Pharmaceutical composition containing a WRN helicase inhibitor

Abstract

Disclosed is a compound of formula (I): TIFF2025522911000684.tif38170 or a solvate thereof, wherein R 1 , R 3 , X, Y, Z and W are as defined herein. This compound is, for example, an inhibitor of WRN helicase and is useful for the treatment of proliferative diseases such as cancer.

Description

Technical Field

[0001]

[0001] The present invention relates to a compound that is an inhibitor of Werner syndrome helicase (WRN helicase), a pharmaceutical composition containing the inhibitor, and a treatment method using the inhibitor.

Background Art

[0002]

[0002] RECQ helicase is a 3' to 5' DNA unwinding DNA-dependent ATPase. Three RECQ helicases, BLM, Werner (WRN), and RECQL4, cause overlapping but symptomatically different human syndromes when their expression changes or disappears (de Renty C, Ellis N A. Ageing Res Rev 2017;33:36-51). In 2019, WRN was independently identified by multiple groups as a potential synthetic lethal target for cancers that express high levels of microsatellite instability (MSI-H cancers) (Chan, E.M. et al., Nature 2019, 568, 551-556; Behan, F.M. et al., Nature 2019, 568, 511-516; Lieb et al. eLife 2019, 8, e43333). There are several reports describing the identification of small molecules that inhibit WRN helicase activity by unknown mechanisms (Aggarwal et al., Cancer Res. 2013, 73, 5497; Aggarwal et al., PNAS 2011, 108, 4, 1525-1530; Sommers et al., PLoS ONE 2019, 14(1), e0210525).

[0003]

[0003] Therefore, there is a need to provide a novel inhibitor of WRN helicase for the treatment of MSI-H cancers.

Summary of the Invention

[0004]

[0004] Some embodiments described herein are compounds of formula (I): TIFF2025522911000002.tif 38170 or a pharmaceutically acceptable salt or solvate thereof [Wherein, X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or, Y and Z together form an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- or 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- or 6-membered heteroaryl), -O-(optionally substituted 5- or 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or, R 1 forms an optionally substituted 5- or 6-membered heterocyclyl together with the carbon atom to which it is attached and X R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo, or, R 4 together with the carbon atom to which it is attached and Z forms an optionally substituted 5- to 6-membered heteroaryl; or, R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is independently H or optionally substituted C1-C6 alkyl; W is W 1 , W 2 , W 3 , W 4 , or W 5 ; W 1is: TIFF2025522911000003.tif32170wherein, TIFF2025522911000004.tif24170it shows that it can exist as either the (Z)- or (E)- geometric isomer, TIFF2025522911000005.tif10170R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 and R 7a together with the carbon atom to which they are attached, form an azetidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 、R 7a 、and R 8 together with the carbon atom to which they are attached, form an azetidinyl or pyrrolidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 、R 7a 、R 8 、and R 9 together with the carbon atom to which they are attached, form a dihydropyrrolyl ring; or, R 7, R 7a , R 8 , R 9 , and R 10 together with the carbon atom to which they are attached form a 2,3-dihydrothiophene 1,1-dioxide ring; or R 8 , R 9 , and R 10 together with the carbon atom to which they are attached form a 1,1-dioxide-2H-thiethyl ring; W 2 is: TIFF2025522911000006.tif32170 In the formula, TIFF2025522911000007.tif26170 It shows that it may exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000008.tif10170R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are each H; or, R 11 together with the nitrogen atom to which it is attached, and also R 12 , R 12a , and R 13 together with the carbon atom to which they are attached form an optionally substituted azetidinyl ring; W 3 is: TIFF2025522911000009.tif32170 In the formula, TIFF2025522911000010.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W4 is: TIFF2025522911000011.tif43170 wherein, TIFF2025522911000012.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; each R a is independently optionally substituted C1-C6 alkyl; W 5 is: TIFF2025522911000013.tif22170 wherein, TIFF2025522911000014.tif22170 indicates that it may exist as either the (Z)- or (E)- geometric isomer, TIFF2025522911000015.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl)] relates to.

[0005]

[0005] Some embodiments described herein are compounds of formula (II): TIFF2025522911000016.tif38170 or a pharmaceutically acceptable salt or solvate thereof [wherein, X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or, Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R 1is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or, R 1 together with the carbon atom to which it is attached and X forms an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; or, R 4 together with the carbon atoms to which they are attached and Z forms an optionally substituted 5- to 6-membered heteroaryl; or R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted C6-C 10 aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is independently H or optionally substituted C1-C6 alkyl; V comprises an electrophile that reacts with the sulfur atom of cysteine 727 set forth in SEQ ID NO: 1 or a variant thereof to form a covalent bond] relates to.

[0006]

[0006] Some embodiments described herein also provide a pharmaceutical composition comprising a compound of formula (I) or formula (II) (or any of its embodiments described herein), or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable additive.

[0007]

[0007] Some embodiments described herein also provide a method of treating a disease (a proliferative disease, such as cancer, etc.) in a patient, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or formula (II) (or any of its embodiments described herein), and / or a pharmaceutically acceptable salt thereof.

[0008]

[0008] Some embodiments described herein also provide a method of inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a patient in need thereof, the method comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I) or formula (II) (or any of its embodiments described herein), or a pharmaceutically acceptable salt or solvate thereof.

[0009]

[0009] Some embodiments described herein also include a method of inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) that results in a non-naturally occurring covalent modification at cysteine 727 as set forth in SEQ ID NO: 1 or a variant thereof, wherein the modification results from a bond-forming reaction between an electrophilic agent and cysteine 727 as set forth in SEQ ID NO: 1 or a variant thereof, and the sulfur atom of the cysteine residue undergoes a reaction with the electrophilic agent.

[0010]

[0010] Some embodiments described herein also include a modified WRN helicase protein comprising a non-naturally occurring small molecule fragment having a covalent bond to cysteine 727 of the WRN helicase protein, comprising SEQ ID NO: 1 or a variant thereof as described herein, having the structure of formula (III): TIFF2025522911000017.tif66170[wherein: S is the sulfur atom of cysteine 727 of SEQ ID NO: 1 or a variant thereof; TIFF2025522911000018.tif8170 represents amino acid positions 1-726 and 7288-1432 of SEQ ID NO: 1 or a variant thereof, respectively; Q is Q 1 、Q 2 、Q 3 、Q 4 、or Q 5 ; Q 1 is: TIFF2025522911000019.tif31170 wherein, TIFF2025522911000020.tif10170R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5-6 membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 and R 7a together with the carbon atom to which they are attached, form an azetidinyl ring; or, R 6 together with the carbon atom to which they are attached, and also R 7 R 7a and R 8 together with the carbon atom to which they are attached, form an azetidinyl or pyrrolidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 R 7a R 8 and R 9 together with the carbon atom to which they are attached, form a dihydropyrrolyl ring; or, R 7 R 7a R 8 R 9 and R 10 together with the carbon atom to which they are attached, form 2,3-dihydrothiophene 1,1-dioxide; or, R 8 R 9 and R 10 together with the carbon atom to which they are attached, form a 1,1-dioxide-2H-thienyl ring; Q 2 is: TIFF2025522911000021.tif28170 wherein, TIFF2025522911000022.tif10170R 11is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are each H; or, R 11 together with the nitrogen atom to which it is attached, and also R 12 R 12a and R 13 together with the carbon atom to which they are attached, form an optionally substituted azetidinyl ring; Q 3 is: TIFF2025522911000023.tif34170 wherein, TIFF2025522911000024.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; Q 4 is: TIFF2025522911000025.tif35170 wherein, TIFF2025522911000026.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; Each R a is independently optionally substituted C1-C6 alkyl; Q 5 is: TIFF2025522911000027.tif26170 wherein, TIFF2025522911000028.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl); U is: TIFF2025522911000029.tif33170 wherein, TIFF2025522911000030.tif10170X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or R 1 forms an optionally substituted 5- to 6-membered heterocyclyl together with the carbon atom to which it is attached and X; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)-(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4-6 membered heterocyclyl or heterocyclenyl, optionally substituted 5-6 membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo, or, R 4 together with the carbon atom to which it is attached and Z forms an optionally substituted 5-6 membered heteroaryl; or, R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl); each R is independently H, or optionally substituted C1-C6 alkyl] To provide a modified WRN helicase protein having

[0011]

[0011] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, which shows and describes only exemplary embodiments of the present disclosure. As will be understood, the present disclosure is capable of other and different embodiments, and some of the details thereof are capable of modification in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive.

[0012] Incorporation by reference

[0012] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. With respect to any portions of the incorporated publications, patents, or patent applications that conflict with the disclosure contained herein, this specification is intended to supersede and / or prevail over such conflicting material.

Mode for Carrying Out the Invention

[0013] Definitions

[0013] Unless otherwise defined, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings. All undefined technical and scientific terms used in this application have the meanings commonly understood by those of ordinary skill in the art to which this disclosure pertains.

[0014]

[0014] As used herein, the phrase "a" or "an" entity refers to one or more of that entity. For example, a compound refers to one or more compounds or at least one compound, unless otherwise specified. For this purpose, the terms "a" (or "an"), "one or more", or "at least one" may be used interchangeably herein.

[0015]

[0015] "Patient" includes both humans and animals. "Patient" and "subject" are used interchangeably herein.

[0016]

[0016] When a range of values is recited, each value and sub-range within that range is intended to be included. For example, "C 1-6 alkyl" (or "C1-C6 alkyl") includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl is intended to be included.

[0017]

[0017] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has 1 to 15 carbon atoms ("C 1-15 alkyl"). In some embodiments, the alkyl group has 1 to 14 carbon atoms ("C 1-14 alkyl"). In some embodiments, the alkyl group has 1 to 13 carbon atoms ("C 1-13 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has 1 to 11 carbon atoms ("C 1-11 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7"Alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has from 2 to 6 carbon atoms ("C 2-6 alkyl"). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like.

[0018]

[0018] "Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds ("C 2-10 alkenyl"). In some embodiments, the alkenyl group has from 2 to 9 carbon atoms ("C 2-9 alkenyl"). In some embodiments, the alkenyl group has from 2 to 8 carbon atoms ("C 2-8 alkenyl"). In some embodiments, the alkenyl group has from 2 to 7 carbon atoms ("C 2-7 alkenyl"). In some embodiments, the alkenyl group has from 2 to 6 carbon atoms ("C 2-6"(alkenyl). In some embodiments, the alkenyl group has from 2 to 5 carbon atoms ("C 2-5 alkenyl). In some embodiments, the alkenyl group has from 2 to 4 carbon atoms ("C 2-4 alkenyl). In some embodiments, the alkenyl group has from 2 to 3 carbon atoms ("C 2-3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal bonds (such as 2-butenyl) or terminal bonds (such as 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. C 2-6 Examples of alkenyl groups include the above C 2-4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like.

[0019]

[0019] "Alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 alkynyl). In some embodiments, the alkynyl group has from 2 to 9 carbon atoms ("C 2-9 alkynyl). In some embodiments, the alkynyl group has from 2 to 8 carbon atoms ("C 2-8 alkynyl). In some embodiments, the alkynyl group has from 2 to 7 carbon atoms ("C 2-7 alkynyl). In some embodiments, the alkynyl group has from 2 to 6 carbon atoms ("C 2-6 alkynyl). In some embodiments, the alkynyl group has from 2 to 5 carbon atoms ("C 2-5 alkynyl). In some embodiments, the alkynyl group has from 2 to 4 carbon atoms ("C2-4 (alkynyl). In some embodiments, the alkynyl group has from 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, the alkynyl group has 2 carbon atoms (“C2 alkynyl”). One or more carbon-carbon triple bonds can be internal bonds (such as 2-butynyl) or terminal bonds (such as 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl C3), 1-butynyl (C4), 2-butynyl (C4), and the like. C 2-6 Examples of alkenyl groups are the above C 2-4 alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0020]

[0020] “Carbocyclic”, “cycloalkyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms (“C 3-14 carbocyclic”) and having zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group has from 3 to 10 ring carbon atoms (“C 3-10 carbocyclic”). In some embodiments, the carbocyclic group has from 3 to 8 ring carbon atoms (“C 3-8 carbocyclic”). In some embodiments, the carbocyclic group has from 3 to 7 ring carbon atoms (“C 3-7 carbocyclic”). In some embodiments, the carbocyclic group has from 3 to 6 ring carbon atoms (“C 3-6 carbocyclic”). In some embodiments, the carbocyclic group has from 4 to 6 ring carbon atoms (“C 4-6 carbocyclic”). In some embodiments, the carbocyclic group has from 5 to 6 ring carbon atoms (“C 5-6 carbocyclic”). In some embodiments, the carbocyclic group has from 5 to 10 ring carbon atoms (“C 5-10 carbocyclic”). Exemplary C 3-6The carbocyclic group includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3-8 The carbocyclic group includes, but is not limited to, the above C 3-6 carbocyclic group, and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3-10 The carbocyclic group includes, but is not limited to, the above C 3-8 carbocyclic group, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), etc. As shown by the foregoing examples, in certain embodiments, the carbocyclic group is either monocyclic ("monocyclic carbocyclic") or polycyclic (including, for example, a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic carbocyclic") or a tricyclic system ("tricyclic carbocyclic")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. "Carbocyclic" also includes a ring system in which the carbocyclic ring defined above is fused to one or more aryl or heteroaryl groups having a bond point on the carbocyclic ring. In such cases, the number of carbons continues to indicate the number of carbons within the carbocyclic ring system.

[0021]

[0021] In some embodiments, "carbocyclic" has 3 to 14 ring carbon atoms ("C 3-14A monocyclic saturated carbocyclic group having (cycloalkyl). In some embodiments, "carbocyclic" has 3 to 10 ring carbon atoms ("C 3-10 A monocyclic saturated carbocyclic group having (cycloalkyl). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 (cycloalkyl). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 (cycloalkyl). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 (cycloalkyl). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 (cycloalkyl). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 (cycloalkyl). C 5-6 Examples of the cycloalkyl group include cyclopentyl (C5) and cyclohexyl (C5). C 3-6 Examples of the cycloalkyl group include the above C 5-6 cycloalkyl group, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of the cycloalkyl group include the above C 3-6 cycloalkyl group, as well as cycloheptyl (C7) and cyclooctyl (C8).

[0022]

[0022] "Cycloalkenyl" has 3 to 14 ring carbon atoms ("C 3-14"Cycloalkenyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having (cycloalkyl)) and having zero heteroatoms in the non-aromatic ring system, where at least two carbon atoms have a carbon-carbon double bond. In some embodiments, the cycloalkenyl group has from 3 to 14 ring carbon atoms and at least one double bond. In some embodiments, the cycloalkenyl group has from 3 to 10 ring carbon atoms and at least one double bond. In some embodiments, the cycloalkenyl group has from 3 to 6 ring carbon atoms and at least one double bond. In some embodiments, the cycloalkenyl has two double bonds.

[0023]

[0023] "Heterocyclyl" or "heterocyclic" refers to a group or radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valence permits. The heterocyclyl group can be either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), can be saturated, or can contain one or more carbon-carbon double or triple bonds. The heterocyclyl polycyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" includes a ring system in which the heterocyclyl ring defined above is condensed with one or more carbocyclyl groups having the point of attachment on either a carbocyclyl ring or a heterocyclyl ring, or a ring system in which the heterocyclyl ring is condensed with one or more aryl or heteroaryl groups having the point of attachment on the heterocyclyl ring. In such cases, the number of ring members continues to indicate the number of ring members within the heterocyclyl ring system.

[0024] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0025] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0026]

[0026] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) ("C 6-14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl such as 1-naphthyl (α-naphthyl) and 2-naphthyl (β-naphthyl)). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthracyl). "Aryl" includes a ring system in which the aryl ring defined above is condensed with one or more carbocyclic or heterocyclic groups having a radical or a bonding point on the aryl ring. In such a case, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system.

[0027]

[0027] "Heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n + 2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 heteroatoms provided in the aromatic ring system (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur) ("5- to 14-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the bonding point can be a carbon atom or a nitrogen atom as long as the valence allows. The heteroaryl polycyclic ring system can include one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring defined above is condensed with one or more carbocyclic or heterocyclic groups having a bonding point on the heteroaryl ring. In such a case, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. The term "heteroaryl" also includes a ring system in which the heteroaryl ring defined above is condensed with one or more aryl groups having a bonding point on either the aryl ring or the heteroaryl ring. In such a case, the number of ring members continues to indicate the number of ring members in the condensed polycyclic (aryl / heteroaryl) ring system. In the case of a polycyclic heteroaryl group having no heteroatom in one ring (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bonding point can be in either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring containing no heteroatom (e.g., 5-indolyl).

[0028] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0029] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0030]

[0030] "Saturated" refers to a ring moiety that does not contain double or triple bonds, i.e., the ring contains all single bonds.

[0031]

[0031] Alkyl, alkenyl, cycloalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be substituted. "May be substituted" refers to a group that may or may not be substituted. Generally, the term "substituted" means that at least one hydrogen present on the group is replaced by a non-hydrogen substituent, resulting in a stable compound, i.e., a compound that does not spontaneously undergo conversions such as rearrangement, cyclization, elimination, or other reactions. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or non-hydrogen substituents, and these substituents satisfy the valence of the heteroatom and form a stable compound.

[0032]

[0032] Exemplary non-hydrogen substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -N(R bb )2, -N(OR cc )R bb , -SH, -SR aa , -C(=O)R aa , -CO2H, -CHO, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bbC(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -S(=O)R aa , -OS(=O)R aa , -B(OR cc )2, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, 3 - to 14 - membered heterocyclyl, C 6-14 aryl, and 5 - to 14 - membered heteroaryl, and may be selected from the group consisting thereof, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, or two geminal hydrogens on a carbon atom are replaced by an =O group;

[0033] R aa each example of which is independently selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 carbocyclic, 3 - to 14 - membered heterocyclyl, C 6-14 aryl, and 5 - to 14 - membered heteroaryl, or two R aa groups are joined to form a 3 - to 14 - membered heterocyclyl or 5 - to 14 - membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0034] R bb each example of which is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(Rcc ) 2, -CO2R aa , -SO2R aa , -SO2N(R cc )2, -SOR aa , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl selected from the group consisting thereof, or two R bb groups are joined to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0035] R cc each instance of which is independently hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl selected from the group consisting thereof, or two R cc groups are joined to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

[0036] R dd each instance of which is independently hydrogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 alkyl, -B(OH)2, -B(OC 1-6 alkyl)2, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic, C 6-10Selected from the group consisting of aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; or two geminal Rs on a carbon atom dd The substituents may combine to form =O.

[0033]

[0037] In a preferred embodiment, any substituent is halogen, cyano, hydroxyl, amino, deuterio, -OC 1-6 alkyl, aryl, oxo, -SC 1-6 alkyl, -N(C 1-6 alkyl)2, -O(aryl), C 1-6 alkyl, -OC 1-6 cycloalkyl, halogen-substituted -OC 1-6 alkyl and C 1-6 selected from the group consisting of cycloalkyl. In a more preferred embodiment, any substituent is selected from the group consisting of fluoro, chloro, trifluoromethyl, cyano, hydroxyl, amino, deuterio, methoxy, methyl, ethyl, phenyl, oxo, methylsulfanyl, dimethylamino, phenoxy, tert-butoxy, cyclopropoxy, difluoromethoxy, cyclopropyl and cyclohexyl. In a preferred embodiment, any substituent is selected from the group consisting of fluoro, trifluoromethyl, hydroxyl, deuterio, methyl, phenyl and cyclopropyl.

[0034] [0038 "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (-I).

[0035]

[0039] It should be noted that in the heteroatom-containing ring systems described herein, there is no hydroxyl group on the carbon atom adjacent to N, O or S, and there is no N or S group on the carbon adjacent to another heteroatom. Thus, for example, in the ring: TIFF2025522911000031.tif21170, -OH is not directly bonded to the carbons at 2 and 5.

[0036]

[0040] Also, for example, the site: It should also be noted that tautomers such as TIFF2025522911000032.tif18170 are considered equivalent unless otherwise specified.

[0037]

[0041] As used herein, the term "composition" is intended to include not only a product containing the specified ingredients in the specified amounts, but also any product directly or indirectly obtained as a result of combining the specified ingredients in the specified amounts.

