Hydantoin-containing deoxyuridine triphosphatase inhibitor

Abstract

The invention relates to a hydantoin-containing deoxyuridine triphosphatase inhibitor and a preparation method thereof. Provided herein are dUTPase inhibitors, compositions comprising these compounds, and methods of using these compounds or compositions.

Description

[0001] This application is a divisional application of the invention patent application entitled "Deoxyuridine Triphosphatase Inhibitor Containing Hydantoin", which entered the Chinese national phase on March 6, 2018, with application number 201680051434.1, application date July 7, 2016, and invention title "Deoxyuridine Triphosphatase Inhibitor Containing Hydantoin". background

[0002] Thymidine metabolism is essential for the production of basic building blocks necessary for replicating DNA in dividing cells and has long been a key therapeutic target for cornerstone cancer drugs. Drugs targeting this pathway, such as 5-fluorouracil (5-FU), inhibit thymidine synthase (TS) and are currently a key standard of care. TS-targeting drugs are used to treat a variety of cancers, including colon cancer, gastric cancer, head and neck cancer, breast cancer, lung cancer, and hematologic malignancies. (Grem, JL, 5-Fluorouracil plus leucovorin in cancer therapy, in Principals and Practice of OncologyUpdate Series, J. De Vita, VT, S. Hellman, and A. Rosenberg, Editors. 1988, JB Lippincott: Philadelphia, Pa.)

[0003] There are two classes of drugs that target the Tse-Stokes enzyme: fluoropyrimidines and antifolate agents. Fluoropyrimidines, 5-FU, S-1, and capecitabine (Xeloda®) are widely used to treat gastrointestinal and breast cancers, while the antifolate agent pemetrexed (Alimta®) is currently used to treat non-small cell lung cancer (NSCLC). Since Charles Heidelberger discovered 5-FU fifty years ago, fluoropyrimidines remain one of the most commonly used and effective anticancer drugs in the world. Therefore, the use of these drugs is based on extensive clinical experience and a deep understanding of their mechanisms of action.

[0004] The TS inhibitor 5-fluorouracil (5FU) remains the cornerstone of many first- and second-line treatment regimens for colorectal cancer. Monotherapy with 5-FU, including oxaliplatin, irinotecan, cetuximab, and avastin, has shown reduced activity in colorectal cancer compared to 5-FU. Besides colorectal cancer, TS inhibitors have demonstrated efficacy in several other solid tumor types. Standards of care now include 5-FU as the lead-line drug in combination with oxaliplatin or irinotecan or other agents.

[0005] Deoxyuridine triphosphatase (“dUTPase”) is a ubiquitous enzyme essential for the survival of both prokaryotes and eukaryotes. As a major regulator of the dUTP pool, dUTPase expression may have a profound impact on the efficacy of chemotherapeutic agents that inhibit thymidine biosynthesis. Under normal conditions, dUTPase mediates its protective effect by limiting the expansion of the dUTP pool and counteracting the cytotoxic effects of misincorporation of uracil. According to this model, elevated dUTPase levels can prevent TS inhibitor-induced dUTP accumulation and induce drug resistance. It has been shown that, compared with controls, dUTPase overexpression leads to a significant reduction in dUTP accumulation and increased resistance to drug therapy.

[0006] Chemotherapy agents targeting the metabolism of nascent thymidine nucleotides are crucial for treating various solid tumors; however, clinical efficacy is often hampered by drug resistance. Since resistance to these drugs is a common phenomenon, the identification and utilization of novel determinants of drug sensitivity within this proven therapeutic pathway is important, as disclosed by Ladner et al. As described in US Patent Publication US2011 / 0212467, the dUTPase enzyme and uracil-DNA misincorporation pathway can play a driving role in mediating the cytotoxicity of chemotherapy for TS.

[0007] For example, nearly half of cancer patients do not benefit from 5-FU-based treatments due to intrinsic or acquired resistance. Because of this fact, overcoming the fundamental challenge of resistance and providing new treatment strategies to improve patient outcomes is of paramount importance. This disclosure addresses this need and offers relevant advantages. Summary of the Invention

[0008] In some aspects, this disclosure provides compounds, compositions, and methods for inhibiting dUTPase when used alone or in combination with at least one chemotherapy targeting dUTPase. In some aspects, this disclosure provides compounds, compositions, and methods for treating cancer, killing cancer cells, and / or inhibiting cancer cell growth when used in combination with at least one TS-targeted chemotherapy. Such compounds include, but are not limited to, compounds of formula (I).

[0009] In one respect, this article provides compounds of formula (I):

[0010]

[0011] Or its tautomers; or a prodrug of each of the above; or a deuterated isotope of each of the above, wherein up to 10, preferably up to 6, more preferably up to 3 hydrogen atoms attached to one or more carbon atoms are substituted with deuterium; or a pharmaceutically acceptable salt of each of the above; or a pharmaceutically acceptable solvate of each of the above.

[0012] in

[0013] A contains the -C(O)NZC(O)- part, the -C(O)OC(O) part, and the -C(O)CR part. 10 C(O) partial or -C(O)NR 10 Optional substitution of the C(O) portion of a 5-membered heterocycle; or

[0014] A is a 5-membered heteroaryl group or a 5-membered substantially planar heterocyclic group (i.e., a heterocyclic group in which at least 3 or at least 4 atoms can be stably located in the same plane) substituted at the 1,3 positions with a substituent selected from halogens, optionally substituted hydroxyl groups, and optionally substituted -SH groups (preferably two fluorine groups), wherein the 5-membered heteroaryl group or substantially planar heterocyclic group is optionally further substituted; or

[0015] A is

[0016]

[0017] Preferred options are:

[0018]

[0019]

[0020] Each R 10 Independently hydrogen, optionally substituted C1-C 10 Alkoxy, optional substituted C1-C 10 Alkyl, preferably, R 10 It is hydrogen;

[0021] Each R 30 Independently hydrogen; optionally substituted C1-C 10 Alkyl group; optionally substituted amino group, such as -NH2 or its mono- or di-substituted form; optionally substituted C1-C 10 Alkyl; optionally substituted hydroxyl; prodrug moiety or Z; or A and L 1 R is preferred 30 , where R 30 Connected to L 1 The atoms connected to each other are adjacent atoms, and L 1 Together with the atoms they are attached to, they form 5-7 membered rings;

[0022] L 1It is a linking group having 2-8 chain atoms selected from C, N, O, S and / or P, wherein the linking group is optionally substituted;

[0023] L 2 It is -SO2NR 50 -, where sulfur is connected to L 1 ;-NR 50 SO2-, where N is connected to L 1 ;-C(O)NR 50 - where C is connected to L 1 ;-NR 50 C(O)-, where N is connected to L 1 ;-NR 50 SO2NR 50 -; or -NR 50 CONR 50 -;

[0024] Each R 50 Independently, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C6 heteroalkenyl, optionally substituted C2-C6 ynynyl, optionally substituted C3-C6 heteroynyl, or Z.

[0025] Z is

[0026] ,

[0027] Where R 51 and R 52 Independently hydrogen or optionally substituted C1-C 10 alkyl;

[0028] X is an optional substituted hydroxyl group, an optional substituted NH2 group, or an optional substituted SH group;

[0029] L 3 It is a bond or linking group, preferably a linking group, having 2-8 chain atoms selected from C, N, O, S and / or P, wherein the linking group is optionally substituted, preferably L 3 It is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 heteroalkylene, optionally substituted C2-C6 alkenyl, optionally substituted C3-C6 heteroalkenyl, optionally substituted C2-C6 alkyneyl, optionally substituted C3-C6 heterokyneyl; and

[0030] B is an optionally substituted 6-10 aryl group; an optionally substituted 5-15 heteroaryl group; an optionally substituted 4-15 heterocyclic group; or an optionally substituted 3-15 cycloalkyl group, preferably at least 4-membered, more preferably 5-10-membered cycloalkyl group if it is a cycloalkyl group.

[0031] In some embodiments, the compounds provided herein are prodrugs. As used herein, a "prodrug" means a compound that, with respect to at least one property, is metabolized or otherwise converted into a biologically active or more active compound (or drug) after administration. A prodrug is chemically modified in a manner less active or inactive than a drug, but such modification results in the production of the corresponding drug through metabolism or other biological processes following administration of the prodrug. A prodrug may have altered metabolic stability or transport properties, fewer side effects or lower toxicity, or improved taste compared to an active drug (see, for example, Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). Prodrugs can be synthesized using reactants other than the corresponding drug. Examples of prodrugs and methods of their preparation are also provided in U.S. Patent Application Publication No. 20160024127, which is incorporated herein by reference in its entirety.

[0032] In some embodiments, the compounds provided herein contain one or more deuterium atoms. Examples of deuterium-containing compounds provided herein (where up to 10, preferably up to 6, more preferably up to 3 hydrogen atoms attached to carbon atoms are replaced by deuterium) include, but are not limited to: compounds in which the methyl group is converted to -CH2D, -CHD2, or -CD3; compounds in which the methylene group is converted to -CHD- or -CD2-; benzene rings in which one or more hydrogen atoms are replaced by deuterium atoms, etc.

[0033] In some embodiments, A is a 5-membered heterocyclic group with optional substitution of the -C(O)NZC(O)- moiety. In some embodiments, A is a 5-membered heterocyclic group with optional substitution of the -C(O)OC(O) moiety. In some embodiments, A is a 5-membered heterocyclic group with -C(O)CR- moiety. 10 A 5-membered heterocyclic group with optional substitution of the C(O) moiety. In some embodiments, A is a -C(O)NR group. 10 Optional substitution of the C(O) portion of a 5-membered heterocyclic group.

[0034] In some implementations, R 10 It is hydrogen. In some implementations, R 10 It is an optional substitution of C1-C 10 Alkyloxy group. In some embodiments, R 10 It is an optional substitution of C1-C 10 alkyl.

[0035] In some embodiments, A is a 5-membered heteroaryl group substituted at the 1,3 positions with a substituent selected from halogens, optionally substituted hydroxyl groups, and optionally substituted -SH groups (preferably two fluorine groups), wherein the 5-membered heteroaryl group is optionally further substituted. In some embodiments, A is a 5-membered heteroaryl group substituted at the 1,3 positions with a halogen, wherein the 5-membered heteroaryl group is optionally further substituted. In some embodiments, A is a 5-membered heteroaryl group substituted at the 1,3 positions with two fluorine groups, wherein the 5-membered heteroaryl group is optionally further substituted. In some embodiments, A is a 5-membered heteroaryl group substituted at the 1,3 positions with an optionally substituted -SH group, wherein the 5-membered heteroaryl group is optionally further substituted.

[0036] Non-limiting and illustrative examples of five-membered heteroaryl groups substituted at the 1,3 positions with substituents selected from halogens, optionally substituted hydroxyl groups, and optionally substituted -SH groups include, but are not limited to:

[0037]

[0038] For example

[0039] ,

[0040] Where Y 10 and Y 11 Independently selected from halogens (preferably chlorine or fluorine), hydroxyl groups, -SH, substituted hydroxyl groups, and substituted -SH; Z 20 -Z 22 Independently selected from optionally substituted CH, optionally substituted NH, N, S, SO2, SO, and O, under the condition Z 20 -Z 22 The combination provides a planar valence-matched heteroaryl group or its tautomer; and Z 23 Each is independently CH or N.

[0041] In some implementations, Y 10 It is a halogen. In some embodiments, Y 10 It is chlorine. In some embodiments, Y 10 It is fluorine. In some embodiments, Y 10 It is a hydroxyl group. In some embodiments, Y 10 It is -SH. In some implementations, Y 10 It is a substituted hydroxyl group. In some embodiments, Y 10 It replaces -SH.

[0042] In some implementations, Y 11It is a halogen. In some embodiments, Y 11 It is chlorine. In some embodiments, Y 11 It is fluorine. In some embodiments, Y 11 It is a hydroxyl group. In some embodiments, Y 11 It is -SH. In some implementations, Y 11 It is a substituted hydroxyl group. In some embodiments, Y 11 It replaces -SH.

[0043] In some implementations, Z 20 CH is an optional substitution. In some implementations, Z 20 It is an optional substituted NH. In some embodiments, Z 20 It is N. In some implementations, Z 20 It is S. In some implementations, Z 20 It is SO2. In some implementations, Z 20 It is SO. In some implementations, Z 20 It is O.

[0044] In some implementations, Z 21 CH is an optional substitution. In some implementations, Z 21 It is an optional substituted NH. In some embodiments, Z 21 It is N. In some implementations, Z 21 It is S. In some implementations, Z 21 It is SO2. In some implementations, Z 21 It is SO. In some implementations, Z 21 It is O.

[0045] In some implementations, Z 22 CH is an optional substitution. In some implementations, Z 22 It is an optional substituted NH. In some embodiments, Z 22 It is N. In some implementations, Z 22 It is S. In some implementations, Z 22 It is SO2. In some implementations, Z 22 It is SO. In some implementations, Z 22 It is O.

[0046] In some implementations, Z 23 CH is an optional substitution. In some implementations, Z 23 It is N.

[0047] In some embodiments, A is a 5-membered substantially planar heterocyclic group (i.e., a heterocyclic group in which at least 3 or at least 4 atoms can be stably located in the same plane) substituted at the 1,3 positions with a substituent selected from halogens, optionally substituted hydroxyl groups, and optionally substituted -SH groups (preferably two fluorine groups), wherein the 5-membered substantially planar heterocyclic group is optionally further substituted. In some embodiments, A is a 5-membered substantially planar heterocyclic group substituted with a halogen at the 1,3 positions, wherein the 5-membered substantially planar heterocyclic group is optionally further substituted. In some embodiments, A is a 5-membered substantially planar heterocyclic group substituted with two fluorine groups at the 1,3 positions, wherein the 5-membered substantially planar heterocyclic group is optionally further substituted. In some embodiments, A is a 5-membered substantially planar heterocyclic group substituted with an optionally substituted hydroxyl group at the 1,3 positions, wherein the 5-membered substantially planar heterocyclic group is optionally further substituted. In some embodiments, A is a 5-membered substantially planar heterocyclic group substituted with -SH at positions 1 and 3, wherein the 5-membered substantially planar heterocyclic group is optionally further substituted.

[0048] Examples of 5-membered substantially planar heterocyclic groups substituted at the 1,3 positions with substituents selected from halogens, optionally substituted hydroxyl groups, and optionally substituted -SH groups have structures similar to the corresponding 5-membered heteroaryl groups, except that the 5-membered ring is not an aromatic ring.

[0049] In some implementations, A is:

[0050] .

[0051] In some implementations, A is:

[0052] .

[0053] In some implementations, A is:

[0054] .

[0055] In some implementations, A is:

[0056] .

[0057] In some implementations, A is:

[0058] .

[0059] In some implementations, A is:

[0060] .

[0061] In some implementations, A is:

[0062] .

[0063] In some implementations, A is:

[0064] .

[0065] In some implementations, A is:

[0066] .

[0067] In some implementations, A is:

[0068] .

[0069] In some implementations, A is:

[0070] .

[0071] In some implementations, A is:

[0072] .

[0073] In some implementations, A is:

[0074] .

[0075] In some implementations, A is:

[0076] .

[0077] In some implementations, R 30 It is hydrogen. In some implementations, R 30 It is an optional substitution of C1-C 10 Alkyloxy group. In some embodiments, R 30 It is an optionally substituted amino group, such as –NH2 or its mono- or di-substituted form. In some embodiments, R 30 It is an optional substitution of C1-C 10 Alkyl group. In some embodiments, R 30 It is an optionally substituted hydroxyl group. In some embodiments, R 30 This is a prodrug portion. Non-limiting and illustrative prodrug portions include formyl ethers and formyl esters as disclosed herein. In some embodiments, R... 30 It's Z.

[0078] R 30 Illustrative and non-limiting examples include substituted hydroxyl groups or -CH2OC(O)R 80 , where R 80 It is H or an optional substituted C1-C 10 Alkyl group. In some embodiments, R80 It is H. In some implementations, R 80 It is an optional substitution of C1-C 10 alkyl.

[0079] In some implementations, A is L 1 Preferably, R 30 and L 1 Together with the atoms they are attached to, they form a 5-7 membered ring.

[0080] In some implementations, A is selected from:

[0081] .

[0082] In some implementations, A is:

[0083] .

[0084] In some implementations, A is:

[0085] .

[0086] In some implementations, A is:

[0087] .

[0088] In some embodiments, the A portion disclosed herein (including those described above) may be represented by 1-3, preferably 1-2, more preferably 1 R portion provided herein. 30 Substituents further substitute. In some embodiments, when R 30 and L 1 When connected to adjacent atoms (i.e., atoms with a 1,2 positional relationship), R 30 and a portion of L 1 Together with intervening atoms, it can form a 5-6 member substituted cycloalkyl or heterocyclic ring.

[0089] In some implementations, A is not:

[0090] .

[0091] In some implementations, A is not:

[0092] .

[0093] In some implementations, L 1It is a linking group having 2-8 chain atoms selected from C, N, O, S and / or P, wherein the linking group is optionally substituted. In several embodiments, L has 2-8 chain atoms selected from C, N, O, S and / or P. 1 It can be: alkylene, alkenylene, or ynylene, wherein one or more carbon atoms are bonded by O, S, SO, or SO₂. 2、 Optional substitution of NH,

[0094]

[0095] Part (where R) Q The alternatives are H or C1-C6 alkyl, optionally substituted -CO-NH-, optionally substituted -SO2-NH-, optionally substituted -P(O)(OH)-, optionally substituted phosphoramides and optionally substituted phosphoramidides (e.g. –P(O)NH2-, –P(O)(OH)NH-, etc.), optionally substituted oligoglycols, optionally substituted oligoethanolamines, etc., which can be obtained by those skilled in the art based on the disclosure herein.

[0096] In some implementations, L 1 It is -(CH2) q In some embodiments, one or more hydrogen atoms are optionally substituted with C1-C3 alkyl groups. In some embodiments, at least two or more geminal hydrogens are optionally substituted with optional 3- to 5-membered heterocyclic groups. In some embodiments, at least two or more geminal hydrogens are optionally substituted with optional 3- to 5-membered cycloalkyl groups. In some embodiments, the optional substituted 3- to 5-membered cycloalkyl group is optionally substituted cyclopropane. In some embodiments, the optional substituted 3- to 5-membered cycloalkyl group is optionally substituted cyclobutane. In some embodiments, the optional substituted 3- to 5-membered cycloalkyl group is optionally substituted cyclopentane. In some embodiments, the optional substituted 3- to 5-membered cycloalkyl group is optionally substituted tetrahydrofuran.

[0097] In some implementations, q is 3. In some implementations, q is 4. In some implementations, q is 5. In some implementations, q is 6. In some implementations, q is 7. In some implementations, q is 8.

[0098] In some implementations, L 1 yes:

[0099] .

[0100] In some related embodiments, one or more hydrogen atoms are optionally substituted with C1-C3 alkyl groups. In some embodiments, at least two or more twin hydrogen atoms are optionally substituted with optional 3-5-membered heterocyclic groups. In some embodiments, at least two or more twin hydrogen atoms are optionally substituted with optional 3-5-membered cycloalkyl groups. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted cyclopropane. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted cyclobutane. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted cyclopentane. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted tetrahydrofuran.

[0101] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5.

[0102] In some implementations, z is 0. In some implementations, z is 1. In some implementations, z is 2. In some implementations, z is 3. In some implementations, z is 4. In some implementations, z is 5.

[0103] In some implementations, L 1 It is -(CH2) m -X 15 -(CH2) n In some embodiments, one or more hydrogen atoms are optionally substituted with a C1-C3 alkyl group. In some embodiments, at least two or more twin hydrogen atoms are optionally substituted with an optionally substituted 3-5-membered heterocyclic group. In some embodiments, at least two or more twin hydrogen atoms are optionally substituted with an optionally substituted 3-5-membered cycloalkyl group. In some embodiments, the optionally substituted 3-5-membered cycloalkyl group is optionally substituted cyclopropane. In some embodiments, the optionally substituted 3-5-membered cycloalkyl group is optionally substituted cyclobutane. In some embodiments, the optionally substituted 3-5-membered cycloalkyl group is optionally substituted cyclopentane. In some embodiments, the optionally substituted 3-5-membered cycloalkyl group is optionally substituted tetrahydrofuran.

[0104] In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3.

[0105] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 5. In some implementations, n is 6. In some implementations, n is 7.

[0106] In some implementations, X 15 It is NR 40 In some implementations, X 15 It is NR 40 (+)-O(-). In some implementations, R 40 It is H. In some implementations, R 40 It is a C1-C3 alkyl group. In some embodiments, X 15 It is O. In some implementations, X 15 It is S. In some implementations, X 15 It is SO. In some implementations, X 15 It is SO2.

[0107] In some implementations, L 1 yes:

[0108] Where X 15 As defined above.

[0109] In some related embodiments, one or more hydrogen atoms are optionally substituted with C1-C3 alkyl groups. In some embodiments, at least two or more twin hydrogen atoms are optionally substituted with optional 3-5-membered heterocyclic groups. In some embodiments, at least two or more twin hydrogen atoms are optionally substituted with optional 3-5-membered cycloalkyl groups. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted cyclopropane. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted cyclobutane. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted cyclopentane. In some embodiments, the optional substituted 3-5-membered cycloalkyl group is optionally substituted tetrahydrofuran.

[0110] In some implementations, o is 0. In some implementations, o is 1. In some implementations, o is 2. In some implementations, o is 3.

[0111] In some implementations, r is 1. In some implementations, r is 2. In some implementations, r is 3.

[0112] In some implementations, s is 0. In some implementations, s is 1. In some implementations, s is 2. In some implementations, s is 3. In some implementations, s is 4.

[0113] In some implementations, L 1 Selected from:

[0114] .

[0115] In some related implementations, L 1 One to five, preferably one to three, hydrogen atoms are optionally substituted, with preferred substituents including, but not limited to, C1-C6 alkyl groups optionally substituted with one to three halogens (e.g., fluorine) and / or C1-C6 alkoxy groups; optionally substituted C1-C6 alkoxy groups; and halogens, preferably fluorine, wherein the left side of the moiety is connected to A, and wherein R 70 It is an optional substitution of C1-C 10 Alkyl group. In some embodiments, L 1 Optionally substituted, wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L 1 The substituents are optionally substituted, wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (e.g., fluorine). In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, halogens. In some embodiments, the substituents include fluorine.

[0116] In some implementations, L 1 yes:

[0117]

[0118] Or in the form of optional substitutions of each of them, wherein 1-5, preferably 1-3, hydrogen atoms are optionally substituted, and preferred substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (e.g., fluorine) and / or C1-C6 alkoxy groups; optional substituted C1-C6 alkoxy groups; and halogens, preferably fluorine, wherein the left side of the moiety is connected to A.

[0119] In some implementations, L 1 yes:

[0120] .

[0121] In some implementations, L 1 yes:

[0122] .

[0123] In some implementations, L 1 Optionally substituted, wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L 1The substituents are optionally substituted, wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (e.g., fluorine). In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, halogens. In some embodiments, the substituents include fluorine.

[0124] In some implementations, L 2 It is -SO2NR 50 -, where sulfur is connected to L 1 In some implementations, L 2 Yes -NR 50 SO2-, where nitrogen is bonded to L 1 In some implementations, L 2 It is -C(O)NR 50 -, where carbon is connected to L 1 In some implementations, L 2 Yes -NR 50 C(O)-, where nitrogen is attached to L 1 In some implementations, L 2 Yes -NR 50 SO2NR 50 -. In some implementations, L 2 Yes -NR 50 CONR 50 -

[0125] In some implementations, R 50 It is hydrogen. In some implementations, R 50 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 50 It is an optionally substituted C2-C6 heteroalkyl group. In some embodiments, R 50 It is an optionally substituted C2-C6 alkenyl group. In some embodiments, R 50 It is an optionally substituted C3-C6 heteroene group. In some embodiments, R 50 It is an optionally substituted C2-C6 ynyl group. In some embodiments, R 50 It is an optionally substituted C3-C6 heteroene group. In some embodiments, R 50 It's Z.

[0126] In some implementations, Z is

[0127] ,

[0128] Each R51 and R 52 Independently hydrogen or optionally substituted C1-C 10 Alkyl group, and X is an optionally substituted hydroxyl group, an optionally substituted NH2 group, or an optionally substituted SH group.

[0129] In some implementations, R 51 It is hydrogen. In some implementations, R 51 It is an optional substitution of C1-C 10 Alkyl group. In some embodiments, R 52 It is hydrogen. In some implementations, R 52 It is an optional substitution of C1-C 10 alkyl.

[0130] In some embodiments, X is an optionally substituted hydroxyl group. In some embodiments, X is an optionally substituted NH2 group. In some embodiments, X is an optionally substituted SH group.

[0131] As used herein, optionally substituted hydroxyl groups refer to (but are not limited to) alkylated, arylated, heteroalkylated, heterocyclic, acylated, carboxylated (i.e., to form carbonates, carbamates, thiocarbonates, thiocarbamates containing alkyl, aryl, heteroaryl and / or heterocyclic groups and other such moieties), phosphorylated, phosphonylated, sulfonated forms of hydroxyl groups readily available to those skilled in the art based on this disclosure.

[0132] As used herein, the optionally substituted NH2 group refers to (but is not limited to) alkylated, arylated, heteroalkylated, heterocyclic, acylated, carboxylated (i.e., to form carbonates, carbamates, thiocarbonates, thiocarbamates containing alkyl, aryl, heteroaryl and / or heterocyclic groups and other such moieties), phosphorylated, phosphonylated, sulfonated forms of NH2 group, which can be readily obtained by those skilled in the art based on this disclosure.

[0133] As used herein, the optionally substituted SH group refers to (but is not limited to) alkylated, arylated, heteroalkylated, heterocyclic, acylated, carboxylated (i.e., to form carbonates, carbamates, thiocarbonates, thiocarbamates containing alkyl, aryl, heteroaryl and / or heterocyclic groups and other such moieties), phosphorylated, phosphonylated, sulfonated -SH groups in the form readily available to those skilled in the art based on this disclosure.

[0134] In some implementations, L 3 It is a key. In some implementations, L 3It is a linking group having 2-8 chain atoms selected from C, N, O, S and / or P, wherein the linking group is optionally substituted, for example, but not limited to those disclosed herein. In some embodiments, L 3 It is a linking group. In some embodiments, L 3 It is an optionally substituted C1-C6 alkenyl group. In some embodiments, L 3 It is -CH2-. In some implementations, L 3 It is an optionally substituted C2-C6 heteroene group. In some embodiments, L 3 It is an optionally substituted C2-C6 alkenyl group. In some embodiments, L 3 It is an optionally substituted C3-C6 heteroene group. In some embodiments, L 3 It is an optionally substituted C2-C6 ynylene group. In some embodiments, L 3 It is an optionally substituted C3-C6 heteroynyl group. In some embodiments, L 1 It is a linking group optionally substituted with a C3-C6 cycloalkyl group (preferably cyclopropyl or cyclobutyl). In some embodiments, the C1-C6 alkylene groups are optionally substituted with C3-C6 cycloalkyl groups.

[0135] In some implementations, L 3 Selected from:

[0136]

[0137] And in its optionally substituted form, wherein 1-5, preferably 1-3, hydrogen atoms are optionally substituted, and preferred substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (e.g., fluorine) and / or C1-C6 alkoxy groups; optionally substituted C1-C6 alkoxy groups; and halogens (preferably fluorine), wherein the left side of these moieties is connected to L. 2 .

[0138] In some implementations, L 3 yes:

[0139] .

[0140] In some implementations, L 3 yes:

[0141] .

[0142] In some implementations, L 3 yes:

[0143] .

[0144] In some implementations, L3 yes:

[0145] .

[0146] In some implementations, L 3 yes:

[0147] .

[0148] In some implementations, L 3 yes:

[0149] .

[0150] In one implementation, the left side is connected to A. In some implementations, L 3 yes:

[0151] .

[0152] In some implementations, L 3 yes:

[0153] .

[0154] In one implementation, the left side is connected to A.

[0155] In some implementations, L 3 Optionally substituted, wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L 3 It is in an optionally substituted form, wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (preferably fluorine). In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, optionally substituted C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, halogens. In some embodiments, the substituents include fluorine.

[0156] In some implementations, when L 3 yes

[0157] ,

[0158] Then A is the hydantoin portion as disclosed in this article.

[0159] In some implementations, when L 3 When it is a bond, then A is the hydantoin moiety as disclosed herein.

[0160] As used in this article, the hydantoin portion refers to:

[0161]

[0162] Where R 30 As defined above.

[0163] In some embodiments, the hydantoin portion is

[0164] .

[0165] In some implementations, L 3 no:

[0166] .

[0167] In some implementations, L 3 Selected from:

[0168]

[0169] And in its optionally substituted form, wherein 1-5 (preferably 1-3) hydrogen atoms are optionally substituted, and preferred substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (preferably fluorine) and / or C1-C6 alkoxy groups; optionally substituted C1-C6 alkoxy groups; and halogens (preferably fluorine), wherein the left side of these moieties is connected to L. 2 .

[0170] In some implementations, L 3 yes:

[0171] ,

[0172] The left side is connected to A.

[0173] In some less preferred embodiments, L 3 yes:

[0174] ,

[0175] The left side is connected to A.

[0176] In some implementations, L 3 yes:

[0177] ,

[0178] The left side is connected to A.

[0179] In some implementations, L 3 yes:

[0180] ,

[0181] The left side is connected to A.

[0182] In some implementations, L 3 yes:

[0183] ,

[0184] The left side is connected to A.

[0185] In some implementations, L 3 yes:

[0186] ,

[0187] The left side is connected to A.

[0188] In some implementations, L 3 Optionally substituted, wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, L 3 It is in an optionally substituted form, wherein 1-3 hydrogen atoms are optionally substituted. In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (preferably fluorine). In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, optionally substituted C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, halogens. In some embodiments, the substituents include fluorine.

[0189] In some embodiments, B is an optionally substituted 6-10-membered aryl group. In some embodiments, B is an optionally substituted 5-15-membered heteroaryl group. In some embodiments, B is an optionally substituted 4-15-membered heterocyclic group. In some embodiments, B is an optionally substituted 3-15-membered cycloalkyl group. In some embodiments, if B is a 3-15-membered cycloalkyl group, then B is at least a 4-membered cycloalkyl group. In some embodiments, if B is a 3-15-membered cycloalkyl group, then B is a 5-10-membered cycloalkyl group.

[0190] In some implementations, B is selected from:

[0191] ,

[0192] in

[0193] Each R 6 Independently hydrogen, optionally substituted C1-C6 alkoxy or halogen;

[0194] Each R 7Independently, it is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C 10 Heteroaryl, optionally substituted C3-C 10 Heterocyclic group, or optionally substituted C6-C 10 Aryl (e.g., optionally substituted phenyl); or

[0195] R 6 and R 7 Together with the atoms they are attached to, they form optionally substituted 5-7 membered rings; or 2 Rs 6 The groups, together with the atoms they are attached to, form optionally substituted 5-7 membered rings;

[0196] Each R 61 and R 62 Independently N or CH, provided R 61 and R 62 At least one of them is N,

[0197] Each R 63 Independent for NR 90 S or O;

[0198] Each R 64 Independently N or CH; and

[0199] Each R 90 Independently hydrogen or R 7 ,

[0200] Furthermore, one or more hydrogen atoms on the 5- and 6-membered aromatic rings or heteroaromatic rings shown above may be optionally substituted.

