen, optionally substituted C １－４ an alkyl group, an optionally substituted 3- to 6-membered ring, or a nitrogen protecting group; AR represents an optionally substituted arylene group or an optionally substituted heteroarylene group; R ３ is hydrogen, optionally substituted C １－４ an alkyl group or an optionally substituted 3- to 10-membered ring; R １’ is hydrogen, deuterium, optionally substituted C １－４ alkyl group, optionally substituted C ２－４ alkenyl group, or optionally substituted C ２－４ is an alkynyl group, R ６ and R ６’ are each independently hydrogen, deuterium, optionally substituted C １－４ alkyl group, optionally substituted C ２－４ alkenyl group, or optionally substituted C ２－４ is an alkynyl group, Integers n1 and n2 are each independently 0, 1, 2, 3, or 4; and R ａ and R ｂ Each occurrence of １－４ alkyl group or optionally substituted C １－４ is a heteroalkylene group, or R ａ Two examples of R ｂ Two examples of R are joined together with the intervening atoms to form an optionally substituted 3- to 6-membered ring, and R ａ and / or R ｂ or a pharmaceutically acceptable salt thereof, wherein any remaining examples are as defined above.

74. R ６ 74. The compound of any one of claims 1 to 73, wherein the carbon linked to has an S-configuration.

75. R ６ 74. The compound of any one of claims 1 to 73, wherein the carbon linked to has the R-configuration.

76. A compound selected from Examples 1-569 or a compound shown in Tables A1-A18 herein, a stereoisomer thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof.

77. 77. A pharmaceutical composition comprising a compound according to any one of claims 1 to 76, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

78. 78. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 76 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 77.

79. These cancers include cancers of the adrenal gland, bone, brain, breast, bronchus, colon and / or rectum, gallbladder, head and neck, kidney, larynx, liver, lung, nervous tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid gland, as well as acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, glioblastoma multiforme, hairy cell tumor, ganglioneuroma, proliferative corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid, 79. The method of claim 78, wherein the tumor is selected from the group consisting of malignant melanoma, malignant hypercalcemia, Marfan's tumor, medullary carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, osteogenic and other sarcomas, ovarian tumor, pheochromocytoma, polycythemia vera, primary brain tumor, small cell lung tumor, ulcerating and papillary squamous cell carcinoma, hyperplasia, seminoma, soft tissue sarcoma, retinoblastoma, rhabdomyosarcoma, small cell renal tumor, localized skin lesions, reticulum cell sarcoma, and Wilms' tumor.

80. 79. The method of claim 78, wherein the cancer is liver cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, or prostate cancer.

81. The method of any one of claims 78 to 80, wherein the cancer has aberrant AKR1C3 activity and / or AKR1C3 overexpression.

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