[0038]

[0042] An "electrophile" is a chemical species that forms a bond with a nucleophile by accepting an electron pair. Such electrophiles are often involved in Michael addition reactions in which a nucleophile adds to an α,β-unsaturated carbonyl compound containing an electron-withdrawing group. This belongs to a larger class of conjugate addition reactions and is widely used for the mild formation of C-C bonds. The term "Michael acceptor moiety" refers to a functional group that can participate in a Michael reaction, and a new covalent bond is formed between a part of the Michael acceptor moiety and the donor part. The Michael acceptor moiety is an electrophile and the "donor part" is a nucleophile.

[0039]

[0043] "Effective amount" or "therapeutically effective amount" means an amount of a compound or composition described herein that is effective to inhibit the above-mentioned enzyme, disease or condition, and thus produces a desired therapeutic, ameliorating, inhibitory and / or prophylactic effect.

[0040]

[0044] "Salt" includes all salts. "Pharmaceutically acceptable salts" are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. within the scope of sound medical judgment, and refer to salts with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, Berge et al. detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4Examples of the (alkyl)4 salts include. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acids.

[0041]

[0045] “Solvate” includes all solvates. As used herein, the term “pharmaceutically acceptable solvate” is a solvate formed from the association of one or more solvent molecules with one or more molecules of a compound disclosed herein. The term solvate includes hydrates (when the solvent molecule is water) (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

[0042]

[0046] As used herein, “microsatellite instability” or “MSI” is defined as a change in the length of a microsatellite due to deletion or insertion of repetitive units that result in new length alleles in tumor DNA when compared to normal / germline DNA from the same individual. A tumor having an “MSI-High” (MSI-H) phenotype is a tumor that has a change in the DNA sequence length in at least two of the mononucleotide or dinucleotide microsatellite loci evaluated (e.g., BAT25, BAT26, D2S123, D5S346, and D17S250). Methods for identifying the state of MSI-H tumors are well known in the art and include, for example, polymerase chain reaction (PCR) assays for the state of MSI. Mononucleotide or dinucleotide markers used for characterizing the MSI state include, but are not limited to, BAT25, BAT26, D2S123, D5S346, and D17S250.

[0043]

[0047] The compounds described herein may contain one or more asymmetric centers and thus may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of mixtures of stereoisomers including racemic mixtures and mixtures enriched in one or more stereoisomers. According to the Cahn-Ingold Prelog rules, an asymmetric carbon atom (chiral carbon atom) can be of the "R" or "S" configuration. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC). The compounds described herein may be in the form of individual isomers substantially free of other isomers or in the form of mixtures of various isomers.

[0044]

[0048] Unless otherwise indicated, the structures shown herein are also intended to include compounds that differ only in that one or more isotopically enriched atoms are present. For example, replacing hydrogen with deuterium or tritium, 19 F with 18 F, replacing carbon with 13 C or 14 C-enriched carbon, and / or replacing an oxygen atom with 18 O, compounds having the present structure except for these replacements are within the scope of this disclosure. Examples of other isotopes include 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl and 123 I. Compounds having such isotopically enriched atoms are useful, for example, as probes in analytical tools and biological assays.

[0045] Certain isotopically labeled compounds of formula (I) (e.g., compounds labeled with 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. Tritiation (i.e.,3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred in terms of the ease of their preparation and detectability. Certain isotopically labeled compounds of formula (I) may be useful for the purposes of medical imaging diagnosis. For example, 11 compounds labeled with a positron-emitting isotope such as 18 C or 123 F may be useful for applications to positron emission tomography (PET), and 2 compounds labeled with a gamma-ray emitting isotope such as 1 / 2 I may be useful for applications to single photon emission computed tomography (SPECT). Further, substitution with a heavier isotope such as deuterium (i.e.,

[0046]

[0050] The present invention provides a series of potent and selective WRN inhibitors that act through irreversible covalent binding of an electrophilic group to cysteine 727 (C727) of WRN. In one embodiment, these inhibitors exhibit potent helicase inhibitory activity, reduce viability only in MSI cell lines but not in MSS cell lines, and completely inhibit tumor growth in a xenograft mouse model of MSI cell lines. In one embodiment, the ATP cooperativity of these inhibitors (potency is improved in the presence of ATP or ADP: i.e., cell assay medium or lysate supplemented with ATP) is a surprising and unexpected feature of these compounds.

[0047]

[0051] The compounds described herein may also be used in combination with one or more additional therapeutic and / or prophylactic agents (see “Combination Therapy” below).

[0048]

[0052] In other embodiments, disclosed herein is a method of inhibiting WRN helicase. In some embodiments, the method comprises administering a compound disclosed herein. In some embodiments, the method comprises administering ATP. In some embodiments, the method comprises administering a compound disclosed herein and ATP. In some embodiments, the method comprises administering ADP. In some embodiments, the method comprises administering a compound disclosed herein and ADP. Administration may be in vivo. For example, WRN helicase may be inhibited in vivo. Administration may be to a subject. Administration may be to a cell. Administration may be in vitro. For example, WRN helicase may be inhibited in vitro.

[0049]

[0053] Disclosed herein are, in some embodiments, methods of performing a WRN helicase activity assay. Some embodiments include methods of measuring WRN helicase activity. The methods can include contacting a WRN helicase with a WRN helicase substrate. The methods can include administering a WRN helicase substrate. The methods can include contacting a WRN helicase with ATP. The methods can include administering ATP. The methods can include administering a WRN helicase substrate and ATP. The methods can include contacting a WRN helicase with ADP. The methods can include administering ADP. The methods can include administering a WRN helicase substrate and ADP. Administration can be in vivo. For example, the WRN helicase activity assay can be performed in cultured cells. Administration can be to cells. Administration can be in vitro. For example, the WRN helicase activity assay can be performed in vitro. In some embodiments, the measurement is performed after administration of ADP. In some embodiments, the measurement is performed after administration of ATP.

[0050] Embodiment

[0054] Examples of embodiments of the present application include the following.

[0055] Embodiment 1

[0056] A compound of formula (I): TIFF2025522911000033.tif38170 or a pharmaceutically acceptable salt or solvate thereof [Wherein, X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or, Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R 1is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or, R 1 together with the carbon atom to which it is attached and X forms an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; or, R 4 together with the carbon atom to which it is attached and Z forms an optionally substituted 5- to 6-membered heteroaryl; or R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted C6-C 10 aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is independently H or optionally substituted C1-C6 alkyl; W is W 1 , W 2 , W 3 , W 4 or W 5 ; W 1 is: TIFF2025522911000034.tif32170 wherein TIFF2025522911000035.tif24170 can exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000036.tif10170R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or R 6 together with the nitrogen atom to which it is attached, and also R 7and R 7a together with the carbon atom to which they are attached forms an azetidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 , R 7a , and R 8 together with the carbon atom to which they are attached forms an azetidinyl or pyrrolidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 , R 7a , R 8 , and R 9 together with the carbon atom to which they are attached forms a dihydropyrrolyl ring; or R 7 , R 7a , R 8 , R 9 , and R 10 together with the carbon atom to which they are attached forms 2,3-dihydrothiophene 1,1-dioxide; or R 8 , R 9 , and R 10 together with the carbon atom to which they are attached forms a 1,1-dioxide-2H-thiethyl ring; W 2 is: TIFF2025522911000037.tif32170wherein, TIFF2025522911000038.tif26170is shown to be able to exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000039.tif10170R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R14 is each H; or R 11 together with the nitrogen atom to which it is attached, and R 12 and R 12a and R 13 together with the carbon atom to which they are attached form an optionally substituted azetidinyl ring; W 3 is: TIFF2025522911000040.tif32170wherein, TIFF2025522911000041.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W 4 is: TIFF2025522911000042.tif43170wherein, TIFF2025522911000043.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; each R a is independently optionally substituted C1-C6 alkyl; W 5 is: TIFF2025522911000044.tif22170wherein, TIFF2025522911000045.tif22170is shown to be able to exist as either the (Z)- or (E)- geometric isomer, TIFF2025522911000046.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl).

[0051]

[0057] Embodiment 1A

[0058] Compound of formula (I): TIFF2025522911000047.tif38170 or a pharmaceutically acceptable salt thereof [wherein, X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or Y and Z together form an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- or 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- or 6-membered heteroaryl), -O-(optionally substituted 5- or 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or R 1 forms an optionally substituted 5- or 6-membered heterocyclyl together with the carbon atom to which it is attached and X; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4-6 membered heterocyclyl or heterocyclenyl, optionally substituted 5-6 membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); Or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or, R 4 together with the carbon atom to which it is attached and Z forms an optionally substituted 5-6 membered heteroaryl; Or, R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); Each R is independently H or optionally substituted C1-C6 alkyl; W is W 1 W 2 W 3 W 4 , or W 5 ; W 1 is: TIFF2025522911000048.tif In the formula 32170, TIFF2025522911000049.tif shows that it can exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000050.tif 10170R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or R 6 together with the nitrogen atom to which it is attached, and also R 7 and R 7a together with the carbon atom to which they are attached, form an azetidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 、R 7a 、and R 8 together with the carbon atom to which they are attached, form an azetidinyl or pyrrolidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 、R 7a 、R 8 、and R 9 together with the carbon atom to which they are attached, form a dihydropyrrolyl ring; or R 7 、R7a , R 8 , R 9 , and R 10 together with the carbon atom to which they are attached form 2,3-dihydrothiophene 1,1-dioxide; or, R 8 , R 9 , and R 10 together with the carbon atom to which they are attached form a 1,1-dioxide-2H-thiethyl ring; W 2 is: TIFF2025522911000051.tif32170 In the formula, TIFF2025522911000052.tif26170 indicates that it may exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000053.tif10170 R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are each H; or, R 11 together with the nitrogen atom to which it is attached, and also R 12 , R 12a , and R 13 together with the carbon atom to which they are attached form an optionally substituted azetidinyl ring; W 3 is: TIFF2025522911000054.tif32170 In the formula, TIFF2025522911000055.tif10170 R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W 4is: TIFF2025522911000056.tif43170 wherein, TIFF2025522911000057.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; each R a is independently optionally substituted C1-C6 alkyl; W 5 is: TIFF2025522911000058.tif22170 wherein, TIFF2025522911000059.tif22170 which may exist as either the (Z)- or (E)- geometric isomer, TIFF2025522911000060.tif10170m is 1, 2, or 3;

[0059] R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl).

[0052]

[0060] Embodiment 1B

[0061] The compound of formula (I): TIFF2025522911000061.tif38170 [wherein, X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or, Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10is aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or, R 1 together with the carbon atom to which it is attached and X forms an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; or, R 4 together with the carbon atom to which it is attached and Z forms an optionally substituted 5- to 6-membered heteroaryl; or, R 3 and R 4together with the carbon atoms to which they are attached, form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl); each R is independently H or optionally substituted C1-C6 alkyl; W is W 1 W 2 W 3 W 4 , or W 5 ; W 1 is: TIFF2025522911000062.tif32170 wherein, TIFF2025522911000063.tif24170 may exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000064.tif10170R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or R 6 together with the nitrogen atom to which it is attached, and also R 7 and R 7atogether with the carbon atom to which they are attached, form an azetidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 R 7a and R 8 together with the carbon atom to which they are attached, form an azetidinyl or pyrrolidinyl ring; or, R 6 together with the nitrogen atom to which it is attached, and also R 7 R 7a R 8 and R 9 together with the carbon atom to which they are attached, form a dihydropyrrolyl ring; or R 7 R 7a R 8 R 9 and R 10 together with the carbon atom to which they are attached, form 2,3-dihydrothiophene 1,1-dioxide; or, R 8 R 9 and R 10 together with the carbon atom to which they are attached, form a 1,1-dioxide-2H-thiethyl ring; W 2 is: TIFF2025522911000065.tif32170wherein, TIFF2025522911000066.tif26170is shown to be able to exist as either the (Z)- or (E)- geometric isomer, TIFF2025522911000067.tif10170R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14is H respectively; or R 11 together with the nitrogen atom to which it is attached, and R 12 R 12a and R 13 together with the carbon atom to which they are attached, form an optionally substituted azetidinyl ring; W 3 is: TIFF2025522911000068.tif32170wherein TIFF2025522911000069.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W 4 is: TIFF2025522911000070.tif43170wherein TIFF2025522911000071.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; each R a is independently optionally substituted C1-C6 alkyl; W 5 is: TIFF2025522911000072.tif22170wherein TIFF2025522911000073.tif22170is shown to be able to exist as either the (Z)- or (E)- geometric isomer, TIFF2025522911000074.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl).

[0053]

[0062] Embodiment 2

[0063] X is N; Y is N; Z is CR 5 ; or Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclic ring; the compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0054]

[0064] In other words, when X is N, Y is N, and Z is CR 5 , formula (I) is formula (IA): TIFF2025522911000075.tif38170wherein R 1 , R 3 , R 5 , and W are as defined for formula (I).

[0055]

[0065] Embodiment 2.1

[0066] X is N; Y is N; Z is CR 5 ; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclic ring), or optionally substituted C3-C8 cycloalkyl; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is, independently, H, or optionally substituted C1-C6 alkyl; W is 1 ; W 1 is: TIFF2025522911000076.tif32170 wherein, TIFF2025522911000077.tif24170 it may exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000078.tif10170 R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl, The compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0056]

[0067] Embodiment 2.1A

[0068] X is N; Y is N; Z is CR 5 and; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4-6 membered heterocyclyl or heterocyclenyl, optionally substituted 5-6 membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is, independently, H, or optionally substituted C1-C6 alkyl; W is W 1 and; W 1 is: TIFF2025522911000079.tif32170 wherein, TIFF2025522911000080.tif24170 indicates that it may exist as either the (Z)- or (E)- geometric isomer, TIFF2025522911000081.tif10170R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl, the compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0057]

[0069] Embodiment 2.1B

[0070] X is N; Y is N; Z is CR 5 ; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)-(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is, independently, H or optionally substituted C1-C6 alkyl; W is W 1 and W 1 is: TIFF2025522911000082.tif32170 wherein TIFF2025522911000083.tif24170 can exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000084.tif10170 R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl, a compound according to Embodiment 1.

[0058]

[0071] Embodiment 2.2

[0072] R 1 is -O-(C6 - C 10 aryl); R 3 is fluorine - substituted C1 - C6 alkyl; R 5 is H; R 6 is H; R 7 is C3 - C8 cycloalkyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is C1 - C6 alkyl, a compound according to Embodiment 2.1, or a pharmaceutically acceptable salt or solvate thereof.

[0059]

[0073] Embodiment 2.2A

[0074] R 1 is -O-(C6 - C 10 aryl); R 3 is fluorine - substituted C1 - C6 alkyl; R 5 is H; R 6 is H; R 7 is C3 - C8 cycloalkyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is C1 - C6 alkyl, a compound according to Embodiment 2.1, or a pharmaceutically acceptable salt thereof.

[0060]

[0075] Embodiment 2.2B

[0076] R 1is -O-(C6-C 10 aryl); R 3 is fluoro-substituted C1-C6 alkyl; R 5 is H; R 6 is H; R 7 is C3-C8 cycloalkyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10 is C1-C6 alkyl, the compound according to Embodiment 2.1.

[0061]

[0077] Embodiment 3

[0078] X is CR 2 ; Y is CR 4 ; Z is CR 5 ; or Y and Z together form an optionally substituted 5- to 6-membered heteroaryl, or an optionally substituted 5- to 6-membered heteroaryl; or R 3 forms, together with the carbon atom to which it is attached and Y, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0062]

[0079] In other words, when X is CR 2 , Y is CR 4 , and Z is CR 5 , formula (I) is formula (IB): TIFF2025522911000085.tif49170 wherein R 1 , R 2 , R 3 , R 4 , R5 and W are as defined for formula (I).

[0063]

[0080] Embodiment 4

[0081] X is CR 2 ; Y is N; Z is CR 5 ; or, R 1 together with the carbon atom to which it is attached and X forms an optionally substituted 5- to 6-membered heterocyclyl. The compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0064]

[0082] In other words, when X is CR 2 , Y is N, and Z is CR 5 , formula (I) is formula (I-C): TIFF2025522911000086.tif38170 wherein R 1 , R 2 , R 3 , R 5 , and W are as defined for formula (I).

[0065]

[0083] Embodiment 5

[0084] The compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof. X is N; Y is CR 4 ; Z is CR 5 ; or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl.

[0066]

[0085] In other words, X is N, and Y is CR 4 and Z is CR 5 When, formula (I) is formula (I-D): TIFF2025522911000087.tif49170 wherein R 1 , R 3 , R 4 , R 5 , and W are as defined for formula (I).

[0067]

[0086] Embodiment 6

[0087] X is N; Y is CR 4 and Z is N, a compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0068]

[0088] In other words, when X is N, Y is CR 4 and Z is N, formula (I) is formula (I-E): TIFF2025522911000088.tif49170 wherein R 1 , R 3 , R 4 , and W are as defined for formula (I).

[0069]

[0089] Embodiment 7

[0090] X is CR 2 and Y is CR 4 and Z is N, a compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0070]

[0091] In other words, when X is CR 2 and Y is CR 4 and Z is N, formula (I) is formula (I-F): TIFF2025522911000089.tif49170 wherein R 1 , R2 , R 3 , R 4 , and W are as defined for formula (I).

[0071]

[0092] Embodiment 8

[0093] A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0094] R 1 in:

[0095] - any substituent of -O-(optionally substituted C3-C8 cycloalkyl) is 1 to 3 substituents selected from the group consisting of halo, cyano, and hydroxy; or when 2 substituents are present on the same ring carbon atom of C3-C8 cycloalkyl, the substituents together with the ring carbon atom to which they are attached form C3-C6 cycloalkyl; or when 2 substituents are present on adjacent ring carbon atoms of C3-C8 cycloalkyl, the substituents together with the ring carbon atom to which they are attached form C3-C6 cycloalkyl;

[0096] - any substituent of -O-(optionally substituted C6-C 10 aryl) is 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, cyano, hydroxy, and -NR2, or 1 to 5 deuterium atoms;

[0097] or, when R 1 forms an optionally substituted 5- to 6-membered heterocyclyl together with the carbon atom to which it is attached and X, 2 substituents on the same ring carbon atom of the 5- to 6-membered heterocyclyl together with the carbon atom to which they are attached form 5- to 6-membered cycloalkyl;

[0098] R 3 in:

[0099] any substituent of optionally substituted C3-C8 cycloalkyl is hydroxy, halo, C1-C6 alkyl, and C6-C 101 to 3 substituents selected from aryl; or when two substituents are present on the same carbon atom of C3-C8 cycloalkyl, do the substituents, together with the ring carbon atom to which they are attached, form C3-C6 cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of C3-C8 cycloalkyl, do the substituents, together with the ring carbon atom to which they are attached, form C6-C 10 form aryl;

[0100] or, R 3 when, together with the carbon atom to which it is attached and Y, forms optionally substituted C3-C8 cycloalkyl or cycloalkenyl, any substituent is 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl; or two geminal hydrogens on the ring carbon atom of C3-C8 cycloalkyl or cycloalkenyl may be replaced by the group =O;

[0101] or, R 3 when, together with the carbon atom to which it is attached and Y, forms optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl, any substituent is 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl;

[0102] any substituent of optionally substituted C6-C 10 aryl is 1 to 3 substituents selected from the group consisting of halo;

[0103] any substituent of optionally substituted C1-C6 alkyl or C6 alkenyl is 1 to 5 substituents selected from the group consisting of halo, hydroxy, -O-(C1-C6 alkyl), and optionally substituted C3-C6 cycloalkyl, and any substituent of C3-C6 cycloalkyl is 1 to 3 substituents selected from the group consisting of C1-C6 alkyl;

[0104] any substituent of C1-C6 alkyl of -NR2 for R is 1 to 3 substituents selected from the group consisting of halo;

[0105] Any substituent of the optionally substituted 4- to 6-membered heterocyclyl may be 1 to 3 substituents selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, and halo; or when two substituents are present on the same carbon atom of the optionally substituted 4- to 6-membered heterocyclyl, the substituents together with the ring carbon atom to which they are attached form a C3-C6 cycloalkyl. A compound, or a pharmaceutically acceptable salt or solvate thereof.