[0201] In some implementations, B is:

[0202] .

[0203] In some implementations, B is:

[0204] .

[0205] In some implementations, B is:

[0206] .

[0207] In some implementations, B is:

[0208] .

[0209] In some implementations, B is:

[0210] .

[0211] In some implementations, B is:

[0212] .

[0213] In some implementations, B is:

[0214] .

[0215] In some implementations, B is:

[0216] .

[0217] In some implementations, B is:

[0218] .

[0219] In some implementations, B is:

[0220] .

[0221] In some implementations, B is:

[0222] .

[0223] In some implementations, B is:

[0224] .

[0225] In some implementations, R 6 It is hydrogen. In some implementations, R 6 It is an optionally substituted C1-C6 alkoxy group. In some embodiments, R 6 It is halogen.

[0226] In some implementations, R 7 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 7 It is an optionally substituted C2-C6 alkenyl group. In some embodiments, R 7 It is an optionally substituted C2-C6 ynyl group. In some embodiments, R 7 It is an optionally substituted C3-C8 cycloalkyl group. In some embodiments, R 7 It is an optional substitution of C3-C 10 heteroaryl. In some embodiments, R 7 It is an optional substitution of C3-C 10 Heterocyclic group. In some embodiments, R 7 It is an optional substitution of C6-C 10Aryl. In some embodiments, optionally substituted C6-C 10 The aryl group is an optional substituted phenyl group.

[0227] In some implementations, R 6 and R 7 Together with the atoms they are attached to, they form optionally substituted 5-7 membered rings. In some embodiments, 2 R... 6 The groups, together with the atoms they are attached to, form optionally substituted 5-7 membered rings.

[0228] In some implementations, R 61 and R 62 One of them is N. In some implementations, R 61 and R 62 All are N.

[0229] In some implementations, R 63 It is NR 90 In some implementations, R 63 It is S. In some implementations, R 63 It is O.

[0230] In some implementations, R 64 It is N. In some implementations, R 64 It is CH.

[0231] In some implementations, R 90 It is hydrogen. In some implementations, R 90 It is R 7 .

[0232] In some implementations, B is

[0233] ,

[0234] in

[0235] Each R 1 -R 3 Independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted 4-15 membered heterocyclic group, or -OR 20 , or if R 1 -R 3 If two of the substituents are on adjacent carbon atoms, then these two substituents together with the atoms they are attached to form an optional substituted 5-7 membered ring;

[0236] R 20 It is (CH2) w -R 21 Optionally substituted C3-C6 cycloalkyl groups, Optionally substituted C1-C6 alkyl groups;

[0237] R 21 It is an optional substitution of C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 5-15-membered heteroaryl, optionally substituted 4-15-membered heterocyclic, or

[0238] ,

[0239] Each R 22 -R 24 Independently, it can be an optionally substituted C1-C3 alkyl or hydroxyl group or R. 22 -R 24 The two atoms in the ring, together with the carbon atoms they are attached to, form 3-7 membered (preferably 3-5 membered) or 5-7 membered rings; and

[0240] w is 1, 2, 3, 4 or 5.

[0241] In some implementations, R 1 It is H. In some implementations, R 1 It is a halogen. In some embodiments, R 1 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 1 It is H. In some implementations, R 1 It is an optionally substituted 4-15 member heterocyclic group. In some embodiments, R 1 Yes - OR 20 .

[0242] In some implementations, R 2 It is H. In some implementations, R 2 It is a halogen. In some embodiments, R 2 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 2 It is H. In some implementations, R 2 It is an optionally substituted 4-15 member heterocyclic group. In some embodiments, R 2 Yes - OR 20 .

[0243] In some implementations, R 3 It is H. In some implementations, R 3 It is a halogen. In some embodiments, R 3 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 It is H. In some implementations, R 3It is an optionally substituted 4-15 member heterocyclic group. In some embodiments, R 3 Yes - OR 20 .

[0244] In some implementations, if R 1 –R 3 If two of the substituents are located on adjacent carbon atoms, then these two substituents together with the carbon atoms they are attached to form an optionally substituted 5-7 membered ring.

[0245] In some implementations, R 20 It is (CH2) w -R 21 In some implementations, R 20 It is an optionally substituted C3-C6 cycloalkyl group. In some embodiments, R 20 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 20 It is a C1-C6 alkyl group. In some embodiments, R 20 It is a C1-C6 alkyl group substituted with 1-3 fluorine atoms. In some embodiments, R 20 It is a C1-C6 alkyl group substituted with 1-2 (preferably a single) hydroxyl groups.

[0246] In some implementations, w is 1. In some implementations, w is 2. In some implementations, w is 3. In some implementations, w is 4. In some implementations, w is 5.

[0247] In some implementations, R 21 It is a C3-C6 cycloalkyl group. In some embodiments, R 21 It is a C3-C6 cycloalkyl group substituted with 1-3 (preferably 1-2) substituents. In some embodiments, R 21 It is cyclopropyl. In some embodiments, R 21 It is a cyclopropyl group substituted with 1-3 (preferably 1-2) substituents. In some embodiments, R 21 It is cyclobutyl. In some embodiments, R 21 It is a cyclobutyl group substituted with 1-3 (preferably 1-2) substituents. In some embodiments, R 21 It is cyclopentyl. In some embodiments, R 21 It is a cyclopentyl group substituted with 1-3 (preferably 1-2) substituents. In some embodiments, R 21 It is an optional substitution of C1-C 10 Alkyl group. In some embodiments, R 21 It is an optional substitution of C2-C 10 Alkenyl. In some embodiments, R 21It is an optional substitution of C2-C 10 Alkyne group. In some embodiments, R 21 It is an optional substituted 4-15 member heterocyclic group.

[0248] In some implementations, R 21 yes

[0249] .

[0250] In some implementations, R 22 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 22 It is a hydroxyl group. In some embodiments, R 22 It is H.

[0251] In some implementations, R 23 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 23 It is a hydroxyl group.

[0252] In some implementations, R 24 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 24 It is a hydroxyl group.

[0253] In some implementations, R 22 -R 24 The two atoms in R, together with the carbon atoms they are attached to, form 3-7 membered rings. In some embodiments, R 22 -R 24 The two atoms in the ring, together with the carbon atoms they are attached to, form a 5-7 membered ring. In some embodiments, the ring is an optionally substituted cycloalkyl group. In some embodiments, the ring is an optionally substituted heteroalkyl group.

[0254] In some implementations, B is

[0255]

[0256] in

[0257] R 1 R 2 and R 3 As defined above, or

[0258] R 1 and R 2 Together with the atoms they are attached to, they form optionally substituted 5-7 membered rings; or

[0259] R 2 and R 3 Together with the atoms they are attached to, they form 5-7 membered rings with optional substitution.

[0260] In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form optionally substituted 5-7 membered rings. In some embodiments, R 2 and R 3 Together with the atoms they are attached to, they form 5-7 membered rings with optional substitution.

[0261] In some implementations, R 1 It is H.

[0262] In some implementations, R 2 It is F. In some implementations, R 2 It is H.

[0263] In some implementations, R 3 It is H. In some implementations, R 3 Yes - OR 20 , where R 20 As defined above.

[0264] In some implementations, B is:

[0265]

[0266] Where R 20 As defined above.

[0267] In some embodiments, this document provides a compound wherein A is

[0268] ;

[0269] Y 1 It is an H or C1-C3 alkyl group;

[0270] L 1 It is an optional substitution of C3-C 10 Alkylene, wherein at least two twin hydrogens are optionally substituted with cyclopropane or cyclobutane; optionally substituted C3-C 10 alkenyl, optionally substituted C3-C 10 Heteroalkylene, optionally substituted C3-C 10 Heteroeneyl or -L 11 -L 12 -L 13 -, where L 11 Connect to A and L 11 It is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C3 heteroalkenylene, L 12 It is arylene or heteroarylene, L 13It is a C1-C5 alkylene group that is bonded or optionally substituted, and R is H or a C1-C3 alkyl group;

[0271] L 2 It is –S(O)2NH-, where sulfur is attached to L 1 Or –NHS(O)2-, where nitrogen is attached to L 1 ;

[0272] L 3 It is a C1-C6 alkylene group with a bond or optional substitution;

[0273] B is

[0274] ;

[0275] Each R 1 -R 3 Independently H, F, Cl, C1-C3 alkyl or -OR 20 ;or

[0276] R 1 and R 2 Together with the atoms they are attached to, they form optionally substituted 5-7 membered rings; or

[0277] R 2 and R 3 Together with the atoms they are attached to, they form arbitrarily substituted 5-7 membered rings;

[0278] R 20 It is CH2-R 21 ; methyl groups optionally substituted with 2 or 3 fluorine atoms; C3-C6 cycloalkyl; or C1-C6 alkyl;

[0279] R 21 It is an optionally substituted C3-C6 cycloalkyl group; an optionally substituted C6-C 10 aryl; optionally substituted 5-15 membered heteroaryl; optionally substituted 4-15 membered heterocyclic; C1-C 10 Alkyl groups, preferably branched C3-C groups optionally substituted with one or more hydroxyl groups or fluorine. 10 Alkyl; C3-C6 cycloalkyl; or

[0280] ,

[0281] Each R 22 -R 24 Independently, it is an optionally substituted C1-C3 alkyl or hydroxyl group; or

[0282] R 22 -R 24 The two atoms in the ring, together with the atoms they are attached to, form optional substituted 3-7 membered rings.

[0283] In some implementations, Y 1 It is H. In some implementations, Y 1 It is a C1-C3 alkyl group.

[0284] In some implementations, L 1 It is an optional substitution of C3-C 10 Alkylene, wherein at least two twin hydrogens are optionally substituted with cyclopropane or cyclobutane. In some embodiments, L 1 It is an optional substitution of C3-C 10 Alkenyl group. In some embodiments, L 1 It is an optional substitution of C3-C 10 Heteroalkylene compounds. In some embodiments, L 1 It is an optional substitution of C3-C 10 Heteroene group.

[0285] In some implementations, L 1 Yes -L 11 -L 12 -L 13 -, where L 11 Connected to A. In some implementations, L 11 It is O. In some implementations, L 11 It is S. In some implementations, L 11 It is a C1-C2 alkylene group. In some embodiments, L 11 It is a C2-olefinic group. In some embodiments, L 11 It is a C2 heteroalkylene group. In some embodiments, L 11 It is a C3 heteroene group.

[0286] In some implementations, L 11 It is NR. In some embodiments, R is H. In some embodiments, R is a C1-C3 alkyl group.

[0287] In some implementations, L 12 It is a aryl group. In some embodiments, L 12 It is a heteroarylene.

[0288] In some implementations, L 13 It is a key. In some implementations, L 13 It is an optional substituted C1-C6 alkylene group.

[0289] In some implementations, R 1 It is H. In some implementations, R 1 It is F. In some implementations, R 1It is Cl. In some implementations, R 1 It is a C1-C3 alkyl group. In some embodiments, R 1 Yes - OR 20 .

[0290] In some implementations, R 2 It is H. In some implementations, R 2 It is F. In some implementations, R 2 It is Cl. In some implementations, R 2 It is a C1-C3 alkyl group. In some embodiments, R 2 Yes - OR 20 .

[0291] In some implementations, R 3 It is H. In some implementations, R 3 It is F. In some implementations, R 3 It is Cl. In some implementations, R 3 It is a C1-C3 alkyl group. In some embodiments, R 3 Yes - OR 20 .

[0292] In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form optionally substituted 5-7 membered rings. In some embodiments, R 2 and R 3 Together with the atoms they are attached to, they form 5-7 membered rings with optional substitution.

[0293] In some implementations, R 20 It is CH2-R 21 In some implementations, R 20 It is a methyl group optionally substituted with 2 or 3 fluorine atoms. In some embodiments, R 20 It is a C3-C6 cycloalkyl group. In some embodiments, R 20 It is a C1-C6 alkyl group.

[0294] In some implementations, R 21 It is C1-C 10 Alkyl group. In some embodiments, R 21 It is a branched C3-C structure optionally substituted with one or more hydroxyl groups or fluorine. 10 Alkyl group. In some embodiments, R 21 It is a C3-C6 cycloalkyl group.

[0295] In some implementations, R 21 yes

[0296] .

[0297] In some implementations, R 22 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 22 It is a hydroxyl group.

[0298] In some implementations, R 23 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 23 It is a hydroxyl group.

[0299] In some implementations, R 24 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 24 It is a hydroxyl group.

[0300] In some implementations, R 22 -R 24 The two atoms in the ring, together with the atoms they are attached to, form optional substituted 5-7 membered rings.

[0301] In some implementations, B is selected from:

[0302]

[0303] .

[0304] In some embodiments, the alkoxy group is further substituted, wherein 1-5 (preferably 1-3) hydrogen atoms are substituted. Preferred substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (e.g., fluorine) and / or C1-C6 alkoxy groups; optionally substituted C1-C6 alkoxy groups; and halogens, preferably fluorine. In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (e.g., fluorine). In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, substituted C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, one or more halogens. In some embodiments, the substituents include one or more fluorines. In some embodiments, the ring moiety (e.g., cyclopropyl) is further substituted with 1-3 halogens (preferably 1-2 halogens). In some embodiments, the ring moiety (e.g., cyclopropyl) is further substituted with 1-2 halogens. In some embodiments, the methylene group between the oxygen atom and the ring moiety (e.g., cyclopropyl) is separated by 1-2 carbon atoms. 1- C6 alkyl (preferably methyl, ethyl, or propyl) substitution. In some embodiments, the methylene group is substituted with a methyl group. In some embodiments, the methylene group is substituted with an ethyl group. In some embodiments, the methylene group is substituted with a propyl group. In some embodiments, R...70 It is an optional substitution of C1-C 10 alkyl.

[0305] In some embodiments, the alkoxy group is optionally further substituted, wherein 1-5 hydrogen atoms are optionally substituted. In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with 1-3 halogens (e.g., fluorine). In some embodiments, the substituents include, but are not limited to, C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, substituted C1-C6 alkoxy groups. In some embodiments, the substituents include, but are not limited to, halogens. In some embodiments, the substituents include fluorine.

[0306] In some embodiments, the ring moiety (e.g., cyclopropyl) is optionally substituted with 1-3 halogens. In some embodiments, the ring moiety (e.g., cyclopropyl) is optionally substituted with 1-2 halogens.

[0307] In some embodiments, the methylene group between the oxygen atom and the ring moiety (e.g., cyclopropyl) is separated by 1-2 carbon atoms. 1- The C6 alkyl group is optionally substituted. In some embodiments, the methylene group is substituted with a methyl group. In some embodiments, the methylene group is substituted with an ethyl group. In some embodiments, the methylene group is substituted with a propyl group.

[0308] In some implementations, B is:

[0309] .

[0310] In some embodiments, compounds of formula (I) are provided herein:

[0311]

[0312] Or its tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein:

[0313] A is:

[0314] ;

[0315] Y 1 It is an H or C1-C3 alkyl group;

[0316] L 1 It is an optional substitution of C3-C 10 Alkylene, wherein at least two twin hydrogens are optionally substituted with cyclopropane or cyclobutane; optionally substituted C3-C 10 alkenyl, optionally substituted C3-C 10 Heteroalkylene, optionally substituted C3-C10 Heteroeneyl or -L 11 -L 12 -L 13 -; where connected to A and L 11 It is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C3 heteroalkenylene, L 12 It is arylene or heteroarylene, L 13 It is a C1-C5 alkylene group with a bond or optional substitution; and R is H or a C1-C3 alkyl group;

[0317] L 2 It is –S(O)2NH-, where sulfur is attached to L 1 Or –NHS(O)2-, where nitrogen is attached to L 1 ;

[0318] L 3 It is a C1-C6 alkylene group with bond or optional substitution, preferably

[0319] ,

[0320] More preferably:

[0321] ;

[0322] B is:

[0323] ;

[0324] Each R 1 -R 3 Independently H, F, Cl, C1-C3 alkyl or -OR 20 ;

[0325] R 20 It is CH2-R 21 ; methyl groups optionally substituted with 2 or 3 fluorine atoms; C3-C6 cycloalkyl; or C1-C6 alkyl;

[0326] R 21 It is an optionally substituted C3-C6 cycloalkyl group; an optionally substituted C6-C 10 aryl; optionally substituted 5-15 membered heteroaryl; optionally substituted 4-15 membered heterocyclic; C1-C 10 Alkyl groups, preferably branched C3-C groups optionally substituted with one or more hydroxyl groups or fluorine. 10 Alkyl (more preferably isopropyl or tert-butyl); C3-C6 cycloalkyl, preferably cyclopropyl, cyclobutyl or cyclophenyl; or

[0327] ,

[0328] Where R22 -R 24 Each is independently a optionally substituted C1-C3 alkyl or hydroxyl group, or

[0329] R 22 -R 24 The two atoms in the ring, together with the carbon atoms they are attached to, form 3-7 membered rings.

[0330] In some embodiments, the compound of formula (I) is not

[0331] .

[0332] This disclosure also provides tautomers of the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0333] This disclosure also provides stereochemically pure enantiomers, tautomers, diastereomers, or pharmaceutically acceptable salts thereof of the compounds described herein. Methods for purifying and identifying pure enantiomers are known in the art and are described herein.

[0334] On the other hand, this document provides compositions comprising one or more of the above-described compounds and a carrier. In one embodiment, the composition is a pharmaceutical composition and therefore also comprises at least one pharmaceutically acceptable carrier or pharmaceutically acceptable excipient. The composition is formulated for various modes of delivery, such as systemic (oral) or local delivery.

[0335] On the other hand, this disclosure provides compositions comprising one or more of the compounds provided herein and a chemotherapeutic agent targeting dUTPase and a carrier (such as a pharmaceutically acceptable carrier). The compounds and chemotherapeutic agents may be in different amounts, and in one respect, when used in combination, each effective amount provides the therapeutic benefit as described herein. The compositions are formulated for various delivery modalities, such as systemic (oral) or local delivery.

[0336] On the one hand, this article provides compositions comprising the compounds provided herein and at least one pharmaceutically acceptable excipient or carrier.

[0337] On the other hand, this document provides a method for inhibiting deoxyuridine triphosphatase (dUTPase), comprising contacting dUTPase with a therapeutically effective amount of a compound or composition provided herein. On the other hand, the method further comprises contacting the dUTPase alone or in combination with a compound provided herein with dUTPase-targeted chemotherapy. Contact can be performed in vitro, in vivo, simultaneously, or concurrently. On the other hand, chemotherapy targeting dUTPase is applied prior to the compound or composition described herein. On the other hand, chemotherapy targeting dUTPase is applied after the compound or composition. In yet another aspect, the compound or composition and chemotherapy targeting dUTPase are administered sequentially over several rounds of treatment. Contact can be performed simultaneously or concurrently and / or in vitro (cell-free), ex vivo, or in vivo. In a further aspect, the compound or composition of this disclosure is given to a patient identified or selected for treatment by determining that the patient has a tumor or mass that overexpresses dUTPase. Methods for identifying such patients are known in the art and are incorporated herein. When applied to subjects such as human patients, the method can be first-line, second-line, third-line, fourth-line, or further treatment.

[0338] This document also provides a method for reversing resistance to chemotherapy against dUTPase, comprising contacting cells overexpressing dUTPase with a therapeutically effective amount of a compound or composition provided herein, either alone or in combination with a chemotherapy treatment targeting dUTPase. In one aspect, cells are first identified as overexpressing dUTPase through screening as disclosed in U.S. Patent No. 5,962,246. In another aspect, the method further comprises subsequently contacting the dUTPase-expressing cells with a chemotherapy treatment targeting dUTPase. This method can be administered as a second-line, third-line, fourth-line, or further therapy.

[0339] This article also provides methods for enhancing the efficacy of chemotherapy against dUTPase, comprising contacting cells (e.g., cells overexpressing dUTPase in one aspect) with a therapeutically effective amount of a compound or composition provided herein. Alternatively, the method further comprises contacting the cells with a chemotherapy therapy against dUTPase. Contact can be simultaneous or concurrent and / or in vitro (cell-free), ex vivo, or in vivo. Alternatively, the chemotherapy therapy against dUTPase may be contacted prior to, or vice versa, the compound or composition described herein. When administered to subjects such as human patients, the method can be a first-line, second-line, third-line, fourth-line, or further treatment.

[0340] On the other hand, this document provides a method for treating diseases associated with the dUTPase pathway (e.g., cancer, viral infection, bacterial infection, or autoimmune disease), comprising administering a therapeutically effective amount of the compound or composition provided herein to a patient requiring such treatment, and administering an agent suitable for treating the disease, thereby treating the disease. The administration of the compound of the invention and the agent suitable for the disease (e.g., a dUTPase inhibitor) may be simultaneous or concurrent and / or administered in vitro (cell-free), ex vivo, or in vivo. Alternatively, the agent suitable for treating the disease may be administered prior to the administration of the compound or composition described herein, and vice versa. In one aspect, patients for treatment are selected by screening for overexpression of dUTPase in cell or tissue samples isolated from the patient. Treatment is then administered to the selected patient after screening and treatment of the selected patient.

[0341] On the other hand, this article provides a method for inhibiting cancer cell growth, which includes contacting cells with a therapeutically effective amount of the compound or composition disclosed herein and an effective amount of a therapeutic agent targeting dUTPase, thereby inhibiting cancer cell growth.

[0342] On the other hand, this document provides kits containing compounds or compositions provided herein. The kits may further contain one or more dUTPase inhibitors (e.g., antitumor agents) and instructions for administering the reagent. The kits also include reagents and instructions for screening dUTPase expression.

[0343] In each of the above embodiments, non-limiting examples of chemotherapy against dUTPase include TS inhibitors, such as 5-FU or 5-FU-containing therapies, such as adjuvant therapies based on 5-FU and its chemical equivalents.

[0344] On the one hand, this article provides one or more methods for inhibiting dUTPase or enhancing the therapeutic efficacy against dUTPase, including contacting dUTPase with a therapeutically effective amount of the compound or composition provided herein.

[0345] In one aspect, this article provides a method for reversing resistance to therapies against dUTPase, the method comprising contacting dUTPase with a therapeutically effective amount of a compound or composition provided herein.

[0346] In one aspect, this article provides methods for treating diseases whose treatment is impaired by the expression or overexpression of dUTPase, including administering a therapeutically effective amount of the compounds or compositions provided herein to a patient in need of such treatment.

[0347] On the one hand, this article provides a method for inhibiting cancer cell growth, which includes contacting cells with a therapeutically effective amount of the compound or composition provided herein and a therapeutically effective amount of a therapeutic agent targeting dUTPase, thereby inhibiting cancer cell growth.

[0348] In some implementations, the cancer cells are selected from colon cancer cells, colorectal cancer cells, gastric cancer cells, head and neck cancer cells, breast cancer cells, lung cancer cells, or blood cells.

[0349] In one aspect, this article provides a method for treating a patient whose treatment is impeded by the expression or overexpression of dUTPase, the method comprising: a) screening cell or tissue samples from the patient; b) determining the expression level of dUTPase in the samples; and c) administering a therapeutically effective amount of the compound or composition provided herein to a patient whose samples show overexpression of dUTPase.

[0350] In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from colon cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, breast cancer, lung cancer, stomach cancer, liver cancer, gallbladder cancer, pancreatic cancer, or leukemia.

[0351] On the one hand, this document provides kits containing the compounds or compositions provided herein, as well as instructions for use in diagnostic or therapeutic methods as described herein. Invention Details

[0352] definition

[0353] Throughout this disclosure, various publications, patents, and published patent specifications are referenced by way of identification. The disclosures of these publications, patents, and published patent specifications are incorporated herein by reference in their entirety to provide a more comprehensive description of the state of the art to which this invention pertains.

[0354] Unless otherwise stated, the practice of this technique will employ conventional techniques within the scope of the art, including those in organic chemistry, pharmacology, immunology, molecular biology, microbiology, cell biology, and recombinant DNA. See, for example, Sambrook, Fritsch and Maniatis, Molecular Cloning: A Laboratory Manual, 2 ndedition (1989); Current Protocols In Molecular Biology (FM Ausubel, et al. eds., (1987)); the series Methods in Enzymology (Academic Press, Inc.): PCR2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, a Laboratory Manual, andAnimal Cell Culture (RI Freshney, ed. (1987)).

[0355] As used in the specification and claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include the plural forms. For example, the term “a cell” includes a plurality of cells, including mixtures thereof.

[0356] As used herein, the term "comprising" is intended to indicate that a compound, composition, or method includes the listed elements but does not exclude others. When used to define compounds, compositions, and methods, "consisting essentially of" should mean excluding other elements that are of any significance to the composition. Therefore, a composition consisting essentially of the elements defined herein does not exclude trace contaminants, such as contaminants from separation and purification methods, as well as pharmaceutically acceptable carriers, preservatives, etc. "Containing" means excluding other components beyond trace elements. Examples defined by each of these converted terms are within the scope of this technology.

[0357] All numerical names (e.g., pH, temperature, time, concentration, and molecular weight (including range)) are approximate values, varying in increments of 1%, 5%, or 10% (+) or (-). It should be understood that, although not always explicitly stated, all numerical names are preceded by the term "about". Although not always explicitly stated, it should be understood that the reagents described herein are merely exemplary, and such equivalents are known in the art.

[0358] "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms (preferably 1 to 6 carbon atoms). As examples, the term includes straight-chain and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3CH2CH2CH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0359] "Alkenyl" refers to a monovalent straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms or more preferably 2 to 4 carbon atoms) and at least one (preferably 1 to 2) vinyl (>C=C<) unsaturated site. These groups are, for example, vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

[0360] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms or more preferably 2 to 3 carbon atoms) and at least one (preferably 1 to 2) alkynyl (C≡C) unsaturated site. Examples of such alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH).

[0361] "Substituted alkyl" refers to an alkyl group having 1 to 5 (preferably 1 to 3, or more preferably 1 to 2) substituents selected from the following groups: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, etc. The substituents are substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0362] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms are substituted, with substituents being -O-, -S-, SO2, or, as provided in this article, the P-containing moiety, -NRQ-, etc.

[0363]

[0364] Part, of which R Q It is an H or C1-C6 alkyl group. A substituted heteroalkyl group refers to a heteroalkyl group having 1-5 (preferably 1-3, more preferably 1-2) substituents, wherein the substituents are selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, etc. The substituents are substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0365] "Substituted alkenyl" refers to an alkenyl group having 1-3 substituents (preferably 1-2 substituents), wherein the substituents are selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, substituted cycloalkyl... Alkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein, provided that any hydroxyl or thio substituent is not attached to a vinyl (unsaturated) carbon atom.

[0366] "Heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms are substituted, with substituents being -O-, -S-, SO2, or, as provided in this article, the P-containing moiety, -NRQ-, etc.

[0367]

[0368] Part, of which R QIt is an H or C1-C6 alkyl group. A substituted heteroalkenyl group refers to a heteroalkenyl group having 1-5 (preferably 1-3, more preferably 1-2) substituents, wherein the substituents are selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, etc. The substituents are substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0369] "Substituted alkynyl" refers to an alkynyl group having 1 to 3 substituents (preferably 1 to 2 substituents), wherein the substituents are selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, etc. The following groups are included: substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein, provided that any hydroxyl or thio substituent is not attached to an alkyne carbon atom.

[0370] "Heteroyynyl" refers to an ynyl group in which one or more carbon atoms are substituted, with substituents being -O-, -S-, SO2, or, as provided in this article, the P-containing moiety, -NRQ-, etc.

[0371]

[0372] Part, of which R Q It is an H or C1-C6 alkyl group. A substituted xyrynyl group refers to a xyrynyl group having 1-5 (preferably 1-3, more preferably 1-2) substituents, wherein the substituents are selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, etc. The substituents are substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0373] "alkylene" refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms (preferably 1 to 6, more preferably 1 to 3 carbon atoms). Examples of this term include, for example, the following groups: methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)- or -CH(CH3)CH2-), butylene (-CH2CH2CH2CH2-), isobutylene (-CH2CH(CH3)CH2-), isosec-butylene (-CH2CH2(CH3)CH-), etc. Similarly, "alkenylene" and "ynylene" refer to alkylene moieties containing 1 or 2 carbon-carbon double or triple bonds, respectively.

[0374] "Substituted alkylene" refers to an alkylene in which one to three hydrogen atoms are substituted by a substituent selected from alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxy, wherein the substituent is as defined herein. In some embodiments, the alkylene has one to two of the above groups, or one to three carbon atoms thereof are substituted with –O-, –S-, or –NR. Q- Partial replacement, where R Q It is an H or C1-C6 alkyl group. Note that when an alkylene group is substituted with an oxygen group, the two hydrogens on the same carbon atom attached to the alkylene group are replaced with "=O". "Substituted alkenyl" and "substituted ynyl" refer to the alkenyl and ynyl moieties substituted with substituents as described above regarding substituted alkylene groups.

[0375] "Immyneyl" refers to a straight-chain or branched divalent hydrocarbon group having 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms or more preferably 2 to 3 carbon atoms) and at least one (preferably at least 1 to 2) alkynyl unsaturation site (-C≡C-). Examples of such imyneyl groups include -C≡C- and -CH2C≡C-.

[0376] "Substituted alkyneylyl group" refers to an alkyneylyl group having 1 to 3 substituents (preferably 1 to 2 substituents), wherein the substituents are selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio Substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein, provided that any hydroxyl or thio substituent is not attached to an alkyne carbon atom.

[0377] "Heteroalkylene" refers to an alkylene group in which one or more carbon atoms are substituted, with substituents being -O-, -S-, SO2, or, as provided in this article, the P-containing moiety, -NRQ-, etc.

[0378]

[0379] Part, of which R Q It is an H or C1-C6 alkyl group. "Substituted heteroalkylene" refers to a heteroalkylene group having 1 to 3 substituents (preferably 1 to 2 substituents) selected from the substituents disclosed with respect to substituted heteroalkylene groups.

[0380] "Heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms are substituted, with substituents being -O-, -S-, SO2, or, as provided in this article, the P-containing moiety, -NRQ-, etc.

[0381]

[0382] Part, of which R Q It is an H or C1-C6 alkyl group. "Substituted heteroene group" refers to a heteroene group having 1 to 3 substituents (preferably 1 to 2 substituents) selected from the substituents disclosed with respect to substituted heteroene groups.

[0383] "Heteroyynyl" refers to an ynoyynyl group in which one or more carbon atoms are substituted, with substituents being -O-, -S-, SO2, or, as provided in this article, the P-containing moiety, -NRQ-, etc.

[0384]

[0385] Part, of which R Q It is an H or C1-C6 alkyl group. "Substituted heteroynyl" refers to a heteroynyl group having 1 to 3 substituents (preferably 1 to 2 substituents), the substituents being selected from those disclosed with respect to substituted heteroynyl.