[0072]

[0106] Embodiment 9

[0107] A compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt or solvate thereof,

[0108] R 1 The optionally substituted 5- to 6-membered heterocyclyl formed together with the carbon atom to which it is attached is The double bond shown in TIFF2025522911000090.tif37170 is between the carbon having the R 1 group and X;

[0109] R 3 The optionally substituted C6-C formed together with the carbon atom to which it is attached and Y 10 aryl is TIFF2025522911000091.tif29170

[0110] R 3 The optionally substituted 5- to 6-membered heterocycrenyl formed together with the carbon atom to which it is attached and Y is TIFF2025522911000092.tif291702 The shown carbon-carbon double bond between the two carbons is between the carbon having the R 3 group and Y;

[0111] R 3when the carbon atom to which it is attached and Y together form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl is TIFF2025522911000093.tif33170 wherein the indicated carbon-carbon double bond is between the carbon having the R 3 group and Y;

[0112] R 4 when the carbon atom to which it is attached and Z together form an optionally substituted 5- or 6-membered heteroaryl, the optionally substituted 5- or 6-membered heteroaryl is TIFF2025522911000094.tif29170 a compound, or a pharmaceutically acceptable salt or solvate thereof.

[0073]

[0113] Embodiment 10

[0114] A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0115] R 1 is:

[0116] -O-(optionally substituted C3-C8 cycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexan-5-yl), -O-(spiro[3.3]heptan-2-yl), -O-(3-chlorocyclobutyl), -O-(bicyclo[3.1.0]hexan-3-yl), -O-(bicyclo[2.2.1]heptan-1-yl), -O-(1-cyanocyclopentanyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl), or -O-(2,2-difluorocyclopentyl),

[0117] -O-(optionally substituted C1-C6 alkyl) is ethoxy, isopropoxy, or cyclopropylmethyloxy;

[0118] -O-(optionally substituted C6-C 10 aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalen-1-yloxy, or phenoxy-d5;

[0119] -O-(optionally substituted 5- to 6-membered heteroaryl) is pyridin-2-yloxy, or pyridin-3-yloxy;

[0120] -O-(optionally substituted 5- to 6-membered heterocyclyl) is tetrahydro-2H-pyran-4-yl, or tetrahydro-2H-pyran-3-yl;

[0121] optionally substituted C3-C8 cycloalkyl is cyclohexyl;

[0122] R 2 wherein:

[0123] optionally substituted C1-C6 alkyl is methyl;

[0124] R 3 wherein:

[0125] The optionally substituted C3-C8 cycloalkyl may be cyclopentyl, cyclobutyl, cyclohexyl, cyclopropyl, hydroxycyclopentyl, fluorocyclopentyl, methylcyclobutyl, methylcyclopropyl, phenylcyclopropyl, methylcyclopentyl, difluorocyclobutyl, fluorocyclopentyl, bicyclo[4.2.0]octa-1,3,5-trien-7-yl, or (trifluoromethyl)cyclopropyl, or spiro[2.3]hexan-5-yl;

[0126] The optionally substituted C3-C8 cycloalkenyl is cyclopentenyl;

[0127] The optionally substituted C6-C 10 The aryl is phenyl;

[0128] The optionally substituted C1-C6 alkyl may be methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl, or cyclopropyldifluoromethyl;

[0129] The optionally substituted C1-C6 alkenyl is 2-methylprop-1-en-1-yl;

[0130] NR2 is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl)2, or -N(methyl)(trifluoroethyl);

[0131] -N(R)(optionally substituted C3-C8 cycloalkyl) is N(methyl)(cyclopropyl);

[0132] -S-(optionally substituted C1-C6 alkyl) is methylthiol;

[0133] -O-(optionally substituted C1-C6 alkyl) is trifluoroethoxy, or methoxy;

[0134] -O-(optionally substituted C3-C8 cycloalkyl) is cyclopentyloxy or cyclopropyloxy;

[0135] Optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptan-7-yl, bicyclo[1.1.1]pentan-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptan-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H-pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl, or 3,3-difluoro-azetidin-1-yl;

[0136] R 5 wherein:

[0137] C1-C6 alkyl is methyl;

[0138] -NR2 is -NH2;

[0139] -N(R)-C(=O)-(C1-C6 alkyl) is -N(H)-C(=O)-CH3, a compound, or a pharmaceutically acceptable salt or solvate thereof.

[0074]

[0140] Embodiment 11

[0141] W is W 1 i.e., W is TIFF2025522911000095.tif26170 wherein R 6 , R 7 , R 7a , R 8 , R 9 , and R 10 are as defined in Embodiment 1; TIFF2025522911000096.tif24170(Z)- or (E)- geometric isomers, respectively, may exist, TIFF2025522911000097.tif10170 The compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof.

[0075]

[0142] Embodiment 12

[0143] The compound according to Embodiment 11, or a pharmaceutically acceptable salt or solvate thereof,

[0144] R 7 Optionally substituted C1-C6 alkyl of is methyl, ethyl, isopropyl, methoxymethyl, cyclopropylmethyl, cyclopropyloxymethyl, tolyl, -CH(CH3)-OCH3, difluoroethyl, phenoxymethyl, -CH2-C(=O)-N(CH3)2, or tert-butoxymethyl, difluoromethoxymethyl;

[0145] R 7 Optionally substituted C3-C8 cycloalkyl of is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, difluorocyclohexyl;

[0146] R 7 Optionally substituted 5-6 membered heterocyclyl of is tetrahydropyranyl, or tetrahydro-2H-pyran-4-yl;

[0147] R 10 Optionally substituted C1-C6 alkyl of is methyl;

[0148] R 10 Optionally substituted C3-C8 cycloalkyl of is cyclopropyl;

[0149] R 10 Optionally substituted 5-6 membered heterocyclyl of is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[0150] Or, W 1 is: TIFF2025522911000098.tif51170 A compound, or a pharmaceutically acceptable salt or solvate thereof.

[0076]

[0151] Embodiment 13

[0152] A compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of embodiments 1 to 10, where W is W 2 i.e., where W is TIFF2025522911000099.tif32170 wherein TIFF2025522911000100.tif26170 It shows that it may exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000101.tif10170 R 11 , R 12 , R 12a , R 13 , and R 14 are as defined in embodiment 1, A compound, or a pharmaceutically acceptable salt or solvate thereof.

[0077]

[0153] Embodiment 14

[0154] A compound, or a pharmaceutically acceptable salt or solvate thereof, according to embodiment 13, where W 2 is: TIFF2025522911000102.tif31170 wherein R 21 is H or C1-C6 alkyl; TIFF2025522911000103.tif31170 It shows that it may exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000104.tif10170 A compound, or a pharmaceutically acceptable salt or solvate thereof.

[0078]

[0155] Embodiment 15

[0156] The compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 3 i.e., W is TIFF2025522911000105.tif32170 wherein TIFF2025522911000106.tif10170R 15 and R 16 are as defined in Embodiment 1, the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0079]

[0157] Embodiment 16

[0158] The compound according to Embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0159] R 16 optionally substituted C1-C6 alkyl of is methyl;

[0160] R 16 optionally substituted C3-C8 cycloalkyl of is cyclopropyl, the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0080]

[0161] Embodiment 17

[0162] The compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 4 i.e., W is TIFF2025522911000107.tif43170 wherein TIFF2025522911000108.tif10170R 17 , R 18 , and R a are as defined in Embodiment 1, the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0081]

[0163] Embodiment 18

[0164] The compound according to Embodiment 17, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0165] R 18 the optionally substituted C1-C6 alkyl is methyl;

[0166] the optionally substituted C1-C6 alkyl is methyl, the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0082]

[0167] Embodiment 19

[0168] The compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 5 that is, W is TIFF2025522911000109.tif22170In the formula, TIFF2025522911000110.tif22170it is shown that it can exist as either the (Z)- or (E)-geometric isomer, TIFF2025522911000111.tif10170m and R 19 are as defined in Embodiment 1, the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0083]

[0169] Embodiment 20

[0170] The compound according to Embodiment 19, or a pharmaceutically acceptable salt or solvate thereof.

[0171] R 19 the C1-C6 alkyl of is methyl;

[0172] R 19 the -O-(C1-C6 alkyl) of is methoxy,

[0084]

[0173] Embodiment 21

[0174] The compound is as follows: (E)-N-(3-(Methylsulfonyl)allyl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide; (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-phenylpyrimidine-5-carboxamide; (S,E)-2-Methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Ethyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Isopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-Cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclohexyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Ethyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Isopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopentylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (R,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclobutyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-4-(4-Chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-4-(4-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (E)-2-Cyclohexyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-N-(3-(methylsulfonyl)allyl)-2-(methylthio)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-N-((1,1-dioxid-2H-thiet-3-yl)methyl)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-N-(1,1-dioxid-2,3-dihydrothiophen-3-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(2-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(3-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(2-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(Cyclohexyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (E)-2-Cyclopentyl-N-methyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-(p-tolyloxy)pyrimidine-5-carboxamide; (E)-N-(3-(methylsulfonyl)allyl)-4-phenoxy-2-(1H-pyrazol-5-yl)pyrimidine-5-carboxamide; (E)-4-(3-Chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3,5-difluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-fluoro-3-methylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3,5-dichlorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (S,E)-2-Cyclopentyl-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(4-Cyanophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3,4-dimethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(m-tolyloxy)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(o-tolyloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-5-carboxamide; (S,E)-2-(Cyclopropylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-Cyclobutoxy-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(1-Hydroxycyclopentyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-2-yloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-3-yloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[3.3]heptan-2-yloxy)pyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-(cyclohexyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-((4,4-difluorocyclohexyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopentyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)oxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[2.3]hexan-5-yloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-4-(cyclopropylmethoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 4-((1R,3S)-3-Chlorocyclobutoxy)-2-cyclopropyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-Cyclohexyl-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 4-[[(1S,5R)-3-Bicyclo[3.1.0]hexanyl]oxy]-2-tert-butyl-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-((1-cyanocyclopentyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-(3,3-difluorocyclobutoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1-Fluorocyclopentyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (S,E)-2-(tert-Butyl)-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Cyclopentylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; (S,E)-4-(3-chloro-5-fluorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(cyclohexylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-(3-aminophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(cyclobutylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-N-(4-(cyclopropylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (Z)-(2-cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone; (E)-(2-cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone; (S,E)-4-(cyclopentyloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-cyclopentyl-4-(((1R,2R)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-amino-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide; (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(naphthalen-1-yloxy)pyrimidine-5-carboxamide; (R,E)-2-(2-Fluorophenyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-cyclopentyl-4-(2-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(Cycloheptyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopentyl-4-(((1S,2R)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopentyl-4-(((1R,2S)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Bicyclo[1.1.1]pentan-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((1S,3R)-3-Methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((1R,3S)-3-Methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(3-Methoxyazetidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-4-((3,3-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopropyl-4-(((S)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopropyl-4-(((R)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2-azaspiro[3.3]heptan-2-yl)pyrimidine-5-carboxamide; 2-(Bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydro-2H-pyran-3-yl)pyrimidine-5-carboxamide; (S,E)-2-(5,6-Dihydro-2H-pyran-3-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-methyl-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(2-Hydroxypropan-2-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Isobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(2-Methylprop-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((2R,5R)-2,5-Dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-(Bicyclo[2.2.1]heptan-1-yloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(3,3-Difluoropyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(2-Methoxypropan-2-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1,1-Difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1-Methylcyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (2-(1-Methylcyclopropyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methylene)azetidin-1-yl)methanone; (2-((1S,3S)-3-Methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (2-((1r,3r)-3-Methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide; (S,E)-2-(2,2-Dimethylpyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((S)-2-Methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((R)-2-Methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 1-(1-(2-(tert-Butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one; (S,E)-2-((1-Methylcyclopropyl)methyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (2-((1-Methylcyclopropyl)methyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (E)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)pyrrolidin-1-yl)methanone; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide; (R,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-phenylcyclopropyl)pyrimidine-5-carboxamide; 2-((1R,3S)-3-Methylcyclopentyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(3,3-Difluorocyclobutyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(1,1-Difluoroethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1-Fluorocyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-(tert-Butyl)-N-(1-(2-(methylsulfonyl)vinyl)cyclopropyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-Acetamido-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide; (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(2-fluoropropan-2-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-((1S,3S)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-((1R,3R)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide; (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-1-yl)methanone; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,Z)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-(tert-Butyl)-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylmethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,Z)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-Cyclopentyl-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclobutyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopropyldifluoromethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(Cyclopropyldifluoromethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1,1-Difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide; (E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(1,1-Difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)pent-1-en-3-yl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-N-(1-Methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(1-fluorocyclopropyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(5,5-difluoro-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(5,5-difluoro-1-(methylsulfonyl)penta-1-en-3-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide; 4-(((1R,3S,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; 4-(((1R,3S,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-cyclopropyl-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (R,E)-N-(1-(tert-Butoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(spiro[2.3]hexan-5-yl)pyrimidine-5-carboxamide; (R,E)-2-(1,1-Difluoroethyl)-N-(1-(difluoromethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1,1-Difluoroethyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylfluoromethyl)-4-phenoxypyrimidine-5-carboxamide; 4-(((1R,3S,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-N-(1-(3,3-Difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-N-(1-(3,3-Difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopropyldifluoromethyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(Cyclopropyldifluoromethyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; 2-(1,1-Difluoroethyl)-N-((3R,4S,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; 4-(((1R,3R,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)pyrimidine-5-carboxamide; (R,E)-N-(1-Cyclopropoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(dimethylamino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(methylamino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropoxy-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(diethylamino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopropyl(methyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-methoxy-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Azetidin-1-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(methyl(2,2,2-trifluoroethyl)amino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3-fluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(ethyl(methyl)amino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoropropyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S)-N-(3-cyanobut-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-(phenoxy-d5)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; and (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-(phenoxy-d5)pyrimidine-5-carboxamide A compound according to any one of embodiments 2 and 8 to 12 selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.

[0085]

[0175] Embodiment 21A

[0176] When the R or S stereochemical configuration at one or more chiral carbons is specified, the compound comprises a mixture of the R or S configuration at that carbon; or a mixture of (E) or (Z) geometric isomers of the aforementioned compound, a compound according to embodiment 21, or a pharmaceutically acceptable salt or solvate thereof.

[0086]

[0177] Embodiment 21.1

[0178] The compound is: (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide A compound according to any one of embodiments 2 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof.

[0087]

[0179] Embodiment 21.1A

[0180] When the R or S stereochemical configuration at one or more chiral carbons is specified, the compound comprises a mixture of the R or S configuration at that carbon; or a mixture of (E) or (Z) geometric isomers of the aforementioned compound, a compound according to embodiment 21.1, or a pharmaceutically acceptable salt or solvate thereof.

[0088]

[0181] Embodiment 21.2

[0182] The compound is: (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide The compound according to any one of Embodiments 2 and 8 to 12, or a pharmaceutically acceptable salt thereof.

[0089]

[0183] Embodiment 21.2A

[0184] When the R or S stereochemical configuration at one or more chiral carbons is specified, the compound includes a mixture of the R or S configuration at that carbon; or a mixture of (E) or (Z) geometric isomers of the aforementioned compound. The compound according to Embodiment 21.2, or a pharmaceutically acceptable salt thereof.

[0090]

[0185] Embodiment 21.3

[0186] The compound is: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide The compound according to any one of Embodiments 2 and 8 to 12.

[0091]

[0187] Embodiment 21.3A

[0188] When the R or S stereochemical configuration at one or more chiral carbons is specified, the compound includes a mixture of the R or S configuration at that carbon; or a mixture of (E) or (Z) geometric isomers of the aforementioned compound. The compound according to Embodiment 21.3.

[0092]

[0189] Embodiment 22

[0190] The compound is as follows: (E)-2-cyclobutoxy-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-2-ethoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-2-isopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)-2-phenoxybenzamide; (E)-4-Cyclopentyl-2-cyclopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; 4-Cyclopentyl-2-cyclopropoxy-N-((1,1-dioxid-2H-thiet-3-yl)methyl)benzamide; (E)-2-Cyclobutoxy-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-Cyclopentyl-2-ethoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-Cyclopentyl-2-isopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-2-phenoxybenzamide; (E)-4-Cyclopentyl-2-cyclopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; 4-Cyclopentyl-2-cyclopropoxy-N-((1,1-dioxid-2H-thiet-3-yl)methyl)benzamide; (S,E)-5-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)quinoline-8-carboxamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (E)-4-Cyclopentyl-2-(cyclopentyloxy)-N-(3-(methylsulfonyl)allyl)benzamide; rac-(R,E)-4-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxybenzamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-oxo-6-phenoxy-2,3-dihydro-1H-indene-5-carboxamide; (S,E)-2,2-Dimethyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-oxo-6-phenoxy-2,3-dihydro-1H-indene-5-carboxamide; and 2,2-Dimethyl-6-(3-((methylsulfonyl)methylene)azetidine-1-carbonyl)-5-phenoxy-2,3-dihydro-1H-inden-1-one A compound according to any one of embodiments 3 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of

[0093]

[0191] Embodiment 22A

[0192] When the R or S stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of R or S configurations at those carbon atoms; or a mixture of (E) or (Z) geometric isomers of the aforementioned compound, a compound according to embodiment 22, or a pharmaceutically acceptable salt or solvate thereof.

[0094]

[0193] Embodiment 23

[0194] The compound is as follows: (S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-Cyclopropyl-5-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-6-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; and (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-4-phenoxynicotinamide A compound according to any one of embodiments 4 and 8 to 12, selected from the group consisting of

[0095]

[0195] Embodiment 23A

[0196] When the R or S stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of R or S configurations at those carbon atoms; or a mixture of (E) and (Z) geometric isomers of the aforementioned compound, a compound according to embodiment 23, or a pharmaceutically acceptable salt or solvate thereof.

[0096]

[0197] Embodiment 24

[0198] The compound is as follows: ((S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxyquinoline-3-carboxamide; (S,E)-5-Cyano-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-5-fluoro-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-Cyclopropyl-5-fluoro-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide; (S,E)-6-Cyclopentyl-5-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxynicotinamide; (S,E)-6-(1,1-Difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-5-fluoro-2-phenoxynicotinamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-7,7-difluoro-2-phenoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-6-carboxamide; and (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-6-(cyclopropyldifluoromethyl)-5-fluoro-2-phenoxynicotinamide A compound according to any one of Embodiments 5 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of

[0097]

[0199] Embodiment 24A

[0200] When the R or S stereochemical configuration at one or more chiral carbon atoms is specified, the compound is a mixture of the R or S configuration at that carbon; or a mixture of (E) or (Z) geometric isomers of the aforementioned compounds, a compound according to Embodiment 24, or a pharmaceutically acceptable salt or solvate thereof.

[0098]

[0201] Embodiment 25

[0202] The compound is: (S,E)-5-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-phenoxypyrazine-2-carboxamide The compound according to any one of embodiments 6 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof.

[0099]

[0203] Embodiment 25A

[0204] When the R or S stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of the R or S configuration at those carbon atoms; or a mixture of the E or Z geometric isomers of the aforementioned compound. The compound according to embodiment 25, or a pharmaceutically acceptable salt or solvate thereof.

[0100]

[0205] Embodiment 26

[0206] The compound is: (S,E)-5-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-phenoxypicolinamide The compound according to any one of embodiments 7 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof.

[0101]

[0207] Embodiment 26A

[0208] When the R or S stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of the R or S configuration at those carbon atoms; or a mixture of the E or Z geometric isomers of the aforementioned compound. The compound according to embodiment 26, or a pharmaceutically acceptable salt or solvate thereof.

[0102]

[0209] Embodiment 27

[0210] The compound is as follows: 2-(1-(2-Cyclopropyl-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetonitrile; 2-(1-(2-Cyclopropyl-4-phenoxypyrimidine-5-carbonyl)-2-methylazetidin-3-ylidene)acetonitrile; (E)-N-(3-Cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide; and (Z)-N-(3-Cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide A compound according to any one of Embodiments 2, 8 to 10, and 13 to 14, selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.

[0103]

[0211] Embodiment 27A When the (E) or (Z) geometric isomer of the compound is specified, a compound according to Embodiment 27, which is a mixture of the (E) or (Z) geometric isomers of the said compound, or a pharmaceutically acceptable salt or solvate thereof.

[0104]

[0212] Embodiment 28

[0213] The compound is as follows: N-(2-Cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide; 2-(tert-Butyl)-N-(2-cyanoallyl)-4-phenoxypyrimidine-5-carboxamide; N-(2-Cyanoallyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; N-(2-Cyanoallyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide; N-(2-Cyanoallyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (R)-N-(3-Cyanobut-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S)-N-(3-Cyanobut-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S)-N-(3-Cyanobut-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; and (S)-N-(2-Cyano-1-cyclopropylallyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide A compound according to any one of embodiments 2, 8 to 10, and 15 to 16 selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.

[0105]

[0214] Embodiment 28A

[0204] When the R or S stereochemical configuration at one or more chiral carbon atoms is specified, a compound according to embodiment 28, wherein the compound comprises a mixture of R or S configurations at those carbon atoms, or a pharmaceutically acceptable salt or solvate thereof.

[0106]

[0215] Embodiment 29

[0216] The compound is: (S)-2-(1,1-Difluoroethyl)-N-(5-(dimethylamino)-5-oxopent-3-yn-2-yl)-4-phenoxypyrimidine-5-carboxamide A compound according to any one of embodiments 2, 8 to 10, and 17 to 18, or a pharmaceutically acceptable salt or solvate thereof.

[0107]

[0217] Embodiment 29A

[0204] When the R or S stereochemical configuration at one or more chiral carbon atoms is specified, a compound according to embodiment 29, wherein the compound comprises a mixture of R or S configurations at those carbons, or a pharmaceutically acceptable salt or solvate thereof.

[0108]

[0218] Embodiment 30

[0219] The compound is as follows: 1-(1-(2-(tert-Butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one; and Methyl 2-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetate A compound according to any one of embodiments 2, 8 to 10, and 19 to 20 selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.

[0109]

[0220] Embodiment 31

[0221] A compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or additive.

[0110]

[0222] Embodiment 31A

[0223] A compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

[0111]

[0224] Embodiment 31B

[0225] A compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, and a pharmaceutically acceptable carrier or additive.

[0112]

[0226] Embodiment 31.1

[0227] A compound according to any one of embodiments 1 to 30 and 21A to 29A, or a pharmaceutically acceptable salt thereof.

[0113]

[0228] Embodiment 31.1A

[0229] A compound according to any one of embodiments 1 to 30 and 21A to 29A.

[0114]

[0230] Embodiment 32

[0231] A method for treating a proliferative disorder in a patient in need of treatment for a proliferative disorder, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, or a pharmaceutically acceptable salt or solvate thereof.

[0115]

[0232] Embodiment 32A

[0233] The method according to Embodiment 32, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, or a pharmaceutically acceptable salt thereof.

[0116]

[0234] Embodiment 32B

[0235] The method according to Embodiment 32, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A.

[0117]

[0236] Embodiment 33

[0237] The method according to Embodiment 32, wherein the proliferative disorder is cancer.

[0118]

[0238] Embodiment 34

[0239] The method according to Embodiment 33, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

[0119]

[0240] Embodiment 35

[0241] A method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a patient in need of inhibition of WRN helicase, comprising administering to the subject a therapeutically effective amount of at least one compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, or a pharmaceutically acceptable salt or solvate thereof.

[0120]

[0242] Embodiment 35A

[0243] A method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a patient in need of inhibition of WRN helicase, the method comprising administering to the subject a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt according to any of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A.

[0121]

[0244] Embodiment 35B

[0245] A method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a patient in need of inhibition of WRN helicase, the method comprising administering to the subject a therapeutically effective amount of at least one compound according to any of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A.

[0122]

[0246] Embodiment 36

[0247] A method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) comprising causing a non-naturally occurring covalent modification at cysteine 727 as set forth in SEQ ID NO: 1 or a variant thereof, wherein the modification results from a bond-forming reaction between an electrophilic agent and cysteine 727 as set forth in SEQ ID NO: 1 or a variant thereof, and the sulfur atom of the cysteine residue undergoes a reaction with the electrophilic agent.

[0123]

[0248] Embodiment 37

[0249] The method according to embodiment 36, wherein the electrophilic agent comprises at least one chemical moiety selected from the group consisting of vinyl sulfone, alkynyl sulfone, vinyl sulfonamide, vinyl sulfoxide, alkynyl sulfoxide, vinyl sulfoximine, alkynyl sulfoximine, acrylamide, acrylonitrile, alkynenitrile, enone, inone, enoate, and inoate.

[0124]

[0250] Embodiment 38

[0251] Vinyl sulfone has the structure TIFF2025522911000112.tif The alkynyl sulfone has the structure TIFF2025522911000113.tif The vinyl sulfonamide has the structure TIFF2025522911000114.tif The vinyl sulfoxide has the structure TIFF2025522911000115.tif The alkynyl sulfoxide has the structure TIFF2025522911000116.tif The vinyl sulfoximine has the structure TIFF2025522911000117.tif The alkynyl sulfoximine has the structure TIFF2025522911000118.tif The acrylamide has the formula TIFF2025522911000119.tif The acrylonitrile has the structure TIFF2025522911000120.tif The enone has the structure TIFF2025522911000121.tif The inone has the structure TIFF2025522911000122.tif The enoate has the structure TIFF2025522911000123.tif The inoate has the structure TIFF2025522911000124.tif Wherein: TIFF2025522911000125.tif Represents a possible bonding point of the chemical moiety to the remaining part of the electrophile, The method according to embodiment 37.

[0125]

[0252] Embodiment 39

[0253] The compound of formula (II): TIFF2025522911000126.tif Or a pharmaceutically acceptable salt or solvate thereof [Wherein, X is CR 2 Or N; Y is CR4 or N; Z is CR 5 or N; or, Y and Z together form an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- or 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- or 6-membered heteroaryl), -O-(optionally substituted 5- or 6-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or, R 1 forms, together with the carbon atom to which it is attached and X, an optionally substituted 5- or 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- or 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or, R 3 forms, together with the carbon atom to which it is attached and Y, an optionally substituted C6-C 10forms aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; or R 4 together with the carbon atom to which it is attached and Z forms optionally substituted 5- to 6-membered heteroaryl; or R 3 and R 4 together with the carbon atom to which they are attached form optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is independently H or optionally substituted C1-C6 alkyl; V comprises an electrophile that reacts with the sulfur atom of cysteine 727 set forth in SEQ ID NO: 1 or a variant thereof to form a covalent bond].

[0126]

[0254] Embodiment 40

[0255] The compound according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein the electrophile comprises at least one chemical moiety selected from the group consisting of vinyl sulfone, alkynyl sulfone, vinyl sulfonamide, vinyl sulfoxide, alkynyl sulfoxide, vinyl sulfoximine, alkynyl sulfoximine, acrylamide, acrylonitrile, alkynenitrile, enone, inone, enoate, and inoate.

[0127]

[0256] Embodiment 41

[0257] The compound according to embodiment 40, or a pharmaceutically acceptable salt or solvate thereof, wherein

[0251] The vinyl sulfone has the structure TIFF2025522911000127.tif18170 The alkynyl sulfone has the structure TIFF2025522911000128.tif20170 The vinyl sulfonamide has the structure TIFF2025522911000129.tif20170 The vinyl sulfoxide has the structure TIFF2025522911000130.tif22170 The alkynyl sulfoxide has the structure TIFF2025522911000131.tif12170 The vinyl sulfoximine has the structure TIFF2025522911000132.tif18170 The alkynyl sulfoximine has the structure TIFF2025522911000133.tif16170 The acrylamide has the formula TIFF2025522911000134.tif22170 The acrylonitrile has the structure TIFF2025522911000135.tif18170 The enone has the structure TIFF2025522911000136.tif22170 The inone has the structure TIFF2025522911000137.tif14170 The enoate has the structure TIFF2025522911000138.tif22170 The inoate has the structure TIFF2025522911000139.tif12170 Wherein: TIFF2025522911000140.tif10170 Represents a possible bonding point of the chemical moiety to the remaining part of the electrophile A compound, or a pharmaceutically acceptable salt or solvate thereof.

[0128]

[0258] Embodiment 42

[0259] The compound according to any one of embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or additive.

[0129]

[0260] Embodiment 42A

[0261] A compound according to any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

[0130]

[0262] Embodiment 42B

[0263] A compound according to any one of Embodiments 39 to 41, and a pharmaceutically acceptable carrier or additive.

[0131]

[0264] Embodiment 42.1

[0265] A compound according to any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt thereof.

[0132]

[0266] Embodiment 42.1A

[0267] A compound according to any one of Embodiments 39 to 41.

[0133]

[0268] Embodiment 43

[0269] A method for treating a proliferative disease in a patient in need of treatment for a proliferative disease, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof.

[0134]

[0270] Embodiment 43A

[0271] The method according to Embodiment 43, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt thereof.

[0135]

[0272] Embodiment 43B

[0273] The method according to Embodiment 43, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 39 to 41.

[0136]

[0274] Embodiment 44

[0275] The method according to Embodiment 43, wherein the proliferative disease is cancer.

[0137]

[0276] Embodiment 45

[0277] The method according to embodiment 44, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

[0138]

[0278] Embodiment 46

[0279] A modified WRN helicase protein comprising an unnatural low molecular fragment having a covalent bond to cysteine 727 of the WRN helicase protein, comprising SEQ ID NO: 1 or a variant thereof, and having the structure of formula (III): TIFF2025522911000141.tif67170[wherein, S is the sulfur atom of cysteine 727 of SEQ ID NO: 1 or a variant thereof; TIFF2025522911000142.tif8170represents amino acid positions 1-726 and 728-1432 of SEQ ID NO: 1 or a variant thereof, respectively; Q is Q 1 、Q 2 、Q 3 、Q 4 、or Q 5 ; Q 1 is: TIFF2025522911000143.tif28170wherein, TIFF2025522911000144.tif10170R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5-6 membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; R 10is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or R 6 together with the nitrogen atom to which it is attached, and also R 7 and R 7a together with the carbon atom to which they are attached form an azetidinyl ring; or R 6 together with the nitrogen atom to which it is attached, and also R 7 , R 7a , and R 8 together with the carbon atom to which they are attached form an azetidinyl or pyrrolidinyl ring; or R 6 together with the nitrogen atom to which it is attached, and also R 7 , R 7a , R 8 , and R 9 together with the carbon atom to which they are attached form a dihydropyrrolyl ring; or R 7 , R 7a , R 8 , R 9 , and R 10 together with the carbon atom to which they are attached form 2,3-dihydrothiophene 1,1-dioxide; or R 8 , R 9 , and R 10 together with the carbon atom to which they are attached form 2,3-dihydrothiophene 1,1-dioxide; Q 2 is: TIFF2025522911000145.tif24170 wherein TIFF2025522911000146.tif10170R 11 is H; R 12is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are each H; or, R 11 together with the nitrogen atom to which it is attached, and also R 12 R 12a and R 13 together with the carbon atom to which they are attached, form an optionally substituted azetidinyl ring; Q 3 is: TIFF2025522911000147.tif34170 wherein, TIFF2025522911000148.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; Q 4 is: TIFF2025522911000149.tif33170 wherein, TIFF2025522911000150.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; each R a is independently optionally substituted C1-C6 alkyl; Q 5 is: TIFF2025522911000151.tif26170 wherein, TIFF2025522911000152.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl); U is: TIFF2025522911000153.tif31170 wherein, TIFF2025522911000154.tif10170X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or, Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclic ring; provided that X, Y, and Z are not simultaneously N; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclic ring), or optionally substituted C3-C8 cycloalkyl; or, R 1 forms, together with the carbon atom to which it is attached and X, an optionally substituted 5- to 6-membered heterocyclic ring; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C 10Aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), -S-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or, R 3 together with the carbon atom to which it is attached and Y forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, halo; or, R 4 together with the carbon atom to which it is attached and Z forms an optionally substituted 5- to 6-membered heteroaryl; or, R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R 5 is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(C1-C6 alkyl); each R is independently H, or optionally substituted C1-C6 alkyl] A modified WRN helicase protein having

[0139]

[0280] Embodiment 47

[0281] X is N; Y is N; Z is CR 5 ; or Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl, a modified helicase protein according to embodiment 46.

[0140]

[0282] In other words, when X is N, Y is N, and Z is CR 5 , U is TIFF2025522911000155.tif34170[wherein R 1 , R 3 , and R 5 are as defined in embodiment 46.

[0141]

[0283] Embodiment 48

[0284] X is CR 2 ; Y is CR 4 ; Z is CR 5 ; or Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heteroaryl; or R 3 forms, together with the carbon atom to which it is attached and Y, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, a modified helicase protein according to embodiment 46.

[0142]

[0285] In other words, when X is CR 2 , Y is CR 4 , and Z is CR 5 , U is TIFF2025522911000156.tif41170 wherein R 1 , R 2 , R 3 , R 4 , and R5 is as defined in Embodiment 46.

[0143]

[0286] Embodiment 49

[0287] X is CR 2 and; Y is N; Z is CR 5 and; or, R 1 forms, together with the carbon atom to which it is attached and X, an optionally substituted 5- to 6-membered heterocyclyl, the modified helicase protein according to Embodiment 46.

[0144]

[0288] In other words, when X is CR 2 and Y is N and Z is CR 5 and, U is TIFF2025522911000157.tif31170 formula, wherein R 1 , R 2 , R 3 , and R 5 are as defined in Embodiment 46.

[0145]

[0289] Embodiment 50

[0290] X is N; Y is CR 4 and; Z is CR 5 and; or, R 3 forms, together with the carbon atom to which it is attached and Y, an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl, the modified helicase protein according to Embodiment 46.

[0146]

[0291] In other words, when X is N and Y is CR 4and Z is CR 5 when U is TIFF2025522911000158.tif41170 wherein R 1 R 3 R 4 and R 5 are as defined in Embodiment 46.

[0147]

[0292] Embodiment 51

[0293] X is N; Y is CR 4 and Z is N, the modified helicase protein described in Embodiment 46.

[0148]

[0294] In other words, when X is N, Y is CR 4 and Z is N, U is TIFF2025522911000159.tif41170 wherein R 1 R 3 and R 4 are as defined in Embodiment 46.

[0149]

[0295] Embodiment 52

[0296] X is CR 2 and Y is CR 4 and Z is N, the modified helicase protein described in Embodiment 46.

[0150]

[0297] X is CR 2 and Y is CR 4 and when Z is N, U is TIFF2025522911000160.tif41170 wherein R 1 R 2 R 3 and R 4 are as defined in Embodiment 46.

[0151]

[0298] Embodiment 53

[0299] A modified helicase protein according to any one of embodiments 46 to 52, wherein:

[0300] R 1 in:

[0301] Any substituent of -O-(optionally substituted C3-C8 cycloalkyl) is 1 to 3 substituents selected from the group consisting of halo, cyano, and hydroxy; or when two substituents are present on the same ring carbon atom of C3-C8 cycloalkyl, the substituents together with the ring carbon atom to which they are attached form a C3-C6 cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of C3-C8 cycloalkyl, the substituents together with the ring carbon atom to which they are attached form a C3-C6 cycloalkyl;

[0302] -O-(optionally substituted C6-C 10 aryl) any substituent is 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, cyano, hydroxy, and -NH2, or 1 to 5 deuterium atoms;

[0303] Or, when R 1 together with the carbon atom to which it is attached and X forms an optionally substituted 5- to 6-membered heterocyclyl, two substituents on the same ring carbon atom of the 5- to 6-membered heterocyclyl together with the carbon atom to which they are attached form a 5- to 6-membered cycloalkyl;

[0304] R 3 in:

[0305] Any substituent of the optionally substituted C3-C8 cycloalkyl is hydroxy, halo, C1-C6 alkyl, and C6-C 101 to 3 substituents selected from aryl; or when two substituents are present on the same carbon atom of C3-C8 cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C3-C6 cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of C3-C8 cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C6-C 10 aryl?

[0306] Or, R 3 when, together with the carbon atom to which it is attached and Y, forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, any substituent is 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl; or two geminal hydrogens on the ring carbon atom of C3-C8 cycloalkyl or cycloalkenyl may be replaced by the group =O;

[0307] Or, R 3 when, together with the carbon atom to which it is attached and Y, forms an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl, any substituent is 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl;

[0308] any substituent of optionally substituted C6-C 10 aryl is 1 to 3 substituents selected from the group consisting of halo;

[0309] any substituent of optionally substituted C1-C6 alkyl or C6 alkenyl is 1 to 5 substituents selected from the group consisting of halo, hydroxy, -O-(C1-C6 alkyl), and optionally substituted C3-C6 cycloalkyl, and any substituent of C3-C6 cycloalkyl is 1 to 3 substituents selected from the group consisting of C1-C6 alkyl;

[0310] any substituent of C1-C6 alkyl of -NR2's R is 1 to 3 substituents selected from the group consisting of halo;

[0311] Any substituent of the optionally substituted 4- to 6-membered heterocyclyl may be 1 to 3 substituents selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, and halo; or when two substituents are present on the same carbon atom of the optionally substituted 4- to 6-membered heterocyclyl, the substituents, together with the ring carbon atom to which they are attached, form a C3-C6 cycloalkyl. Modified helicase protein.

[0152]

[0312] Embodiment 54

[0313] A modified helicase protein according to any one of embodiments 46 to 53,

[0314] R 1 The optionally substituted 5- to 6-membered heterocyclyl formed together with the carbon atom to which it is shown to be attached is TIFF2025522911000161.tif37170 wherein the double bond shown is between the carbon having the R 1 group and X;

[0315] R 3 The optionally substituted C6-C 10 aryl formed together with the carbon atom to which it is shown to be attached and Y is TIFF2025522911000162.tif25170

[0316] R 3 The optionally substituted 5- to 6-membered heterocycrenyl formed together with the carbon atom to which it is shown to be attached and Y is TIFF2025522911000163.tif24170 The double bond shown between two carbons having is between the carbon having the R 3 group and Y;

[0317] R 3 When R, together with the carbon atom to which it is shown to be attached and Y, forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl is TIFF2025522911000164.tif33170 wherein the carbon-carbon double bond shown is between the carbon having the R 3 group and Y;

[0318] R 4 together with the carbon atom to which it is attached and Z forms an optionally substituted 5- to 6-membered heteroaryl, TIFF2025522911000165.tif29170 wherein in each structure, TIFF2025522911000166.tif10170 Modified helicase protein.

[0153]

[0319] Embodiment 55

[0320] A modified helicase protein according to any one of embodiments 46 to 54, R 1 wherein: -O-(optionally substituted C3-C8 cycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexan-5-yl), -O-(spiro[3.3]heptan-2-yl), -O-(3-chlorocyclobutyl), -O-(bicyclo[3.1.0]hexan-3-yl), -O-(bicyclo[2.2.1]heptan-1-yl), -O-(1-cyanocyclopentanyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl), or -O-(2,2-difluorocyclopentyl),

[0321] -O-(optionally substituted C1-C6 alkyl) is ethoxy, isopropoxy, or cyclopropylmethyloxy;

[0322] -O-(optionally substituted C6-C 10Aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalen-1-yloxy, or phenoxy-d5;

[0323] -O-(Optionally substituted 5- to 6-membered heteroaryl) is pyridin-2-yloxy or pyridin-3-yloxy;

[0324] -O-(Optionally substituted 5- to 6-membered heterocyclyl) is -O-tetrahydro-2H-pyran-4-yl or -O-tetrahydro-2H-pyran-3-yl;

[0325] Optionally substituted C3-C8 cycloalkyl is cyclohexyl;

[0326] R 2 wherein:

[0327] Optionally substituted C1-C6 alkyl is methyl;

[0328] R 3 wherein:

[0329] Optionally substituted C3-C8 cycloalkyl is cyclopentyl, cyclobutyl, cyclohexyl, cyclopropyl, hydroxymethylcyclopentyl, fluorocyclopentyl, methylcyclobutyl, methylcyclopropyl, phenylcyclopropyl, methylcyclopentyl, difluorocyclobutyl, fluorocyclopentyl, bicyclo[4.2.0]octa-1,3,5-trien-7-yl, or (trifluoromethyl)cyclopropyl, or spiro[2.3]hexan-5-yl;

[0330] Optionally substituted C3-C8 cycloalkenyl is cyclopentenyl;

[0331] C6-C may be substituted 10 The aryl is phenyl;

[0332] The optionally substituted C1-C6 alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl, or cyclopropyldifluoromethyl;

[0333] The optionally substituted C1-C6 alkenyl is 2-methylprop-1-en-1-yl;

[0334] NR2 is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl)2, or -N(methyl)(trifluoroethyl);

[0335] -N(R)(optionally substituted C3-C8 cycloalkyl) is N(methyl)(cyclopropyl);

[0336] -S-(optionally substituted C1-C6 alkyl) is methylthiol;

[0337] -O-(optionally substituted C1-C6 alkyl) is trifluoroethoxy, or methoxy;

[0338] -O-(optionally substituted C3-C8 cycloalkyl) is cyclopentyloxy, or cyclopropyloxy;

[0339] A 4- to 6-membered heterocyclyl or heteroarenyl which may be substituted is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptan-7-yl, bicyclo[1.1.1]pentan-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptan-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H-pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl, or 3,3-difluoro-azetidin-1-yl;

[0340] R 5 wherein:

[0341] C1-C6 alkyl is methyl;

[0342] -NR2 is -NH2;

[0343] -N(R)-C(=O)-(C1-C6 alkyl) is -N(H)-C(=O)-CH3, Modified helicase protein.