[0386] "Alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined herein. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

[0387] "Substituted alkoxy" refers to an -O- (substituted alkyl) group, wherein the substituted alkyl group is as defined herein.

[0388] "Acyl" refers to the following groups: HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl -C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl groups include "acetyl" CH3C(O)-.

[0389] "Acylamino" refers to the group -NR 47 C(O)alkyl, -NR47 C(O) substituted alkyl groups, -NR 47 C(O)cycloalkyl, -NR 47 C(O) substituted cycloalkyl groups, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47 C(O) alkenyl, -NR 47 C(O)-substituted alkenyl groups, -NR 47 C(O) ynyl group, -NR 47 C(O) substituted alkynyl groups, -NR 47 C(O)aryl, -NR 47 C(O)-substituted aryl, -NR 47 C(O) heteroaryl, -NR 47 C(O)-substituted heteroaryl, -NR 47 C(O) heterocyclic group and -NR 47 C(O)-substituted heterocyclic groups, where R 47 It is hydrogen or alkyl, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic as defined herein.

[0390] "Acyloxy group" refers to the following groups: alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-. )O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O- and substituted heterocyclic-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0391] Animals, subjects, or patients used for diagnosis or treatment refer to animals such as mammals or humans, sheep, cattle, felines, canines, equines, apes, etc. Non-human animals used for diagnosis or treatment include, for example, apes, rodents (e.g., rats, mice), canines, rabbits, livestock, livestock, and pets.

[0392] "Amino" refers to the -NH2 group.

[0393] "Substituted amino" refers to the -NR group. 48 R 49 , where R 48 and R 49 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO2-alkyl, -SO2-substituted amino, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic and -SO2-substituted heterocyclic, and wherein R 48 and R 49 Optionally linked to the bound nitrogen to form a heterocyclic group or a substituted heterocyclic group, provided that R 48 and R 49 None of them are hydrogen, and they include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic as defined herein. When R 48 It is hydrogen and R 49 When it is an alkyl group, the substituted amino group is sometimes referred to as an alkylamino group in this text. When R... 48 and R 49 When both are alkyl groups, the substituted amino group is sometimes referred to as a dialkylamino group in this text. When referring to a monosubstituted amino group, it means R... 48 Or R 49 It contains hydrogen, but not all of it is hydrogen. When referring to disubstituted amino groups, it means R... 48 and R 49 Neither of them are hydrogen.

[0394] "Amino carbonyl" refers to the group -C(O)NR 50 R 51 , where R 50 and R 51 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0395] "Aminothiocarbonyl" refers to the group -C(S)NR 50 R 51 , where R 50 and R 51 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0396] "Amino carbonyl amino" refers to the group -NR 47 C(O)NR 50 R 51 , where R 47 It is hydrogen or alkyl, and R 50 and R 51 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0397] "alkylthiocarbonylamino" refers to the group -NR 47 C(S)NR 50 R 51 , where R 47 It is hydrogen or alkyl, and R 50 and R 51Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0398] "Aminocarbonyloxy group" refers to the group -OC(O)NR 50 R 51 , where R 50 and R 51 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0399] "Aminosulfonyl" refers to the group -SO2NR 50 R 51 , where R 50 and R 51 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0400] "Aminosulfonyloxy" refers to the group -O-SO2NR. 50 R 51 , where R50 and R 51 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0401] "Aminosulfonylamino" refers to the group -NR 47 SO2NR 50 R 51 , where R 47 It is hydrogen or alkyl, and R 50 and R 51 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51 Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0402] "Amino group" refers to the group -C (=NR) 52 )NR 50 R 51 , where R 50 R 51 and R 52 Independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein R 50 and R 51Optionally linked with the nitrogen to form a heterocyclic group or a substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic groups are as defined herein.

[0403] "Ar" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms and a single ring (such as phenyl) or multiple fused rings (such as naphthyl or anthracene), wherein the fused rings may or may not be aromatic (such as 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl), provided that the bonding point is located on an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0404] "Substituted aryl" refers to an aryl group having 1 to 5 (preferably 1 to 3, or more preferably 1 to 2) substituents, wherein the substituents are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, etc. The following are substituents: substituted cycloalkyl, cycloalkyloxy, substituted cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0405] "Arylidene" refers to a divalent aromatic carbocyclic group having 6 to 14 carbon atoms having a monocyclic or multiple fused rings. "Substituted arylidene" refers to an arylidene having 1 to 5 (preferably 1 to 3, or more preferably 1 to 2) substituents as defined with respect to aryl groups.

[0406] "Heteroarylene" refers to a divalent aromatic compound having 1 to 10 carbon atoms and 1 to 4 heteroatoms in the ring, the heteroatoms being selected from oxygen, nitrogen, and sulfur. "Substituted heteroarylene" refers to a heteroarylene substituted with 1 to 5 (preferably 1 to 3, or more preferably 1 to 2) substituents selected from the same substituents as defined above with respect to substituted aryl groups.

[0407] "Aryloxy group" refers to the group -O-aryl, where aryl is as defined herein, including, for example, phenoxy and naphthoxy.

[0408] "Substituted aryloxy group" refers to the group -O- (substituted aryl group), wherein the substituted aryl group is as defined herein.

[0409] "Arylthio" refers to the group -S-aryl, where aryl is as defined in this article.

[0410] "Substituted aryl thio" refers to the group -S- (substituted thio), where the substituted aryl group is as defined herein.

[0411] "Carbonyl" refers to the divalent group -C(O)-, which is equivalent to -C(=O)-.

[0412] "Carboxyl group" refers to -COOH or its salt.

[0413] "Carboxylate" refers to groups such as -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)(O)-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-ynyl, -C(O)(O)-substituted ynyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, - C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic and -C(O)(O)-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0414] "(Carboxylate)amino" refers to the following groups: -NR47C(O)(O)-amino, -NR47C(O)(O)-substituted amino, -NR47C(O)(O)-alkenyl, -NR47C(O)(O)-substituted alkenyl, -NR47C(O)(O)-ynyl, -NR47C(O)(O)-substituted ynyl, -NR47C(O)(O)-aryl, -NR47C(O)(O)-substituted aryl, -NR47C(O)(O)-cycloalkyl, -NR47C(O)(O)-substituted cycloalkyl, -NR47C(O)(O)-... - cycloalkenyl, -NR47C(O)(O)-substituted cycloalkenyl, -NR47C(O)(O)-heteroaryl, -NR47C(O)(O)-substituted heteroaryl, -NR47C(O)(O)-heterocyclic and -NR47C(O)(O)-substituted heterocyclic, wherein R47 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0415] "(Carboxyl ester)oxy group" refers to the following groups: -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-ynyl, -OC(O)O-substituted alkenyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -O C(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0416] As used herein, “composition” refers to an active agent (such as the compounds disclosed herein) and a support (inert or active). The support may be, but is not limited to, a solid (such as beads or resin) or a liquid (such as phosphate-buffered saline).

[0417] "Combined" administration or treatment refers to the administration of two agents so that their effects are simultaneously manifested. While combination may include simultaneous or substantially simultaneous administration, it is not mandatory.

[0418] "Cyano" refers to the group -CN.

[0419] "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms and one or more rings (including fused rings, bridged rings, and spiro rings). The fused ring can be an aromatic ring, provided that the non-aryl portion is attached to the rest of the molecule. Suitable examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0420] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group having one or more rings and at least one >C=C< ring unsaturation site (preferably one or two >C=C< ring unsaturation sites) with 3 to 10 carbon atoms.

[0421] "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl or cycloalkenyl groups having 1 to 5, or preferably 1 to 3, substituents selected from oxygen, thiooxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano. Cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0422] "Cyclopropane" refers to:

[0423] .

[0424] "Cyclobutane" refers to:

[0425] .

[0426] “Cycloalkyloxy” refers to -O-cycloalkyl.

[0427] "Substituted cycloalkyloxy" refers to -O- (substituted cycloalkyl).

[0428] "Cycloalkylthio" refers to -S-cycloalkyl.

[0429] "Substituted cycloalkyl thio" refers to -S- (substituted cycloalkyl).

[0430] "Cycloalkenyloxy group" refers to -O-cycloalkenyl group.

[0431] "Substituted cycloalkenyloxy group" refers to -O- (substituted cycloalkenyl group).

[0432] "Cycloalenylthio" refers to -S-cycloalenyl.

[0433] "Substituted cycloalkenylthio" refers to -S- (substituted cycloalkenyl).

[0434] "Guidinyl" refers to the group -NHC(=NH)NH2.

[0435] "Substituted guanidine group" refers to -NR 53 C(=NR 53 )N(R 53 )2, where each R 53 The two R groups are independently selected from hydrogen, alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic, and are attached to a common guanidine nitrogen atom. 53 The group may optionally form a heterocyclic group or a substituted heterocyclic group together with the nitrogen atom it is bonded to, provided that at least one R 53 It is not hydrogen, and the substituents therein are as defined herein.

[0436] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0437] "Hydroxy group" refers to the -OH group.

[0438] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. Such heteroaryl groups may have a single ring (such as pyridyl or furanyl) or multiple fused rings (such as indolyl or benzothiophene), wherein the fused rings may be or partially aromatic, and / or contain heteroatoms, provided that the connection point is achieved through atoms of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Certain non-limiting examples include pyridyl, pyrroleyl, indolyl, thiophene, oxazolyl, thiazolyl, and furanyl.

[0439] "Substituted heteroaryl" refers to a heteroaryl group substituted by 1 to 5 (preferably 1 to 3, or more preferably 1 to 2) substituents selected from the same substituents as defined with respect to substituted aryl.

[0440] "Heteroaryloxy group" refers to -O-heteroaryl group.

[0441] "Substituted heteroaryloxy group" refers to -O- (substituted heteroaryl group).

[0442] "Heteroarylethio" refers to the group -S-heteroaryle.

[0443] "Substituted heteroarylthio" refers to the group -S- (substituted heteroaryl).

[0444] "Heterocyclic group" or "heterocyclic alkyl group" refers to a saturated or partially saturated (but not aromatic) group having 1 to 10 cyclic carbon atoms and 1 to 4 cyclic heteroatoms selected from nitrogen, sulfur, or oxygen. Heterocyclic groups include monocyclic or multiple fused rings, including fused bridging ring systems and spirocyclic systems. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the connection point is achieved through a non-heteroaryl ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocycle are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0445] "Substituted heterocyclic group" or "substituted heterocyclic alkyl group" refers to a heteroaryl group substituted with 1 to 5 or preferably 1 to 3 substituents, the same substituents as defined with respect to substituted cycloalkyl groups.

[0446] "Heterocyclic oxygen group" refers to the -O-heterocyclic group.

[0447] "Substituted heterocyclic oxygen group" refers to the group -O- (substituted heterocyclic group).

[0448] "Heterocyclic thio group" refers to the -S-heterocyclic group.

[0449] "Substituted heterocyclic thio" refers to the group -S- (substituted heterocyclic group).

[0450] Examples of heterocyclic and heteroaryl groups include, but are not limited to, azacyclic butane, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, indoleyl, dihydroindolyl, indazolyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnamolinel, pteridinyl, carbazolyl, carbamolinel, phenanthridinel, acridinel, phenanthrolyl, and others. Isothiazolyl, phenazinyl, isoxazolyl, phenoxazinyl, phenthiazinyl, imidazoalkyl, imidazolinyl, piperidinyl, piperazinyl, dihydroindolyl, phthalimide, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazoyl, thiazoalkyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0451] "Nitro" refers to the group -NO2.

[0452] "Oxygen" refers to oxygen atoms (=O).

[0453] Phenylidene refers to a divalent aromatic ring containing 6 carbon atoms.

[0454] Substituted phenylene refers to a phenylene substituted with 1 to 4 (preferably 1 to 3, or more preferably 1 to 2) substituents, wherein the substituents are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, Substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkathio, and substituted alkathio, wherein the substituents are as defined herein.

[0455] "Spirocycloalkyl" and "spirocyclic" refer to divalent cyclic groups with 3 to 10 carbon atoms, which are cycloalkyl or heterocycloalkyl groups with a spirocyclic linkage (formed by a single atom that is the only common member of these rings), such as the following structures:

[0456] .

[0457] "Sulfoyl" refers to the divalent group -S(O)2-.

[0458] "Substituted sulfonyl" refers to the groups -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl groups include, for example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0459] "Substituted xanthoxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0460] "Thioacyl" refers to the following groups: HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl -C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)- and substituted heteroaryl-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0461] "Thiol" refers to -SH.

[0462] "Thiocarbonyl" is a divalent group -C(S)-, which is equivalent to -C(=S)-.

[0463] "Thio" refers to the atom (=S).

[0464] "alkylthio" refers to the group -S-alkyl, where alkyl is as defined herein.

[0465] "Substituted alkyl thio" refers to the group -S- (substituted alkyl), wherein the substituted alkyl is as defined herein.

[0466] The "substituted ring" may be substituted by one or more fused rings and / or spirocyclic rings. Such fused rings include fused cycloalkyl, fused heterocyclic, fused aryl, and fused heteroaryl rings, each of which may be unsubstituted or substituted. Such spirocyclic rings include fused cycloalkyl and fused heterocyclic groups, each of which may be unsubstituted or substituted.

[0467] "Optionally substituted" refers to a group selected from that group and the substituted form of that group. Substituents are those defined above herein. In one embodiment, the substituent is selected from C1-C1. 10 Or C1-C6 alkyl, substituted C1-C 10 Or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C6-C 10 Aryl, C3-C8 cycloalkyl, C2-C 10 Heterocyclic groups, C1-C 10 Heteroaryl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C6-C 10 Aryl, substituted C3-C8 cycloalkyl, substituted C2-C 10 Heterocyclic groups, substituted C1-C 10 Heteroaryl, halogen, nitro, cyano, -CO2H or their C1-C6 alkyl esters.

[0468] Unless otherwise stated, the naming of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group and then naming the adjacent functional group toward the junction point. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[0469] It should be understood that polymers obtained by defining substituents with other substituents (e.g., substituted aryl groups with substituted aryl groups as substituents, which themselves are substituted by substituted aryl groups, etc.) are not intended to be included herein. In this case, the maximum number of such substituents is three. That is, each of the above definitions is limited, for example, substituted aryl is limited to substituted aryl-(substituted aryl)-substituted aryl.

[0470] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., methyl groups substituted with five fluorine groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0471] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enolones and imine enamines, or heteroaryl forms containing ring atoms attached to the -NH- and =N- portions of the ring, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles.

[0472] "Uracil isosteres" refers to isosteres of uracil, excluding uracil or any halogenated uracil. Such portions provide some or all of the hydrogen-bonded acceptor-donor-acceptor properties of uracil, and optionally provide other structural features of uracil. Those skilled in the art will further understand the meaning of this term by reading the non-limiting examples of such uracil isosteres provided herein.

[0473] As used herein, the term stereochemically pure indicates a compound having 80% by weight or more of the indicated stereoisomer and 20% by weight or less of other stereoisomers. In another embodiment, the compound of formula (I), (II), or (III) has 90% by weight or more of the stated stereoisomer and 10% by weight or less of other stereoisomers. In another embodiment, the compound of formula (I), (II), or (III) has 95% by weight or more of the stated stereoisomer and 5% by weight or less of other stereoisomers. In yet another embodiment, the compound of formula (I), (II), or (III) has 97% by weight or more of the stated stereoisomer and 3% by weight or less of other stereoisomers.

[0474] "Pharmaceutically acceptable salts" refers to salts of compounds suitable for pharmaceutical use and derived from a variety of organic and inorganic counterions known in the art, including, for example, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium when the compound contains acidic functional groups; and salts of organic or inorganic acids, such as hydrochlorides, hydrobromic acids, tartrates, methanesulfonates, acetates, maleates, and oxalates, when the molecule contains basic functional groups (for a discussion of pharmaceutically acceptable salts, their selection, preparation, and use, see Stahl and Wermuth, eds., "Handbook of Pharmaceutically Acceptable Salts," (2002), Verlag Helvetica Chimica Acta, Zürich, Switzerland).

[0475] Generally, pharmaceutically acceptable salts are those that substantially retain one or more of the desired pharmacological activities of the parent compound and are suitable for in vivo administration. Pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, but are not limited to, hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, etc.

[0476] Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, but are not limited to, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkyl sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, etc.), aryl sulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc.

[0477] Pharmaceutically acceptable salts also include those formed when acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions) or ammonium ions (e.g., ammonium ions obtained from organic bases such as ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).

[0478] "Effective amount" is the amount sufficient to achieve a beneficial or desired result. Effective amounts can be administered once or multiple times, by application, or by dose. This delivery depends on many variables, including the time period for which a single dose unit is used, the bioavailability of the therapeutic agent, the route of administration, etc. However, it should be understood that a specific dose level of the therapeutic agent disclosed herein for any particular subject depends on a variety of factors, including the activity of the specific compound used, the bioavailability of the compound, the route of administration, the age and weight of the animal, its general health condition, sex, diet, time of administration, rate of excretion, drug combination, and the severity and form of administration of the specific condition being treated. Generally, it is desirable to administer an amount of compound that effectively achieves serum levels equivalent to effective concentrations in the body. These considerations, as well as effective formulations and administration procedures, are well known in the art and described in standard textbooks.

[0479] A “therapeutic effective amount” of a drug or agent refers to an amount sufficient to produce a pharmacological response (e.g., inhibition of dUTPase); or alternatively, an amount sufficient to have the intended effect (e.g., treat, alleviate, improve, reduce, or eliminate one or more manifestations of the patient’s specific condition or disease) when administered to a patient with that condition or disease. A therapeutic effect does not necessarily occur with a single dose and may occur only after a series of doses. Therefore, a therapeutic effective amount can be administered in one or more doses.

[0480] As used herein, “treatment” for a disease in a patient means (1) preventing the development of symptoms or disease in a susceptible animal or an animal that has not yet shown symptoms of disease; (2) suppressing or halting the development of disease; or (3) improving or causing the disease or the symptom of disease to subside. As understood in the art, “treatment” is a method for obtaining a beneficial or desired outcome (including clinical outcomes). For the purposes of this technique, a beneficial or desired outcome may include, but is not limited to, the reduction or improvement of one or more symptoms, a reduction in the severity of a symptom (including disease), stabilization (i.e., no worsening) of the state of a symptom (including disease), a delay or mitigation of a symptom (including disease), progression, improvement or remission of a disease (including disease), and a state and remission (whether partial or complete), whether detectable or undetectable.

[0481] “dUTPase” refers to any of the following, which are considered synonyms: “deoxyuridine triphosphate nucleotide hydrolase,” “deoxyuridine triphosphate pyrophosphatase,” “dUTP nucleoside hydrolase,” “dUTP pyrophosphatase,” and other equivalent names for the dUTPase enzyme. In one respect, dUTPase means both DUT-N and DUT-M. In other respects, it means only DUT-N, or only DUT-M. The amino acid and coding sequence of dUTPase are known in the art and are disclosed in U.S. Patent No. 5,962,246. Methods for expressing and screening the expression levels of this enzyme are disclosed in U.S. Patent No. 5,962,246 and Ladner et al. (U.S. Patent Publication No. 2011 / 0212467A1).

[0482] “DUT-N” refers to the nuclear form of dUTPase.

[0483] “DUT-M” refers to the mitochondrial or cytoplasmic form of dUTPase.

[0484] "Therapies targeting dUTPase" means therapeutic agents that target (e.g., in the case of cancer) the dUTPase pathway, such as therapies for TS and fluoropyrimidines (e.g., 5-FU), pemetrexed (Alimta®), capecitabine (Xeloda®), S-1, and antifolate agents (e.g., methotrexate) and their chemical equivalents. Non-limiting examples include 5-fluorouracil (5-FU), therapies for TS, and 5-FU-based adjuvant therapies. As is well known to those skilled in the art, combination therapies may include any intervention that alters the nucleotide library and / or sensitizes immune cells or viruses to dUTPase inhibitors. For example, for rheumatoid arthritis, the combination may be with a dihydrofolate reductase (DHFR) inhibitor (such as methotrexate).

[0485] 5-Fluorouracil (5-FU) belongs to a family of therapeutic agents called pyrimidine antimetabolites. It is a pyrimidine analog that is converted into various cytotoxic metabolites, which are then incorporated into DNA and RNA, thereby inducing cell cycle arrest and apoptosis. The chemical equivalent is a pyrimidine analog that disrupts DNA replication. The chemical equivalent inhibits cell cycle progression in the S phase, leading to cell cycle disruption and thus apoptosis. Drugs equivalent to 5-FU include their prodrugs, analogs, and derivatives, such as 5'-deoxy-5-fluorouridine (doxifluoroidine), 1-tetrahydrofuran-5-fluorouracil (ftorafur), capecitabine (Xeloda®), S-1 (MBMS-247616, composed of tegafur and two modifiers, 5-chloro-2,4-dihydroxypyridine and potassium oxoacid), raltitrexed (tomudex), noratrexed (Thymitaq, AG337), LY231514, and ZD9331, see, for example, Papamicheal (1999) The Oncologist 4:478-4874:478-487.

[0486] "Adjuvant therapy based on 5-FU" refers to 5-FU alone or optionally in combination with other treatments, including but not limited to radiation, methyl-CCNU, leucovorin, oxaliplatin, irinotecan, mitomycin, cytarabine, and levamisole. Specific adjuvant therapy regimens known in the art include FOLFOX, FOLFOX4, FOLFIRI, and MOF (smustine (methyl-CCNU), vincristine (Oncovin®), and 5-FU). For reviews of these treatments, see Beaven and Goldberg (2006) Oncology 20(5):461-470. One such example is an effective amount of 5-FU and leucovorin. Other chemotherapeutic agents, such as oxaliplatin or irinotecan, may be added.

[0487] Capecitabine is a prodrug of (5-FU), which is converted to its active form via a three-enzymatic pathway and two intermediate metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), through the tumor-specific enzyme PynPase. Capecitabine is marketed by Roche under the brand name Xeloda®.

[0488] Leucovorin is an adjuvant used in cancer treatment. It is used in synergistic combination with 5-FU to improve the efficacy of chemotherapeutic agents. Unbound by theory, the addition of leucovorin is thought to enhance the efficacy of 5-FU by inhibiting thymidylate synthase. It has been used as an antidote to protect normal cells from high doses of the anticancer drug methotrexate and to enhance the antitumor effects of fluorouracil (5-FU) and tegafurazole. It is also known as citrovorum factor and Wellcovorin. The chemical name of this compound is L-glutamic acid N[4[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridyl)methyl]amino]benzoyl], calcium salt (1:1).

[0489] Eloxatin is a platinum-based chemotherapy drug belonging to the same family as cisplatin and carboplatin. It is often used in combination with fluorouracil and leucovorin (called FOLFOX) to treat colorectal cancer. Compared to cisplatin, two amino groups are replaced by cyclohexyldiamine to improve antitumor activity. The chloride ligand is replaced by bidentate oxalate derived from oxalate to improve water solubility. Equivalents of oxaliplatin are known in the art, including but not limited to cisplatin, carboplatin, aloin, lobaplatin, nedaplatin, and JM-216 (see McKeage et al. (1997) J. Clin. Oncol. 201:1232-1237 and in general, Chemotherapy for Gynecological Neoplasm, Curr. Therapy and Novel Approaches, in the Series Basic and Clinical Oncology, Angioli et al. Eds., 2004).

[0490] "FOLFOX" is an abbreviation for a combination therapy used to treat cancer. This therapy includes 5-FU, oxaliplatin, and leucovorin. "FOLFIRI" is an abbreviation for a class of combination therapies used to treat cancer that contain 5-FU, leucovorin, and irinotecan, or consist primarily of or mainly of 5-FU, leucovorin, and irinotecan. Information about these treatments can be found on the National Cancer Institute website cancer.gov, last accessed on January 16, 2008.

[0491] Irinotecan (CPT-11), marketed under the trade name Camptosar, is a semi-synthetic analog of the alkaloid camptothecin, which is activated by hydrolysis to SN-38 and targets topoisomerase I. The chemical equivalent is one that inhibits the interaction between topoisomerase I and DNA to form the catalytically active topoisomerase I-DNA complex. This chemical equivalent inhibits cell cycle progression in the G2-M phase, leading to the disruption of cell proliferation.

[0492] The term "adjuvant" therapy refers to the administration of a treatment or chemotherapy regimen to a patient after surgical removal of a tumor. Adjuvant therapy is typically given to minimize or prevent possible cancer recurrence. Alternatively, "neoadjuvant" therapy refers to the administration of a treatment or chemotherapy regimen prior to surgery, usually to shrink the tumor before surgery to minimize the amount of tissue removed during the procedure.

[0493] The terms "first-line," "second-line," or "third-line" refer to the order in which a patient receives treatment. First-line treatment is administered first, while second-line or third-line treatment is given after first-line or second-line treatment, respectively. The National Cancer Institute (NCI) defines first-line treatment as "the first course of treatment for a disease or condition. In patients with cancer, the primary treatment may be surgery, chemotherapy, radiation therapy, or a combination of these therapies. First-line treatment is also referred to by those skilled in the art as the primary therapy and treatment." See the NCI website www.cancer.gov, last accessed May 1, 2008. Typically, patients receive subsequent chemotherapy regimens because they have not shown a positive clinical or subclinical response to first-line treatment, or because first-line treatment has been discontinued.

[0494] As used in this article, the term "antifolic acid inhibitor" refers to drugs or biological agents that impair the function of folic acid, such as antimetabolites, which inhibit the use of metabolites (i.e., another chemical substance that is part of normal metabolism). In cancer treatment, antimetabolites interfere with DNA production, thereby affecting tumor cell division and growth. Non-limiting examples of these drugs are dihydrofolate reductase inhibitors, such as methotrexate, aminopterin, and pemetrexed; thymidine synthase inhibitors, such as raltitrexed or pemetrexed; purines, namely adenosine deaminase inhibitors (such as pentostatin), thiopurines (such as thioguanine and mercaptopurine), halogenated / ribonucleotide reductase inhibitors (such as cladribine, clofarabine, and fludarabine), or guanine / guanosine:thiopurine (such as thioguanine); or pyrimidines, namely cytosine / cytidine:hypomethylating agents (such as azacitidine and decitabine), DNA polymerase inhibitors (such as cytarabine), ribonucleotide reductase inhibitors (such as gemcitabine), or thymidine / thymidine:thymidine synthase inhibitors (such as fluorouracil (5-FU)).

[0495] In one aspect, the term "chemical equivalent" refers to the ability of a chemical substance to selectively interact with its target protein, DNA, RNA, or fragments thereof, an ability determined by inactivation of the target protein, incorporation of the chemical substance into DNA or RNA, or other suitable methods. Chemical equivalents include, but are not limited to, those reagents having the same or similar biological activity, and include, but are not limited to, pharmaceutically acceptable salts or mixtures thereof that interact with and / or inactivate the same target protein, DNA, or RNA as a reference.

[0496] The terms “oligonucleotide” or “polynucleotide”, or their “parts” or “fragments”, refer to a polynucleotide residue that is long enough to be used in PCR or various hybridization procedures to identify or amplify the same or related portions of an mRNA or DNA molecule. As will be readily understood by those skilled in the art, the polynucleotide compositions of the present invention comprise RNA, cDNA, genomic DNA, synthetic forms, and mixed polymers (both sense and antisense strands), and may be chemically or biochemically modified, or may contain non-natural or derived nucleotide bases. Such modifications include, for example, labeling, methylation, substitution of one or more naturally occurring nucleotides with analogs, internucleotide modifications such as uncharged bonds (e.g., methylphosphonates, triphosphates, phosphatidyl esters, carbamates, etc.), charged bonds (e.g., thiophosphates, dithiophosphates, etc.), pendent moieties (e.g., polypeptides), intercalating agents (e.g., acridine, psoralen, etc.), chelating agents, alkylating agents, and modified linkages (e.g., α-anomeric nucleic acids, etc.). Synthetic molecules that mimic the ability of polynucleotides to bind specified sequences via hydrogen bonds and other chemical interactions are also included. Such molecules are known in the art, and include, for example, those in which peptide bonds replace phosphate ester bonds in the molecular backbone.

[0497] When a genetic marker (e.g., overexpression of dUTPase) is used as the basis for selecting patients for the treatment described herein, the genetic marker is measured before and / or during treatment, and the values ​​obtained are used by clinicians to assess any of the following: (a) the likelihood of an individual receiving initial treatment; (b) the potential unsuitability of an individual receiving initial treatment; (c) the response to treatment; (d) the potential suitability of an individual to continue treatment; (e) the potential unsuitability of an individual to continue treatment; (f) dose adjustment; (g) the likelihood of predicting clinical benefit; or (h) toxicity. As will be well understood by those skilled in the art, measurement of a genetic marker in a clinical setting clearly indicates that the parameter is used as the basis for initiating, continuing, adjusting, and / or discontinuing the treatment described herein.

[0498] Cancer, medically known as a malignant tumor, is a large class of diseases involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming a malignant tumor and invading nearby parts of the body. Non-limiting examples include colon cancer, colorectal cancer, stomach cancer, esophageal cancer, head and neck cancer, breast cancer, lung cancer, liver cancer, gallbladder cancer, pancreatic cancer, or leukemia.

[0499] compound

[0500] On the one hand, this article provides compounds of formula (I):

[0501]

[0502] Or its tautomers, a pharmaceutically acceptable salt of each, or a pharmaceutically acceptable solvate of each of the foregoing, wherein

[0503] A is

[0504] ;

[0505] Y 1 It is an H or C1-C3 alkyl group;

[0506] L 1 It is an optional substitution of C3-C 10 Alkylene, wherein at least two twin hydrogens are optionally substituted with cyclopropane or cyclobutane; optionally substituted C3-C 10 alkenyl, optionally substituted C3-C 10 Heteroalkylene, optionally substituted C3-C 10 Heteroeneyl or -L 11 -L 12 -L 13 -, where L 11 Connect to A and L 11It is O, S, NR, C1-C2 alkylene, C2 alkenylene, C2 heteroalkylene, C2 heteroalkenylene, L 12 It is arylene or heteroarylene, L 13 It is a C1-C5 alkylene group that is bonded or optionally substituted, and R is H or a C1-C3 alkyl group;

[0507] L 2 It is –S(O)2NH-, where sulfur is attached to L 1 Or –NHS(O)2-, where nitrogen is attached to L 1 ;

[0508] L 3 It is a C1-C6 alkylene group with a bond or optional substitution, preferably a C1-C6 alkylene group.

[0509] ,

[0510] Better:

[0511] ;

[0512] B is

[0513] ;

[0514] Each R 1 -R 3 Independently H, F, Cl, C1-C3 alkyl or -OR 20 ;

[0515] R 20 It is CH2-R 21 ; methyl groups optionally substituted with 2 or 3 fluorine atoms; C3-C6 cycloalkyl; or C1-C6 alkyl;

[0516] R 21 It is C1-C 10 Alkyl groups, preferably branched C3-C groups optionally substituted with one or more hydroxyl groups or fluorine. 10 Alkyl (more preferably isopropyl or tert-butyl); C3-C6 cycloalkyl, preferably cyclopropyl, cyclobutyl or cyclophenyl; or

[0517] ,

[0518] Where R 22 -R 24 Each is independently a C1-C3 alkyl or hydroxyl group that is optionally substituted.