[0154]

[0344] Embodiment 56 TIFF2025522911000167.tif28170

[0345] The modified WRN helicase protein according to any one of claims 46 to 55, wherein Q is Q 1 That is, Q is: wherein, in the formula, TIFF2025522911000168.tif10170U, R 6 R 7 R 7a R 8 R 9 and R 10 are as defined in embodiment 46, the modified WRN helicase protein.

[0155]

[0346] Embodiment 57

[0347] The modified helicase protein according to Embodiment 56,

[0348] R 7 The optionally substituted C1-C6 alkyl of is methyl, ethyl, isopropyl, methoxymethyl, cyclopropylmethyl, cyclopropyloxymethyl, tolyl, -CH(CH3)-OCH3, difluoroethyl, phenoxymethyl, -CH2-C(=O)-N(CH3)2, or tert-butoxymethyl, difluoromethoxymethyl;

[0349] R 7 The optionally substituted C3-C8 cycloalkyl of is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, difluorocyclohexyl;

[0350] R 7 The optionally substituted 5- to 6-membered heterocyclyl of is tetrahydropyranyl, or tetrahydro-2H-pyran-4-yl;

[0351] R 10 The optionally substituted C1-C6 alkyl of is methyl;

[0352] R 10 The optionally substituted C3-C8 cycloalkyl of is cyclopropyl;

[0353] R 10 The optionally substituted 5- to 6-membered heterocyclyl of is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[0354] Or, Q 1 is: TIFF2025522911000169.tif60170 wherein, in each structure, TIFF2025522911000170.tif10170 modified helicase protein.

[0156]

[0355] Embodiment 58

[0356] Q is Q 2 that is, Q is: TIFF2025522911000171.tif In formula 28170, TIFF2025522911000172.tif 10170U, R 11 , R 12 , R 12a , R 13 , and R 14 are modified WRN helicase proteins as defined in Embodiment 46 and described in any one of Embodiments 46 to 55.

[0157]

[0357] Embodiment 59

[0358] Q 2 is TIFF2025522911000173.tif In formula 34170, R 21 is H or C1-C6 alkyl; TIFF2025522911000174.tif The modified helicase protein described in Embodiment 58.

[0158]

[0359] Embodiment 60

[0360] Q is Q 3 i.e., Q is: TIFF2025522911000175.tif In formula 32170, TIFF2025522911000176.tif 10170U, R 15 , and R 16 are modified WRN helicase proteins as defined in Embodiment 46 and described in any one of Embodiments 46 to 55.

[0159]

[0361] Embodiment 61

[0362] A modified helicase protein described in Embodiment 60, wherein

[0363] R 16 The optionally substituted C1-C6 alkyl of is methyl;

[0364] R 16 The optionally substituted C3-C8 cycloalkyl of is cyclopropyl, Modified helicase protein.

[0160]

[0365] Embodiment 62

[0366] Q is Q 4 and that is to say, Q is: TIFF2025522911000177.tif35170 wherein, TIFF2025522911000178.tif10170U, R 17 , R 18 , and R a are as defined in Embodiment 46, a modified WRN helicase protein described in any one of Embodiments 46 to 55.

[0161]

[0367] Embodiment 63

[0368] A modified helicase protein described in Embodiment 62,

[0369] R 18 optionally substituted C1-C6 alkyl of which is methyl;

[0370] optionally substituted C1-C6 alkyl of which is methyl, modified helicase protein

[0162]

[0371] Embodiment 64

[0372] Q is Q 5 and that is to say, Q is: TIFF2025522911000179.tif26170 wherein, TIFF2025522911000180.tif10170U, m, and R 19 are as defined in Embodiment 46, a modified WRN helicase protein described in any one of Claims 46 to 55.

[0163]

[0373] Embodiment 65

[0374] A modified helicase protein described in Embodiment 64,

[0375] R 19 C1-C6 alkyl of which is methyl;

[0376] R 19 -O-(C1-C6 alkyl) of which is methoxy, Modified helicase protein

[0164]

[0377] Embodiment 66

[0378] A compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A and 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a proliferative disorder.

[0165]

[0379] Embodiment 66A

[0380] A compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A and 39 to 41, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

[0166]

[0381] Embodiment 66B

[0382] A compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A and 39 to 41, for use in the treatment of a proliferative disorder.

[0167]

[0383] Embodiment 67

[0384] A compound according to embodiment 66, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a proliferative disorder wherein the proliferative disorder is cancer.

[0168]

[0385] Embodiment 67A

[0386] A compound according to embodiment 66, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder wherein the proliferative disorder is cancer.

[0169]

[0387] Embodiment 67B

[0388] A compound according to embodiment 66, for use in the treatment of a proliferative disorder wherein the proliferative disorder is cancer.

[0170]

[0389] Embodiment 68

[0390] For use according to embodiment 67, a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

[0171]

[0391] Embodiment 68A

[0392] For use according to embodiment 67, a compound, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

[0172]

[0393] Embodiment 68B

[0394] For use according to embodiment 67, a compound, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

[0173]

[0395] Embodiment 69

[0396] A method for measuring WRN helicase activity in an assay comprising ATP and a compound according to any one of embodiments 1-30, 2.1, 2.2, 21.1, 21.1A, 21A-29A, and 39-41, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the assay is an in vitro assay. In some embodiments, the assay is a WRN helicase activity assay.

[0174]

[0397] Embodiment 69A

[0398] A method for measuring WRN helicase activity in an assay comprising ATP and a compound according to any one of embodiments 1-30, 2.1, 2.2, 21.1, 21.1A, 21A-29A, and 39-41, or a pharmaceutically acceptable salt thereof. In some embodiments, the assay is an in vitro assay. In some embodiments, the assay is a WRN helicase activity assay.

[0175]

[0399] Embodiment 69B

[0400] A method for measuring WRN helicase activity in an assay comprising ATP and a compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A, and 39 to 41. In some embodiments, the assay is an in vitro assay. In some embodiments, the assay is a WRN helicase activity assay.

[0176] Administration and Pharmaceutical Composition

[0401] Generally, the compounds described herein are administered in a therapeutically effective amount by any of the acceptable modes of administration for agents that serve a similar utility. The therapeutically effective amount of the compounds described herein is from about 0.01 to about 500 mg per kg of patient body weight per day and can be administered as a single dose or multiple doses. Appropriate dosage levels are from about 0.1 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg, or from about 0.1 to about 50 mg / kg. Within this range, the dosage can be from about 0.05 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg / kg per day. For oral administration, the composition can be provided in the form of tablets containing from about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound, i.e., the active ingredient, depends on many factors such as the severity of the disease to be treated, the age and relative health of the patient, the efficacy of the compound to be utilized, the route of administration and the form of administration.

[0177]

[0402] Generally, the compounds described herein are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., by transdermal, nasal, or suppository), parenteral (e.g., intramuscular, intravenous, intrapleural, or subcutaneous), topical (e.g., application to the skin), or via implant. The preferred mode of administration is oral using a convenient once-daily dosing regimen that can be adjusted according to the degree of pain. The composition can take the form of tablets, pills, capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or other suitable compositions.

[0178]

[0403] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, tablets, pills, or capsules including enteric-coated or sustained-release tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. In recent years, pharmaceutical formulations have been developed based on the principle that the bioavailability can be enhanced by increasing the surface area, i.e., reducing the particle size, especially for drugs with low bioavailability. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 to 1,000 nm in which the active substance is supported on a polymeric cross-linked matrix. U.S. Patent No. 5,145,684 describes a method for manufacturing a pharmaceutical formulation in which the drug substance is pulverized into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to obtain a pharmaceutical formulation showing significantly high bioavailability.

[0179]

[0404] The composition generally consists of the compounds described herein in combination with at least one pharmaceutically acceptable carrier / additive. The acceptable additives are non-toxic, assist in administration, and do not adversely affect the therapeutic effect of the compound. Such additives may be any solid, liquid, semisolid, or gaseous additive in the case of an aerosol composition that is generally available to those skilled in the art.

[0180]

[0405] Solid pharmaceutical additives include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid additives can be selected from various oils including glycerol, propylene glycol, water, ethanol, and those derived from petroleum, animal, plant or synthetic sources (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). In particular, in the case of injection solutions, preferred liquid carriers include water, physiological saline, aqueous dextrose, and glycols.

[0181]

[0406] Compressed gases can be used to disperse the compounds described herein in the form of aerosols. Suitable inert gases for this purpose are nitrogen, carbon dioxide, etc.

[0182]

[0407] Other suitable pharmaceutical additives and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 20th ed., 2000).

[0183]

[0408] The level of the compound in the formulation can vary within the full range employed by those skilled in the art. Typically, the formulation contains about 0.01 to 99.99 wt% of the described compound based on the total weight of the formulation (wt%), and the remainder is one or more suitable pharmaceutical additives. Preferably, the compound is present at a level of about 1 to 80 wt%.

[0184]

[0409] The compounds described herein may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds described herein or other drugs may have utility, where the combination of drugs is safer or more effective than either drug alone. Such other drugs may be administered simultaneously with or sequentially to the compounds described herein by the commonly used routes and amounts. When the compounds described herein are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compounds described herein is preferred. However, combination therapy also includes therapies in which the compounds described herein and one or more other drugs are administered on different overlapping schedules. Further, when used in combination with one or more other active ingredients, it is contemplated that the compounds described herein and the other active ingredients may be used at lower doses than when each is used alone.

[0185]

[0410] Accordingly, the pharmaceutical compositions described herein may include those containing one or more other active ingredients in addition to the compounds described herein. The subjects that can be treated using the methods described herein are subjects having a cancer characterized by an MSI-H phenotype. In some embodiments, an MSI-H phenotype characterized by the presence of DNA sequence length changes in at least two of the mononucleotide markers or dinucleotide markers selected from the group consisting of BAT25, BAT26, D25123, D55346, and D175250. In some embodiments, an MSI-H phenotype characterized by the presence of DNA sequence length changes in at least two mononucleotide markers selected from the group consisting of NR-21, NR-24, BAT-25, BAT-26, and NR-27 / Mono-27 in an MSI analysis system sold by Promega Corporation (Madison, Wisconsin, USA). In some embodiments, the cancer has mismatch repair deficiency (MMRd). In some embodiments, MMRd is caused by mutations in the MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2, and / or EPCAM genes. In some embodiments, MMRd is caused by mutations in the MLH1, MSH2, MSH6, PMS2, and / or EPCAM genes. In some embodiments, MMRd is caused by mutations in the MLH1 gene. In some embodiments, the cancer further has a mutation that results in loss of function of ARIDlA. In some embodiments, MMRd is caused by mutations in the MMR gene promoter or epigenetic silencing.

[0186]

[0411] Cancer types can include, for example, MSI-H cancer, adrenocortical carcinoma, bladder cancer, breast cancer, cervical squamous cell carcinoma, endocervical adenocarcinoma, cholangiocarcinoma, chronic lymphocytic leukemia, colorectal cancer, colon adenocarcinoma, ovarian cancer, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma of lymphoid tumors, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, acute myeloid leukemia, low-grade glioma, hepatocellular carcinoma of the liver, lung adenocarcinoma, lung squamous epithelial cell carcinoma, mesothelioma, nasopharyngeal carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, endometrial cancer of the uterine body, uterine carcinosarcoma, choroidal melanoma, pediatric acute myeloid leukemia, pediatric neuroblastoma, pediatric high-risk Wilms tumor, or other types of cancer described herein. The cancer can be early-stage cancer or advanced cancer (e.g., recurrent cancer or metastatic cancer). In some embodiments, the subject has previously received anti-cancer therapy. In some embodiments, the subject has not been previously treated with anti-cancer therapy. In some embodiments, the cancer is resistant to immunotherapy (e.g., checkpoint inhibitors described herein). In some embodiments, the cancer is resistant to targeted therapy. In some embodiments, the treatment resistance is caused by deficiency of MMR, such as resistance to endocrine therapy in breast cancer and resistance to targeted therapy (e.g., temozolomide) in glioblastoma.

[0187]

[0412] MSI-H is found in many types of cancer, including but not limited to colorectal cancer, endometrial cancer, cholangiocarcinoma, bladder cancer, breast cancer, esophageal cancer, gastric cancer or gastroesophageal junction cancer, pancreatic cancer, prostate cancer, renal cell cancer, retroperitoneal adenocarcinoma, sarcoma, small cell lung cancer, small intestine cancer, thyroid.

[0188]

[0413] Combination therapy: An agent that reduces the level and / or activity of WRN in a subject's cells, as described herein, can be administered alone or in combination with an additional anti-cancer therapy. The anti-cancer therapy can be an additional therapeutic agent (e.g., another agent that treats cancer or a symptom associated therewith), or can be used in combination with other types of therapy for treating cancer (e.g., radiation therapy or surgical procedures). In some embodiments, the second therapeutic agent is selected based on the type of tumor, the primary tissue of the tumor, the stage of the tumor, or the mutational status. In combination therapy, the dose of one or more of the therapeutic agents can be reduced from the standard dose when administered alone. For example, the dose can be determined empirically from drug combinations and permutations, or can be estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, combining the doses of the agents or compounds should result in a therapeutic effect.

[0189]

[0414] In some embodiments, the anti-cancer therapy is a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA4 antibody or a fusion protein, e.g., ipilimumab / YERVOY® or tremelimumab, etc.). In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; or pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL1 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., MPDL3280A1 / RG7446 / atezolizumab; MED14736 / durvalumab; MSB0010718C / avelumab; BMS 936559 / semiprimab). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL2 (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) (e.g., a PDL2 / Ig fusion protein, e.g., AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof (e.g., an inhibitory antibody or a small molecule inhibitor).

[0190]

[0415] In some embodiments, the cancer therapy is a biological agent, such as a cytokine (e.g., interferon or interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biological agent is an anti-angiogenic agent, such as an anti-VEGF agent, such as bevacizumab (AVASTIN®). In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer.Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG™ (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-I-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab (TJstekinumab)); ARZERRA® (ofatumumab); PROLIA® (denosumab); Numax (motavizumab); ABThrax (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado-trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates.

[0191]

[0416] In some embodiments, the anticancer therapy is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, YMCA alkaloids, epipodopyyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin, irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bratasin and bratasinone); camptothecin (including the synthetic analog topotecan), bryostatin; calicheamycin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, methiophosphamide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics such as engine antibiotics (e.g., calicheamicin, especially calicheamicin gamma I and calicheamicin omega I); see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994); dynemicin (including dynemicin A); bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoproteins engine antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycinis, daunorubicin, daunomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin)), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin ribomycin, peplomycin, potfiromycin, puromycin, keramycin, rhodomycin, streptozocin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil; folic acid analogs such as denopterin, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epithioestanol, mepitiostane, testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; dexamethasone; diacodone; elformithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate;Hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; lysocine; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2’’-trichloroethylamine; trichothecene (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; taxoids, for example, TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® albumin-engineered nanoparticle formulation of paclitaxel without cremophor (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; XELODA®; ibandronate; irinotecan (for example, CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine;and pharmaceutically acceptable salts, acids, or derivatives thereof, as described above. Two or more chemotherapeutic agents can be used in a cocktail and administered in combination with the first therapeutic agent described herein. Appropriate dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).;

[0192]

[0417] In some embodiments, the cancer therapy is adoptive T cell transfer therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing an appropriate expression vector encoding the CAR into the T cells. Prior to the expansion and genetic modification of the T cells, the source of the T cells is obtained from a subject. T cells can be obtained from many sources including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue at the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the invention, any available T cell line in the art can be used. In some embodiments, the T cells are autologous T cells. The T cells can be generally activated and expanded using methods such as those described in, for example, U.S. Patent Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No. 20060121005, either before or after genetically modifying the T cells to express the desired protein (e.g., CAR).

[0193]

[0418] The additional anti-cancer therapy may be a non-drug therapy. For example, the additional therapeutic agent is radiotherapy, cryotherapy, thermotherapy, and / or surgical resection of tumor tissue.

[0194]

[0419] In any of the embodiments of the combinations described herein, the agent that reduces the level and / or activity of WRN in the cells of the subject and the additional therapeutic agent are administered simultaneously or sequentially, in either order. The agent that reduces the level and / or activity of WRN in the cells of the subject is administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, up to 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or within 1 to 7 days, 1 to 14 days, 1 to 21 days, 1 to 30 days before or after the additional therapeutic agent (e.g., anti-cancer therapy).

Example

[0195] TIFF2025522911000181.tif255170TIFF2025522911000182.tif255170TIFF2025522911000183.tif20170

[0196] Example 1

[0420] (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000184.tif34170

[0197]

[0421] Procedure A

[0422] Step 1 TIFF2025522911000185.tif18170

[0423] A mixture of diethyl ((methylsulfonyl)methyl)phosphonate (6 g, 26.06 mmol), N-Boc-2-aminoacetaldehyde (4.56 g, 28.67 mmol) and potassium carbonate (9.00 g, 65.16 mmol) in THF (50 mL, 0.521 M) was stirred at 60 °C for 3 hours. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent: 20 - 25% ethyl acetate / petroleum ether, gradient: 100 mL / min) to give tert-butyl N-[(E)-3-methylsulfonylallyl]carbamate (5 g, 82% yield) as a white solid.

[0198]

[0424] Step 2 TIFF2025522911000186.tif16170

[0425] To a solution of tert-butyl N-[(E)-3-methylsulfonylallyl]carbamate (3 g, 12.75 mmol) in MeCN (40 mL, 0.319 M) was added p-toluenesulfonic acid monohydrate (2.91 g, 15.3 mmol). The mixture was stirred at 50 °C for 12 hours. The mixture was cooled to rt and concentrated under reduced pressure to give crude [(E)-3-methylsulfonylallyl]amine 4-methylbenzenesulfonate as a white solid (2.50 g, 64% yield).

[0199]

[0426] Step 3 TIFF2025522911000187.tif25170

[0427] A solution of cyclopentanecarboxamidine (1.0 g, 8.92 mmol) in ethanol (15 mL, 0.594 M) was added with NaOEt (1.82 g, 26.75 mmol) at 0 °C. A solution of diethyl ethoxymethylenemalonate (1.9 g, 8.92 mmol) in ethanol (5 ml) was added dropwise to the above mixture over 5 minutes. The mixture was heated at 90 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 2-cyclopentyl-4-hydroxy-pyrimidine-5-carboxylate as a yellow solid (1.3 g, 62%).

[0200]

[0428] Step 4 TIFF2025522911000188.tif25170

[0429] Ethyl 2-cyclopentyl-4-hydroxy-pyrimidine-5-carboxylate (500 mg, 2.12 mmol) was added to a solution of phosphorus oxychloride (5 mL, 53.64 mmol, 1.645 g / ml). The mixture was heated at 80 °C for 2 hours. The mixture was concentrated and dried under reduced pressure to obtain crude ethyl 4-chloro-2-cyclopentyl-pyrimidine-5-carboxylate as a brown oil (0.5 g).

[0201]

[0430] Step 5 TIFF2025522911000189.tif34170

[0431] To a solution of ethyl 4-chloro-2-cyclopentyl-pyrimidine-5-carboxylate (200 mg, 0.79 mmol) and phenol (88.7 mg, 0.94 mmol) in MeCN (3 mL, 0.262 M) was added K2CO3 (326 mg, 2.36 mmol). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was extracted with EtOAc (2×10 ml) and brine (10 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude ethyl 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylate as a white solid (240 mg).

[0202]

[0432] Step 6 TIFF2025522911000190.tif34170

[0433] To a solution of ethyl 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylate (240 mg, 0.77 mmol) in THF (3 mL, 0.128 M) was added lithium hydroxide monohydrate (96.9 mg, 2.31 mmol). The mixture was stirred at 25 °C for 3 h. The aqueous phase was adjusted to about pH = 5-6 by gradually adding 2 M HCl. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give crude 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylic acid as a white solid (200 mg).

[0203]

[0434] Step 7 TIFF2025522911000191.tif34170

[0435] To a solution of 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylic acid (100 mg, 0.35 mmol) in DMF (2 mL, 0.176 M) were added [(E)-3-methylsulfonylallyl]amine 4-methylbenzenesulfonic acid (113.5 mg, 0.37 mmol), HATU (200.6 mg, 0.53 mmol) and DIPEA (0.2 mL, 1.06 mmol) at 25 °C. The mixture was stirred at 25 °C under N2 for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in DMF (2 mL) and the resulting solution was purified by preparative HPLC [column: Welch Xtimate C18 100*25mm*3um, eluent: water (0.04% HCl) / MeCN = 25-65%, flow rate: 25 ml / min] to give the title compound as a white solid (34.3 mg, yield 24%). LC-MS m / z: 402.1 [M+1].

[0204] Example 2

[0436] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000192.tif34170

[0205]

[0437] Step 1 TIFF2025522911000193.tif17170

[0438] To a solution of Boc-L-alaninol (10 g, 57.07 mmol) in MeCN (1 L, 0.0571 M) was added 1-hydroxy-1-oxo-1λ5,2-benziodoxol-3-one (40.0 g, 142.67 mmol) at 25 °C. The reaction mixture was stirred at 65 °C for 6 h. The reaction mixture was filtered and concentrated under reduced pressure to afford crude tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate as a yellow oil (10 g).

[0206]

[0439] In Procedure A, using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1, the title compound was obtained. LC-MS m / z: 416.1 [M+1].[[]END]]

[0207] Example 3

[0440] (S,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000194.tif34170

[0441] Using a small amount of the olefin isomer tert-butyl N-[(Z,1S)-1-methyl-3-methylsulfonyl-allyl]carbamate obtained in Step 1 for the compound of Example 2, the title compound was obtained. LC-MS m / z: 416.2 [M+1].[[]END]]

[0208] Example 4

[0442] (R,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000195.tif34170

[0443] In Procedure A, in Step 1, tert-butyl N-[(1R)-1-methyl-2-oxo-ethyl]carbamate / NaH was used to obtain the title compound. LC-MS m / z: 416.1 [M+1].

[0209] Example 5

[0444] (R,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000196.tif34170

[0445] Using a small amount of the olefin isomer tert-butyl N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]carbamate obtained in Step 1 for the compound of Example 4, the title compound was obtained. LC-MS m / z: 416.2 [M+1].

[0210] Example 6

[0446] (S,E)-2-Cyclopentyl-N-(1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000197.tif32170

[0447] In Procedure A, for the preparation of 1-hydroxy-1-oxo-1λ5,2-benziodoxol-3-one in Step 1, tert-butyl N-[(1S)-1-(hydroxymethyl)propyl]carbamate / IBX / MeCN was used with NaH as the base in Step 1 to obtain the title compound. LC-MS m / z: 430.2 [M+1].

[0211] Example 7

[0448] (S,E)-2-Cyclopentyl-N-(4-methyl-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000198.tif34170

[0449] In Procedure A, Boc-D-valinol / IBX was used to prepare tert-butyl N-[(1S)-1-formyl-2-methyl-propyl]carbamate in Step 1, and NaH was used as the base in Step 1 to obtain the title compound. LC-MS m / z: 444.2 [M+1].

[0212] Example 8

[0450] (S,E)-2-Cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000199.tif34170

[0213]

[0451] Step 1 TIFF2025522911000200.tif21170

[0452] To a solution of tert-butyl N-[(1S)-1-cyclopropyl-2-hydroxy-ethyl]carbamate (500 mg, 2.48 mmol) in DCM (8 mL, 0.311 M) was added Dess-Martin periodinane (2.1 g, 4.97 mmol). The reaction mixture was stirred at 25 °C for 1 hour under N2. The mixture was filtered through a filter, and the filter cake was washed with DCM (3×15 ml). Then, the combined filtrates were concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (using a 12 g Agela flash silica gel column, eluting with 0% to 8% ethyl acetate in petroleum ether) to obtain tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate as a colorless oil (300 mg, 61% yield).

[0214]

[0453] In Procedure A, the title compound was obtained using N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in Step 1. LC-MS m / z: 442.1 [M+1].

[0215] Example 9

[0454] (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000201.tif34170

[0455] In Step A, tert-Butyl N-[(1S)-1-cyclobutyl-2-oxo-ethyl]carbamate was prepared by using tert-Butyl N-[(1S)-1-cyclobutyl-2-hydroxy-ethyl]carbamate / Dess-Martin periodinane / DCM, and NaH as the base in Step 1 to obtain the title compound. LC-MS m / z: 456.1 [M+1].

[0216] Example 10

[0456] (R,E)-2-Cyclopentyl-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000202.tif34170

[0217]

[0457] Step 1 TIFF2025522911000203.tif21170

[0458] (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-methoxypropanoic acid (5 g, 22.81 mmol) in THF (100 mL, 0.228 M) was added to 1,1’-carbonyl-diimidazole (4.07 g, 25.09 mmol). The mixture was stirred at 20 °C for 30 minutes, and then DIBAL-H (47.9 mL, 47.90 mmol, 1.23 g / ml) was added dropwise to the mixture at -70 °C. The mixture was quenched by adding saturated ammonium chloride (100 ml), stirred for 30 minutes, and then extracted with DCM (3×50 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate as a yellow oil (3.20 g).

[0218]

[0459] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH in Step 1. LC-MS m / z: 446.1 [M+1].

[0219] Example 11

[0460] (S,E)-2-Methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000204.tif28170

[0461] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and ethyl 4-hydroxy-2-methyl-pyrimidine-5-carboxylate in Step 4. LC-MS m / z: 362.1 [M+1].

[0220] Example 12

[0462] (E)-2-Ethyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000205.tif28170

[0463] In Procedure A, the title compound was obtained using propanamidine hydrochloride in Step 3. LC-MS m / z: 362.2 [M+1].

[0221] Example 13

[0464] (S,E)-2-Ethyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000206.tif28170

[0465] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and propanamidine hydrochloride in Step 3. LC-MS m / z: 376.2 [M+1].

[0222] Example 14

[0466] (E)-2-Isopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000207.tif32170

[0467] In Procedure A, the title compound was obtained using 2-methylpropanamidine hydrochloride in Step 3. LC-MS m / z: 376.1 [M+1].

[0223] Example 15

[0468] (S,E)-2-Isopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000208.tif32170

[0469] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2-methylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 390.1 [M+1].

[0224] Example 16

[0470] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000209.tif32170

[0471] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2-methylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 416.1 [M+1].

[0225] Example 17

[0472] (E)-2-Cyclopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000210.tif32170

[0473] In Procedure A, the title compound was obtained using cyclopropanecarboxamidine in Step 3. LC-MS m / z: 374.0 [M+1].

[0226] Example 18

[0474] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000211.tif32170

[0475] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and cyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 388.0 [M+1].

[0227] Example 19

[0476] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(2-fluoropropan-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000212.tif32170

[0477] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used for Step 1, and cyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 414.1 [M+1].

[0228] Examples 20 and 21

[0478] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 20) TIFF2025522911000213.tif32170

[0479] (S,Z)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 21) TIFF2025522911000214.tif32170

[0480] In Procedure A, for Step 1, tert-butyl N-[(1S)-1-benzyl-2-oxo-ethyl]carbamate / NaH was used, and cyclopropanecarboxamidine was used in Step 3 to obtain a mixture of the title compounds. The mixture was separated by preparative HPLC (reverse phase, MeCN / H2O (0.1% FA) = 5 - 95%) to obtain Peak 1 (E isomer, LC-MS m / z: 464.2 [M+1]) and Peak 2 (Z isomer, LC-MS m / z: 464.2 [M+1]).

[0229] Example 22

[0481] (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone TIFF2025522911000215.tif32170

[0482] In Procedure 1, for Step 1, tert-butyl 3-formylazetidine-1-carboxylate / n BuLi was used, and cyclopropanecarboxamidine was used in Step 3 to obtain the title compound as a mixture of olefin isomers (E:Z = 1.6:1). LC-MS m / z: 400.2 [M+1].

[0230] Examples 23 and 24

[0483] (Z)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone (Example 23) TIFF2025522911000216.tif32170

[0484] (E)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone (Example 24) TIFF2025522911000217.tif32170

[0485] The compound of Example 22 was separated by chiral SFC (column: Chiralpak AS-3) to obtain Peak 1 (Z isomer, LC-MS m / z: 400.2 [M+1]) and Peak 2 (E isomer, LC-MS m / z: 400.2 [M+1]).

[0231] Example 25

[0486] (S,E)-2-Cyclopropyl-N-(4-(cyclopropylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000218.tif32170

[0232]

[0487] Step 1 TIFF2025522911000219.tif21170

[0488] A solution of sodium cyclopropanesulfinate (922 mg, 7.19 mmol) in DMSO (6 mL, 0.600 M) was stirred at rt for 1 hour to completely dissolve the salt. Then, diethyl iodomethylphosphonate (0.60 mL, 3.60 mmol) was added and the mixture was heated at 80 °C overnight. Additional sodium cyclopropanesulfinate (922 mg, 7.19 mmol) was added and the mixture was heated at 100 °C for 1 hour. The mixture was diluted with EtOAc, washed with 1 M HCl and brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified via normal phase column chromatography using Biotage Isolera (0 - 10% MeOH / DCM) to give diethoxyphosphorylmethylsulfonylcyclopropane as a yellow oil (432 mg, 47% yield).

[0233]

[0489] In Procedure A, diethoxyphosphorylmethylsulfonylcyclopropane / tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and cyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 414.0 [M+1].

[0234] Example 26

[0490] (2-Cyclopropyl-4-phenoxy-pyrimidin-5-yl)-[(3Z)-3-(methylsulfonylmethylene)pyrrolidin-1-yl]methanone TIFF2025522911000220.tif32170

[0491] In Procedure A, for Step 1, N-Boc-3-pyrrolidinone / NaH was used, and in Step 3, cyclopropanecarboxamidine was used to obtain the title compound. LC-MS m / z: 400.0 [M+1].

[0235] Example 27

[0492] 2-Cyclopropyl-N-(1,1-dioxide-2,3-dihydrothiophen-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000221.tif32170

[0493] According to Step 7 of Procedure A, using 2-cyclopropyl-4-phenoxy-pyrimidine-5-carboxylic acid and 3-amino-2,3-dihydrothiophene 1,1-dioxide, the title compound was obtained. LC-MS m / z: 372.0 [M+1].

[0236] Example 28

[0494] (S,E)-2-Cyclopropyl-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000222.tif32170

[0237]

[0495] Step 1 TIFF2025522911000223.tif28170

[0496] CDI (592 mg, 3.65 mmol) was slowly added to a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid; N-cyclohexylcyclohexanamine (1.0 g, 2.44 mmol) in DCM, and the mixture was stirred at rt for 30 minutes until the evolution of CO2 ceased. DIPEA (0.64 mL, 3.65 mmol) was added dropwise to the reaction mixture, followed by the addition of solid N,O-dimethylhydroxylamine hydrochloride (356 mg, 3.65 mmol). After the addition was complete, the resulting mixture was stirred at rt for 16 hours. Then, the reaction was quenched by adding water, and the resulting solution was extracted with DCM (3 × 20 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain crude tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (356 mg).

[0238]

[0497] Step 2 TIFF2025522911000224.tif23170

[0498] DIBAL-H (0.86 mL, 4.8 mmol) was added dropwise to a solution of tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (356 mg, 1.31 mmol) in Et2O at -78 °C. After 1 hour, the excess DIBAL-H was quenched by adding EtOAc, and the mixture was stirred at -78 °C for an additional 15 minutes. The reaction mixture was poured into a mixture of citric acid and Et2O (15 ml), the layers were gently shaken, and then separated. Then, the aqueous layer was washed with Et2O (3 × 20 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via normal phase chromatography (SiO2, EtOAc / heptane = 0 - 100%) to obtain tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (209.8 mg, yield 74%).

[0239]

[0499] In Procedure A, tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate / Cs2CO3 was used in Step 1, and cyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 428.0 [M+1].

[0240] Example 29

[0500] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000225.tif32170

[0501] In Step 1, (2S)-2-(tert-butoxycarbonylamino)-2-cyclobutyl-acetic acid was used, and the title compound was obtained according to the procedure for the compound of Example 28. LC-MS m / z: 428.0 [M+1].

[0241] Example 30

[0502] (S,E)-2-cyclopropyl-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000226.tif33170

[0503] In Step 1, (2S)-2-(tert-butoxycarbonylamino)-2-(3,3-difluorocyclobutyl)acetic acid was used, and the title compound was obtained according to the procedure for the compound of Example 28. LC-MS m / z: 464.0 [M+1].

[0242] Example 31

[0504] (R,E)-2-cyclopropyl-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000227.tif32170

[0505] In Step 1, using (2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propanoic acid, the title compound was obtained according to the procedure for the compound of Example 28. LC-MS m / z: 434.0 [M+1].

[0243] Example 32

[0506] 2-Cyclopropyl-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000228.tif32170

[0507] In Step 1, using (2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxy-butanoic acid, the title compound was obtained according to the procedure for the compound of Example 28. LC-MS m / z: 432.0 [M+1].

[0244] Example 33

[0508] (S,E)-2-Cyclopropyl-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000229.tif33170

[0509] In Step 1, using (2S)-2-(tert-butoxycarbonylamino)-2-tetrahydropyran-4-yl-acetic acid, the title compound was obtained according to the procedure for the compound of Example 28. LC-MS m / z: 458.0 [M+1].

[0245] Example 34

[0510] (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-1-yl)methanone TIFF2025522911000230.tif32170

[0246]

[0511] Step 1 TIFF2025522911000231.tif22170

[0512] tert-Butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (1 g, 5.91 mmol), sodium methanesulfonate (1.2 g, 11.82 mmol), element (1.65 g, 6.50 mmol) and sodium acetate (727 mg, 8.86 mmol) were placed in a mixture of ethyl acetate (15 mL, 0.236 M) and water (10 mL, 0.236 M) and stirred at 70 °C (illuminated with a 1000 W lamp) for 1 hour. The reaction mixture was poured into a saturated aqueous Na2S2O3 solution (15 ml) and extracted with EtOAc (3 × 15 ml). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 30 - 60% ethyl acetate / petroleum ether, gradient: 100 mL / min) to obtain tert-butyl 3-iodo-4-methylsulfonyl-pyrrolidine-1-carboxylate as a yellow oil (600 mg, yield 27%).

[0247]

[0513] Step 2 TIFF2025522911000232.tif19170

[0514] To a solution of tert-butyl 3-iodo-4-methylsulfonyl-pyrrolidine-1-carboxylate (600 mg, 1.60 mmol) in toluene (3 mL, 0.533 M), 1,8-diazabicyclo[5.4.0]undec-7-ene (292.1 mg, 1.92 mmol) was added at 20 °C and the mixture was stirred at 20 °C for 0.5 hour. The mixture was washed with aqueous HCl (1 N, 3 mL), saturated NaHCO3 (3 mL) and brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2,, PE:EtOAc = 1:1) to obtain tert-butyl 3-methylsulfonyl-2,5-dihydropyrrole-1-carboxylate as a white solid (400 mg).

[0248]

[0515] In Procedure A, tert-butyl 3-methylsulfonyl-2,5-dihydropyrrole-1-carboxylate was used in Step 2, and cyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 386.0 [M+1].

[0249] Example 35

[0516] (S,E)-2-(Cyclopropylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000233.tif28170

[0517] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 2-cyclopropylacetamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 402.1 [M+1].

[0250] Example 36

[0518] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylmethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000234.tif28170

[0519] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used for Step 1, and 2-cyclopropylacetamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 428.1 [M+1].

[0251] Example 37

[0520] N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylfluoromethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000235.tif34170

[0252]

[0521] Step 1 TIFF2025522911000236.tif34170

[0522] A solution of ethyl 2-(cyclopropylmethyl)-4-phenoxy-pyrimidine-5-carboxylate (100.3 mg, 0.34 mmol) in MeCN (10 mL, 0.034 M) was added with lithium carbonate (127.6 mg, 1.68 mmol) and N-fluorobenzenesulfonimide (530.3 mg, 1.68 mmol). The mixture was stirred at 75 °C for 12 h under N2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (8 ml), and the aqueous phase was extracted with EtOAc (3×10 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DMF (1 ml), and the resulting solution was purified by preparative HPLC (Waters Xbridge BEH C18 100*30mm*10um, gradient: water (NH4HCO3)-MeCN: 30~50%B, 25 mL / min) to give ethyl 2-[cyclopropyl(fluoro)methyl]-4-phenoxy-pyrimidine-5-carboxylate as a yellow solid (10 mg, yield 9.4%).

[0253]

[0523] In Procedure A, ethyl 2-[cyclopropyl(fluoro)methyl]-4-phenoxy-pyrimidine-5-carboxylate was used according to Step 6, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used according to Step 7 to obtain the title compound. LC-MS m / z: 446.1 [M+1].

[0254] Example 38

[0524] (S,E)-2-(1-Methylcyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000237.tif32170

[0525] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 1-methylcyclopropanecarboxamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 402.0 [M+1].

[0255] Example 39

[0526] (2-(1-Methylcyclopropyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone TIFF2025522911000238.tif32170

[0527] In Procedure A, t-butyl 3-oxoazetidine-1-carboxylate / NaH was used in Step 1 and 1-methylcyclopropanecarboxamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 400.0 [M+1].

[0256] Example 40

[0528] (S,E)-2-((1-Methylcyclopropyl)methyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000239.tif30170

[0529] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2-(1-methylcyclopropyl)acetamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 416.0 [M+1].

[0257] Example 41

[0530] (2-((1-Methylcyclopropyl)methyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone TIFF2025522911000240.tif30170

[0531] In Procedure A, the title compound was obtained using tert-butyl 3-oxoazetidine-1-carboxylate / NaH in Step 1 and 2-(1-methylcyclopropyl)acetamidine in Step 3. LC-MS m / z: 414.0 [M+1].

[0258] Example 42

[0532] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-phenylcyclopropyl)pyrimidine-5-carboxamide TIFF2025522911000241.tif32170

[0533] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and 1-phenylcyclopropanecarboxamidine in Step 3. LC-MS m / z: 464.0 [M+1].

[0259] Example 43

[0534] (E)-2-Cyclobutyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000242.tif32170

[0535] In Procedure A, the title compound was obtained using cyclobutanecarboxamidine in Step 3. LC-MS m / z: 388.1 [M+1].

[0260] Example 44

[0536] (S,E)-2-Cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000243.tif32170

[0537] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and cyclobutanecarboxamidine hydrochloride in Step 3. LC-MS m / z: 402.1 [M+1].

[0261] Example 45

[0538] (S,E)-2-Cyclobutyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000244.tif32170

[0539] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, cyclobutanecarboxamidine hydrochloride was used to obtain the title compound. LC-MS m / z: 428.1 [M+1].

[0262] Examples 46 and 47

[0540] 2-((1s,3R)-3-Methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 46) TIFF2025522911000245.tif34170

[0541] 2-((1r,3S)-3-Methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 47) TIFF2025522911000246.tif34170

[0542] In Procedure A, for Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, 3-methylcyclobutanecarboxamidine was used to obtain the title compound. The mixture was separated by chiral HPLC (column: Chiralpak AD-3) to obtain Peak 1 (compound of Example 46) (LC-MS m / z: 416.2 [M+1]) and Peak 2 (compound of Example 47) (LC-MS m / z: 416.2 [M+1]).

[0263] Examples 48 and 49

[0543] N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-((1s,3R)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide (Example 48) TIFF2025522911000247.tif34170

[0544] N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-((1r,3S)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide (Example 49) TIFF2025522911000248.tif34170

[0545] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, 3-methylcyclobutanecarboxamidine was used to obtain a mixture of the title compounds. The mixture was separated by chiral HPLC (column: Waters Xbridge BEH C18 (100*30mm*10um), mobile phase: water (NH4HCO3)-MeCN, gradient 30 - 65%B, flow rate: 60 mL / min) to obtain Peak (compound of Example 48) (LC-MS m / z: 442.2 [M+1]) and Peak 2 (compound of Example 49).