[0519] In one implementation, Y 1 It is H. In another implementation, Y 1 It is a C1-C3 alkyl group.

[0520] In one implementation, L 1 It is an optional substitution of C3-C 10 Alkylene, wherein at least two twin hydrogens are optionally substituted with cyclopropane or cyclobutane. In another embodiment, L 1 It is an optional substitution of C3-C 10 Alkenyl group. In another embodiment, L 1 It is an optional substitution of C3-C 10 Heteroalkylene. In another embodiment, L 1 It is an optional substitution of C3-C 10 Heteroene group.

[0521] In one implementation, L 1 Yes -L 11 -L 12 -L 13 -, where L 11 Connected to A. In one implementation, L 11 It is O. In one implementation, L 11 It is S. In one implementation, L 11 It is NR. In one embodiment, R is H. In another embodiment, R is a C1-C3 alkyl group.

[0522] In one implementation, L 11 It is a C1-C2 alkylene group. In one embodiment, L 11 It is a C2-olefinic group. In one embodiment, L 11 It is a C2 heteroalkylene group. In one embodiment, L 11 It is a C3 heteroene group.

[0523] In one implementation, L 12 It is a aryl group. In another embodiment, L 12 It is a heteroarylene.

[0524] In one implementation, L 13 It is a key. In another implementation, L 13 It is an optional substituted C1-C5 alkylene group.

[0525] In one implementation, L 2 It is –S(O)2NH-, where sulfur is attached to L 1 In another implementation, L 2 It is –NHS(O)2-, where nitrogen is attached to L 1 .

[0526] In one implementation, L 3 It is a key. In another implementation, L3 It is an optional substituted C1-C6 alkylene group.

[0527] In one implementation, L 3 yes

[0528]

[0529] The left side is connected to A.

[0530] In one implementation, L 3 yes

[0531]

[0532] The left side is connected to A.

[0533] In one implementation, L 3 yes

[0534]

[0535] The left side is connected to A.

[0536] In one implementation, L 3 yes

[0537]

[0538] The left side is connected to A.

[0539] In one implementation, L 3 yes

[0540]

[0541] The left side is connected to A.

[0542] In one implementation, L 3 yes

[0543]

[0544] The left side is connected to A.

[0545] In one implementation, L 3 yes

[0546]

[0547] The left side is connected to A.

[0548] In one implementation, L 3 yes

[0549]

[0550] The left side is connected to A.

[0551] In one implementation, L 3 yes

[0552]

[0553] The left side is connected to A.

[0554] In one implementation, L 3 yes

[0555]

[0556] The left side is connected to A.

[0557] In one implementation, R 1 -R 3 Each is independently H. In one implementation, R 1 -R 3 Each is independently F. In one implementation, R 1 -R 3 Each is independently Cl. In one implementation, R 1 -R 3 Each is independently a C1-C3 alkyl group. In one embodiment, R 1 -R 3 Each independently for OR 20 .

[0558] In one implementation, R 20 It is CH2-R 21 In one implementation, R 20 It is a methyl group optionally substituted with 2 or 3 fluorine atoms. In one embodiment, R 20 It is a C3-C6 cycloalkyl group. In one embodiment, R 20 It is a C1-C6 alkyl group.

[0559] In one implementation, R 21 It is C1-C 10 Alkyl group. In one embodiment, R 21 It is a C3-C that is optionally substituted with one or more hydroxyl groups or fluorine. 10 Alkyl group. In another embodiment, R 21 It is an isopropyl or tert-butyl group optionally substituted with one or more hydroxyl groups or fluorine. In another embodiment, R 21 It is a C3-C6 cycloalkyl group. In another embodiment, R 21 It is cyclopropyl, cyclobutyl, or cyclopentyl.

[0560] In one implementation, R 21 yes

[0561]

[0562] Where R 22 -R 24 Each is independently a C1-C3 alkyl or hydroxyl group that is optionally substituted.

[0563] In one implementation, R 22 -R 24 Each is independently a optionally substituted C1-C3 alkyl group. In another embodiment, R 22 -R 24 Each is independently a hydroxyl group.

[0564] In one implementation, R 21 yes

[0565] .

[0566] In one implementation, R 21 yes

[0567] .

[0568] In one implementation, R 21 yes

[0569] .

[0570] In one implementation, R 21 yes

[0571] .

[0572] In one implementation, R 21 yes

[0573] .

[0574] In one implementation, R 21 yes

[0575] .

[0576] In one implementation, R 21 yes

[0577] .

[0578] In one implementation, R 21 yes

[0579] .

[0580] In one implementation, A is selected from:

[0581] .

[0582] In one implementation, A is

[0583] .

[0584] In one implementation, A is

[0585] .

[0586] In one implementation, A is

[0587] .

[0588] In one implementation, L 1 It is -(CH2) q - wherein one or more hydrogens are optionally substituted with C1-C3 alkyl groups, and / or at least two or more twin hydrogens are optionally substituted with cyclopropane or cyclobutane; and wherein q is 4, 5, 6, 7 or 8.

[0589] In another implementation, L 1 yes

[0590] One or more hydrogens are optionally substituted with C1-C3 alkyl groups, and / or at least two or more twin hydrogens are optionally substituted with cyclopropane or cyclobutane; and wherein p is 0, 1, 2, 3, 4 or 5, and z is 0, 1, 2, 3, 4 or 5.

[0591] In another implementation, L 1 It is -(CH2) m -X-(CH2) n - wherein one or more hydrogens are optionally substituted with C1-C3 alkyl groups, and / or at least two or more twin hydrogens are optionally substituted with cyclopropane or cyclobutane; and wherein m is 0, 1, 2 or 3 and n is 3, 4, 5, 6 or 7.

[0592] In another implementation, L 1 yes

[0593] One or more hydrogens are optionally substituted with C1-C3 alkyl groups, and / or at least two or more twin hydrogens are optionally substituted with cyclopropane or cyclobutane; and wherein o is 0, 1, 2 or 3; r is 1, 2 or 3; and s is 0, 1, 2, 3 or 4; and

[0594] Where X is NR 40 , O or S, where R 40 It is a C1-C3 alkyl group.

[0595] In one implementation, L 1 Selected from:

[0596]

[0597] The left side of these parts is connected to A.

[0598] In another implementation, -L 11 -L 12 -L 13 -yes

[0599]

[0600] The left side of these parts is connected to A.

[0601] In one implementation, R 1 It is H.

[0602] In one implementation, R 2 Is it H or -OR 20 .

[0603] In one implementation, R 3 It is either F or H.

[0604] In one implementation, B is

[0605] .

[0606] In one implementation, B is selected from:

[0607] .

[0608] In one implementation, B is

[0609] .

[0610] On the one hand, this article provides compounds selected from Table 1 below.

[0611] Table 1

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634] On the one hand, this article provides compounds selected from Table 2 below.

[0635] Table 2

[0636]

[0637] Where R 70 As defined above, and R 30 As defined above.

[0638] In some embodiments, the compounds provided by the present invention exclude the compounds listed in Tables 3, 4 and 5.

[0639] Table 3

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] Table 4

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671] Table 5

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679] In some embodiments, the compounds provided herein are not:

[0680] .

[0681] synthesis

[0682] The compounds described herein, along with other compounds, were synthesized according to methods generally accepted in the art, with appropriate substitutions for commercially available reagents as needed. For example (but not limited to), methods for synthesizing certain other compounds are described in the following literature: US2011 / 0082163; US 2012 / 0225838; WO 2014 / 107622; PCT / US2015 / 010059; Miyahara et al., J. Med. Chem. (2012) 55, 2970-2980; Miyakoshi et al., J. Med. Chem. (2012) 55, 2960-2969; Miyahara et al., J. Med. Chem. (2012) 55 (11), pp5483–5496; and Miyakoshi et al., J. Med. Chem. (2012) 55 (14), pp5483–5496. 6427–6437 (see above), those skilled in the art can, upon reading this disclosure and / or by modifying these methods based on synthetic methods well known in the art, prepare the compounds provided herein. Protection and deprotection methods for this purpose, as well as protecting groups, are well known in the art; see, for example, Greene's Protective Groups in Organic Synthesis, 4 th Edition, Wiley, 2006, or a more recent edition of the book.

[0683] When necessary, the compound and intermediates are separated from the reaction mixture using methods known in the art (e.g., crystallization, chromatography, distillation, etc.). The compound and intermediates are characterized by methods known in the art, such as thin-layer chromatography, nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, etc. As described in detail herein, mixtures of racemic or diastereomers of the compound can be separated or enriched into enantiomers and diastereomers, and used for diagnostic or therapeutic tests as described herein.

[0684] The methods for testing and using the compounds provided herein are in accordance with methods generally accepted in the art, such as in vitro (cell-free), ex vivo, or in vivo methods. For example (but not limited to), certain methods for testing and using other compounds are described in the following literature: US2011 / 0082163; US 2012 / 0225838; Miyahara et al., J. Med. Chem. (2012) 55, 2970-2980; Miyakoshi et al., J. Med. Chem. (2012) 55, 2960-2969; Miyahara et al., J. Med. Chem. (2012) 55 (11), pp 5483–5496; Miyakoshi et al., J. Med. Chem. (2012) 55 (14), pp 6427–6437 (each of which is incorporated herein by reference). Those skilled in the art can modify these methods to test and use the compounds provided herein after reading this disclosure and / or based on synthetic methods well known in the art.

[0685] Pharmaceutical Composition

[0686] On the other hand, this document provides compositions comprising the compounds provided herein and at least one pharmaceutically acceptable excipient.

[0687] Pharmaceutical compositions (including those containing the compounds described herein) can be manufactured by conventional processes of mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, sealing, or lyophilizing. Compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate the processing of the compounds provided herein into pharmaceutically acceptable formulations.

[0688] The compounds of the present invention can be administered via parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracerebrospinal injection or infusion, subcutaneous injection or implantation), oral, nasal, vaginal, rectal, sublingual, urethral (e.g., urethral suppositories) or local routes of administration (e.g., gels, ointments, creams, aerosols, etc.), and can be formulated alone or together into suitable dosage units containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants, excipients, and carriers suitable for each route of administration.

[0689] In one embodiment, the technology relates to a composition comprising a compound and a carrier as described herein.

[0690] In another embodiment, the technology relates to a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable carrier.

[0691] In another embodiment, the technology relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein and a pharmaceutically acceptable carrier.

[0692] Pharmaceutical compositions for administering the compound can be conveniently presented in dosage units and can be prepared by any method well known in the pharmaceutical field. For example, a pharmaceutical composition can be prepared by homogenizing and tightly binding the compound provided herein with a liquid carrier, a finely chopped solid carrier, or both, and then shaping the product into a desired formulation if desired. In the pharmaceutical composition, the amount of the compound provided herein is sufficient to produce the desired therapeutic effect. For example, pharmaceutical compositions of this technology can be in forms suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, infusion, transdermal, rectal, and vaginal administration, or in forms suitable for inhalation or blowing.

[0693] For topical administration, compounds can be formulated into solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

[0694] Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, infusion, intramuscular, intrathecal, or intraperitoneal injection) as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0695] Useful injectable formulations include sterile suspensions, solutions, or emulsions of the compounds described herein in aqueous or oily carriers. The composition may also contain formulations such as suspending agents, stabilizers, and / or dispersants. Formulations for injection may be in unit dose form, for example in ampoules or in multi-dose containers, and may contain added preservatives.

[0696] Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable carrier (including, but not limited to, sterile pyrogen-free water, buffer solutions, and glucose solutions) prior to use. For this purpose, the compounds provided herein may be dried using any technique known in the art (e.g., lyophilization) and reconstituted prior to use.

[0697] For transmucosal administration, a penetrant suitable for the permeability barrier is used in the formulation. Such penetrants are known in the art.

[0698] For oral administration, the pharmaceutical composition may be in the form of, for example, lozenges, tablets, or capsules, which may be prepared in a conventional manner using pharmaceutically acceptable excipients (such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated with, for example, sugar, film, or enteric coating using methods known in the art.

[0699] Compositions intended for oral use may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable formulation. Tablets contain a mixture of the compounds provided herein with non-toxic, pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants (e.g., corn starch or alginate); binders (e.g., starch, gelatin, or gum arabic); and lubricants (e.g., magnesium stearate, stearic acid, or talc). Tablets may be uncoated, or may be coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged duration of action. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated using techniques well known to those skilled in the art. Pharmaceutical compositions of this technique may also be in the form of an oil-in-water emulsion.

[0700] Liquid formulations for oral administration may take the form of elixirs, solutions, syrups, or suspensions, or they may be presented as dry products for reconstitution with water or other suitable carriers prior to use. Such liquid formulations can be prepared using conventional methods with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); and non-aqueous carriers (e.g., almond oil, oily esters, ethanol, cromophores). TM Or fractionated vegetable oils); and preservatives (e.g., methylparaben, propylparaben, or sorbic acid). Where appropriate, the formulation may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners.

[0701] Uses of compounds in the preparation of drugs

[0702] The compounds and compositions of the present invention can also be used to prepare medicaments for treating the various conditions described herein. Methods and techniques for preparing the medicamentous compositions are known in the art. For illustrative purposes only, pharmaceutical formulations and delivery routes are described in detail herein.

[0703] Therefore, those skilled in the art will readily recognize that, by applying standard pharmaceutical manufacturing procedures, any one or more of the above-described compositions, including many specific embodiments, can be used to prepare a medicament for treating many of the conditions described herein. Such a medicament can be delivered to a subject using delivery methods known in the pharmaceutical field.

[0704] Treatment methods and therapies

[0705] The compositions and compounds disclosed herein can be used to inhibit dUTPase or enhance the efficacy of therapies against dUTPase or further reverse resistance to dUTPase therapies. The method includes, or consists substantially of, the step of contacting dUTPase with a therapeutically effective amount of the disclosed compound or composition, or further comprises the step of contacting dUTPase with an effective amount of the therapy against dUTPase, or consists substantially of the step of contacting dUTPase with an effective amount of the therapy against dUTPase, or further comprises the step of contacting dUTPase with an effective amount of the therapy against dUTPase. In one aspect, the contact with the therapy against dUTPase is performed before, simultaneously with, or after contact with the disclosed compound or composition.

[0706] Those skilled in the art can also determine whether a compound or combination inhibits dUTPase in vitro by contacting the compound or combination with purified or recombinant dUTPase in a cell-free system. Purified or recombinant dUTPase can be derived from any species, such as primates, canines, bovines, sheep, rats, mice, or humans. In one aspect, dUTPase is DUT-N or DUT-M. The isolation, characterization, and expression of dUTPase isotypes are disclosed in U.S. Patent No. 5,962,246 and are known in the art.

[0707] Contact can be performed in vitro in a cell-free environment, or in vitro in the presence of cells, or in cell cultures. When performed in vitro or in vitro, the compound, composition, or reagent can be added directly to the enzyme solution or to the cell culture medium. When performed in vitro or in vitro, this method can be used to screen new combination therapies, formulations, or treatment regimens before administration to animals or human patients. Methods for quantifying inhibitory effects are known in the art, see U.S. Patent Publications 2010 / 0075924 and 2011 / 0212467 and U.S. Patent No. 7,601,702. For example, a fixed dose of dUTPase-targeted therapy (e.g., 5-FU or pemetrexed) can be added to the system, followed by the addition of different amounts of the compound. Alternatively, a fixed dose of the compound of the present invention can be added to the system, followed by the addition of different amounts of dUTPase-targeted therapy (e.g., 5-FU or pemetrexed) compound.

[0708] On the one hand, the contact is ex vivo and the cells or tissues to be contacted overexpress dUTPase. These cells can be isolated from the patient before administration to the patient or can be purchased from a depository such as the American Center for Type Culture Collection (ATCC). Non-limiting examples of animals (e.g., dogs, horses, cattle, felines, sheep, mice, rats, or apes) and human cells that overexpress dUTPase include, but are not limited to, cancer cells (e.g., colon cancer, colorectal cancer, gastric cancer, head and neck cancer, breast cancer, gastric cancer, or lung cancer cells). The cancer can be metastatic or non-metastatic. Methods for quantifying inhibitory effects are known in the art, see U.S. Patent Publications 2010 / 0075924 and 2011 / 0212467, and U.S. Patent Nos. 7,601,702 and Wilson et al. (2012) Mol. Cancer Ther. 11:616-628.

[0709] When administered in patients, such as animals or humans, the treating physician takes into account the patient, disease, and other factors, administering the compound, composition, or agent in an effective amount via an appropriate route of administration. When administered in non-human animals, such as suitable mouse models, this method can be used to screen new combination therapies, formulations, or treatment regimens before administration to human patients.

[0710] This disclosure also provides a method for treating a disease whose treatment is impaired by dUTPase expression, comprising administering a therapeutically effective amount of the disclosed compound or composition to a patient in need of such treatment, or substantially comprising, or further comprising, this step, thereby treating the disease. In one aspect, the method further comprises isolating cell or tissue samples from the patient and screening for dUTPase expression levels, wherein overexpression of dUTPase in the samples, compared to control samples, serves as the basis for selecting patients suitable for the method and treatment. Methods for quantifying inhibition are known in the art, see U.S. Patent Publications 2010 / 0075924 and 2011 / 0212467 and U.S. Patent Nos. 7,601,702 and Wilson et al. (2012) Mol. Cancer Ther. 11:616-628. If the patient sample shows dUTPase overexpression, the therapy is administered to the patient. If the patient sample does not show overexpression, an alternative therapy is selected. Screening can be repeated throughout the treatment process as a means of monitoring treatment and / or dosing regimens.

[0711] In practicing this method, the samples are patient samples containing tumor tissue, normal tissue adjacent to the tumor, normal tissue distant from the tumor, or peripheral blood lymphocytes. On the other hand, the patients or patient groups awaiting treatment are also treatment-naïve.

[0712] On the one hand, this method requires the separation of the sample containing the genetic material to be tested; however, it is conceivable that those skilled in the art will be able to analyze and identify genetic markers in situ at some point in the future. Therefore, in one aspect, the invention of this application is not limited to requiring the separation of genetic material before analysis.

[0713] These methods are not limited to the techniques used to identify expression levels or aspects related to expression polymorphism (i.e., the polymorphism of interest). Suitable methods include, but are not limited to, the use of hybridization probes, antibodies, primers for PCR analysis, and gene chips, slides, and software for high-throughput analysis. Other genetic markers can be analyzed and used as negative controls.

[0714] In one respect, the object or patient is an animal or human patient. Non-limiting examples of animals include cats, dogs, cattle, horses, sheep, mice, rats, or monkeys.

[0715] Treatment of diseases impaired by dUTPase expression includes, but is not limited to, cancer, viral infections, bacterial infections, or autoimmune diseases. For example, in inflammatory bowel disease or other autoimmune conditions, dUTPase inhibitors can be used in combination with antifolate agents or fluoropyrimidine or other thymidine synthase and dihydrofolate reductase inhibitors; similarly, combination therapy including dUTPase inhibitors can treat parasitic, viral, or bacterial infections. Non-limiting examples of cancer include colon cancer, colorectal cancer, gastric cancer, head and neck cancer, breast cancer, ovarian cancer, stomach cancer, lung cancer, or leukemia. The cancer can be metastatic or non-metastatic.

[0716] On the other hand, the compounds or compositions provided herein can be used in methods for inhibiting cancer cell growth. These methods include, or consist essentially of, contacting cells with a therapeutically effective amount of the disclosed compounds or compositions and a therapeutically effective amount of a dUTPase-targeted therapeutic agent, thereby inhibiting cancer cell growth.

[0717] In one embodiment, the cancer cells are selected from colon cancer cells, colorectal cancer cells, gastric cancer cells, head and neck cancer cells, breast cancer cells, lung cancer cells, or blood cells.

[0718] In one aspect, the compound or composition is administered as one or more of the following: first-line or alternative therapy, second-line therapy, third-line or fourth-line therapy, or a follow-up therapy to the administration of a therapy targeting dUPTase. Non-limiting examples of therapies targeting dUPTase include antimetabolites or fluoropyrimidine therapies or 5-FU-based adjunctive therapies or their respective equivalents, such as 5-FU, tegafur, gemmelacin, otetracil potassium, capecitabine, 5-fluoro-2'-deoxyuridine, methotrexate, or pemetrexed or their respective equivalents.

[0719] Some of the compounds provided herein, for example, exhibit significant (e.g., 1% to over 100%, e.g., 100-140%, 100-200%, or 120-200%) dUTPase inhibition compared to a positive control, i.e., the ability to inhibit dUTPase under the conditions described below and / or known to those skilled in the art, with the positive control being:

[0720] .

[0721] In some embodiments, certain compounds provided herein exhibit 100-140% dUTPase inhibition compared to, for example, a positive control, i.e., the ability to inhibit dUTPase under the conditions described below and / or known to those skilled in the art. In some embodiments, certain compounds provided herein exhibit 120-200% dUTPase inhibition compared to, for example, a positive control, i.e., the ability to inhibit dUTPase under the conditions described below and / or known to those skilled in the art. In some embodiments, certain compounds provided herein exhibit 100-200% dUTPase inhibition compared to, for example, a positive control, i.e., the ability to inhibit dUTPase under the conditions described below and / or known to those skilled in the art.

[0722] Reagent test kit

[0723] The compounds and compositions described herein are available in kit form. This kit may further contain additional dUTPase inhibitors and optionally include instructions for use. Alternatively, the kit may contain reagents and instructions for performing screening to identify patients more likely to respond to treatment as described above.

[0724] Screening test

[0725] This disclosure also provides screening assays to identify known and novel compounds and combinations as potential therapeutic agents. For example, those skilled in the art can also determine whether a compound or combination inhibits dUTPase in vitro by contacting the compound or combination with purified or recombinant dUTPase in a cell-free system. Purified or recombinant dUTPase can be derived from any species, such as primates, canines, bovines, sheep, rats, mice, or humans. In one aspect, dUTPase is DUT-N or DUT-M. The isolation, characterization, and expression of dUTPase isotypes are disclosed in U.S. Patent No. 5,962,246 and are known in the art.

[0726] Contact can be performed in vitro in a cell-free environment, or in vitro in the presence of cells, or in cell cultures. When performed in vitro or in vitro, the compound, composition, or reagent can be added directly to the enzyme solution or to the cell culture medium. When performed in vitro or in vitro, this method can be used to screen new combination therapies, formulations, or treatment regimens before administration to animals or human patients. Methods for quantifying inhibitory effects are known in the art, see U.S. Patent Publications 2010 / 0075924 and 2011 / 0212467 and U.S. Patent No. 7,601,702. For example, a fixed dose of dUTPase-targeted therapy (e.g., 5-FU or pemetrexed) can be added to the system, followed by the addition of different amounts of the compound. Alternatively, a fixed dose of the compound of the present invention can be added to the system, followed by the addition of different amounts of dUTPase-targeted therapy (e.g., 5-FU or pemetrexed) compound.

[0727] On the other hand, the assay requires contacting a first sample containing suitable cells or tissue (“control sample”) with an effective amount of the composition of the present invention and an optional dUTPase inhibitor, and contacting a second sample of suitable cells or tissue (“test sample”) with the reagent to be measured and an optional dUTPase inhibitor. In one aspect, the cells or tissue overexpress dUTPase. The inhibition of growth on the first and second cell samples is determined. If the growth inhibition of the second sample is substantially equal to or greater than that of the first sample, then the drug is a potential therapeutic agent. In one aspect, substantially equal or greater cell growth inhibition is less than about 1%, or less than about 5%, or less than about 10%, or greater than about 10%, or greater than about 20%, or greater than about 50%, or greater than about 90%. Contact can be in vitro or in vivo. The means of determining cell growth inhibition are well known in the art.

[0728] In a further aspect, the test reagent is brought into contact with a third cell or tissue sample (or cells that do not overexpress dUTPase) containing normal cells or tissue corresponding to the control, and the test sample is contacted with a reagent selected to treat the second cell or tissue sample without adversely affecting the third sample. For the purposes of the assays described herein, suitable cells or tissues are described, such as those associated with cancer or other diseases as described herein. Such examples include, but are not limited to, cancer cells or tissues obtained through biopsy, blood, breast cells, and colon cells.

[0729] The efficacy of the test composition was determined using methods known in the art, including but not limited to cell viability assays or apoptosis assessments.

[0730] On the other hand, the experiment requires at least two cell types, the first being suitable control cells.

[0731] This test can also be used to predict whether a subject will be appropriately treated with the present invention, by delivering the composition to a sample containing cells to be treated and measuring changes in pathology, or for screening new drugs and combinations. In one aspect, cells or tissue are obtained from a subject or patient via biopsy. The applicant provides a kit for determining whether pathological cells or a patient will be appropriately treated with the therapy, which is achieved by providing at least one composition of the present invention and instructions for use.

[0732] Test cells can be grown in small multi-well plates and used to detect the bioactivity of test compounds. For the purposes of this invention, a successful drug candidate will inhibit growth or kill pathogens, but leave control cell types unharmed.

[0733] The following examples illustrate some implementations of this disclosure. However, based on this disclosure, those skilled in the art should understand that many changes can be made to the specific implementations disclosed, and similar or analogous results can still be obtained without departing from the spirit and scope of the invention. Example

[0734] Synthetic Examples

[0735] Exemplary steps for the preparation of N-allyl cyanamide (I):

[0736] A solution of CNBr (3.33 g, 0.31 mmol) in Et₂O was added dropwise to a stirred solution of propen-2-en-1-amine (3.0 g, 0.52 mmol) in 50 mL of Et₂O at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered, and the filtrate was washed with water and dried to obtain I.

[0737] Yield: 1.7 g, 39.4%; 1 ¹H NMR (400 MHz, chloroform-d) δ 5.91–5.87 (m, 1H), 5.40–5.26 (m, 2H), 3.72–3.68 (m, 2H), 3.53–3.43 (m, 1H).

[0738] Exemplary steps for the preparation of N-allyl-N-cyanoglycine ethyl ester (II):

[0739] To a stirred solution of I (1.7 g, 20.7 mmol) in dry THF (8 mL), NaH (0.54 mL, 22.7 mmol) was added, and the mixture was stirred at room temperature. After 1 h, a solution of 3 (3.34 g, 20.7 mmol) in THF (8 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was quenched with water and then extracted with DCM. The combined DCM layers were dried and concentrated under reduced pressure to obtain II.

[0740] Yield: 2.7 g, 77.5%; NMR: 1 ¹H NMR (400 MHz, chloroform-d) δ 5.88–5.84 (m, 1H), 5.40–5.28 (m, 2H), 4.25 (d, J = 7.0 Hz, 2H), 3.80–3.73 (m, 4H), 0.88–0.85 (m, 3H).

[0741] Exemplary steps for the preparation of 1-allylimidazolidine-2,4-one(III):

[0742] 50% H₂SO₄ (13.5 mL) was added dropwise to a stirred solution of II (2.70 g, 16.0 mmol) in Et₂O (27 mL) at 0 °C. The reaction mixture was stirred for 30 min at the same temperature and allowed to cool to room temperature for 7 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was treated with ice-cold water, and the precipitated solid was filtered off and washed with diethyl ether to give III.

[0743] Yield: 0.1 g, 7.14%; 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 5.90–5.69 (m, 1H), 5.25–5.05 (m, 2H), 3.91–3.79 (m, 4H).

[0744] Exemplary steps for the preparation of but-3-ene-1-sulfonic acid (IV)

[0745] Na₂SO₃ (8.33 g, 66.11 mmol) was added to a stirred aqueous solution of 4-bromobut-1-ene (4.00 g, 33.05 mmol) (30 mL), and the mixture was heated at 100°C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and washed with diethyl ether. The aqueous layer was concentrated to dryness to give the title compound IV.

[0746] Yield: 7 g, crude product; 1 H NMR (400 MHz, D2O) δ 5.97-5.95 (m, 1H), 5.29–5.06 (m, 2H), 3.17–2.89 (m, 2H), 2.57–2.46 (m, 2H).

[0747] Exemplary steps for the preparation of but-3-ene-1-sulfonyl chloride (V)

[0748] DMF (1.5 mL) was added to a stirred solution of IV (7 g, 48.61 mmol) in (COCl)₂ (70 mL), and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated and the residue was purified by grinding with diethyl ether to give V.

[0749] Yield: 2 g, Crude product: 1 H NMR (400 MHz, CDCl3) δ 5.94–5.74 (m, 1H), 5.30–5.02 (m, 2H), 3.15–3.03 (m, 2H), 2.86–2.73 (m, 2H).

[0750] Exemplary steps for the preparation of methyl 3-(cyclopropylmethoxy)-4-fluorobenzoate (VI):

[0751] To a stirred MeOH solution (100 mL) of 3-(cyclopropylmethoxy)-4-fluorobenzoic acid (3.00 g, 14.28 mmol), concentrated H₂SO₄ (1 mL) was added dropwise, and the reaction mixture was heated at 65°C for 8 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was neutralized with NaHCO₃ in the aqueous phase and evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography using 20% ​​EtOAc / hexane to give VI.

[0752] Yield: 2.3 g, 71.87%; 1H NMR (400 MHz, DMSO-d6) δ 7.65–7.53 (m, 2H),7.41–7.24 (m, 1H), 3.96 (d, J = 7.0 Hz, 2H), 3.85 (s, 2H), 1.28-1.25 (m, 1H),0.58-0.56 (m, 2H), 0.36-0.33 (m, 2H).

[0753] Exemplary steps for the preparation of (3-(cyclopropylmethoxy)-4-fluorophenyl)methanol (VII):

[0754] LiBH4 (1M DCM solution, 20 mL, 20.53 mmol) was added dropwise to VI (2.30 g, 10.26 mmol) of stirred DCM solution at 0 °C, and the reaction mixture was heated at 80 °C for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give VII.

[0755] Yield: 2 g, crude product; 1 H NMR (400 MHz, DMSO-d6) δ 7.36–7.00 (m, 2H), 6.87-6.85 (m, 1H), 5.18 (t, J = 5.7 Hz, 1H), 4.44 (d, J = 5.7 Hz, 2H), 4.08–3.75(m, 2H), 1.32–1.13 (m, 1H), 0.64–0.49 (m, 2H), 0.35–0.32 (m, 2H).

[0756] Exemplary steps for the preparation of 3-(cyclopropylmethoxy)-4-fluorobenzaldehyde (VIII):

[0757] PCC (4.38 g, 20.40 mmol) was added to 20 mL of dry DCM solution of VII (2.00 g, 10.20 mmol) under stirring, and the mixture was heated to room temperature for 5 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain VIII.

[0758] Yield: 2.00 g, crude product; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.71–7.52 (m, 2H), 7.52–7.06 (m, 1H), 3.99 (d, J = 7.1 Hz, 2H), 1.34–1.16 (m, 1H),0.68–0.51 (m, 2H), 0.38-0.36 (m, 2H).