[0546] ((LC-MS m / z: 442.2 [M+1]).

[0264] Examples 50 and 51

[0547] (2-((1s,3s)-3-Methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone (Example 50) TIFF2025522911000249.tif34170

[0548] (2-((1r,3r)-3-Methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone (Example 51) TIFF2025522911000250.tif34170

[0549] In Procedure A, in Step 1, t-butyl 3-oxoazetidine-1-carboxylate / NaH was used, and in Step 3, 3-methylcyclobutanecarboxamidine was used to obtain a mixture of the title compounds. The mixture was separated by chiral SFC (column: Daicel ChiralPak IC (250 mm * 30 mm * 10 um), mobile phase: neutral MeOH) to obtain Peak 1 (LC-MS m / z: 414.1 [M+1]) and Peak 2 (LC-MS m / z: 414.2 [M+1]).

[0265] Example 52

[0550] 2-(Bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000251.tif32170

[0551] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, bicyclo[4.2.0]octa-1,3,5-trien-7-carboxamidine was used to obtain the title compound. LC-MS m / z: 450.0 [M+1].

[0266] Example 53

[0552] (S,E)-2-(Cyclobutylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000252.tif28170

[0553] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, 2-cyclobutylacetamidine was used to obtain the title compound. LC-MS m / z: 416.2 [M+1].

[0267] Example 54

[0554] (S,E)-2-(Cyclopentylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000253.tif28170

[0555] In step A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in step 1 and 2-cyclopentylacetamidine was used in step 3 to obtain the title compound. LC-MS m / z: 430.2 [M+1].

[0268] Example 55

[0556] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(spiro[2.3]hexan-5-yl)pyrimidine-5-carboxamide TIFF2025522911000254.tif36170

[0269]

[0557] Step 1 TIFF2025522911000255.tif16170

[0558] Trimethylaluminum (16.1 mL, 32.21 mmol, 2 M) was added to a solution of ammonium chloride (1.90 g, 35.43 mmol) in toluene (50 mL, 0.644 M) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. Then, 3-methylenecyclobutanecarbonitrile (3 g, 32.21 mmol) was added dropwise to the mixture. The mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was cooled to room temperature and slowly poured into a slurry of silica gel in DCM (15 ml) and stirred for 10 min. The silica was filtered off and washed with MeOH (3 × 20 mL). The filtrate and washings were combined and concentrated under reduced pressure to give crude 3-methylenecyclobutanecarboxamidine as a white solid (2.35 g, 66% yield).

[0270]

[0559] Step 2 TIFF2025522911000256.tif25170

[0560] A solution of 3-methylenecyclobutanecarboxamidine (4.3 g, 39.03 mmol) in ethanol (40 mL, 0.781 M) was added with sodium methoxide (23.4 mL, 117.1 mmol, 5 M) at 0 °C. A solution of diethyl ethoxymethylenemalonate (8.44 g, 39.03 mmol) in ethanol (10 mL, 0.781 M) was added dropwise to the mixture over 5 minutes. The mixture was stirred at 90 °C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (5 ml), the pH was adjusted to about 6 with saturated aqueous citric acid, and extracted with DCM (3 × 50 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (15 ml). The resulting solid was collected by filtration, washed with MTBE (20 ml), and dried to obtain ethyl 4-hydroxy-2-(3-methylenecyclobutyl)pyrimidine-5-carboxylate as a pale yellow solid (3.6 g, yield 39%).

[0271]

[0561] Step 3 TIFF2025522911000257.tif25170

[0562] Diiodomethane (1.7 mL, 21.35 mmol) was added to diethylzinc (21.4 mL, 21.35 mmol, 1 M) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then, a solution of ethyl 4-hydroxy-2-(3-methylenecyclobutyl)pyrimidine-5-carboxylate (500 mg, 2.13 mmol) in DCM (1 mL, 2.135 M) was slowly added to the mixture at 0 °C. After stirring at that temperature for 2 hours, the mixture was warmed to rt and stirred at 25 °C for 12 hours. Then, the mixture was filtered and the filter cake was rinsed with EtOAc (3 × 5 ml). The combined filtrates were concentrated under reduced pressure to obtain crude ethyl 4-hydroxy-2-spiro[2.3]hexan-5-yl-pyrimidine-5-carboxylate (160 mg).

[0272]

[0563] In Procedure A, following Steps 4, 5, 6, and 7 (using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid), ethyl 4-hydroxy-2-spiro[2.3]hexane-5-yl-pyrimidine-5-carboxylate was used to obtain the title compound. LC-MS m / z: 428.2 [M+1].

[0273] Example 56

[0564] (E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000258.tif32170

[0565] In Procedure A, the title compound was obtained using 2,2-dimethylpropanamidine hydrochloride in Step 3. LC-MS m / z: 390.1 [M+1].

[0274] Example 57

[0566] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000259.tif32170

[0567] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 404.2 [M+1].

[0275] Example 58

[0568] (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000260.tif32170

[0569] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 430.2 [M+1].

[0276] Example 59

[0570] 2-(tert-Butyl)-N-(1-(2-(methylsulfonyl)vinyl)cyclopropyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000261.tif32170

[0571] In Procedure A, tert-butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate / Dess-Martin periodinane / DCM was used to prepare tert-butyl (1-formyl-cyclopropyl)-carbamate for the steps, and NaH was used as the base in Step 1, and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound as a mixture of olefin isomers (E:Z = 3.7:1). LC-MS m / z: 416.2 [M+1].

[0277] Examples 60 and 61

[0572] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 60) TIFF2025522911000262.tif32170

[0573] (S,Z)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 61) TIFF2025522911000263.tif32170

[0574] In Procedure A, for Step 1, tert-butyl N-[(1S)-1-benzyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, 2,2-dimethylpropanamidine hydrochloride was used to obtain the title compound. The mixture was separated by preparative HPLC (reverse phase, MeCN / H2O (0.1% FA) = 5 - 95%) to obtain Peak 1 (E isomer, LC-MS m / z: 480.2 [M+1]) and Peak 2 (Z isomer, LC-MS m / z: 480.0 [M+1]).

[0278] Example 62

[0575] (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methylene)azetidin-1-yl)methanone TIFF2025522911000264.tif34170

[0279]

[0576] Step 1 TIFF2025522911000265.tif22170

[0577] To a solution of 4-methylsulfonyltetrahydropyran (580 mg, 3.53 mmol) in THF (5 mL, 0.122 M) was added n-butyllithium solution (3.1 mL, 7.77 mmol, 2.5 M) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then diphenyl phosphorochloridate (948.8 mg, 3.53 mmol) was added. The mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl solution (30 ml) and extracted with EtOAc (3 × 30 ml). The combined organic layers were washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO (registered trademark); 12 g SepaFlash (registered trademark) silica flash column, eluent: 0 - 40% ethyl acetate / petroleum ether, gradient: 100 mL / min) to obtain 4-(diphenoxyphosphorylmethylsulfonyl)tetrahydropyran as a yellow solid (1.0 g, yield 72%).

[0280]

[0578] In Procedure A, 4-(diphenoxyphosphorylmethylsulfonyl)tetrahydropyran / t-butyl 3-oxoazetidine-1-carboxylate / NaH was used in Step 1, and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 472.1 [M+1].

[0281] Example 63

[0579] (R,E)-2-(tert-butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000266.tif32170

[0580] In Procedure A, tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH was used in Step 1, and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 434.2 [M+1].

[0282] Example 64

[0581] (S,E)-2-(tert-butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000267.tif32170

[0582] Using (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-methoxypropanoic acid in the first step, the title compound was obtained according to the procedure for the compound of Example 63. LC-MS m / z: 434.2 [M+1].

[0283] Example 65

[0583] (S,E)-2-(tert-butyl)-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000268.tif32170

[0584] In Procedure A, tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate / Cs2CO3 was used in Step 1, and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 444.2 [M+1].

[0284] Example 66

[0585] (S,E)-2-(tert-Butyl)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000269.tif32170

[0586] In Procedure A, tert-butyl N-[(1S)-1-cyclobutyl-2-oxo-ethyl]carbamate / Cs2CO3 was used in Step 1, and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 444.2 [M+1].

[0285] Example 67

[0587] (S,E)-2-(tert-Butyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000270.tif33170

[0588] In Procedure A, tert-butyl N-[(1S)-1-(3,3-difluorocyclobutyl)-2-oxo-ethyl]carbamate / Cs2CO3 was used in Step 1, and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 480.2 [M+1].

[0286] Example 68

[0589] (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000271.tif32170

[0590] In Procedure A, tert-butyl N-[(1R)-1-formyl-2-methylsulfanyl-ethyl]carbamate / Cs2CO3 was used in Step 1 and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 450.0 [M+1].

[0287] Example 69

[0591] 2-(tert-Butyl)-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000272.tif32170

[0592] In Procedure A, tert-butyl N-[(1S,2R)-1-formyl-2-methoxy-propyl]carbamate / Cs2CO3 was used in Step 1 and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 448.2 [M+1].

[0288] Example 70

[0593] (S,E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000273.tif33170

[0594] In Procedure A, tert-butyl N-[(1S)-2-oxo-1-tetrahydropyran-4-yl-ethyl]carbamate / Cs2CO3 was used in Step 1 and 2,2-dimethylpropanamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 474.2 [M+1].

[0289] Example 71

[0595] (S,E)-2-(tert-Butyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000274.tif32170

[0596] In Step 1, (2S)-2-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-oxo-butyric acid was used, and tert-butyl N-[(1S)-3-(dimethylamino)-1-formyl-3-oxo-propyl]carbamate was obtained according to Step 2 of the procedure for the compound of Example 28. In Procedure A, tert-butyl N-[(1S)-3-(dimethylamino)-1-formyl-3-oxo-propyl]carbamate / Cs2CO3 in Step 1 and 2,2-dimethylpropanamidine hydrochloride in Step 3 were used to obtain the title compound. LC-MS m / z: 475.2 [M+1].

[0290] Example 72

[0597] (S,E)-2-(tert-butyl)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000275.tif38170

[0598] In Step 1, (2S)-2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid was used, and tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]carbamate was obtained according to Step 2 of the procedure for the compound of Example 28. In Procedure A, tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]carbamate / Cs2CO3 in Step 1 and 2,2-dimethylpropanamidine hydrochloride in Step 3 were used to obtain the title compound. LC-MS m / z: 508.2 [M+1].

[0291] Example 73

[0599] (S,E)-2-(tert-butyl)-N-(5,5-difluoro-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000276.tif32170

[0600] In Step 1 of Project 1, using (2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro-butyric acid, following the procedure of Step 2 for the compound of Example 28, tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate was obtained. In Procedure A, in Step 1, tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate / Cs2CO3 and in Step 3, using 2,2-dimethylpropanamidine hydrochloride, the title compound was obtained. LC-MS m / z: 454.0[M+1].

[0292] Examples 74 and 75

[0601] (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide / (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000277.tif39170

[0602] 2-(tert-Butoxycarbonylamino)-3-phenoxy-propanoic acid was converted to tert-butyl N-(1-formyl-2-phenoxy-ethyl)carbamate via LiBH4 reduction followed by DMP oxidation. In Procedure A, in Step 1, tert-butyl N-(1-formyl-2-phenoxy-ethyl)carbamate / NaH and in Step 3, using 2,2-dimethylpropanamidine hydrochloride, the title compound was obtained. The mixture was separated by chiral SFC (column: Chiralpak IG-3) to obtain Peak 1 (LC-MS m / z: 496.3[M+1]) and Peak 2 (LC-MS m / z: 496.3[M+1]). The absolute stereochemistry of the title compound was not confirmed.

[0293] Example 76

[0603] (E)-2-Cyclohexyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000278.tif34170

[0604] In Procedure A, in Step 3, cyclohexanecarboxamidine hydrochloride was used to obtain the title compound. LC-MS m / z: 416.1 [M+1].

[0294] Example 77

[0605] (S,E)-2-Cyclohexyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000279.tif34170

[0606] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, cyclohexanecarboxamidine hydrochloride was used to obtain the title compound. LC-MS m / z: 430.2 [M+1].

[0295] Example 78

[0607] N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-2-yl)pyrimidine-5-carboxamide TIFF2025522911000280.tif32170

[0608] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, tetrahydrofuran-2-carboxamidine was used to obtain the title compound. LC-MS m / z: 418.1 [M+1].

[0296] Example 79

[0609] N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide TIFF2025522911000281.tif34170

[0610] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and tetrahydrofuran-3-carboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 418.1 [M+1].

[0297] Example 80

[0611] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-phenylpyrimidine-5-carboxamide TIFF2025522911000282.tif34170

[0612] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and benzamidine hydrochloride was used in Step 3 to obtain the title compound. LC-MS m / z: 424.1 [M+1].

[0298] Example 81

[0613] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide TIFF2025522911000283.tif34170

[0614] In Procedure A, starting from Step 5, ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate was used in Step 5, and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in Step 7 to obtain the title compound. LC-MS m / z: 416.0 [M+1].

[0299] Example 82

[0615] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide TIFF2025522911000284.tif34170

[0616] In Procedure A, starting from Step 5, ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate in Step 5 was used to obtain the title compound with [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in Step 7. LC-MS m / z: 442.1 [M+1].

[0300] Example 83

[0617] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000285.tif32170

[0618] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 was used to obtain the title compound with 2,2,3,3,3-pentafluoropropanamidine in Step 3. LC-MS m / z: 466.1 [M+1].

[0301] Example 84

[0619] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000286.tif32170

[0620] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in Step 1 was used to obtain the title compound with 1,2,2,3,3,3-pentafluoropropanamidine in Step 3. LC-MS m / z: 492.1 [M+1].

[0302] Example 85

[0621] (R,E)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000287.tif32170

[0622] In Procedure A, tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH was used in Step 1, and 2,2,3,3,3-pentafluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 496.1 [M+1].

[0303] Example 86

[0623] (S,E)-2-(1,1-Difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000288.tif32170

[0304]

[0624] Step 1 TIFF2025522911000289.tif19170

[0625] Ammonium chloride (3.87 g, 72.41 mmol) was suspended in toluene (40 mL, 0.362 M) under an argon atmosphere, and the mixture was cooled to 0 °C. Hexane (41 mL, 2 M) containing triethylaluminum was added dropwise, and the reaction mixture was stirred at 25 °C until gas evolution ceased. After the addition of ethyl 2,2-difluoropropanoate (2 g, 14.48 mmol), the mixture was stirred at 80 °C for 12 hours. Then it was cooled to 0 °C, methanol (80 ml) was added, and the mixture was stirred at 25 °C for 1 hour. After filtration, the solid was washed several times with methanol, and the solution was concentrated under reduced pressure to obtain crude 2,2-difluoropropanamidine as a white solid (1.40 g, yield 89%).

[0305]

[0626] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 2,2-difluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 412.1 [M+1].

[0306] Example 87

[0627] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000290.tif32170

[0628] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2,2-difluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 438.1 [M+1].

[0307] Example 88

[0629] (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000291.tif32170

[0630] In Procedure A, tert-butyl N-[(1S)-1-cyclobutyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2,2-difluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 452.1 [M+1].

[0308] Example 89

[0631] (R,E)-2-(1,1-Difluoroethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000292.tif32170

[0632] In Procedure A, tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH was used in Step 1 and 2,2-difluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 442.1 [M+1].

[0309] Example 90

[0633] (S,E)-N-(5,5-difluoro-1-(methylsulfonyl)penta-1-en-3-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000293.tif32170

[0634] In Procedure A, tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate / NaH was used in Step 1 and 2,2-difluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 462.0 [M+1].

[0310] Example 91

[0635] (S,E)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000294.tif38170

[0636] In Procedure A, tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2,2-difluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 516.0 [M+1].

[0311] Example 92

[0637] (S,E)-2-(1,1-difluoroethyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000295.tif32170

[0638] In Procedure A, tert-butyl N-[(1S)-3-(dimethylamino)-1-formyl-3-oxo-propyl]carbamate / Cs2CO3 was used in Step 1 and 2,2-difluoropropanamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 483.0 [M+1].

[0312] Example 93

[0639] 2-(1,1-Difluoroethyl)-N-((3R,4S,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000296.tif32170

[0640] In Step 1, using (2S,3S)-2-(tert-butoxycarbonylamino)-3-methoxy-butanoic acid, the title compound was obtained according to the procedure for the compound of Example 28. LC-MS m / z: 456.0 [M+1].

[0313] Examples 94 and 95

[0641] (S,E)-2-(1,1-Difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)pyrimidine-5-carboxamide / (R,E)-2-(1,1-Difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)pyrimidine-5-carboxamide TIFF2025522911000297.tif33170

[0314]

[0642] Step 1 TIFF2025522911000298.tif19170

[0643] Potassium tert-butoxide (25.8 g, 23.02 mmol) was added dropwise to a mixture of diethyl 2-acetamidopropanedioate (5.0 g, 23.02 mmol) in THF (50 mL, 0.460 M) at 0 °C. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (10.7 g, 46.04 mmol) was added. The resulting mixture was stirred at 75 °C for 48 h. The mixture was poured into saturated aqueous NH4Cl (80 ml) and extracted with EtOAc (2 × 100 ml). The combined organic layers were washed with brine (100 ml), filtered, and concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent: 0 - 70% ethyl acetate / petroleum ether, gradient: 60 mL / min) to give diethyl 2-acetamido-2-(2,2,2-trifluoroethyl)propanedioate as a yellow oil (2.0 g, yield 29%).

[0315]

[0644] Step 2 TIFF2025522911000299.tif21170

[0645] A mixture of diethyl 2-acetamido-2-(2,2,2-trifluoroethyl)propanedioate (2.0 g, 6.68 mmol) in 6N HCl (10 ml) was stirred at 100 °C for 15 min. The mixture was adjusted to pH = 10 with NaOH(aq, 6M). THF (20 ml) was added to the mixture, followed by di-tert-butyl dicarbonate (1.33 g, 6.11 mmol). The mixture was stirred at room temperature for 16 h. The turbid reaction mixture was neutralized with 1.0M HCl (pH = 4 - 5) and extracted with EtOAc (2 × 50 ml). The combined organic layers were dried over Na2SO4 and concentrated to give crude 2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butanoic acid as a yellow oil (400 mg).

[0316]

[0646] Step 3 TIFF2025522911000300.tif21170

[0647] A solution of 2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butyric acid (100 mg, 0.39 mmol) in DCM (2 mL, 0.389 M) was added with CDI (69 mg, 0.43 mmol) at 0 °C. After stirring at 0 °C for 1 h, DIBAl-H (0.82 mL, 0.82 mmol, 1 M) was added at -70 °C. The reaction mixture was stirred at -70 °C for 0.5 h. Saturated Seniet salt (0.8 mL) and EtOAc (0.8 mL) were added dropwise to the reaction mixture at -70 °C. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude tert-butyl N-(3,3,3-trifluoro-1-formyl-propyl)carbamate as a yellow oil (50 mg).

[0317]

[0648] In Procedure A, tert-butyl N-(3,3,3-trifluoro-1-formyl-propyl)carbamate was used in Step 1, followed by chiral HPLC separation (column: Phenomenex-Cellulose-2 (250 mm * 30 mm * 5 μm)), and the subsequent steps were carried out separately using 2,2-difluoropropaneamidine in Step 3 to obtain the title compounds separately. Both showed LC-MS m / z: 480.1 [M+1]. The absolute stereochemistry of the title compounds was not confirmed.

[0318] Example 96

[0649] (R,E)-N-(1-(tert-butoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000301.tif34170

[0319]

[0650] Step 1 TIFF2025522911000302.tif30170

[0651] N-(tert-Butoxycarbonyl)-O-(tert-butyl)-L-serine (1 g, 3.83 mmol) was added to a solution of DCM (10 mL, 0.348 M) and methanol (1 mL, 0.348 M), and (trimethylsilyl)diazomethane (3.83 mL, 7.65 mmol, 2 M) was added at 0 °C under N2. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous AcOH (1 ml) and concentrated under reduced pressure to give crude methyl (2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoate as a yellow oil (1.0 g).