[0759] Exemplary steps for the preparation of (Z)-N-(tert-butyl(1-hydroxy)-1,3-thio)-1-(3-(cyclopropylmethoxy)-4-fluorophenyl)methylimine (IX):

[0760] Add Ti(O) to a 20 mL dry toluene solution of VIII (2.00 g, 10.25 mmol) and tert-butyl-3-sulfanamine (1.2 g, 10.25 mmol) under stirring. i Pr)4 (5.82 g, 20.50 mmol) was heated at 90 °C for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give IX.

[0761] Yield: 2.3 g, 75.65%; NMR: 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.57-7.55 (m, 1H), 7.38 (dd, J = 11.2, 8.4Hz, 1H), 5.75 (s, 1H), 4.01–3.91 (m, 2H), 1.18 (s, 9H), 0.64–0.52 (m, 2H), 0.40–0.28 (m, 2H).

[0762] Exemplary steps for the preparation of (R)-1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl-1-amine (X):

[0763] CH3MgBr (2M THF solution, 7.7 mL, 77.44 mmol) was added dropwise to a dry THF solution (2.30 g, 38.72 mmol) of stirred IX at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. A dioxane solution of HCl (4 mL) was added to the residue, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by grinding with diethyl ether to give X.

[0764] Yield: 2 g, NMR: 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 7.48 (dd, J =8.3, 2.2 Hz, 1H), 7.22 (dd, J = 11.4, 8.3 Hz, 1H), 7.07-7.04 (m, 1H), 4.34(p, J = 5.9 Hz, 1H), 3.93 (d, J = 7.1 Hz, 2H), 1.50 (d, J = 6.7 Hz, 3H), 1.30-1.24 (m, 1H), 0.60-0.58 (m, 2H), 0.40–0.27 (m, 2H).

[0765] Exemplary steps for the preparation of (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)but-3-ene-1-sulfonamide (XI):

[0766] Add Et3N (0.241 g, 2.39 mmol) to a dry DCM solution (5 mL) of X (0.2 g, 0.93 mmol) under stirring and stir at room temperature (rt) for 10 min. Then add a DCM solution (5 mL) of V (0.176 g, 1.14 mmol) dropwise and stir at room temperature for 2 h. Monitor the reaction progress by TLC. After the reaction is complete, quench the reaction mixture with water and extract with DCM. Wash the combined organic layers with brine, dry over anhydrous Na2SO4, and concentrate under reduced pressure. Purify the crude product by column chromatography using a DCM solution of 3% MeOH to give XI.

[0767] Yield: 0.15g, 48%.

[0768] Production Example 3. Synthesis of (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0769] To a stirred solution (2 mL) of compound XI (0.292 g, 0.89 mmol) and compound III (0.125 g, 0.89 mmol) in DCM, 0.015 g (0.017 mmol) of Grubb's second-generation catalyst was added, and the reaction mixture was stirred at room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography with 60% EtOAc / hexane to give (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide.

[0770] Yield: 0.07 g, 17%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.70 (d, J= 8.9 Hz, 1H), 7.19-7.15 (m, 2H), 6.95-6.89 (m, 1H), 5.49-5.45 (m, 1H), 5.42–5.23 (m, 1H), 4.47–4.35 (m, 1H), 3.92 –3.70 (m, 2H), 3.85 (s, 2H), 3.79 (d, J= 7.5 Hz, 2H), 2.89–2.81 (m, 2H), 2.75–2.70 (m, 2H), 2.31–2.17 (m, 2H), 1.43–1.14 (m, 4H), 0.60–0.57 (m, 2H), 0.38–0.29 (m, 2H); ESI-MS (m / z): Calculated value: C 20 H 26 FN3O5S: 439.50; Observation quality: 456.97 (M+H2O); HPLC purity: 99.5%; R t: : 5.8.

[0771] Production Example 8. Synthesis of (R,E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-isobutoxyphenyl)ethyl)pent-3-ene-1-sulfonamide:

[0772] The title compound was prepared using 1-allylimidazolidine-2,4-dione and (R)-N-(1-(4-fluoro-3-isobutoxyphenyl)ethyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0773] Yield: 0.075 g, 14%; 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.73(dd, J = 8.9, 1.7 Hz, 1H), 7.26–7.08 (m, 2H), 6.93-6.89 (m, 1H), 5.53–5.41(m, 1H), 5.34–5.23 (m, 1H), 4.48–4.35 (m, 1H), 3.87–3.70 (m, 6H), 2.90 -2.87(m, 1H), 2.63-2.59(m, 1H), 2.23-2.19 (m, 2H), 2.06-2.01 (m, 1H), 1.37 (d, J= 7.0 Hz, 3H), 0.99 (d, J = 6.9, Hz, 6H); ESI-MS (m / z): Calculated value: C 20 H 28 FN3O5S: 441.52; Observed mass: 464.10 (M+Na); HPLC purity: 99.3%; R t; 8.2.

[0774] Production Example 26. Synthesis of (R,E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(neopentyloxy)phenyl)ethyl)pent-3-ene-1-sulfonamide:

[0775] The title compound was prepared using (R)-N-(1-(4-fluoro-3-(neopteroxy)phenyl)ethyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0776] Yield: 0.05 g, 20%; 1 H NMR (400 MHz, DMSO-d 6) δ 10.7 (s, 1H), 7.73 (d, J= 8.6 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.16-7.12 (m, 1H), 6.95–6.87 (m,1H), 5.49-5.46 (m, 1H), 5.30-5.27 (m, 1H), 4.41 (t, J = 8.2 Hz, 1H), 3.79 (s,2H), 3.75–3.64 (m, 4H), 2.90-2.87 (m, 1H), 2.41-2.22 (m, 1H), 2.24-2.20 (m,2H), 1.40–1.31 (m, 3H), 1.01 (s, 9H); ESI-MS (m / z): Calculated value: C 21 H 30 FN3O5S: 455.55; Observation mass: 473.20 (M+H2O); HPLC purity: 97.1%; R t; 8.6.

[0777] Production Example 28. Synthesis of (R,E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)pent-3-ene-1-sulfonamide:

[0778] The title compound was prepared using (R)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0779] Yield: 0.11 g, 36%; 1 H NMR (400 MHz, DMSO-d 6) δ 10.75 (s, 1H), 7.74 (d,J = 8.8 Hz, 1H), 7.23 (dd, J = 8.3, 2.1 Hz, 1H), 7.13 (dd, J = 11.4, 8.3 Hz,1H), 6.93-6.90 (m, 1H), 5.47-5.42 (m, 1H), 5.29-5.20 (m, 1H), 4.69 (s, 1H), 4.48–4.35 (m, 1H), 3.82–3.69 (m, 6H), 2.90-2.88 (m, 1H), 2.66-6.32 (m, 1H),2.33–2.12 (m, 2H), 1.37 (d, J = 6.9 Hz, 3H), 1.21 (s, 6H); ESI-MS (m / z): Calculated value: C 20 H 28 FN3O6S: 457.52; observed mass: 456.10 (MH); HPLC purity: 99.8%; R t; 6.8.

[0780] Production Example 29. Synthesis of (R,E)-N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0781] The title compound was prepared using (R)-N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0782] Yield: 0.09 g, 16.5%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.74(d, J = 8.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.01–6.88 (m, 2H), 6.79-6.74(m, 1H), 5.41-5.38 (m, 1H), 5.32–5.20 (m, 1H), 4.46–4.32 (m, 1H), 3.87–3.64(m, 6H), 2.88-2.83 (m, 1H), 2.58-2.52 (m, 1H), 2.25-2.20 (m, 2H), 1.41–1.31(m, 3H), 1.29–1.13 (m, 1H), 0.61–0.50 (m, 2H), 0.38–0.24 (m, 2H); ESI-MS (m / z): Calculated value: C 20 H 27 N3O5S: 421.51; Observed mass: 422.10 (M+H); HPLC purity: 94.1%; R t; 7.7.

[0783] Production Example 57. Synthesis of [(R,E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(3-isobutoxyphenyl)ethyl]pent-3-ene-1-sulfonamide:

[0784] The title compound was prepared using (R)-N-(1-(3-isobutoxyphenyl)ethyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0785] Yield: 0.16 g, 25%; 1 H NMR (400 MHz, DMSO-d 6) δ 10.7 (s, 1H), 7.74 (d,J = 8.6 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J = 7.5 Hz,1H), 6.78 (dd, J = 8.5, 2.6 Hz, 1H), 5.45-5.40 (m, 1H), 5.28-5.23 (m, 1H),4.39-4.30 (m, 1H), 3.74-3.70 (m, 6H), 2.88-2.83 (m, 1H), 2.59-2.54 (m, 1H),2.25-2.20 (m, 2H), 2.04-1.99 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.7 Hz, 6H); ESI-MS (m / z): Calculated value: C 20 H 29 N3O5S: 423.53; Observed mass: 422.20 (M⁻¹); HPLC purity: 97.3%; R t; 7.9.

[0786] Production Example 67. Synthesis of (R,E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)pent-3-ene-1-sulfonamide:

[0787] The title compound was prepared using (R)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0788] Yield: 0.11 g, 36%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.23 (dd, J = 8.3, 2.1 Hz, 1H), 7.13 (dd, J = 11.4, 8.3 Hz,1H), 6.93-6.90 (m, 1H), 5.47-5.40 (m, 1H), 5.29-5.52 (m, 1H), 4.69 (s, 1H), 4.48–4.35 (m, 1H), 3.82–3.69 (m, 6H), 2.90-2.88 (m, 1H), 2.66-6.32 (m, 1H),2.33–2.12 (m, 2H), 1.37 (d, J = 6.9 Hz, 3H), 1.21 (s, 6H); ESI-MS (m / z): Calculated value: C 20 H 28 FN3O6S: 457.52; observed mass: 456.10 (MH); HPLC purity: 99.8%; R t : 6.8.

[0789] Production Example 43. Synthesis of (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)propyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0790] The title compound was prepared using (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)propyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0791] Yield: 0.108 g, 12.5%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.70(d, J = 9.4 Hz, 1H), 7.22–7.08 (m, 2H), 6.90 (d, J = 5.0 Hz, 1H), 5.47–5.29(m, 1H), 5.23-5.20 (m, 1H), 4.11-4.08 (m, 1H), 3.92–3.84 (m, 2H), 3.78 (s,2H), 3.71 (d, J = 5.7 Hz, 2H), 2.83-2.79 (m, 1H), 2.28–2.07 (m, 2H), 1.66-1.62 (m, 2H), 1.25–1.20 (m, 3H), 0.85–0.77 (m, 3H), 0.58–0.50 (m, 2H), 0.32–0.30 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 28 FN3O5S: 453.53; Observation quality: 454.10 (M +1); HPLC purity: 99.9%; R t; 8.0.

[0792] Production Example 95. Synthesis of (R,E)-N-(1-(3-(cyclopropylmethoxy)phenyl)propyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0793] The target compound was prepared using (R)-N-(1-(3-(cyclopropylmethoxy)phenyl)propyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0794] Yield: 0.095 g, 17.6%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.73(d, J = 9.1 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.96-6.92 (m, 1H), 6.88 (d, J= 7.5 Hz, 1H), 6.77 (dd, J = 8.2, 2.4 Hz, 1H), 5.35-5.30 (m, 1H), 5.20-5.17(m, 1H), 4.08-4.00 (m, 1H), 3.89–3.62 (m, 6H), 2.81-2.78 (m, 1H), 2.45-2.42(m, 1H), 2.21–2.18 (m, 2H), 1.76–1.55 (m, 2H), 1.23–1.20 (m, 1H), 0.82 (t, J = 7.3 Hz, 3H), 0.61–0.50 (m, 2H), 0.38–0.26 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 29 N3O5S: 435.54 μm (observed mass); 434.20 μm (MH); HPLC purity: 99.1%; R t; 7.7.

[0795] Production Example 1. Synthesis of (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0796] Rh / Al₂O₃ (6 mg) was added to a stirred MeOH solution (4 mL) of (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide (0.06 g, 0.13 mmol), and the mixture was stirred for 16 h at room temperature under a hydrogen atmosphere (balloon pressure). The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography using 50% EtOAc / hexane to give (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide.

[0797] Yield: 0.03 g, 50%; 1¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.23–7.09 (m, 2H), 6.95–6.89 (m, 1H), 4.46–4.33 (m, 1H), 3.89–3.84 (m, 4H), 3.13 (t, J = 7.0 Hz, 2H), 2.80–2.76 (m, 1H), 2.56–2.32 (m, 1H), 1.57–1.00 (m, 10H), 0.60–0.57 (m, 2H), 0.33–0.30 (m, 2H); ESI-MS (m / z): Calculated values: C 20 H 28 FN3O5S: 441.52 μg / L (observed mass); 464.15 μg / L (M+Na); HPLC purity: 95.9%; R t 7.8.

[0798] Production Example 20. Synthesis of 5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)pentane-1-sulfonamide:

[0799] The title compound was prepared using (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0800] Yield: 0.045 g, 56%; 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 8.17 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 11.3, 8.4 Hz, 1H), 6.96–6.88 (m, 1H), 3.89–3.77 (m, 4H), 3.12 (t, J = 7.1 Hz, 2H), 2.54 (d, J = 7.3 Hz, 2H), 2.06–2.02 (m, 1H), 1.43–1.40 (m, 2H), 1.35–1.14 (m, 4H), 1.11–0.95 (m, 10H); ESI-MS (m / z): Calculated values: C 21 H 30FN3O5S: 455.55; Observation mass: 456.20 (M+H); HPLC purity: 99.4%; R t; 8.2.

[0801] Production Example 22. Synthesis of (R)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)pentane-1-sulfonamide:

[0802] The title compound was prepared using (R,E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)ethyl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0803] Yield: 0.09 g, 93%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.69 (d,J = 8.7 Hz, 1H), 7.23 (dd, J = 8.3, 2.0 Hz, 1H), 7.19–7.09 (m, 1H), 6.93-6.90(m, 1H), 4.69 (s, 1H), 4.47–4.34 (m, 1H), 3.87 (s, 2H), 3.77 (s, 2H), 3.13 (t, J = 7.1 Hz, 2H), 2.81–2.78 (m, 1H), 2.61–2.50 (m, 1H), 1.60–1.40 (m, 2H),1.34-1.30 (m, 5H), 1.30 (s, 6H), 1.10–1.00 (m, 2H); ESI-MS (m / z): Calculated value: C 20 H 30 FN3O6S: 459.53; Observed mass: 482.20 (M+Na); HPLC purity: 93.3%; R t; 6.9.

[0804] Production Example 63. Synthesis of (R)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(3-isobutoxyphenyl)ethyl)pentane-1-sulfonamide: The title compound was prepared using ((R,E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(3-isobutoxyphenyl)).

[0805] Yield: 0.1 g, 77%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.67 (d, J= 8.7 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J = 7.6 Hz,1H), 6.80 (d, J = 8.2 Hz, 1H), 4.38-4.30 (m, 1H), 3.86 (s, 2H), 3.72 (d, J =6.4 Hz, 2H), 3.22–3.08 (m, 2H), 2.78-2.74 (m, 1H), 2.58-2.44 (m, 1H), 2.04-1.99 (m, 1H), 1.58–1.21 (m, 6H), 1.19–0.91 (m, 9H); ESI-MS (m / z): Calculated value: C 20 H 31 N3O5S: 425.54; observed mass: 424.15 (MH); HPLC purity: 96.8%; R t; 7.9.

[0806] Production Example 64. Synthesis of (R)-N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0807] The title compound was prepared using (R,E)-N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0808] Yield: 0.04 g, 61.3%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.68(d, J = 8.8 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.00–6.88 (m, 2H), 6.82–6.74(m, 1H), 4.48–4.31 (m, 1H), 3.87 (s, 2H), 3.79 (d, J = 7.0 Hz, 2H), 3.12 (t,J = 7.0 Hz, 2H), 2.78-2.74 (m, 1H), 2.58-2.42 (m, 1H), 1.58–0.96 (m, 10H),0.61–0.50 (m, 2H), 0.38–0.27 (m, 2H); ESI-MS (m / z): Calculated value: C 20 H 29 N3O5S: 423.53 (observed mass); 422.10 (MH); HPLC purity: 99.9%; R t; 7.5.

[0809] Production Example 80. Synthesis of (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)propyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0810] The title compound was prepared using (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)propyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0811] Yield: 0.082 g, 93%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.64 (d,J = 9.2 Hz, 1H), 7.22–7.09 (m, 2H), 6.90-6.88 (m, 1H), 4.10 (q, J = 7.9 Hz,1H), 3.92–3.81 (m, 4H), 3.16–3.04 (m, 2H), 2.74–2.70 (m, 1H), 2.48–244 (m,1H), 1.67–1.64 (m, 2H), 1.52–1.42 (m, 1H), 1.41–1.34 (m, 1H), 1.33–1.19 (m,3H), 1.09–1.05 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H), 0.6–0.57 (m, 2H), 0.39–0.27 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 30 FN3O5S: 455.55; Observation mass: 456.10 (M+H); HPLC purity: 98.4%; R t; 8.0.

[0812] Production Example 96. Synthesis of (R)-N-(1-(3-(cyclopropylmethoxy)phenyl)propyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0813] The title compound was prepared using (R,E)-N-(1-(3-(cyclopropylmethoxy)phenyl)propyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0814] Yield: 0.082 g, 93%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.66 (d,J = 9.3 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.99–6.93 (m, 1H), 6.88 (d, J =7.6 Hz, 1H), 6.78 (dd, J = 8.1, 2.6 Hz, 1H), 4.07 (q, J = 7.9 Hz, 1H), 3.85(s, 1H), 3.79 (d, J = 7.0 Hz, 2H), 3.14–3.05 (m, 2H), 2.72-2.69 (m, 1H),2.39-2.35 (m, 1H), 1.69–1.64 (m, 2H), 1.43–1.15 (m, 6H), 1.09–1.04 (m, 1H), 0.96–0.92 (m, 1H), 0.82 (t, J = 7.2 Hz, 3H), 0.61–0.50 (m, 2H), 0.33–0.30 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 31 N3O5S: 437.56; Observed mass: 436.15 (MH); HPLC purity: 93.4%; R t; 7.8.

[0815] Production Example 21: Synthesis of (R,E)-N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0816] The title compound was prepared using (R)-N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)ethyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0817] Yield: 0.051 g, 13%; 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.72 (d,J = 8.8 Hz, 1H), 7.33–7.16 (m, 2H), 7.025-7.01 (m, 1H), 6.42 (tt, J = 56.0,3.6 Hz, 1H), 5.55–5.36 (m, 1H), 5.34-5.29 (m, 1H), 4.50–4.27 (m, 3H), 3.87–3.68 (m, 4H), 2.95-2.89 (m, 1H), 2.73-2.69 (m, 1H), 2.24-2.22 (m, 2H), 1.38(d, J = 6.8 Hz, 3H); ESI-MS (m / z): Calculated value: C 18 H 22 F3N3O5S: 449.45; observed mass: 472.90 (M+Na); HPLC purity: 95.5%; R t; 7.4.

[0818] Production Example 23. Synthesis of (R)-N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0819] The title compound was prepared using (R,E)-N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0820] Yield: 0.03 g, 86%; 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.33–7.16 (m, 2H), 7.05–7.01 (m, 1H), 6.42 (tt, J = 56.0, 3.6 Hz, 1H), 4.4–4.37 (m, 3H), 3.87 (s, 2H), 3.13 (t, J = 7.0 Hz, 2H), 2.82–2.79 (m, 1H), 2.63–2.60 (m, 1H), 1.60–1.27 (m, 9H); ESI-MS (m / z): Calculated values: C 18 H 24F3N3O5S: 451.46; Observation mass: 469.10 (M+H2O); HPLC purity: 97.9%; R t; 7.5.

[0821] Exemplary steps for the preparation of 3-(cyclopropylmethoxy)-4-fluorobenzonitrile (XII)

[0822] To a dry DMF solution (100 mL) of stirred 4-fluoro-3-hydroxybenzonitrile (10.0 g, 78.74 mmol), K₂CO₃ (21.73 g, 157.4 mmol) was added, followed by cyclopropylmethyl bromide (12.85 g, 94.48 mmol). The reaction mixture was heated at 90°C for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with ice-cold water, and the precipitated solid was filtered and washed with pentane to give XII.

[0823] Yield: 12 g, 94%; 1 H NMR (400 MHz, CDCl3) δ 7.28–7.11 (m, 3H), 3.90 (d,J = 7.1 Hz, 2H), 1.32–1.29 (m, 1H), 0.76–0.63 (m, 2H), 0.45–0.32 (m, 2H).

[0824] Exemplary steps for the preparation of 1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropane-1-amine (XIII)

[0825] Ti(O) was added to a dry THF solution (40 mL) of XII (7.8 g, 40.83 mmol) under stirring at -78 °C. i Pr)4 (12.75 g, 44.92 mmol). CH3CH2MgBr (3M Et2O solution, 29 mL, 89.82 mmol) was added dropwise under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1 h. BF3·OEt2 (5.68 g, 80.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with 1N HCl and stirred for 10 min. The reaction mixture was then neutralized with aqueous NaOH and extracted with Et2O. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography using 30% EtOAC / hexane to give XIII.

[0826] Yield: 4.1 g, 47%. NMR: 1H NMR (400 MHz, DMSO-d6) δ 4.04 (d, J = 7.1 Hz, 2H), 2.54 (d, J = 9.9 Hz, 2H), 2.48–2.27 (m, 5H), 1.90–1.72 (m, 2H), 1.17–1.10 (m, J = 7.0 Hz, 2H).

[0827] Exemplary steps for the preparation of N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)but-3-ene-1-sulfonamide (XIV)

[0828] Et3N (0.08 mL, 0.57 mmol) was added to 4 mL of dried DCM solution (0.1 g, 0.44 mmol) of XIII under stirring, and the mixture was stirred at room temperature for 10 min. Subsequently, 4 mL of DCM solution (0.083 g, 0.53 mmol) of V was added dropwise, and the mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and purified with EtOA. C Extraction. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentration was then achieved using 30% EtOA. C The crude product was purified by column chromatography using hexane DCM solution to obtain XIV.

[0829] Yield: 0.043 g, 30%; NMR: 1 H NMR (400 MHz, CDCl3) δ 7.11–6.92 (m, 3H),5.60-5.55 (m, 1H), 5.10 (s, 1H), 5.04–4.89 (m, 2H), 3.89 (d, J = 6.9 Hz, 2H),2.79–2.63 (m, 342.10 (M+H).

[0830] Production Example 8: Synthesis of (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)pent-3-ene-1-sulfonamide:

[0831] The title compound was prepared using N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0832] Yield: 0.1 g, 15.2%; 0.1 g, 15.2%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s,1H), 8.17 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 11.3, 8.4 Hz, 1H), 6.96–6.88 (m, 1H), 5.53–5.41 (m, 1H), 5.34–5.23 (m, 1H), 3.89–3.77 (m, 4H), 3.86–3.76 (m, 2H), 2.66–2.52 (m, 2H), 2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.23(s, 4H), 1.12–0.90 (m, 7H); ESI-MS (m / z): Calculated value: C 21 H 28 FN3O5S: 453.53; Observation mass: 454.1 (M+H); HPLC purity: 98.5%; R t; 8.2.

[0833] Production Example 10: Synthesis of (E)-N-(1-(3-(cyclobutylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0834] The title compound was prepared using N-(1-(3-(cyclobutylmethoxy)-4-fluorophenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Example 3 above.

[0835] Yield: 0.1 g, 15.22%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.22 (s, 1H), 7.24 (dd, J = 8.3, 2.2 Hz, 1H), 7.22–7.05 (m, 1H), 6.95-6.90 (m,1H), 5.45-5.39 (m, 1H), 5.36–5.18 (m, 1H), 4.01 (d, J = 6.7 Hz, 2H), 3.89 (s,2H), 3.79–3.69 (m, 1H), 2.78–2.72 (m, 1H), 2.66–2.57 (m, 2H), 2.32–1.75 (m,8H), 1.29–1.05 (m, 5H); ESI-MS (m / z): Calculated value: C 22 H 28 FN3O5S: 465.54 (observed mass); 466.20 (M+H); HPLC purity: 91.4%; R t; 8.4.

[0836] Production Example 11: Synthesis of (E)-N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0837] The title compound was prepared using N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0838] Yield: 0.03 g, 7.59%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.20(s, 1H), 7.25–7.13 (m, 2H), 7.05-7.02(m, 1H), 6.20 (tt, J = 56.0, 3.6 Hz,1H), 5.49–5.21 (m, 2H), 4.37 (dt, J = 14.6, 3.6 Hz, 2H), 3.86 (s, 2H), 3.72 (d, J = 5.9 Hz, 2H), 2.67 (dd, J = 8.8, 6.5 Hz, 2H), 2.17 (q, J = 7.1 Hz,2H), 1.30–1.08 (m, 4H); ESI-MS (m / z): Calculated value: C19 H 22 F3N3O5S: 461.46; Observation mass: 462.05 (M+H); HPLC purity: 98.0%; R t; 7.4.

[0839] Production Example 12: Synthesis of (E)-N-(1-(3-(cyclopentylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0840] The title compound was prepared using N-(1-(3-(cyclopentylmethoxy)-4-fluorophenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0841] Yield: 0.08 g, 12.3%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.23 ​​(d, J = 6.1 Hz, 1H), 7.29–7.16 (m, 1H), 7.16–7.06 (m, 1H), 6.96–6.88 (m, 1H),5.41-5.38 (m, 1H), 5.25-5.20 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.78 (s, 2H), 3.72 (d, J = 6.0 Hz, 2H), 3.36–3.20 (m, 1H), 2.65–2.56 (m, 2H), 2.35-2.23 (m,1H), 2.15–2.00 (m, 1H), 1.79–1.75 (m, 2H), 1.59–1.55 (m, 4H), 1.39–1.04 (m, 6H); ESI-MS (m / z): Calculated value: C 23 H 30 FN3O5S: 479.57; Observation mass: 480.20 (M+H); HPLC purity: 98.3%; R t; 8.6.

[0842] Production Example 13: Synthesis of (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(neopteroxy)phenyl)cyclopropyl)pent-3-ene-1-sulfonamide:

[0843] The title compound was prepared using N-(1-(4-fluoro-3-(neopteroxy)phenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0844] Yield: 0.045 g, 15%; 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.22 (s,1H), 7.25 (dd, J = 8.3, 2.2 Hz, 1H), 7.11 (dd, J = 11.4, 8.5 Hz, 1H), 5.41(d, J = 15.4 Hz, 1H), 5.29–5.19 (m, 1H), 3.80–3.66 (m, 6H), 2.66–2.57 (m,2H), 2.16-2.13 (m, 2H), 1.23 (d, J = 4.7 Hz, 3H), 1.09 (t, J = 3.6 Hz, 2H),1.01 (s, 9H); ESI-MS (m / z): Calculated value: C 22 H 30 FN3O5S: 467.56; Observation mass: 468.05 (M+H); HPLC purity: 98.7%; R t; 8.5.

[0845] Production Example 14: Synthesis of (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)cyclopropyl)pent-3-ene-1-sulfonamide:

[0846] The title compound was prepared from N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0847] Yield: 0.035 g, 5.32%; 1¹H NMR (400 MHz, DMSO-d⁶) δ 10.8 (s, 1H), 8.23 ​​(s, 1H), 7.25–7.08 (m, 2H), 6.96–6.92 (m, 1H), 5.37–5.31 (m, 1H), 5.23–5.19 (m, 1H), 4.64 (s, 1H), 3.88 (d, J = 7.1 Hz, 4H), 3.51 (d, J = 6.0 Hz, 2H), 2.61–2.52 (m, 2H), 2.15–2.12 (m, 2H), 1.38–1.03 (m, 8H), 0.90–0.76 (m, 2H); ESI-MS (m / z): Calculated C 21 H 28 FN3O6S: 469.53; Observed mass: 491.75 (M+Na); HPLC purity: 97.5%; R t; 6.8.

[0848] Production Example 60: Synthesis of (E)-N-(1-(3-(2,2-difluoroethoxy)phenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0849] The title compound was prepared using N-(1-(3-(2,2-difluoroethoxy)phenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0850] Yield: 0.076 g, 19%; 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.24 (s,1H), 7.24-7.20 (m, 1H), 7.07–6.96 (m, 2H), 6.88–6.74 (m, 1H), 6.34 (tt, J =56.0, 3.7 Hz, 1H), 5.45-5.33 (m, 1H), 5.32–5.20 (m, 1H), 4.28 (dt, J = 14.8,3.6 Hz, 2H), 3.89–3.75 (m, 2H), 3.72 (d, J = 5.7 Hz, 2H), 2.65-2.61 (m, 2H),2.18-2.15 (m, 2H), 1.30–1.14 (m, 2H), 1.10–1.04 (m, 2H); ESI-MS (m / z): Calculated value: C19 H 23 F2N3O5S: 443.47 (observed mass); 443.75 (M+H); HPLC purity: 98.0%; R t; 7.3.

[0851] Production Example 57: Synthesis of (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(3-isobutoxyphenyl)cyclopropyl)pent-3-ene-1-sulfonamide:

[0852] The title compound was prepared using N-(1-(3-isobutoxyphenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0853] Yield: 0.06 g, 11%; 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.25 (s,1H), 7.19 (t, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.80–6.72 (m, 1H), 5.39-5.35 (m, 1H), 5.28–5.16 (m, 1H), 3.79–3.67 (m, 6H), 2.63–2.55 (m, 2H), 2.16-2.13 (m, 2H), 2.02-1.98 (m, 1H), 1.30–1.03 (m, 4H), 0.97(d, J = 6.5 Hz, 6H); ESI-MS (m / z): Calculated value: C 21 H 29 N3O5S: 435.54 (observed mass); 435.85 (M+H); HPLC purity: 93.4%; R t; 8.0.

[0854] Production Example 58: Synthesis of (E)-N-(1-(3-(cyclopropylmethoxy)phenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide

[0855] The title compound was prepared using N-(1-(3-(cyclopropylmethoxy)phenyl)cyclopropyl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0856] Yield: 0.11 g, 16.3%;1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.22(s, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.99 (s, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.73 (dd, J = 8.0, 2.6 Hz, 1H), 5.36-5.31 (m, 1H), 5.25-5.20 (m, 1H), 3.77-3.72 (m, 4H), 3.70 (d, J = 5.8 Hz, 2H), 2.59 (dd, J = 9.8, 6.1 Hz, 2H), 2.15-2.12 (m, 2H), 1.21–1.15 (m, 3H), 1.06–1.00 (m, 2H), 0.60–0.50 (m, 2H), 0.30–0.26 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 27 N3O5S: 433.52; Observation mass: 434.10 (M+H); HPLC purity: 99.5%; R t; 7.6.

[0857] Production Example 5: Synthesis of N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[0858] The title compound was prepared using (E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0859] Yield: 0.09 g, 90%; 1¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 8.17 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 11.3, 8.4 Hz, 1H), 6.96–6.88 (m, 1H), 3.89–3.77 (m, 4H), 3.12–3.10 (m, 2H), 2.56–2.53 (m, 2H), 1.42–1.03 (m, 11H), 0.65–0.60 (m, 2H), 0.38–0.32 (d, J = 5.0 Hz, 2H); ESI-MS (m / z): Calculated values: C 21 H 28 FN3O5S: 453.53; Observation mass: 454.10 (M+H); HPLC purity: 99.3%; R t; 7.9.

[0860] Production Example 7: Synthesis of 5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)pentane-1-sulfonamide:

[0861] The title compound was prepared using (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0862] Yield: 0.045 g, 56%; 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 8.17 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 11.3, 8.4 Hz, 1H), 6.96–6.88 (m, 1H), 3.89–3.77 (m, 4H), 3.12 (t, J = 7.1 Hz, 2H), 2.54–2.50 (m, 2H), 2.06–2.02 (m, 1H), 1.43–1.40 (m, 2H), 1.35–1.14 (m, 4H), 1.11–0.95 (m, 10H); ESI-MS (m / z): Calculated values: C 21 H 30 FN3O5S: 455.55; observed mass 456.20 (M+H); HPLC purity: 99.4%; Rt; 8.2.

[0863] Production Example 9: Synthesis of N-(1-(3-(cyclobutylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0864] The title compound was prepared using (E)-N-(1-(3-(cyclobutylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0865] Yield: 0.06 g, 60%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.17 (s,1H), 7.24 (dd, J = 8.3, 2.2 Hz, 1H), 7.12 (dd, J = 11.4, 8.4 Hz, 1H), 6.95-6.91 (m, 1H), 4.02 (d, J = 6.7 Hz, 2H), 3.87 (s, 2H), 3.12 (t, J = 7.1 Hz,2H), 2.78-2.71 (m, 1H), 2.54-2.51 (m, 2H), 2.10-2.05 (m, 2H), 1.96–1.75 (m,4H), 1.49–1.37 (m, 2H), 1.36–0.98 (m, 8H); ESI-MS (m / z): Calculated value: C 22 H 30 FN3O5S: 467.56; Observed mass: 468.10 (M+H); HPLC purity: 99.2%; R t; 8.3.

[0866] Production Example 35: Synthesis of N-(1-(3-(cyclopentylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0867] The title compound was prepared using (E)-N-(1-(3-(cyclopentylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0868] Yield: 0.025 g, 40.2%; 1¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 8.17 (s, 1H), 7.25 (dd, J = 8.5, 2.2 Hz, 1H), 7.12 (dd, J = 11.4, 8.4 Hz, 1H), 6.95–6.91 (m, 1H), 3.94–3.80 (m, 4H), 3.12 (t, J = 7.0 Hz, 2H), 2.63–2.47 (m, 2H), 2.35–2.30 (m, 1H), 1.84–1.71 (m, 2H), 1.68–0.97 (m, 16H); ESI-MS (m / z): Calculated values: C 23 H 32 FN3O5S: 481.58; Observation mass: 482.15 (M+H); HPLC purity: 95.8%; R t; 8.7.

[0869] Production Example 36: Synthesis of N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0870] The title compound was prepared using (E)-N-(1-(3-(2,2-difluoroethoxy)-4-fluorophenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0871] Yield: 0.05 g, 83.3%; 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 8.14 (s, 1H), 7.19–7.15 (m, 2H), 7.05–7.00 (m, 1H), 6.40 (tt, J = 56.0, 3.3 Hz, 1H), 4.37 (dt, J = 14.6, 3.5 Hz, 2H), 3.86 (s, 2H), 3.11 (t, J = 7.1 Hz, 2H), 2.62–2.53 (m, 2H), 1.43–1.40 (m, 2H), 1.36–1.00 (m, 8H); ESI-MS (m / z): Calculated values: C 19 H 24 F3N3O5S: 463.47; Observation mass: 464.07 (M+H); HPLC purity: 97.1%; Rt; 7.4.

[0872] Production Example 37: Synthesis of 5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(neopteroxy)phenyl)cyclopropyl)pentane-1-sulfonamide:

[0873] The title compound was prepared using (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(neopteroxy)phenyl)cyclopropyl)pent-3-ene-1-sulfonamide and Rh.Al2O3 in a manner similar to that described in Production Example 1 above.

[0874] Yield: 0.022 g, 73.3%; 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 8.18 (s, 1H), 7.25 (dd, J = 8.3, 2.2 Hz, 1H), 7.13 (dd, J = 11.4, 8.4 Hz, 1H), 6.96–6.91 (m, 1H), 3.86 (s, 2H), 3.69 (s, 2H), 3.12 (t, J = 7.0 Hz, 2H), 2.54–2.51 (m, 2H), 1.42–1.38 (m, 2H), 1.36–1.16 (m, 8H), 1.01 (s, 9H); ESI-MS (m / z): Calculated values: C 22 H 32 FN3O5S: 469.57 (observed mass); 470.15 (M+H); HPLC purity: 95.4%; R t; 8.7.

[0875] Production Example 38: 5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)cyclopropyl)pentane-1-sulfonamide:

[0876] The title compound was prepared using (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)cyclopropyl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0877] Yield: 0.022 g, 73.3%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.16 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 10.0 Hz, 1H), 6.93-6.89 (m,1H), 4.67 (s, 1H), 3.86 (s, 2H), 3.76 (s, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.54(dd, J = 6.6, 4.1 Hz, 2H), 1.47-1.45 (m, 2H), 1.43-1.40 (m, 2H), 1.33–1.14(m, 8H), 1.05-0.98 (m, 4H); ESI-MS (m / z): Calculated value: C 21 H 30 FN3O6S: 471.54; observed mass: 470 (MH); HPLC purity: 98.1%; R t; 7.0.

[0878] Production Example 75: Synthesis of (R,E)-N-(1-(3-(cyclopropylmethoxy)phenyl)propyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0879] The title compound was prepared using (R)-N-(1-(3-(cyclopropylmethoxy)phenyl)propyl)but-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0880] Yield: 0.095 g, 17.6%; 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.73(d, J = 9.1 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.96 (t, J = 2.0 Hz, 1H), 6.88(d, J = 7.5 Hz, 1H), 6.77 (dd, J = 8.2, 2.4 Hz, 1H), 5.37-5.32 (m, 1H), 5.20-5.17 (m, 1H), 4.08-4.02 (m, 1H), 3.89–3.62 (m, 6H), 2.81-2.78 (m, 1H), 2.45-2.42 (m, 1H), 2.21–2.18 (m, 2H), 1.76–1.55 (m, 2H), 1.23–1.20 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H), 0.61–0.50 (m, 2H), 0.38–0.26 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 29 N3O5S: 435.54; observed mass: 434.20 (MH); HPLC purity: 99.1%; R t; 7.7.

[0881] Production Example 76: Synthesis of N-(1-(3-(cyclopropylmethoxy)phenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0882] The title compound was prepared using (E)-N-(1-(3-(cyclopropylmethoxy)phenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0883] Yield: 0.082 g, 68%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.18 (s,1H), 7.19 (t, J = 7.9 Hz, 1H), 7.00 (t, J = 1.9 Hz, 1H), 6.96–6.89 (m, 1H),6.76 (dd, J = 8.1, 2.4 Hz, 1H), 3.87 (s, 2H), 3.79 (d, J = 7.0 Hz, 2H), 3.12(t, J = 7.0 Hz, 2H), 2.54-2.51 (m, 2H), 1.43-1.40 (m, 3H), 1.36–0.95 (m, 8H),0.61–0.50 (m, 2H), 0.35–0.26 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 29 N3O5S: 435.54; Observation mass: 436.19 (M+H); HPLC purity: 98.0%; R t; 7.5.

[0884] Production Example 78: Synthesis of N-(1-(3-(2,2-difluoroethoxy)phenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0885] The title compound was prepared using (E)-N-(1-(3-(2,2-difluoroethoxy)phenyl)cyclopropyl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0886] Yield: 0.082 g, 68%; 1H NMR (400 MHz, DMSO- d6) δ 10.7 (s, 1H), 8.18(s, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.07–6.98 (m, 2H), 6.90–6.83 (m, 1H), 6.38(tt, J = 56.0, 3.6 Hz, 1H), 4.29 (dt, J = 14.7, 3.5 Hz, 2H), 3.87 (s, 2H), 3.14 (t, J = 9.5, 7.1 Hz, 2H), 2.58-2.54 (m, 2H), 1.45-1.42 (m, 2H), 1.30-1.27 (m, 4H), 1.09–1.04 (m, 4H); ESI-MS (m / z): Calculated value: C 19 H 25 F2N3O5S: 445.48; Observation mass: 446.10 (M+H); HPLC purity: 96.7%; R t; 7.3.

[0887] Exemplary steps for the preparation of 2-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-2-ol (XV):

[0888] A solution of CH3MgBr (176.0 mL, 246.6 mmol, 1.4 M THF solution) was added dropwise to a stirred solution of VI (11.0 g, 49.3 mmol) in dry THF at 0 °C under a nitrogen atmosphere, and the reaction mixture was then heated and stirred at 80 °C for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was quenched with aqueous NH4Cl solution and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give XV.

[0889] Yield: 10.13 g, crude product, LCMS: 225.45 (M+1).

[0890] Exemplary steps for the preparation of 4-(2-azidopropane-2-yl)-2-(cyclopropylmethoxy)-1-fluorobenzene (XVI):

[0891] NaN3 (27.00 g 406.8 mmol) and TFA (50 mL) were added to a dry DCM solution (10.13 g, 45.8 mmol) of XV under stirring at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and then extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and then evaporated under reduced pressure to give XVI.

[0892] Yield: 10.10 g, crude product; 1 ¹H NMR (400 MHz, chloroform-d) δ 7.10–6.99 (m, 2H), 6.96–6.93 (m, 1H), 3.91 (d, J = 7.0 Hz, 2H), 1.62–1.56 (m, 6H), 1.38–1.19 (m, 2H), 0.71–0.57 (m, 2H), 0.42–0.28 (m, 2H).

[0893] Exemplary steps for the preparation of 2-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-2-amine (XVII):

[0894] 10% Pd / C (4.0 g) was added to 150 mL of a stirred solution of XVI (10.0 g, 40.11 mmol) in MeOH, and the mixture was stirred for 24 h at room temperature under a hydrogen atmosphere (balloon pressure). The reaction progress was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography using a 5% MeOH solution in DCM to obtain XVII.

[0895] Yield: 4.1 g, 45.8%; 1 H NMR (400 MHz, DMSO-d6) ä 7.28 (dd, J = 8.6, 2.2Hz, 1H), 7.11–6.96 (m, 2H), 3.89 (d, J = 6.9 Hz, 2H), 1.89–1.83 (m, 2H), 1.34(s, 6H), 0.60-0.58 (m, 2H), 0.34-0.32 (m, 2H).

[0896] Exemplary steps for the preparation of N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-2-yl)but-3-ene-1-sulfonamide (XVIII):

[0897] Et3N (1.87 mL, 13.4 mmol) was added to a dry DCM solution (10 mL) of XVII (1.0 g, 4.47 mmol) under stirring, and the mixture was stirred at room temperature for 10 min. Subsequently, a DCM solution (10 mL) of V (1.17 g, 7.61 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with EtOAC. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography of 15% EtOAC / hexane to give XVIII.

[0898] Yield: 1.04 g, 64.8%; 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.26 (td, J = 7.9, 7.4, 2.3 Hz, 1H), 7.13 (dd, J = 11.3, 8.5 Hz, 1H), 7.05-7.0 (m,1H), 5.78–5.63 , 1.24(td, J = 7.8, 4.0 Hz, 1H), 0.63–0.52 (m, 2H), 0.42–0.31 (m, 2H).

[0899] Production Example 44: (E)-N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-2-yl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0900] The title compound was prepared using N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-2-yl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0901] Yield: 0.095 g, 20.65%; 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.47(s, 1H), 7.26 (dd, J = 8.3, 2.3 Hz, 1H), 7.12 (dd, J = 11.2, 8.5 Hz, 1H), 7.06–6.97 (m, 1H), 5.56-5.53 (m, 1H), 5.39-5.36 (m, 1H), 3.92–3.80 (m, 2H), 3.76 (s, 2H), 3.70-3.68 (m, 2H), 2.74–2.65 (m, 2H), 2.33–2.24 (m, 2H), 1.58(s, 6H), 1.24–1.20 (m, 1H), 0.63–0.53 (m, 2H), 0.37–0.29 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 28 FN3O5S: 453.53: observed mass; 471.25 (M+H2O); HPLC purity: 99.8%; R t; 8.0.

[0902] Production Example 48: Synthesis of (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(2-(4-fluoro-3-isobutoxyphenyl)propane-2-yl)pent-3-ene-1-sulfonamide:

[0903] The title compound was prepared using N-(2-(4-fluoro-3-isobutoxyphenyl)propane-2-yl)but-3-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0904] Yield: 0.056 g, 11%; 1H NMR (400 MHz, DMSO- d6) δ 10.8 (s, 1H), 7.49 (d,J = 4.7 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 11.3, 8.1 Hz, 1H), 7.01 (dd, J = 7.7, 4.0 Hz, 1H), 5.54-5.51 (m, 1H), 5.37-5.34 (m, 1H), 3.89–3.73 (m, 6H), 2.70-2.67 (m, 2H), 2.30-2.26 (m, 2H), 2.08-2.04 (m, 1H), 1.59(s, 6H), 0.99 (d, J = 6.6 Hz, 6H); ESI-MS (m / z): Calculated value: C 21 H 30 FN3O5S: 455.55; observed mass: 454.20 (MH); HPLC purity: 98.9%; R t; 8.2.

[0905] Production Example 81: Synthesis of N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-2-yl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0906] The title compound was prepared using (E)-N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-2-yl)-5-(2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0907] Yield: 0.05 g, 71.4%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.41 (s,1H), 7.26 (dd, J = 8.3, 2.3 Hz, 1H), 7.13 (dd, J = 11.3, 8.5 Hz, 1H), 7.05-7.01 (m, 1H), 3.89-3.85 (m, 4H), 3.21–3.13 (m, 2H), 2.66–2.57 (m, 2H), 1.56-1.54 (m, 8H), 1.40-1.38 (m, 2H), 1.31–1.12 (m, 3H), 0.63–0.53 (m, 2H), 0.38–0.29 (m, 2H); ESI-MS (m / z): Calculated value: C 21 H 30 FN3O5S: 455.55; Observed mass: 473.15 (M+H2O); HPLC purity: 94.7%; R t; 7.9.

[0908] Production Example 86: Synthesis of 5-(2,4-dioxoimidazolidine-1-yl)-N-(2-(4-fluoro-3-isobutoxyphenyl)prop-2-yl)pentane-1-sulfonamide:

[0909] The title compound was prepared using (E)-5-(2,4-dioxoimidazolidine-1-yl)-N-(2-(4-fluoro-3-isobutoxyphenyl)prop-2-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0910] Yield: 0.028 g, 70%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 7.42 (s,1H), 7.32–7.24 (m, 1H), 7.12 (dd, J = 11.4, 8.4 Hz, 1H), 7.00-6.98 (m, 1H), 3.89 (s, 2H), 3.81 (d, J = 6.5 Hz, 2H), 3.17 (t, J = 7.1 Hz, 2H), 2.50-2.48(m, 2H), 2.05-2.01 (m, 1H), 1.56-1.54 (m, 8H), 1.40-1.37 (m, 2H), 1.20-1.00(m, 2H), 0.99 (d, J = 6.6 Hz, 6H); ESI-MS (m / z): Calculated value: C21 H 32 FN3O5S: 457.56; Observed mass: 479.85 (M+Na); HPLC purity: 96.3%; R t; 8.2.

[0911] Exemplary steps for the preparation of N-allyl cyanamide (XIX):

[0912] Et3N (10.0 mL, 71.0 mmol) was added to a dry ACN solution (25 mL) of L-alanine methyl ester (5.0 g, 35 mmol) under stirring, and the mixture was stirred at room temperature for 10 min. Subsequently, a 25 mL ACN solution of 3-bromoprop-1-ene (2.78 mL, 32.0 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography using 10% MeOH / DCM to obtain product XIX.

[0913] Yield: 0.8 g, 15.6%; 1 H NMR (400 MHz, DMSO-d6) δ 5.80-5.77 (m, 1H),5.22–4.98 (m, 2H), 4.03 (d, J = 7.1 Hz, 1H), 3.35–3.10 (m, 3H), 3.10–2.98 (m,1H), 2.13–2.08 (m, 1H), 1.99 (s, 1H), 1.17 (dd, J = 7.1, 5.3 Hz, 5H).

[0914] Exemplary steps for the preparation of N-allyl-N-cyano-L-alanine methyl ester (XX):

[0915] BrCN (7.11 g, 6.7 mmol) and NaHCO3 (1.40 g, 16.6 mmol) were added dropwise to a stirred solution of XIX (0.8 g, 5.5 mmol) in 10 mL of EtO2 at 0°C, and the mixture was stirred for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with EtO2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give XX.

[0916] Yield: 0.8 g, crude product; NMR: 1 H NMR (400 MHz, DMSO-d6) δ 5.84-5.81 (m, 1H), 5.36–5.21 (m, 2H), 3.93 (d, J = 7.3 Hz, 1H), 3.79–3.58 (m, 5H), 1.46–1.34 (m,3H).

[0917] Exemplary steps for the preparation of (S)-1-allyl-5-methylimidazolidine-2,4-dione (XXI)

[0918] Dibutyl phosphate (2.5 mL, 1.1 mmol) was added to a stirred toluene solution (0.8 g, 4.7 mmol) of XX (8 mL), and the reaction mixture was heated under reflux for 5 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated, and the residue was dissolved in Et₂O:hexane (2:8 mL). The precipitated solid was filtered off and purified by grinding with cold hexane to give XXI.

[0919] Yield: 0.25 g, 34%; NMR: 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H),5.80-5.77 (m, 1H), 5.27–5.11 (m, 2H), 4.14–3.94 (m, 2H), 3.70 (dd, J = 16.1,6.3 Hz, 1H), 1.41–1.22 (m, 3H).

[0920] Production Example 15: Synthesis of (R,E)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0921] The title compound was prepared using N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)but-3-ene-1-sulfonamide and (R)-1-allyl-5-methylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0922] Yield: 0.028 g, 18%; 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.23 ​​(s,1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15–7.05 (m, 1H), 6.92 (s, 1H), 5.48–5.36 (m,1H), 5.24-5.20 (m, 1H), 3.98–3.86 (m, 2H), 3.83–3.76 (m, 2H), 3.51-3.48 (m,1H), 2.57-2.54 (m, 2H), 2.19–1.95 (m, 4H), 1.29–1.12 (m, 4H), 1.07 (s, 2H), 1.01–0.94 (m, 6H); ESI-MS (m / z): Calculated value: C 22 H 30 FN3O5S: 467.56; Observation mass: 468.15 (M+H); HPLC purity: 94.7%; R t; 8.2.

[0923] Production Example 16: Synthesis of (S,E)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide:

[0924] The title compound was prepared using N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)but-3-ene-1-sulfonamide and (S)-1-allyl-5-methylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0925] Yield: 0.025 g, 18%; 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.23 ​​(s,1H), 7.28–7.06 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 5.49–5.37 (m, 1H), 5.26-5.23 (m, 1H), 4.05–3.87 (m, 2H), 3.81 (d, J = 6.4 Hz, 2H), 3.53-3.50 (m, 1H), 2.59-2.50 (m, 3H), 2.10-2.07 (m, 2H), 1.27–1.16 (m, 5H), 1.09-1.04 (m, 2H),0.99 (d, J = 6.6 Hz, 6H); ESI-MS (m / z): Calculated value: C 22 H 30 FN3O5S: 467.56; Observation mass: 468.20 (M+H); HPLC purity: 99.8%; R t; 8.2.

[0926] Production Example 17: Synthesis of (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pent-3-en-1-yl-sulfonamide:

[0927] The title compound was prepared using N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)but-3-ene-1-sulfonamide and (R)-1-allyl-5-methylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0928] Yield: 0.038 g, 14%; 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.22 (s,1H), 7.20 (dd, J = 8.3, 2.2 Hz, 1H), 7.11 (dd, J = 11.4, 8.4 Hz, 1H), 6.96-6.91 (m, 1H), 5.49–5.37 (m, 1H), 5.30–5.18 (m, 1H), 3.99–3.85 (m, 4H), 3.53(dd, J = 15.6, 6.9 Hz, 1H), 2.59-2.56 (m, 2H), 2.14-2.11 (m, 2H), 1.29–1.17(m, 6H), 1.11–1.03 (m, 2H), 0.63–0.53 (m, 2H), 0.38–0.29 (m, 2H); ESI-MS (m / z): Calculated value: C 22 H 28 FN3O5S: 465.54; Observation mass: 466.15 (M+H); HPLC purity: 99.9%; R t; 7.8.

[0929] Production Example 18: (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pent-3-en-1-yl)sulfonamide

[0930] The title compound was prepared using N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)but-3-ene-1-sulfonamide and (S)-1-allyl-5-methylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0931] Yield: 0.06 g, 23%; 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 8.12 (s,1H), 7.26 (dt, J = 7.9, 7.4, 2.3 Hz, 1H), 7.13 (dd, J = 11.3, 8.5 Hz, 1H), 7.05-7.0 (m, 1H), 5.45–5.38 (m, 1H), 5.12–5.08 (m, 1H), 3.99–3.85 (m, 4H), 3.37–3.25 (m, 1H), 2.59 (t, J = 7.8 Hz, 2H), 2.15 (t, J = 7.7 Hz, 2H), 1.26–1.17 (m, 6H), 1.08–1.04 (m, 2H), 0.63–0.53 (m, 2H), 0.36–0.30 (m, 2H); ESI-MS (m / z): Calculated value C 22 H 28 FN3O5S: 465.54; Observed mass: 464.20 (MH); HPLC purity: 99.4%; R t; 7.7.

[0932] Production Example 71: Synthesis of (R)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0933] The target compound was prepared using N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)but-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0934] Yield: 0.022 g, 62%; 1H NMR (400 MHz, DMSO- d6) δ 10.7 (d, J = 11.1 Hz, 1H), 8.19 (d, J = 13.7 Hz, 1H), 7.25 (dd, J = 8.5, 2.2 Hz, 1H), 7.12 (dd, J =11.4, 8.3 Hz, 1H), 6.96-6.90 (m, 1H), 4.01-3.38 (m, 1H), 3.81 (d, J = 6.6 Hz,2H), 2.96-2.91 (m, 1H), 2.57-2.54 (m, 3H), 2.06-2.02 (m, 1H), 1.49 – 1.18 (m,8H), 1.11 – 0.92 (m, 11H); ESI-MS (m / z): Calculated value: C 22 H 32 FN3O5S: 469.57; Observation mass: 470.20 (M+H); HPLC purity: 92.2%; Rt: 8.5.

[0935] Production Example 72: Synthesis of (S)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0936] The title compound was prepared using N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)but-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0937] Yield: 0.042 g, 83.6%; 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.18 (s, 1H), 7.25 (dd, J = 8.4, 2.3 Hz, 1H), 7.12 (dd, J = 11.4, 8.4 Hz, 2H),6.94–6.90 (m, 1H), 4.01–3.39 (m, 1H), 3.81 (d, J = 6.6 Hz, 2H), 3.32–3.28 (m,2H), 2.98–2.95 (m, 2H), 2.06–2.03 (m, 2H), 1.43–1.40 (m, 2H), 1.36–1.18 (m, 8H), 1.11–0.95 (m, 7H); ESI-MS (m / z): Calculated: C22H32FN3O5S: 469.57; Observed quality: 470.2 (M+H); HPLC purity: 98.0%; Rt: 8.3.

[0938] Production Example 73: (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0939] The title compound was prepared using N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)but-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0940] Yield: 0.02 g, 80.0%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.15 (s,1H), 7.20 (d, J = 8.2 Hz, 1H), 7.11 (t, J = 10.1 Hz, 1H), 6.96–6.92 (m, 1H),4.03–4.00 (m, 1H), 3.88 (d, J = 7.0 Hz, 2H), 2.98–2.92 (m, 1H), 2.51–2.40 (m,2H), 1.41–1.38 (m, 2H), 1.28–1.17 (m, 9H), 1.04–1.00 (m, 4H), 0.60–0.55 (m,2H), 0.32–0.30 (m, 2H); ESI-MS (m / z): Calculated value: C 22 H 30FN3O5S: 467.56; Observed mass: 468.20 (M+H); HPLC purity: 94.1%; R t 7.7.

[0941] Production Example 74: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide:

[0942] The target compound was prepared using (S,E)-N-(1-(4-fluoro-3-isobutoxyphenyl)cyclopropyl)-5-(5-methyl-2,4-dioxoimidazolidine-1-yl)pent-3-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0943] Yield: 0.035 g, 77.7%; 1 H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.16(s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.12 (dd, J = 11.4, 8.2 Hz, 1H), 6.97–6.89(m, 1H), 4.02–3.98 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 2.99–2.87 (m, 2H), 2.58–2.48 (m, 2H), 1.48–1.18 (m, 12H), 1.05–1.02 (m, 2H), 0.59–0.54 (m, 2H),0.33–0.31 (m, 2H); ESI-MS (m / z): Calculated value: C 22 H 30 FN3O5S: 467.56; Observation mass: 468.15 (M+H); HPLC purity: 96.9%; R t 7.7.

[0944] Exemplary steps for the preparation of 3-(cyclopropylmethoxy)-4-fluoro-N-methoxy-N-methylbenzamide (XXII):

[0945] To a mixture of 131 mL of a dry DMF solution of 3-(cyclopropylmethoxy)-4-fluorobenzoic acid (10.12 g, 4.80 mmol), N,O-dimethylhydroxylamine (5.63 g, 5.70 mmol), HOBt (7.69 g, 5.70 mmol), Et3N (8.75 mL, 6.20 mmol), and EDCI·HCl (13.85 g, 7.20 mmol), the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using 40% EtOAc / hexane to give XXII.

[0946] Yield: 10.5 g, 86.1%; 1 H NMR (400 MHz, CDCl3) δ 7.39–7.24 (m, 2H), 7.08(dd, J = 10.9, 8.4 Hz, 1H), 3.90 (d, J = 7.0 Hz, 2H), 3.55 (s, 3H), 3.35 (s,3H), 1.37–1.23 (m, 1H), 0.72–0.59 (m, 2H), 0.43–0.29 (m, 2H).

[0947] Exemplary steps for the preparation of 1-(3-(cyclopropylmethoxy)-4-fluorophenyl)prop-1-one (XXIII):

[0948] CH3CH2MgBr (1.0 M THF solution, 34.5 mL, 103.0 mmol) was added dropwise to a dry THF solution (10.5 g, 41.40 mmol) of stirred XXII at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 25% EtOAc / hexane to give XXIII.

[0949] Yield: 7.58 g, 82.3%; ESI-MS (m / z): 222.85 (M+H).

[0950] Exemplary steps for the preparation of 4-(but-1-en-2-yl)-2-(cyclopropylmethoxy)-1-fluorobenzene (XXIV):

[0951] NaHMDS (1M, THF 50 mL, 50.2 mmol) was added to a dry THF solution (120 mL) of Ph3PCH3Br (17.93 g, 50.2 mmol) under stirring at 0 °C, and the mixture was stirred for 2 h at room temperature. A THF solution of XXIII (6.2 g, 27.8 mmol) was added dropwise at 0 °C, and the mixture was stirred for 12 h at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using 5% EtOAc / hexane to give XXIV.

[0952] Yield: 5.6 g, 91.2%; 1 H NMR (400 MHz, CDCl3) δ 7.06–6.88 (m, 3H), 5.19 (s, 1H), 5.05–5.00 (m, 1H), 3.89 (d, J = 7.0 Hz, 2H), 2.46 (q, J = 7.3 Hz, 2H), 1.33–1.30 (m, 1H), 1.09 (td, J = 7.4, 1.3 Hz, 3H), 0.70–0.58 (m, 2H), 0.43–0.32 (m, 2H).

[0953] Exemplary steps for the preparation of (S)-2-(3-(cyclopropylmethoxy)-4-fluorophenyl)butane-1,2-diol (XXV):

[0954] AD-mix-alpha (18.0 g) was added to a mixture of XXIV (3.0 g, 13.6 mmol) in t-butanol (48 mL) and water (48 mL) at 0°C, and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with anhydrous Na₂SO₄ and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography using 35% EtOAc / hexane to give XXV.

[0955] Yield: 2.8 g, 80.92%; 1H NMR (400 MHz, CDCl3) δ 7.13–7.00 (m, 2H),6.88-6.85 (m, 1H), 3.90 (d, J = 7.0 Hz, 2H), 3.81 (dd, J = 11.1, 4.6 Hz, 1H), 3.67 (dd, J = 11.0, 8.0 Hz, 1H), 2.54 (s, 1H), 1.83–1.79 (m, 2H), 1.58 (dd, J= 8.1, 4.7 Hz, 1H), 1.29–1.27 (m, 2H), 0.77 (dd, J = 8.0, 6.8 Hz, 3H), 0.70–0.58 (m, 2H), 0.37 (t, J = 5.2 Hz, 2H).

[0956] Exemplary steps for the preparation of (S)-2-(3-(cyclopropylmethoxy)-4-fluorophenyl)-1-(methylsulfonyl)but-2-ol (XXVI):

[0957] MsCl (0.31 mL, 4.06 mmol) was added to a dry DCM solution (8.6 mL) of XXV (0.86 g, 3.38 mmol) and Et3N (0.711 mL, 5.07 mmol) under stirring at 0°C, and the mixture was stirred for 30 min at room temperature. After the reaction was complete, the reaction mixture was quenched with NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give XXVI.

[0958] Yield: 1.0 g, crude product.

[0959] Exemplary steps for the preparation of (S)-1-azido-2-(3-(cyclopropylmethoxy)-4-fluorophenyl)but-2-ol (XXVII):

[0960] Sodium azide (0.586 g, 9.02 mmol) was added dropwise to a stirred DMF solution (15 mL) of XXVI (0.75 g, 2.20 mmol) and stirred at 90°C for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using 35% EtOAc / hexane to give XXVII.

[0961] Exemplary steps for the preparation of (S)-1-amino-2-(3-(cyclopropylmethoxy)-4-fluorophenyl)but-2-ol (XXVIII):

[0962] 10% Pd / C (0.06 g) was added to a stirred EtOH solution (6 mL) of XXVII (0.3 g, 10.7 mmol), and the mixture was stirred for 3 h at room temperature under a hydrogen atmosphere (balloon pressure). The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography using 40% EtOAc / hexane to give XXVIII.

[0963] Yield: 0.097 g, 34.7%; 1 H NMR (400 MHz, DMSO- d6) δ 7.15–7.05 (m, 2H), 6.93-6.89 (m, 1H), 4.82 (s, 1H), 3.87 (d, J = 7.1 Hz, 2H), 2.79 (d, J = 13.1Hz, 1H), 2.70 (d, J = 13.1 Hz, 1H), 1.75–1.61 (m, 2H), 1.25–1.22 (m, 1H), 0.68–0.50 (m, 5H), 0.40–0.26 (m, 2H).

[0964] Exemplary steps for the preparation of (S)-N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-hydroxybutyl)prop-2-ene-1-sulfonamide (XXIX):

[0965] Et3N (3.0 mL, 2.1 mmol) was added to a 25 mL solution of dry DCM containing 1 g (7.1 mmol) of XXVIII and stirred at room temperature for 10 min. Subsequently, a 25 mL solution of DCM containing 1.49 g (1.0 mmol) of V was added dropwise and stirred at room temperature for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using 20–30% EtOAc / hexane to give XXIX.

[0966] Yield: 0.8 g, 32%; 1H NMR (400 MHz, DMSO- d6) δ 7.16-7.11 (m, 2H), 6.95-6.91 (m, 1H), 6.70 (t, J = 6.0 Hz, 1H), 5.72-5.69 (m, 1H), 5.34–5.25 (m, 2H), 4.94 (d, J = 2.0 Hz, 1H), 3.92–3.85 (m, 2H), 3.65–3.60 (m, 2H), 3.39–3.15 (m, 1H), 1.74 (q, J = 7.5 Hz, 2H), 1.25-1.21 (m, 2H), 0.66–0.52 (m, 5H),0.33 (t, J = 4.3 Hz, 2H).

[0967] Production Example 97: (S,E)-N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-hydroxybutyl)-4-(2,4-dioxoimidazolidine-1-yl)but-2-ene-1-sulfonamide:

[0968] The title compound was prepared using (S)-N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-hydroxybutyl)prop-2-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0969] Yield: 0.037 g, 7.1%; 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.13–7.10 (m, 2H), 6.96–6.88 (m, 1H), 6.79–6.76 (m, 1H), 5.71–5.68 (m, 1H), 5.53–5.50 (m, 1H), 4.94 (s, 1H), 3.88–3.84 (m, 6H), 3.70–3.68 (m, 2H), 3.25–3.20 (m, 2H), 1.73–1.70 (m, 2H), 1.22–1.20 (m, 1H), 0.65–0.54 (m, 5H), 0.33–0.30(m, 2H); ESI-MS (m / z): Calculated value: C 21 H 28 FN3O6S: 469.53; observed mass: 492.20 (M+Na); HPLC purity: 96.5%; R t 7.7.

[0970] Production Example 82: Synthesis of (S,E)-4-(2,4-dioxoimidazolidine-1-yl)-N-(2-(4-fluoro-3-isobutoxyphenyl)-2-hydroxybutyl)but-2-ene-1-sulfonamide:

[0971] The title compound was prepared using (S,E)-4-(2,4-dioxoimidazolidine-1-yl)-N-(2-(4-fluoro-3-isobutoxyphenyl)-2-hydroxybutyl)but-2-ene-1-sulfonamide and 1-allylimidazolidine-2,4-dione in a manner similar to that described in Production Example 3 above.

[0972] Yield: 0.022 g, 3.67%; 1 H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 7.18–7.06 (m, 2H), 6.98–6.92 (m, 1H), 6.77 (t, J = 6.3 Hz, 1H), 5.70–5.67 (m, 1H),5.52–5.49 0.98 (d, J = 6.6 Hz, 6H),0.60 (t, J = 7.4 Hz, 3H); ESI-MS (m / z): Calculated value: C 21 H 30 FN3O6S: 471.54; Observed mass: 489.30 (M+H2O); HPLC purity: 94.7%; R t : 7.9.

[0973] Production Example 98: Synthesis of (S)-N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-hydroxybutyl)-4-(2,4-dioxoimidazolidine-1-yl)butane-1-sulfonamide:

[0974] The title compound was prepared using (S,E)-N-(2-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-hydroxybutyl)-4-(2,4-dioxoimidazolidine-1-yl)but-2-ene-1-sulfonamide in a manner similar to that described in Production Example 1 above.

[0975] Yield: 0.06 g, 48%; 1¹H NMR (400 MHz, DMSO-d⁶) δ 10.7 (s, 1H), 7.15–7.11 (m 2H), 6.97–6.89 (m, 1H), 6.65 (t, J = 6.2 Hz, 1H), 4.92 (s, 1H), 3.89–3.86 (m, 4H), 3.20–3.17 (m, 4H), 2.89–2.86 (m, 2H), 1.74–1.71 (m, 2H), 1.48–1.41 (m, 4H), 1.29–1.13 (m, 1H), 0.60–0.56 (m, 5H), 0.33–0.30 (m, 2H); ESI-MS (m / z): Calculated values: C 21 H 30 FN3O6S; observed mass; 470.25 (MH); HPLC purity: 97.9; R t 7.3.

[0976] Production Example 66a: Synthesis of (S)-N-(1-(4-chloro-3-(cyclopropylmethoxy)phenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[0977] Option 1.

[0978]

[0979] Step 1: Synthesis of 1-(4-chloro-3-(cyclopropylmethoxy)phenyl)ethyl-1-one (3-a)

[0980] K₂CO₃ (7.3 g, 52.9 mmol) was added to a stirred 25 mL solution of 1-a (3.0 g, 17.6 mmol), followed by (bromomethyl)cyclopropane (2.8 g, 21.1 mmol), and the reaction mixture was refluxed for 4 h (the reaction was confirmed to be complete by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 3-a (3.2 g, crude).

[0981] Step 2: N-(1-(4-chloro-3-(cyclopropylmethoxy)phenyl)ethylene)-2-methylpropane-2-sulfinamide (5-a)

[0982] Ti(O) was added to a dry toluene solution (150 mL) of compound 3-a (3.2 g, 14.2 mmol) and compound 4-a (2.5 g, 21.4 mmol) under stirring. i Pr)4 (8.1 g, 28.5 mmol). The mixture was heated at 90°C for 16 h (the reaction was confirmed to be complete by TLC). The reaction mixture was diluted with EtOAc, quenched with water, and filtered through a diatomaceous earth mat. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 5-a (2.4 g, crude). LCMS: 327.95 (M+1).

[0983] Step 3: Synthesis of (S)-N-((S)-1-(4-chloro-3-(cyclopropylmethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (6-a)

[0984] A 10 mL solution of dry toluene in DIBAL-H (1 M toluene solution, 22 mL, 22.0 mmol) was added dropwise to a 10 mL solution of toluene in compound 5-a (2.4 g, 7.33 mmol) under stirring at -78°C. The resulting mixture was stirred at the same temperature for 3 h (the reaction was confirmed to be complete by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-a (1.6 g, 66%). LCMS: 330.1 (M+1).

[0985] Step 4: Synthesis of (S)-1-(4-fluoro-3-propoxyphenyl)ethyl-1-amine hydrochloride (7-a)

[0986] A 4M HCl solution (2.4 mL, 9.72 mmol) of dioxane was added to a 15 mL MeOH solution of compound 6-a (1.6 g, 4.86 mmol) under stirring, and the resulting mixture was stirred at room temperature for 3 h (the reaction was confirmed to be complete by TLC). The reaction mixture was concentrated, and the residue was purified by grinding with diethyl ether to give 7-a (0.9 g, 75%). LCMS: 208.9 (M-18).

[0987] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 3H), 7.42 (d, J = 8.7 Hz 1H),7.20 (s, 1H), 4.42–4.38 (m, 1H), 3.96 (t, J = 7.0 Hz, 2H), 1.45 – 1.42(s,3H), 1.28 – 1.0 (m, 2H), 0.62 – 0.56 (m, 2H), 0.38 – 0.34 (m, 2H).

[0988] Step 5: Synthesis of 3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (9-a)

[0989] SEM-Cl (12.7 mL, 72.0 mmol) was added to a CH2Cl2 solution (60 mL) of compound 8-a (6.0 g, 60.0 mmol) and DIPEA (30 mL, 180 mmol) under stirring at 0 °C for more than 1 h, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC to ensure complete consumption of compound 8-a. The reaction mixture was quenched with NH4Cl solution (150 mL) and extracted with CH2Cl2 (150 mL x 2). The combined organic extracts were washed with 2N HCl (75 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 9-a (9.2 g, crude).

[0990] 1 H NMR (400 MHz, DMSO-d6) δ 4.98 (s, 2H), 4.0 (s, 3H), 3.60 – 3.55 (m,2H), 0.98 – 0.95 (m, 2H), 0.09 (s, 9H).

[0991] Step 6: (1-(5-bromopentyl)-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-2,4-dione (11-a)

[0992] To a stirred ACN solution (50 mL) of compound 9-a (3.0 g, 13.0 mmol), CS₂CO₃ (12.7 g, 39.1 mmol) was added, followed by compound 10-a (6.0 g, 26.0 mmol), and the mixture was stirred at 80°C for 4 h. Afterward, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in a saturated aqueous solution (150 mL), and extracted with EtOAc (150 mL x 2). The organic extracts were washed separately with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM solution of 3–4% MeOH) to give 11-a (2.8 g, 56%).

[0993] 1 H NMR (400 MHz, DMSO-d6) δ 4.73 (s, 2H), 4.02 (s, 2H), 3.52 – 3.50(m, 4H), 3.22–3.20(m, 2H), 1.85 – 1.79(m, 2H), 1.59 – 1.55(m, 2H), 1.41 –1.34(m, 2H), 0.88 – 0.82 (m, 2H), 0.09 (s, 9H).

[0994] Step 7: Synthesis of S-(5-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-1-yl)pentyl)ethylthioester (12-a)

[0995] AcSK (1 g, 8.86 mmol) was added to a DMF solution (30 mL) of compound 11-a (2.8 g, 7.38 mmol) at 0°C, and the mixture was stirred at room temperature for 1 h. After the starting material was complete, the reaction mixture was diluted with water (75 mL) and extracted with EtOAc (75 mL x 3). The organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 12-a (2.6 g, crude). It was transferred to the next step without purification.

[0996] Step 8: Synthesis of 5-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolium-1-yl)pentane-1-sulfonyl chloride (13-a)

[0997] At 0 °C, 4 mL of 2N HCl was added to a 40 mL acetonitrile solution of compound 12-a (2.6 g, 6.87 mmol) under stirring. Then, N-chlorosuccinimide (3.67 g, 27.5 mol) was added in portions over 30 min, and the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC. Once 12-a was completely consumed, the reaction mixture was quenched with ice-cold water (150 mL) and extracted with diethyl ether (150 mL x 2). The combined organic layers were washed with saturated sodium bicarbonate solution (150 mL) and brine (75 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 13-a (1.9 g, 69.3%) as a grayish-white solid.

[0998] 1 H NMR (400 MHz, DMSO) δ 4.90 (s, 2H), 3.89 (s, 2H), 3.69-3.59 (m,2H), 3.46-3.42 (m, 2H), 2.13 -2.0 (m, 2H), 1.70-1.64 (m, 2H), 1.62-1.52 (m,2H),1.27-1.23(m,2H), 0.96-0.92(m,2H), 0.004(s,9H).

[0999] Step 9: Synthesis of (S)-N-(1-(4-chloro-3-(cyclopropylmethoxy)phenyl)ethyl)-5-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)imidazolidine-1-yl)pentane-1-sulfonamide (14-a)

[1000] Triethylamine (0.25 mL, 2.28 mmol) was added to a 5 mL CH₂Cl₂ solution of compound 7-a – HCl salt (0.2 g, 0.76 mmol) under stirring at 0 °C. A 5 mL CH₂Cl₂ solution of compound 13-a (0.33 g, 0.83 mmol) was added dropwise to this reaction mixture over 25 minutes at 0 °C, and the mixture was stirred at the same temperature for 3 h. The reaction was monitored by TLC to ensure complete consumption of compound 7-a. The reaction mixture was quenched with water (25 mL) and extracted with CH₂Cl₂ (25 mL x 2). The combined organic extracts were washed with water (25 mL x 2) and brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography with 15–20% EtOAc / hexane to give 14-a (0.155 g, 34%) as a grayish-white solid. LCMS: 588.05 (M+1).

[1001] Step 10: Synthesis of (S)-N-(1-(4-chloro-3-(cyclopropylmethoxy)phenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide (Production Example 66a)

[1002] TFA (0.3 mL) was added to a DCM solution (10 mL) of compound 14-a (0.15 g, 0.52 mmol) under stirring at 0°C, and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC until compound 14-a was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated solution of NaHCO3 (50 mL) and extracted with EtOAc (50 mL x 2). The organic extract was washed with water (50 mL x 2) and brine (10 mL), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. The residue was purified by rapid chromatography (eluting with DCM solution of 3-4% MeOH) to give Production Example 66a (75 mg, 64% yield) as a white viscous solid.

[1003] 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4.40 – 4.35(m, 1H), 3.94 – 3.84 (m, 4H), 3.12 (t, J = 7.0 Hz, 2H), 2.82 –2.77 (m, 1H), 2.63 – 2.60 (m, 1H), 1.59 – 1.38 (m, 2H), 1.38 – 0.99 (m, 8H), 0.58 (d, J =7.8 Hz, 2H), 0.35 (d, J = 7.6 Hz, 2H); ESI-MS (m / z): Calculated value: C 20 H 28 ClN3O5S: 457.97, observed mass; 456.05 (MH); HPLC purity: 97.7%.

[1004] Production Example 67a: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[1005] Option 2.

[1006]

[1007] Step 1: Synthesis of 3-hydroxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (2-b)

[1008] Triethylamine (4.72 mL, 33.9 mmol) was added to a stirred DCM solution (35 mL) of compound 1-b (3.5 g, 16.9 mmol), followed by N,O-dimethylhydroxylamine hydrochloride (4.72 mL, 33.9 mmol), and the mixture was stirred at room temperature for 20 min. EDC·HCl (4.88 g, 25.4 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 30 min (the reaction was confirmed by TLC). The reaction mixture was quenched with NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 2-b (2.0 g, crude). LCMS: 250.15 (M+1).

[1009] Step 2: Synthesis of 3-(cyclopropylmethoxy)-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (4-b)

[1010] K₂CO₃ (2.21 g, 16.0 mmol) was added to a stirred DMF solution (20 mL), followed by (bromomethyl)cyclopropane (0.9 mL, 9.63 mmol), and the reaction mixture was refluxed for 5 h (the reaction was confirmed by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography using 25–30% EtOAc / hexane to give compound 4-b (1.0 g, 40%). LCMS: 304.05 (M+1).

[1011] Step 3: Synthesis of 1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl-1-one (6-b)

[1012] Magnesium methyl bromide (1.5 mL, 3.0 M THF solution, 4.62 mmol) was added to a dry THF solution of compound 4-b (0.7 g, 2.31 mmol) under stirring at -10°C. The resulting mixture was stirred at room temperature for 12 h (the reaction was confirmed to be complete by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-b (0.4 g, 67.4%). LCMS: 259.20 (M+1).

[1013] Step 4: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (8-b)

[1014] Ti(O) was added to a 10 mL dry toluene solution of compound 6-b (0.4 g, 1.55 mmol) and compound 7-b (0.3 g, 2.48 mmol) under stirring. iPr)4 (1.32 g, 4.65 mmol). The resulting mixture was heated under reflux for 16 h (the reaction was confirmed by TLC). The reaction mixture was filtered through a diatomaceous earth filter, the filtrate was diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 8-b (0.33 g, 60%). LCMS: 362.1 (M+1).

[1015] Step 5: Synthesis of (S)-N-((S)-1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (9-b)

[1016] A toluene solution (5 mL) of compound 8-b (0.33 g, 0.92 mmol) was added dropwise to a solution (5 mL) of dried toluene in a stirred solution of DIBAL-H (1 M toluene solution, 1.85 mL, 2.77 mmol) at -78°C. The mixture was stirred at the same temperature for 3 h (the reaction was confirmed to be complete by TLC). The reaction mixture was quenched with NH4Cl solution, diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give compound 9-b (0.33 g, crude). LCMS: 364.15 (M+1).

[1017] Step 6: Synthesis of (S)-1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride (10-b)

[1018] A solution of dioxane in 4M HCl (0.5 mL) was added to a stirred MeOH solution (0.33 g, 0.91 mmol) of compound 9-b (8 mL), and the mixture was stirred at room temperature for 3 h (the reaction was confirmed to be complete by TLC). The reaction mixture was concentrated, and the residue was purified by milling with diethyl ether to give 10-b (0.14 g, 53%). LCMS: 261.1 (M+1).

[1019] Step 7: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl)-5-(1,3-dioxoisoindoline-2-yl)pentane-1-sulfonamide (12-b)

[1020] Triethylamine (0.24 mL, 2.42 mmol) was added to a CH2Cl2 solution (5 mL) of compound 10-b-hydrochloride (0.14 g, 0.48 mmol) under stirring at °C. A CH2Cl2 solution (5 mL) of compound 11-b (0.22 g, 0.72 mmol) was added dropwise to the reaction mixture at 0 °C for 25 min, and the mixture was stirred at the same temperature for 3 h. The reaction was monitored by TLC to ensure complete consumption of compound 11-b. The reaction mixture was quenched with water (25 mL) and extracted with CH2Cl2 (75 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography using 15–20% EtOAc / hexane to give 12-b (0.17 g, 67%) as a grayish-white solid. LCMS: 539.15 (M+1).

[1021] Step 8: Synthesis of (S)-5-amino-N-(1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl)pentane-1-sulfonamide (13-b)

[1022] Hydrazine hydrate (99%, 0.19 mL, 1.62 mmol) was added to a methanol solution (5 mL) of compound 12-b (0.17 g, 0.32 mmol) under stirring at 0°C. The ice bath was then removed, and the reaction mixture was brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, methanol was removed from the reaction mixture under reduced pressure. The starting material was dissolved in 2N HCl (6 mL) and washed with diethyl ether (10 mL x 3). The aqueous layer was alkalized with ammonia (pH = ~8) and extracted with ethyl acetate (10 mL x 2). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 13-b (0.11 g, crude) as a viscous mass. This product was transferred to the next step without purification. LCMS: 409.2 (M+1).

[1023] Step 9: Synthesis of (S)-(5-(N-(1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl)aminosulfonyl)pentyl)glycine ethyl ester (15-b)

[1024] An ethanol solution (5 mL) of compound 13-b (0.11 g, 0.28 mmol) was added to ethyl 2-oxoacetate (50% toluene solution, 0.03 mL, 0.31 mmol), and the mixture was stirred at room temperature for 1 h. After 10 min, an ethanol solution (3 mL; containing 1 drop of AcOH) of NaCNBH3 (20 mg, 0.33 mmol) was added dropwise to this mixture at room temperature, and the reaction mixture was stirred further for 5 h. The reaction was monitored by TLC to ensure complete consumption of compound 13-b. Ethanol was removed under reduced pressure. The residue was dissolved in a saturated NaHCO3 solution (25 mL) and extracted with EtOAc (25 mL x 2). The organic extract was washed separately with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 15-b (0.04 g, crude). It was transferred to the next step without purification. LCMS: 495.1 (M+1).

[1025] Step 10: (S)-N-(1-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide (Production Example 67a)

[1026] KOCN (14 mg, 0.16 mmol) was added to a 2 mL solution of AcOH containing 0.04 g (0.08 mmol) of compound 15-b under stirring, and the reaction mixture was stirred for 16 h at room temperature, followed by heating at 60 °C for 12 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated solution of NaHCO3 (15 mL) and extracted with EtOAc (15 mL x 2). The organic extract was washed with water (15 mL x 2) and brine (20 mL), respectively, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Production Example 67a (40 mg, crude product) was obtained by rapid chromatography (eluting with DCM solution of 3-4% MeOH) as a white solid. The 40 mg crude product was purified preparatively by HPLC to obtain 4 mg of compound Production Example 67a with 76% HPLC purity.

[1027] Production Example 68a: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[1028] Option 3.

[1029]

[1030] Step 1: Synthesis of 1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl-1-one (2-c)

[1031] K₂CO₃ (8.2 g, 60.0 mmol) was added to a stirred DMF solution (50 mL) of compound 1-c (3.0 g, 20.0 mmol), followed by (bromomethyl)cyclopropane (3.2 g, 24 mmol), and the reaction mixture was refluxed for 4 h (the reaction was confirmed to be complete by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 3-c (3.2 g, crude). LCMS: 205.05 (M+1).

[1032] Step 2: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (5-c)

[1033] Ti(O) was added to a 150 mL dry toluene solution of compound 3-c (3.2 g, 15.6 mmol) and compound 4-c (2.8 g, 23.5 mmol) under stirring. i Pr)4 (8.9 g, 31.3 mmol). The reaction mixture was diluted with EtOAc and quenched with water, then filtered through a diatomaceous earth pad. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 5-c (2.8 g, 62%). LCMS: 308.15 (M+1).

[1034] Step 3: Synthesis of (S)-N-((S)-1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (6-c)

[1035] At -78°C, a dry toluene solution (15 mL) of compound 5-c (2.8 g, 9.1 mmol) was added dropwise to a toluene solution (10 mL) of compound 5-c (2.8 g, 9.1 mmol) in stirred DIBAL-H (1 M toluene solution, 2.7 mL, 27.3 mmol). The resulting mixture was stirred at the same temperature for 3 h (the reaction was confirmed by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-c (2.0 g, 71%). LCMS: 310 (M+1).

[1036] Step 4: Synthesis of (S)-1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl-1-amine hydrochloride (7-c)

[1037] A solution of dioxane in 4M HCl (3.2 mL, 12.9 mmol) was added to a 20 mL MeOH solution of compound 6-c (2.0 g, 6.47 mmol) under stirring, and the resulting mixture was stirred at room temperature for 3 h (the reaction was confirmed to be complete by TLC). The reaction mixture was concentrated, and the residue was purified by grinding with diethyl ether to give 7-c (0.9 g, 61%). LCMS: 207.85 (M+1).

[1038] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 3H), 7.10 – 7.07 (d, J = 8.9 Hz, 2H), 6.98 – 6.88 (d, J = 7.5 Hz, 1H), 4.15 – 4.12 (m, 1H), 4.05 – 4.0 (m,1H), 3.83 – 3.85 (m, 2H), 2.12 (s, 3H), 1.46 – 1.35 (m, 3H), 0.62 – 0.50 (m,2H), 0.33 – 0.23 (m, 2H).

[1039] Step 5: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl)-5-(1,3-dioxoisoindoline-2-yl)pentane-1-sulfonamide (9-c)

[1040] Triethylamine (0.68 mL, 4.89 mmol) was added to a CH2Cl2 solution (5 mL) of compound 7-c-hydrochloride (0.3 g, 1.23 mmol) under stirring at 0 °C. A CH2Cl2 solution (5 mL) of compound 8-c (0.47 g, 1.48 mmol) was added dropwise to this reaction mixture at 0 °C for 25 min, and the mixture was stirred at the same temperature for 3 h. The reaction was monitored by TLC to ensure complete consumption of compound 7-c. The reaction mixture was quenched with water (50 mL) and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography using 15–20% EtOAc / hexane to give 9-c (0.42 g, 70%) as a grayish-white solid. LCMS: 485.2 (M+1).

[1041] Step 6: Synthesis of (S)-5-amino-N-(1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl)pentane-1-sulfonamide (10-c)

[1042] Hydrazine hydrate (99%, 227 mL, 4.54 mmol) was added to a methanol solution (0.44 g, 0.9 mmol) of compound 9-c (5 mL) under stirring at 0°C, and the mixture was stirred at room temperature for 3 h. The ice bath was then removed, and the reaction mixture was heated to room temperature and stirred for 5 h. The reaction was monitored by TLC until compound 9-c was completely consumed. After completion, methanol was removed from the reaction mixture under reduced pressure. The starting material was dissolved in 2N HCl (10 mL) and washed with diethyl ether (10 mL x 3). The aqueous layer was alkalized with ammonia (pH = ~8) and extracted with ethyl acetate (10 mL x 4). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 10-c (0.22 g, 68% yield) as a viscous mass. This product was transferred to the next step without purification. LCMS: 355.15 (M+1).

[1043] Step 7: Synthesis of (S)-(5-(N-(1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl)aminosulfonyl)pentyl)glycine ethyl ester (11-c)

[1044] An ethanol solution (5 mL) of compound 10-c (0.22 g, 0.62 mmol) was added to ethyl 2-oxoacetate (50% toluene solution, 0.15 mL, 0.68 mmol) and stirred at room temperature for 1 h. A solution of NaCNBH3 (47 mg, 0.74 mmol) in ethanol (5 mL; containing 2 drops of AcOH) was added dropwise over 10 min at room temperature, and the reaction mixture was stirred further for 3 h. The reaction was monitored by TLC to ensure complete consumption of compound 10-c. Ethanol was removed under reduced pressure. The residue was dissolved in a saturated NaHCO3 solution (10 mL) and extracted with EtOAc (10 mL x 3). The organic extract was washed separately with water (5 mL x 3) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11-c (0.3 g, crude). It was transferred to the next step without purification. LCMS: 441.15 (M+1).

[1045] Step 8: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-4-methylphenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide (Production Example 68a)

[1046] KOCN (110 mg, 1.36 mmol) was added to a stirred AcOH solution of compound 11-c (0.3 g, 0.68 mmol) in 5 mL, and the reaction mixture was stirred at room temperature for 16 h, followed by heating at 60 °C for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and treated with a saturated solution of NaHCO3 (10 mL), followed by extraction with EtOAc (15 mL x 2). The organic extract was washed with water (10 mL x 2) and brine (10 mL), respectively, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM solution of 3-4% MeOH) to give Production Example 68a (120 mg, 40%) as a white solid.

[1047] 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H), 6.81 (dd, J = 7.6, 1.6Hz, 1H), 4.40 – 4.28 (m, 1H), 3.89 – 3.80 (m, 4H), 3.11 (t, J = 7.0 Hz, 2H), 2.72 – 2.62(m, 2H), 2.51 – 2.40 (m, 2H), 2.12 (s, 3H), 1.46 – 1.35 (m, 3H), 1.38 – 1.18 (m, 2H), 1.11–1.05 (m, 2H), 0.98–0.95 (m, 1H), 0.62 – 0.50 (m, 2H), 0.33 – 0.23 (m, 2H).; ESI-MS (m / z): Calculated value: C 21 H 31 N3O5S: 437.56, observed mass; 436.1 (MH); HPLC purity: 96.07%.

[1048] Production Example 69a: Synthesis of (S)-N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[1049] Option 4.

[1050]

[1051] Step 1: Synthesis of 1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl-1-one (3-d)

[1052] To a stirred solution of 1-d (2.5 g, 16.2 mmol) in DMF (30 mL), K₂CO₃ (6.7 g, 48.7 mmol) was added, followed by (bromomethyl)cyclopropane (2.6 g, 19.4 mmol), and the reaction mixture was refluxed for 5 hours (considered complete by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 3-d (2.6 g, crude). LCMS: 209.0 (M+1).

[1053] Step 2: Synthesis of N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethylidene)trimethylacetamide (5-d)

[1054] Ti(O) was added to a stirred solution of compound 3-d (2.06 g, 12.44 mmol) and compound 4-d (2.25 g, 18.6 mmol) in dry toluene (50 mL). i Pr)4 (7.0 g, 24.8 mmol). The resulting mixture was heated at 90 °C for 16 hours (the reaction was considered complete by TLC). The reaction mixture was diluted with EtOAc and quenched with water, then filtered through a diatomaceous earth mat. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 5-d (1.6 g, 42%). LCMS: 292.05 (M+1).

[1055] Step 3: Synthesis of (S)-N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)trimethylacetamide (6-d)

[1056] A solution of compound 5-d (1.6 g, 5.14 mmol) in toluene (10 mL) was added dropwise to a stirred solution of DIBAL-H (1 M solution in toluene, 12.8 mL, 12.86 mmol) in dry toluene (5 mL) at -78°C. The resulting mixture was stirred at the same temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-d (0.8 g, 50%). LCMS: 294.15 (M+1).

[1057] Step 4: Synthesis of (S)-N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)trimethylacetamide (7-d)

[1058] To a stirred solution of compound 6-d (0.8 g, 2.55 mmol) in MeOH (5 mL), 4 M HCl in dioxane (1.27 mL, 5.11 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was concentrated, and the residue was purified by grinding with diethyl ether to give 7-d (0.4 g, 63%).

[1059] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 3H), 7.10– 7.09 (m, 2H), 6.98 –6.94 (m, 1H), 4.60 – 4.55 (m, 1H), 3.82 (s, 2H), 1.45 (s, 3H), 1.25 – 1.20 (m, 2H), 0.61 – 0.52 (m, 2H), 0.35 – 0.27 (m, 2H).

[1060] Step 5: Synthesis of (S)-N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-5-(1,3-dioxoisoindoline-2-yl)pentane-1-sulfonamide (9-d)

[1061] At 0 °C, triethylamine (0.68 mL, 4.89 mmol) was added to a stirred solution of compound 7-d-HCl salt (0.4 g, 1.63 mmol) in CH2Cl2 (10 mL) and stirred. Compound 8-d (0.56 g, 1.79 mmol) in CH2Cl2 (5 mL) was added dropwise to the reaction mixture at 0 °C over 25 minutes, and the mixture was stirred at the same temperature for 3 hours. The reaction was monitored by TLC to ensure complete consumption of compound 7. The reaction mixture was quenched with water (50 mL) and extracted with CH2Cl2 (50 mL x 2). The combined organic extracts were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography with 15–20% EtOAc / hexane to give 9-d (0.25 g, 31%) as a pale white solid. LCMS: 489.2 (M+1).

[1062] Step 6: Synthesis of (S)-5-amino-N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)pentane-1-sulfonamide (10-d)

[1063] At 0 °C, hydrazine hydrate (99%, 13 µL, 2.56 mmol) was added to a stirred solution of compound 9-d (0.25 g, 0.51 mmol) in methanol (2 mL) and stirred at room temperature for 3 h. The ice bath was then removed, and the reaction mixture was warmed to room temperature and stirred for 5 h. The reaction was monitored by TLC until compound 9-d was completely consumed. After completion, methanol was removed from the reaction mixture under reduced pressure. The crude substance was dissolved in 2N HCl (10 mL) and washed with diethyl ether (10 mL x 3). The aqueous layer was alkalized with ammonia (pH = ~8) and extracted with ethyl acetate (10 mL x 4). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 10-d (0.15 g, 84% yield) as a viscous substance. This product was proceeded to the next step without purification. LCMS: 359.05 (M+1).

[1064] Step 7: Synthesis of ethyl (S)-(5-(N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)aminosulfonyl)pentyl)glycine salt (11-d)

[1065] To a solution of compound 10-d (0.15 g, 0.43 mmol) in ethanol (2 mL), ethyl 2-oxoacetate (50% solution in toluene, 0.1 mL, 0.47 mmol) was added, and the mixture was stirred at room temperature for 1 hour. At room temperature, a solution of NaCNBH3 (33.1 mg, 0.51 mmol) in ethanol (5 mL; containing 2 drops of AcOH) was added dropwise over 10 minutes, and the reaction mixture was stirred further for 4 hours. The reaction was monitored by TLC to ensure complete consumption of compound 10-d. Ethanol was removed under reduced pressure. The residue was dissolved in a saturated NaHCO3 solution (10 mL) and extracted with EtOAc (10 mL x 3). The organic extract was washed with water (5 mL x 3) and brine (10 mL), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11-d (0.2 g, crude). It was proceeded to the next step without purification. LCMS: 445.1 (M+1).

[1066] Step 8: Synthesis of (S)-N-(1-(5-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide (Production Example 69a)

[1067] To a stirred solution of compound 11-d (0.2 g, 0.44 mmol) in AcOH (2 mL), KOCN (73 mg, 0.89 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h, followed by heating at 60 °C for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated NaHCO3 solution (10 mL) and extracted with EtOAc (15 mL x 2). The organic extract was washed with water (10 mL x 2) and brine (10 mL), respectively, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by combiflash chromatography (eluting with 3-4% MeOH in DCM) to give Production Example 69a (65 mg, 32% yield) as a white solid.

[1068] 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.13 – 7.01 (m, 2H), 6.81 – 6.78(m, 1H), 4.68 – 4.62 (m, 1H), 3.88 (s, 2H),3.78 (d, J = 7.0 Hz, 2H), 3.14 (t, J = 7.1 Hz, 2H), 2.88 – 2.80(m, 1H), 2.64– 2.60 (m, 1H), 1.58 – 1.43 (m, 2H), 1.36 – 1.31(m, 6H), 1.28 – 1.04 (m, 2H), 0.61 – 0.52 (m, 2H), 0.35 – 0.27 (m, 2H); ESI-MS (m / z): Calculation: C 20 H 28 FN3O5S: 441.52, observed mass; 440 (MH); HPLC purity: 97.51%.

[1069] Production Example 70a: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[1070] Option 5.

[1071]

[1072] Step 1: Synthesis of 1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl-1-one (3-e)

[1073] To a stirred solution of 1-e (3.0 g, 19.4 mmol) in DMF (30 mL), K₂CO₃ (8.0 g, 58.4 mmol) was added, followed by (bromomethyl)cyclopropane (2-e) (3.1 g, 23.3 mmol), and the reaction mixture was refluxed for 4 hours (considered complete by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 3-e (3.4 g, crude product).

[1074] Step 2: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (5-e)

[1075] Ti(O) was added to a stirred solution of compound 3-e (3.4 g, 16.2 mmol) and compound 4-e (2.95 g, 24.4 mmol) in dry toluene (50 mL). i Pr)4 (9.2 g, 32.5 mmol). The resulting mixture was heated at 90 °C for 16 hours (the reaction was considered complete by TLC). The reaction mixture was diluted with EtOAc and quenched with water, then filtered through a diatomaceous earth mat. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 5-e (3.2 g, 63%).

[1076] 1 H NMR (400 MHz, DMSO-d6) δ 7.12 – 7.08 (m, 1H), 7.05 – 7.01 (m, 2H), 3.82 – 3.87 (m, 2H), 2.76 (s, 2H), 1.32 (s, 9H), 0.67 – 0.64 (m, 2H), 0.38 –0.36 (m, 2H).

[1077] Step 3: Synthesis of (S)-N-((S)-1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (6-e)

[1078] A solution of compound 5-e (3.2 g, 10.2 mmol) in toluene (10 mL) was added dropwise at -78°C to a stirred solution of DIBAL-H (1 M solution in toluene, 30.0 mL, 30.8 mmol) in dried toluene (10 mL). The resulting mixture was stirred at the same temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-e (1.8 g, 56%).

[1079] Step 4: Synthesis of (S)-1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl-1-amine hydrochloride (7-e)

[1080] To a stirred solution of compound 6-e (1.8 g, 5.75 mmol) in MeOH (20 mL), 4 M HCl in dioxane (2.8 mL, 11.5 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was concentrated, and the residue was purified by grinding with diethyl ether to give 7-e (0.9 g, 64%).

[1081] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 3H), 7.21 – 7.08 (m, 3H), 4.61 – 4.48 (m, 1H), 3.82 – 3.80 (m, 2H), 1.42 – 1.40 (m, 2H), 1.22 – 1.18 (m, 1H), 0.60 – 0.56 (m, 2H), 0.38–0.26 (m, 2H).

[1082] Step 5: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-5-(1,3-dioxoisoindoline-2-yl)pentane-1-sulfonamide (9-e):

[1083] At 0 °C, triethylamine (0.5 mL, 3.67 mmol) was added to a stirred solution of the 7-e-HCl salt of compound 7-e in CH₂Cl₂ (5 mL) and stirred. At 0 °C, compound 8-e (0.46 g, 1.46 mmol) in CH₂Cl₂ (5 mL) was added dropwise to the reaction mixture over 25 minutes, and the mixture was stirred at the same temperature for 3 hours. The reaction was monitored by TLC to ensure complete consumption of compound 7-e. The reaction mixture was quenched with water (50 mL) and extracted with CH₂Cl₂ (50 mL x 2). The combined organic extracts were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography with 15–20% EtOAc / hexane to give 9-e (0.43 g, 72%) as a pale white solid. LCMS: 489.15 (M+1).

[1084] Step 6: Synthesis of (S)-5-amino-N-(1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)pentane-1-sulfonamide (10-e)

[1085] At 0 °C, hydrazine hydrate (99%, 215 mg, 4.30 mmol) was added to a stirred solution of compound 9-e (0.42 g, 0.86 mmol) in methanol (5 mL) and stirred at room temperature for 3 h. The ice bath was then removed, and the reaction mixture was warmed to room temperature and stirred for 5 h. The reaction was monitored by TLC until compound 9-e was completely consumed. After completion, methanol was removed from the reaction mixture under reduced pressure. The crude substance was dissolved in 2N HCl (10 mL) and washed with diethyl ether (25 mL x 3). The aqueous layer was alkalized with ammonia (pH = ~8) and extracted with ethyl acetate (20 mL x 2). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 10-e (0.15 g, 84% yield) as a viscous substance. This product was proceeded to the next step without purification. LCMS: 359 (M+1).

[1086] Step 7: Synthesis of (S)-(5-(N-(1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)aminosulfonyl)pentyl)glycine salt (11-e)

[1087] To a solution of compound 10-e (0.26 g, 0.72 mmol) in ethanol (4 mL), ethyl 2-oxoacetate (50% solution in toluene, 163 µL, 0.79 mmol) was added, and the mixture was stirred at room temperature for 1 hour. At room temperature, a solution of NaCNBH4 (56.7 mg, 0.87 mmol) in ethanol (5 mL; containing 2 drops of AcOH) was added dropwise over 10 minutes, and the reaction mixture was stirred further for 4 hours. The reaction was monitored by TLC to ensure complete consumption of compound 10-e. Ethanol was removed under reduced pressure. The residue was dissolved in a saturated NaHCO3 solution (25 mL) and extracted with EtOAc (25 mL x 3). The organic extract was washed with water (20 mL x 2) and brine (20 mL), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11-e (0.3 g, crude). It was proceeded to the next step without purification. LCMS: 445.15 (M+1).

[1088] Step 8: Synthesis of (S)-N-(1-(3-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide (Production Example 70a)

[1089] To a stirred solution of compound 11-e (0.3 g, 0.67 mmol) in AcOH (2 mL), KOCN (0.1 g, 1.34 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours, followed by heating at 60 °C for 6 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated NaHCO3 solution (15 mL) and extracted with EtOAc (15 mL x 2). The organic extract was washed with water (15 mL x 2) and brine (15 mL), respectively, and dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was purified by combiflash chromatography (eluting with 3-4% MeOH in DCM) to give Production Example 70a (0.123 mg, 41%) as a white solid.

[1090] 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.13 – 6.94 (m, 3H), 4.71–4.65 (m, 1H), 3.89 – 3.77 (m, 4H), 3.13 (t, J = 7.0Hz, 2H), 2.84 – 2.80 (m, 1H), 2.62 – 2.59 (m, 1H), 1.58 – 1.51 (m, 2H), 1.35(t, J = 7.8 Hz, 5H), 1.28 – 1.02 (m, 3H), 0.56 – 0.52 (m, 2H), 0.29–0.22 (m, 2H); ESI-MS (m / z): Calculation: C 20 H 28 FN3O5S: 441.52, observed mass; 440.05 (MH); HPLC purity: 99.08%.

[1091] Production Example 71a: Synthesis of (S)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-propoxyphenyl)ethyl)pentane-1-sulfonamide

[1092] Option 6.

[1093]

[1094] Step 1: Synthesis of 1-(4-fluoro-3-propoxyphenyl)ethyl-1-one (3-f)

[1095] To a stirred solution of 1-f (3.0 g, 19.4 mmol) in DMF (50 mL), K₂CO₃ (8.0 g, 58.4 mmol) was added, followed by 1-bromopropane (2-f) (4.75 g, 38.9 mmol), and the reaction mixture was refluxed for 4 hours (considered complete by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 3-f (4.0 g, crude).

[1096] 1H NMR (400 MHz, DMSO-d6) δ 7.65–7.57 (m, 1H), 7.52–7.48 (m, 1H), 7.12(t, J = 53 Hz, 1H), 4.06-4.03 (m, 2H), 2.66 (s, 3H), 1.92-1.82 (m, 2H).1.07-1.04 (m, 3H).

[1097] Step 2: Synthesis of (S)-N-(1-(4-fluoro-3-propoxyphenyl)ethylene)-2-methylpropane-2-sulfinamide (5-f)

[1098] Ti(O) was added to a stirred solution of compound 3-f (4.0 g, 20.4 mmol) and compound 4-f (3.95 g, 51.0 mmol) in dry toluene (40 mL). i Pr)4 (14.4 g, 32.6 mmol). The resulting mixture was heated at 90 °C for 16 hours (the reaction was considered complete by TLC). The reaction mixture was diluted with EtOAc and quenched with water, then filtered through a diatomaceous earth mat. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 5-f (5.82 g, crude). LCMS: 300.05 (M+1).

[1099] Step 3: Synthesis of (S)-N-((S)-1-(4-fluoro-3-propoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (6-f)

[1100] A solution of compound 5-f (3.0 g, 10.0 mmol) in toluene (10 mL) was added dropwise to a stirred solution of DIBAL-H (1 M solution in toluene, 25 mL, 25.0 mmol) in dry toluene (10 mL) at -78°C. The resulting mixture was stirred at the same temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-f (1.6 g, 8.53%). LCMS: 302.15 (M+1).

[1101] Step 4: Synthesis of (S)-1-(4-fluoro-3-propoxyphenyl)ethyl-1-amine hydrochloride (7-f)

[1102] To a stirred solution of compound 6-f (1.6 g, 5.31 mmol) in MeOH (5 mL), 4 M HCl in dioxane (1.5 mL, 5.84 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was concentrated, and the residue was purified by grinding with diethyl ether to give 7-f (0.7 g, 57%).

[1103] Step 5: Synthesis of (S)-5-(1,3-dioxoisoindoline-2-yl)-N-(1-(4-fluoro-3-propoxyphenyl)ethyl)pentane-1-sulfonamide (9-f)

[1104] At 0 °C, triethylamine (2.0 mL, 15.0 mmol) was added to a stirred solution of the HCl salt of compound 7-f (0.7 g, 3.0 mmol) in CH₂Cl₂ (5 mL) and stirred. At 0 °C, compound 8-f (1.4 g, 4.5 mmol) in CH₂Cl₂ (5 mL) was added dropwise over 25 minutes and stirred at the same temperature for 3 hours. The reaction was monitored by TLC to ensure complete consumption of compound 7-f. The reaction mixture was quenched with water (50 mL) and extracted with CH₂Cl₂ (50 mL x 2). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel rapid chromatography with 15–20% EtOAc / hexane to give 9-f (1.4 g, 98%) as a pale white solid. LCMS: 494.2 (M-18).

[1105] Step 6: Synthesis of (S)-5-amino-N-(1-(4-fluoro-3-propoxyphenyl)ethyl)pentane-1-sulfonamide (10-f)

[1106] At 0 °C, hydrazine hydrate (99%, 0.78 mL, 15.5 mmol) was added to a stirred solution of compound 8-f (1.5 g, 3.15 mmol) in methanol (5 mL) and stirred at room temperature for 3 h. The ice bath was then removed, and the reaction mixture was warmed to room temperature and stirred for 5 h. The reaction was monitored by TLC. After completion, methanol was removed from the reaction mixture under reduced pressure. The crude substance was dissolved in 2N HCl (10 mL) and washed with diethyl ether (10 mL x 3). The aqueous layer was alkalized with ammonia (pH = ~8) and extracted with ethyl acetate (10 mL x 4). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 10-f (1.0 g, 91.7% yield) as a viscous substance. This product was proceeded to the next step without purification. LCMS: 347.05 (M+1).

[1107] Step 7: Synthesis of ethyl (S)-(5-(N-(1-(4-fluoro-3-propoxyphenyl)ethyl)aminosulfonyl)pentyl)glycine salt (11-f)

[1108] To a solution of compound 10-f (1.0 g, 2.89 mmol) in ethanol (10 mL), ethyl 2-oxoacetate (50% solution in toluene, 0.3 mL, 3.17 mmol) was added, and the mixture was stirred at room temperature for 1 hour. At room temperature, a solution of NaCNBH3 (0.21 mg, 3.46 mmol) in ethanol (5 mL; containing 2 drops of AcOH) was added dropwise over 10 minutes, and the reaction mixture was stirred further for 4 hours. The reaction was monitored by TLC to ensure complete consumption of compound 10-f. Ethanol was removed under reduced pressure. The residue was dissolved in a saturated NaHCO3 solution (25 mL) and extracted with EtOAc (25 mL x 3). The organic extract was washed with water (25 mL x 3) and brine (25 mL), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11-f (0.5 g, crude). It was proceeded to the next step without purification. LCMS: 433.1 (M+1).

[1109] Step 8: Synthesis of (S)-5-(2,4-dioxoimidazolidine-1-yl)-N-(1-(4-fluoro-3-propoxyphenyl)ethyl)pentane-1-sulfonamide (Production Example 71a)

[1110] To a stirred solution of compound 11-f (0.5 g, 1.16 mmol) in AcOH (4 mL), KOCN (0.18 g, 2.32 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h, followed by heating at 60 °C for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL x 2). The organic extract was washed with water (50 mL x 2) and brine (10 mL), respectively, and dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was purified by combiflash chromatography (eluting with 3-4% MeOH in DCM) to give Production Example 71a (30 mg, yield 6.48%) as a white solid.

[1111] 1 H NMR (400 MHz, DMSO-d6) δ 10.71 – 10.66 (m, 1H), 7.67 (d, J = 8.8Hz, 1H), 7.25 – 7.09 (m, 2H), 6.91 (t, J = 5.8 Hz, 1H), 4.40 (p, J = 7.1 Hz,1H), 3.99 (t, J = 6.6 Hz, 2H), 3.87 (s, 3H), 3.13 (t, J = 7.1 Hz, 2H), 2.78 –2.70 (m, 1H), 2.62 – 2.52 (m, 1H), 1.82 – 1.68 (m, 3H), 1.58 – 1.40 (m, 3H), 1.40 – 0.94 (m, 7H); ESI-MS (m / z): Calculation: C 20 H 28 FN3O5S: 441.52, observed mass; 440 (MH); HPLC purity: 97.51%.

[1112] Production Example 72a: Synthesis of (S)-N-(1-(3-(allyloxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[1113] Option 7.

[1114]

[1115] Step 1: Synthesis of 1-(3-(allyloxy)-4-fluorophenyl)ethyl-1-one (3-g)

[1116] To a stirred solution of 1-g (2.0 g, 12.9 mmol) in DMF (10 mL), K₂CO₃ (5.37 g, 38.9 mmol) was added, followed by 3-bromoprop-1-ene (3-g) (3.14 g, 25.9 mmol), and the reaction mixture was refluxed for 2 hours (considered complete by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 3-g (1.8 g, crude product). LCMS: 195.05 (M+1).

[1117] Step 2: Synthesis of (S)-N-(1-(3-(allyloxy)-4-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (5-g)

[1118] Ti(O) was added to a stirred solution of compound 3-g (1.8 g, 9.27 mmol) and compound 4-g (1.79 g, 14.8 mmol) in dry toluene (20 mL). i Pr)4 (6.58 g, 23.1 mmol). The resulting mixture was heated at 90 °C for 16 hours (the reaction was considered complete by TLC). The reaction mixture was diluted with EtOAc and quenched with water, then filtered through a diatomaceous earth mat. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography to give 5 g (2.7 g, crude) of the compound. LCMS: 298.10 (M+1).

[1119] Step 3: Synthesis of (S)-N-((S)-1-(3-(allyloxy)-4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (6-g)

[1120] A solution of compound 5-g (2.7 g, 9.09 mmol) in toluene (25 mL) was added dropwise to a stirred solution of DIBAL-H (1 M solution in toluene, 1.94 mL, 10.9 mmol) in dry toluene (5 mL) at -78°C. The resulting mixture was stirred at the same temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-g (2.0 g, 73.5%). LCMS: 300.1 (M+1).

[1121] Step 4: Synthesis of (S)-1-(3-(allyloxy)-4-fluorophenyl)ethyl-1-amine hydrochloride (7-g)

[1122] To a stirred solution of 6-g (2.0 g, 6.68 mmol) of the compound in MeOH (20 mL), 4 M HCl in dioxane (2.0 mL, 7.35 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was concentrated, and the residue was purified by grinding with diethyl ether to give 7-g (0.65 g, 50%).

[1123] 1 H NMR (400 MHz, DMSO-d6) δ 7.07–7.01 (m, 2H), 6.89 – 6.87 (m, 1H), 6.12–6.02 (m, 1H), 5.45 (d, J = 13 Hz, 1H), 5.30 (d, J = 13 Hz, 1H), 4.63 (s,2H), 2.97 (s,3H).

[1124] Step 5: Synthesis of (S)-N-(1-(3-(allyloxy)-4-fluorophenyl)ethyl)-5-(1,3-dioxoisoindoline-2-yl)pentane-1-sulfonamide (9-g)

[1125] At 0 °C, triethylamine (0.26 mL, 8.60 mmol) was added to a stirred solution of compound 7-g -HCl salt (0.65 g, 3.31 mmol) in CH2Cl2 (5 mL) and stirred. Compound 8-g (1.5 g, 4.97 mmol) in CH2Cl2 (5 mL) was added dropwise to the reaction mixture at 0 °C over 25 minutes, and the mixture was stirred at the same temperature for 3 hours. The reaction was monitored by TLC to ensure complete consumption of compound 7-g. The reaction mixture was quenched with water (50 mL) and extracted with CH2Cl2 (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel rapid chromatography with 15–20% EtOAc / hexane to give 9-g (0.8 g, 53.3%) as a pale white solid. LCMS: 475.05 (M+1).

[1126] Step 6: Synthesis of ((S)-N-(1-(3-(allyloxy)-4-fluorophenyl)ethyl)-5-aminopentane-1-sulfonamide (10-g)

[1127] At 0 °C, hydrazine hydrate (99%, 0.25 mL, 8.4 mmol) was added to a stirred solution of 9-g (0.8 g, 1.68 mmol) of compound in methanol (10 mL) and stirred at room temperature for 3 h. The ice bath was then removed, and the reaction mixture was warmed to room temperature and stirred for 5 h. The reaction was monitored by TLC until the 9-g of compound was completely consumed. After completion, methanol was removed from the reaction mixture under reduced pressure. The crude substance was dissolved in 2N HCl (25 mL) and washed with diethyl ether (25 mL x 2). The aqueous layer was alkalized with ammonia (pH = ~8) and extracted with ethyl acetate (25 mL x 2). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 10-g (0.59 g, 86.6% yield) as a viscous substance. This product was proceeded to the next step without purification. LCMS: 345.15 (M+1).

[1128] Step 7: Synthesis of ethyl (S)-(5-(N-(1-(3-(allyloxy)-4-fluorophenyl)ethyl)aminosulfonyl)pentyl)glycine salt (11-g)

[1129] To a solution of 10-g (0.5 g, 1.45 mmol) of compound in ethanol (5 mL), ethyl 2-oxoacetate (50% solution in toluene, 0.16 mL, 1.59 mmol) was added, and the mixture was stirred at room temperature for 1 hour. At room temperature, a solution of NaCNBH3 (0.10 mg, 1.74 mmol) in ethanol (5 mL; containing 2 drops of AcOH) was added dropwise over 10 minutes, and the reaction mixture was stirred further for 4 hours. The reaction was monitored by TLC to ensure complete consumption of 10-g of compound. Ethanol was removed under reduced pressure. The residue was dissolved in a saturated NaHCO3 solution (15 mL) and extracted with EtOAc (20 mL x 2). The organic extract was washed with water (20 mL) and brine (15 mL), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11-g (0.5 g, crude). It was proceeded to the next step without purification. LCMS: 431.15 (M+1).

[1130] Step 8: Synthesis of (S)-N-(1-(3-(allyloxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide (Production Example 72a)

[1131] To a stirred solution of 11 g (0.5 g, 1.16 mmol) of compound in AcOH (4 mL), KOCN (0.18 g, 2.32 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h, followed by heating at 60 °C for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL x 2). The organic extract was washed with water (50 mL) and brine (15 mL), respectively, and dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was purified by combiflash chromatography (eluting with 3-4% MeOH in DCM) to give Production Example 72a (25 mg, 5% yield) as a white solid.

[1132] 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.27 – 7.11 (m, 2H), 6.98 – 6.90 (m, 1H), 6.05 – 6.0 (m, 1H), 5.43 (dd, J =17.2, 1.8 Hz, 1H), 5.29 (d, J = 10.5 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H), 4.40(p, J = 7.1 Hz, 1H), 3.87 (s, 2H), 3.13 (t, J = 7.1 Hz, 2H), 2.77 – 2.75 (m,1H), 2.62 – 2.53 (m, 1H), 1.49 – 1.40 (m, 2H), 1.40 – 1.00 (m, 7H); ESI-MS (m / z): Calculation: C 20 H 26 FN3O5S: 427.49, observed mass; 426 (MH); HPLC purity: 99.9%.

[1133] Production Example 73a: Synthesis of (S)-N-(1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide

[1134] Option 8.

[1135]

[1136] Step 1: Synthesis of 1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl-1-one (3-h)

[1137] K₂CO₃ (4.65 g, 33.7 mmol) was added to a stirred solution of 1–h (2.6 g, 16.8 mmol) in DMF (25 mL), followed by (2-bromoethyl)cyclopropane (3.0 g, 20.2 mmol), and the reaction mixture was refluxed for 2 hours (considered complete by TLC). The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3–h (3.5 g, crude). LCMS: 223.15 (M+1).

[1138] Step 2: Synthesis of (S)-N-(1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (5-h)

[1139] Ti(O) was added to a stirred solution of compound 3-h (2.0 g, 9.00 mmol) and compound 4-h (1.63 g, 13.5 mmol) in dry toluene (40 mL). i Pr)4 (5.33 mL, 18.0 mmol). The resulting mixture was heated at 90 °C for 16 hours (the reaction was considered complete by TLC). The reaction mixture was diluted with EtOAc and quenched with water, then filtered through a diatomaceous earth mat. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 5-h (3.0 g, crude). LCMS: 326.0 (M+1).

[1140] Step 3: Synthesis of (S)-N-((S)-1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (6-h)

[1141] A solution of compound 5-h (3.0 g, 9.23 mmol) in toluene (15 mL) was added dropwise to a stirred solution of DIBAL-H (1 M solution in toluene, 18.4 mL, 27.6 mmol) in dry toluene (20 mL) at -78°C. The resulting mixture was stirred at -78°C for 3 hours (the reaction was considered complete by TLC). The reaction mixture was quenched with NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to give compound 6-h (1.3 g, 43.1%). LCMS: 328.2 (M+1).

[1142] Step 4: Synthesis of (S)-1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl-1-amine hydrochloride (7-h)

[1143] To a stirred solution of compound 6-h (1.3 g, 3.97 mmol) in dioxane (8 mL), 4 M HCl in dioxane (8 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours (the reaction was considered complete by TLC). The reaction mixture was concentrated, and the residue was purified by grinding with pentane to give 7-h (0.9 g, 87.3%). LCMS: 224.05 (M+1).

[1144] Step 5: Synthesis of (S)-N-(1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl)-5-(1,3-dioxoisoindoline-2-yl)pentane-1-sulfonamide (9-h)

[1145] At 0 °C, triethylamine (1.68 mL, 12. mmol) was added to a stirred solution of compound 7-h-HCl salt (0.63 g, 2.41 mmol) in DCM (5 mL) and stirred. Compound 8-h (1.14 g, 3.62 mmol) in DCM (5 mL) was added dropwise to the reaction mixture at 0 °C over 25 minutes and stirred at the same temperature for 3 hours. The reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel rapid chromatography with 15–20% EtOAc / hexane to give 9-h (0.52 g, 43%) as a pale white solid. LCMS: 501.05 (M⁻¹).

[1146] Step 6: Synthesis of (S)-5-amino-N-(1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl)pentane-1-sulfonamide (10-h)

[1147] At 0 °C, hydrazine hydrate (99%, 0.24 mL, 4.98 mmol) was added to a stirred solution of compound 9-h (0.5 g, 0.99 mmol) in MeOH (5 mL), and the ice bath was removed. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was monitored by TLC until compound 9-h was completely consumed. After completion, MeOH was removed from the reaction mixture under reduced pressure. The crude substance was dissolved in 2N HCl (25 mL) and washed with diethyl ether (25 mL x 2). The aqueous layer was alkalized with ammonia (pH = ~8) and extracted with ethyl acetate (25 mL x 2). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 10-h (0.33 g, crude) as a yellow viscous substance. This product was proceeded to the next step without purification. LCMS: 373.05 (M+1).

[1148] Step 7: Synthesis of ethyl(S)-(5-(N-(1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl)aminosulfonyl)pentyl)glycine salt (11-h)

[1149] To a solution of compound 10-h (0.33 g, 0.88 mmol) in ethanol (8 mL), ethyl 2-oxoethyl acetate (50% solution in toluene, 99 µL, 0.97 mmol) was added, and the mixture was stirred at room temperature for 1 hour. At room temperature, a solution of NaCNBH3 (67 mg, 1.04 mmol) in ethanol (8 mL) and AcOH (2 drops) were added dropwise over 10 minutes, and the reaction mixture was stirred further for 4 hours. The complete consumption of compound 10-h was monitored by TLC. Ethanol was removed under reduced pressure. The residue was dissolved in a saturated NaHCO3 solution (15 mL) and extracted with EtOAc (20 mL x 2). The organic extract was washed with water (20 mL) and brine (15 mL), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11-h (0.5 g, crude), which was proceeded to the next step without purification. LCMS: 459.15 (M+1).

[1150] Step 8: Synthesis of (S)-N-(1-(3-(2-cyclopropylethoxy)-4-fluorophenyl)ethyl)-5-(2,4-dioxoimidazolidine-1-yl)pentane-1-sulfonamide (Production Example 73a)

[1151] To a stirred solution of compound 11-h (0.34 g, 0.74 mmol) in AcOH (5 mL), KOCN (0.12 g, 1.48 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours, followed by heating at 60 °C for 6 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL x 2). The organic extract was washed with water (50 mL) and brine (15 mL), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. The residue was purified by combiflash chromatography (eluting with 3-4% MeOH in DCM) to give Production Example 73a (85 mg, 25% yield) as a white solid.

[1152] 1 H NMR (400 MHz, CDCl3) δ 7.17 (dd, J = 8.4, 6.6 Hz, 1H), 6.73 – 6.60(m, 2H), 5.40 – 5.29 (m, 1H), 4.72 – 4.59 (m, 1H), 4.09 (t, J = 6.4 Hz, 2H),3.88 (s, 2H), 3.33 – 3.32 (m, 2H), 2.77 – 2.60 (m, 1H), 2.69 – 2.60 (m, 1H),1.84 – 1.51 (m, 7H), 1.49 – 1.39 (m, 2H), 1.35 – 1.17 (m, 3H), 0.85 (...

Claims

1. Compounds of formula (I): (I) Or a deuterated isotope of each of the above, wherein up to 10 hydrogen atoms attached to one or more carbon atoms are replaced by deuterium, or a pharmaceutically acceptable salt of each of the foregoing. in A is L 1 It is -(CH2)5-; L 2 It is -SO2NR 50 -, where sulfur is connected to L 1 ;R 50 It is hydrogen; L 3 yes The left side of these parts is connected to L. 2 ;and B is in Each R 6 It can be hydrogen, C1-C6 alkoxy, or halogen independently; Each R 7 Independently, it is a C1-C6 alkyl group, or a C2-C6 alkenyl group, optionally substituted with 1-3 halogens or hydroxyl groups; or R 6 and R 7 Together with the atoms they are attached to, they form 5-7 membered rings; or 2 Rs 6 Groups, together with the atoms they are attached to, form 5-7 membered rings; Each R 1 -R 3 Independently H, halogen, C1-C6 alkyl, or -OR 20 ; R 20 It is (CH2) w -R 21 C3-C6 cycloalkyl or C1-C6 alkyl; R 21 It is a C3-C6 cycloalkyl group optionally substituted with a C1-C6 alkyl group, or a C1-C6 cycloalkyl group. 10 Alkyl, C2-C 10 alkenyl; and w is 1, 2, 3, 4 or 5.

2. The compound of claim 1, wherein A is:

3. The compound of claim 1, wherein L 3 Selected from: The left side of these parts is connected to L. 2 .

4. The compound of claim 1, wherein R 1 It is H.

5. The compound of claim 1, wherein R 3 Is it H or -OR 20 .

6. The compound of claim 1, wherein R 2 It is either F or H.

7. The compound of claim 1, wherein B is Where R 20 As defined in claim 1.

8. The compound of claim 1, wherein B is selected from:

9. The compound of claim 1, wherein B is 10. Selected from the following compounds , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,#imgpt48#, #imgpt49#,#imgpt50#, #imgpt51#,#imgpt52#, #imgpt53#,#imgpt54#, #imgpt55#,#imgpt56#, #imgpt57#,#imgpt58#, #imgpt59#,#imgpt60#, #imgpt61#,#imgpt62#, 11. A composition comprising a compound of any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient or carrier.

12. Use of the compound of any one of claims 1 to 10 in the preparation of one or more medicaments for inhibiting dUTPase or enhancing the effects of a therapy against dUTPase.

13. Use of the compound of any one of claims 1 to 10 in the preparation of a medicament for reversing resistance to therapies targeting dUTPase.

14. Use of the compound of any one of claims 1 to 10 in the preparation of a medicament for treating diseases whose expression or overexpression is inhibited by dUTPase.

15. The application of claim 14, wherein the disease is cancer.

16. The application of claim 15, wherein the cancer is selected from colon cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, breast cancer, lung cancer, stomach cancer, liver cancer, gallbladder cancer, pancreatic cancer, or leukemia.

17. Use of the compound of any one of claims 1 to 10 in the preparation of a medicament for inhibiting the growth of cancer cells.

18. The application of claim 17, wherein the cancer cells are selected from colon cancer cells, colorectal cancer cells, gastric cancer cells, head and neck cancer cells, breast cancer cells, lung cancer cells, or blood cells.

19. A kit comprising a compound of any one of claims 1 to 10 and instructions for use in the diagnostic or therapeutic methods described herein.

Images