[0320]

[0652] Step 2 TIFF2025522911000303.tif28170

[0653] To a solution of methyl (2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoate (1 g, 3.63 mmol) in THF (10 mL, 0.363 M) was added lithium aluminum hydride solution (0.35 g, 9.08 mmol) at 0 °C. The mixture was stirred at 25 °C for 8 h. The reaction mixture was quenched with Na2SO4·10H2O, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 3:1) to give tert-butyl N-[(1R)-1-(tert-butoxymethyl)-2-hydroxy-ethyl]carbamate as a colorless oil (900 mg, 95% yield).

[0321]

[0654] In procedure A, tert-butyl N-[(1R)-1-(tert-butoxymethyl)-2-hydroxy-ethyl]carbamate / Dess-Martin periodinane / DCM was used to prepare butyl N-[(1S)-1-(tert-butoxymethyl)-2-oxo-ethyl]carbamate in step 1, NaH was used as the base in step 1, and 2,2-difluoropropaneamidine was used in step 3 to obtain the title compound. LC-MS m / z: 484.1 [M+1].

[0322] Example 97

[0655] (R,E)-N-(1-Cyclopropoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000304.tif34170

[0323]

[0656] Step 1 TIFF2025522911000305.tif28170

[0657] To 1-(tert-butyl) 2-methyl (S)-aziridine-1,2-dicarboxylate (800 mg, 3.98 mmol) was added DCM (15 mL, 0.265 M) containing boron trifluoride diethyl etherate (84.6 mg, 0.60 mmol) and cyclopropanol (461.8 mg, 7.95 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h under N2. The reaction mixture was diluted with NaHCO3 (50 ml) and extracted with DCM (3 × 50 ml). The obtained organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE / EA = 0 / 1 to 5 / 1) to give methyl (2R)-2-(tert-butoxycarbonylamino)-3-(cyclopropoxy)propanoate as a colorless oil (530 mg, yield 51%).

[0324]

[0658] Methyl (2R)-2-(tert-butoxycarbonylamino)-3-(cyclopropoxy)propanoate was converted to tert-butyl N-[(1S)-1-(cyclopropoxymethyl)-2-oxo-ethyl]carbamate via LAH reduction and DMP oxidation as described above. In Procedure A, tert-butyl N-[(1S)-1-(cyclopropoxymethyl)-2-oxo-ethyl]carbamate / NaH in Step 1 and 2,2-difluoropropanamidine in Step 3 were used to obtain the title compound. LC-MS m / z: 468.1 [M+1].

[0325] Example 98

[0659] (R,E)-2-(1,1-Difluoroethyl)-N-(1-(difluoromethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000306.tif33170

[0660] Step 1 TIFF2025522911000307.tif31170

[0661] [Bromo(difluoro)methyl]trimethylsilane (4.5 g, 22.01 mmol) was added to a mixture of 3-tert-butyl (S)-4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (2 g, 8.65 mmol) and potassium hydrogen fluoride (3.51 g, 44.97 mmol) in DCM (10 mL, 0.432 M) and water (10 mL, 0.432 M) at 0 °C. The mixture was heated at 50 °C for 16 h. The reaction mixture was poured into water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0 - 5% ethyl acetate / petroleum ether, gradient: 100 mL / min) to give tert-butyl (4R)-4-(difluoromethoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylate as a pale yellow oil (1.20 g, 49% yield).

[0326]

[0662] Step 2 TIFF2025522911000308.tif29170

[0663] p-Toluenesulfonic acid monohydrate (162.29 mg, 0.85 mmol) was added to methanol (20 mL, 0.213 M) containing tert-butyl (4R)-4-(difluoromethoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylate (1.2 g, 4.27 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–20% ethyl acetate / petroleum ether, gradient: 100 mL / min) to give tert-butyl N-[(1R)-1-(difluoromethoxymethyl)-2-hydroxy-ethyl]carbamate as a colorless oil (800 mg, 78% yield).

[0327]

[0664] In Procedure A, N-[(1R)-1-(difluoromethoxymethyl)-2-hydroxy-ethyl]carbamate / Dess-Martin periodinane / THF was used to prepare tert-butyl N-[(1S)-1-(difluoromethoxymethyl)-2-oxo-ethyl]carbamate in Step 1, NaH was used as the base in Step 1, and 2,2-difluoropropanamidine was used in Step 3 to give the title compound. LC-MS m / z: 478.1 [M+1].

[0328] Example 99

[0665] (S,E)-2-(1-Fluorocyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000309.tif32170

[0666] As in the procedure for the compound of Example 86, 1-fluorocyclopropanecarboxamidine was prepared using methyl 1-fluorocyclopropanecarboxylate. In Step A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 1-fluorocyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 406.1 [M+1].

[0329] Example 100

[0667] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1-fluorocyclopropyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000310.tif32170

[0668] In Step A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 1-fluorocyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 432.1 [M+1].

[0330] Example 101

[0669] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide TIFF2025522911000311.tif32170

[0670] As in the procedure for the compound of Example 86, 1-(trifluoromethyl)cyclopropanecarboxamidine was prepared using ethyl 1-(trifluoromethyl)cyclopropanecarboxylate. In Step A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 1-(trifluoromethyl)cyclopropanecarboxamidine was used in Step 3 to obtain the title compound. LC-MS m / z: 456.1 [M+1].

[0331] Example 102

[0671] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide TIFF2025522911000312.tif32170

[0672] In Step A, the title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in Step 1 and 1-(trifluoromethyl)cyclopropanecarboxamidine in Step 3. LC-MS m / z: 482.2 [M+1].

[0332] Example 103

[0673] (S,E)-2-(3,3-Difluorocyclobutyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000313.tif36170

[0333]

[0674] Step 1 TIFF2025522911000314.tif18170

[0675] Diethylaminosulfur trifluoride (8.5 g, 52.58 mmol) was added to a solution of 3-oxocyclobutanecarbonitrile (2.5 g, 26.29 mmol) in DCM (100 mL, 0.263 M) at 0 °C over 0.5 h. The mixture was stirred at 25 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 ml) and the aqueous phase was extracted with DCM (3 × 30 ml). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude 3,3-difluorocyclobutanecarbonitrile as a brown oil (3.0 g).

[0334]

[0676] Step 2 TIFF2025522911000315.tif21170

[0677] A solution of ammonium chloride (685 mg, 12.81 mmol) in toluene (15 mL, 0.854 M) was added with triethylaluminum (923 mg, 12.81 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. 3,3-Difluorocyclobutanecarbonitrile (1.5 g, 12.81 mmol) was added dropwise to the mixture. The mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and slowly poured into a slurry of silica gel in DCM (10 mL) and stirred for 10 min. The silica was filtered off and washed with MeOH (3×15 mL). The filtrate was concentrated under reduced pressure to give crude 3,3-difluorocyclobutanecarboxamidine as a light brown solid (1.0 g).

[0335]

[0678] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 3, 3,3-difluorocyclobutanecarboxamidine was used to obtain the title compound. LC-MS m / z: 438.1 [M+1].[

[0336] Example 104

[0679] (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-(p-tolyloxy)pyrimidine-5-carboxamide TIFF2025522911000316.tif32170

[0680] In Procedure A, in Step 5, p-cresol was used to obtain the title compound. LC-MS m / z: 416.1 [M+1].[

[0337] Example 105

[0681] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(m-tolyloxy)pyrimidine-5-carboxamide TIFF2025522911000317.tif32170

[0682] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and m-cresol was used in Step 5 to obtain the title compound. LC-MS m / z: 430.1 [M+1].

[0338] Example 106

[0683] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(o-tolyloxy)pyrimidine-5-carboxamide TIFF2025522911000318.tif32170

[0684] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and o-cresol was used in Step 5 to obtain the title compound. LC-MS m / z: 430.2 [M+1].

[0339] Example 107

[0685] (S,E)-2-Cyclopentyl-4-(4-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000319.tif32170

[0686] In Procedure A, wtert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 4-ethylphenol was used in Step 5 to obtain the title compound. LC-MS m / z: 444.2 [M+1].

[0340] Example 108

[0687] (S,E)-2-Cyclopentyl-4-(3-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000320.tif32170

[0688] In Procedure A, wtert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 3-ethylphenol was used in Step 5 to obtain the title compound. LC-MS m / z: 444.2 [M+1].

[0341] Example 109

[0689] (S,E)-2-Cyclopentyl-4-(3,4-dimethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000321.tif38170

[0690] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 3,4-dimethylphenol was used in Step 5 to obtain the title compound. LC-MS m / z: 444.2 [M+1].

[0342] Example 110

[0691] (S,E)-2-Cyclopentyl-4-(4-fluoro-3-methylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000322.tif32170

[0692] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 3-fluoro-4-methylphenol was used in Step 5 to obtain the title compound. LC-MS m / z: 448.2 [M+1].

[0343] Example 111

[0693] (E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide TIFF2025522911000323.tif32170

[0694] In Procedure A, 3-fluorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 420.1 [M+1].

[0344] Example 112

[0695] (E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide TIFF2025522911000324.tif33170

[0696] In Procedure A, in Step 5, 4-fluorophenol was used to obtain the title compound. LC-MS m / z: 420.1 [M+1].

[0345] Example 113

[0697] (S,E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000325.tif33170

[0698] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 5, 4-fluorophenol was used to obtain the title compound. LC-MS m / z: 434.1 [M+1].

[0346] Example 114

[0699] (S,E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000326.tif32170

[0700] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 5, 3-fluorophenol was used to obtain the title compound. LC-MS m / z: 434.1 [M+1].

[0347] Example 115

[0701] (S,E)-2-Cyclopentyl-4-(2-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000327.tif33170

[0702] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 2-fluorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 434.1 [M+1].

[0348] Example 116

[0703] (S,E)-2-Cyclopentyl-4-(3,5-difluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000328.tif40170

[0704] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 3,5-difluorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 452.1 [M+1].

[0349] Example 117

[0705] (E)-4-(3-Chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide TIFF2025522911000329.tif32170

[0706] In Procedure A, 3-chlorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 436.1 [M+1].

[0350] Example 118

[0707] (S,E)-4-(3-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000330.tif32170

[0708] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 3-chlorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 450.1 [M+1].

[0351] Example 119

[0709] (S,E)-4-(2-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000331.tif33170

[0710] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 2-chlorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 450.1 [M+1].

[0352] Example 120

[0711] (E)-4-(4-Chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide TIFF2025522911000332.tif33170

[0712] In Procedure A, 4-chlorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 436.1 [M+1].

[0353] Example 121

[0713] (S,E)-4-(4-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000333.tif33170

[0714] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 4-chlorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 450.1 [M+1].

[0354] Example 122

[0715] (S,E)-4-(3-Chloro-5-fluorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000334.tif40170

[0716] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 3-chloro-5-fluorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 468.1 [M+1].

[0355] Example 123

[0717] (S,E)-2-Cyclopentyl-4-(3,5-dichlorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000335.tif40170

[0718] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 3,5-dichlorophenol was used in Step 5 to obtain the title compound. LC-MS m / z: 484.1 [M+1].

[0356] Example 124

[0719] (S,E)-4-(4-Cyanophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000336.tif33170

[0720] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 4-hydroxybenzonitrile was used in Step 5 to obtain the title compound. LC-MS m / z: 441.2 [M+1].

[0357] Example 125

[0721] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-3-yloxy)pyrimidine-5-carboxamide TIFF2025522911000337.tif32170

[0722] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 3-hydroxypyridine was used in Step 5 to obtain the title compound. LC-MS m / z: 417.1 [M+1].

[0358] Example 126

[0723] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-2-yloxy)pyrimidine-5-carboxamide TIFF2025522911000338.tif32170

[0724] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and pyridin-2-ol was used in Step 5 to obtain the title compound. LC-MS m / z: 417.2 [M+1].

[0359] Example 127

[0725] (S,E)-4-Cyclobutoxy-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000339.tif30170

[0726] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and cyclobutanol / potassium tert-butoxide / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 394.2 [M+1].

[0360] Example 128

[0727] (S,E)-4-(Cycloheptyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000340.tif34170

[0728] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and cycloheptanol / tBuOK / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 436.2 [M+1].

[0361] Examples 129 and 130

[0729] 2-Cyclopentyl-4-[(1S,2R)-2-hydroxycyclohexoxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 129) TIFF2025522911000341.tif33170

[0730] 2-Cyclopentyl-4-[(1R,2S)-2-hydroxycyclohexoxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 130) TIFF2025522911000342.tif33170

[0731] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and rac-(1R,2S)-cyclohexane-1,2-diol / NaH / THF was used in Step 5 to obtain a mixture of the title compounds. The mixture was separated by preparative HPLC (neutral conditions) to obtain Peak 1 (the compound of Example 129) (LC-MS m / z: 438.2 [M+1]) and Peak 2 (the compound of Example 130) LC-MS m / z: 438.2 [M+1]).

[0362] Examples 131 and 132

[0732] 2-Cyclopentyl-4-[(1S,2S)-2-hydroxycyclohexoxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 131) TIFF2025522911000343.tif33170

[0733] 2-Cyclopentyl-4-[(1R,2R)-2-hydroxycyclohexyloxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 132) TIFF2025522911000344.tif33170

[0734] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 5, rac-(1S,2S)-cyclohexane-1,2-diol / NaH / THF was used to obtain the title compound. The mixture was separated by preparative HPLC (neutral conditions) to obtain Peak 1 (LC-MS m / z: 438.2 [M+1]) and Peak 2 (LC-MS m / z: 438.2 [M+1]).

[0363] Example 133

[0735] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-5-carboxamide TIFF2025522911000345.tif32170

[0736] In Procedure A, in Step 1, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used, and in Step 5, tetrahydro-2H-pyran-4-ol / NaH / DMF was used to obtain the title compound. LC-MS m / z: 424.2 [M+1].

[0364] Example 134

[0737] 2-Cyclopentyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)oxy)pyrimidine-5-carboxamide TIFF2025522911000346.tif32170

[0738] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and (3S)-tetrahydro-2H-pyran-3-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 424.2 [M+1].

[0365] Example 135

[0739] (S,E)-2-Cyclopentyl-4-(4-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000347.tif33170

[0740] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and hydroquinone was used in Step 5 to obtain the title compound. LC-MS m / z: 432.2 [M+1].

[0366] Example 136

[0741] (S,E)-2-Cyclopentyl-4-(3-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000348.tif32170

[0742] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and resorcinol was used in Step 5 to obtain the title compound. LC-MS m / z: 432.2 [M+1].

[0367] Example 137

[0743] (S,E)-2-Cyclopentyl-4-(2-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000349.tif33170

[0744] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and catechol was used in Step 5 to obtain the title compound. LC-MS m / z: 432.2 [M+1].

[0368] Example 138

[0745] (S,E)-4-(3-aminophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000350.tif32170

[0746] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and tert-butyl 3-hydroxyphenylcarbamate was used in Step 5 to obtain tert-butyl N-[3-[2-cyclopentyl-5-[[(E,1S)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]pyrimidin-4-yl]oxyphenyl]carbamate as a yellow solid. TIFF2025522911000351.tif34170

[0747] To a solution of tert-butyl N-[3-[2-cyclopentyl-5-[[(E,1S)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]pyrimidin-4-yl]oxyphenyl]carbamate (50 mg, 0.094 mmol) in DCM (2 ml) was added TFA (0.4 ml) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in MeCN (1 ml) and the resulting solution was purified by preparative HPLC to obtain the title compound as a yellow solid (17.8 mg). LC-MS m / z: 431.2 [M+1].

[0369] Example 139

[0748] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(naphthalen-1-yloxy)pyrimidine-5-carboxamide TIFF2025522911000352.tif40170

[0749] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and naphthalen-1-ol was used in Step 3 to obtain the title compound. LC-MS m / z: 466.2 [M+1].

[0370] Example 140 TIFF2025522911000353.tif38170

[0750] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and 1,2,3,4,5-pentadeuterio-6-deuteriooxy-benzene was used in Step 5 to obtain the title compound. LC-MS m / z: 393.2 [M+1].

[0371] Example 141

[0751] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[3.3]heptan-2-yloxy)pyrimidine-5-carboxamide TIFF2025522911000354.tif32170

[0752] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and spiro[3.3]heptan-2-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 406.2 [M+1].

[0372] Example 142

[0753] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[2.3]hexan-5-yloxy)pyrimidine-5-carboxamide TIFF2025522911000355.tif31170

[0754] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and spiro[2.3]hexan-5-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 392.0 [M+1].

[0373] Example 143

[0755] (S,E)-4-(Bicyclo[2.2.1]heptan-1-yloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000356.tif32170

[0756] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and norbornan-1-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 406.2 [M+1].

[0374] Example 144

[0757] (S,E)-4-(Cyclopentyloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000357.tif29170

[0758] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and cyclopentanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 380.2 [M+1].

[0375] Example 145

[0759] 4-(((1R,3s,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide TIFF2025522911000358.tif36170

[0760] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and (1S,5R)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 378.0 [M+1].

[0376] Example 146

[0761] 2-Cyclopropyl-4-((3,3-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000359.tif30170

[0762] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and 3,3-difluorocyclopentanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 416.0 [M+1].

[0377] Examples 147 and 148

[0763] 2-Cyclopropyl-4-(((S)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide / 2-Cyclopropyl-4-(((R)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000360.tif37170

[0764] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and 2,2-difluorocyclopentanol / LiHMDS / THF was used in Step 5 to obtain the title compound. The mixture was purified by preparative HPLC (reverse phase, H2O / MeCN = 5 - 95%) to obtain Peak 1 (LC-MS m / z: 416.0 [M+1]) and Peak 2 (LC-MS m / z: 416.0 [M+1]). The absolute stereochemistry of these compounds was not confirmed.

[0378] Example 149

[0765] 2-Cyclopropyl-4-(((1R,2R)-2-fluorocyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; or 2-cyclopropyl-4-(((1S,2S)-2-fluorocyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000361.tif32170

[0766] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and rac-(1R,2R)-2-fluorocyclohexanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 412.0 [M+1]. The absolute stereochemistry of these compounds was not confirmed.

[0379] Example 150

[0767] (S,E)-2-Cyclopropyl-4-(cyclopropylmethoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000362.tif23170

[0768] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and cyclopropanemethanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 366.0 [M+1].

[0380] Example 151

[0769] 4-((1r,3S)-3-chlorocyclobutoxy)-2-cyclopropyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000363.tif31170

[0770] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine was used in Step 3, and 3-chlorocyclobutanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 400.2 [M+1].

[0381] Example 152

[0771] (S,E)-2-(tert-butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide TIFF2025522911000364.tif38170

[0772] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and 1,2,3,4,5-pentadeuterio-6-deuteriooxy-benzene was used in Step 5 to obtain the title compound. LC-MS m / z: 409.2 [M+1].

[0382] Example 153

[0773] (S,E)-2-(tert-butyl)-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000365.tif30170

[0774] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and cyclopentanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 396.0 [M+1].

[0383] Example 154

[0775] (S,E)-2-(tert-Butyl)-4-(cyclohexyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000366.tif32170

[0776] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and cyclohexanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 410.2 [M+1].

[0384] Example 155

[0777] (S,E)-2-(tert-Butyl)-4-((4,4-difluorocyclohexyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000367.tif36170

[0778] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and 4,4-difluorocyclohexanol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 446.2 [M+1].

[0385] Example 156

[0779] (S,E)-2-(tert-Butyl)-4-(3,3-difluorocyclobutoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000368.tif33170

[0780] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and 3,3-difluorocyclobutan-1-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 418.2 [M+1].

[0386] Example 157

[0781] 4-[[(1S,5R)-3-Bicyclo[3.1.0]hexanyl]oxy]-2-tert-butyl-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide TIFF2025522911000369.tif32170

[0782] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and (1S,5R)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 408.2 [M+1].

[0387] Example 158

[0783] 4-(((1R,3r,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)pyrimidine-5-carboxamide TIFF2025522911000370.tif32170

[0784] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-difluoropropanamidine was used in Step 3, and (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol / NaH / DMF was used in Step 5 to obtain the title compound. LC-MS m / z: 442.2 [M+1].

[0388] Example 159

[0785] 4-(((1R,3s,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide TIFF2025522911000371.tif36170

[0786] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and (1R,3s,5S)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 394.2 [M+1].

[0389] Example 160

[0787] 4-(((1R,3s,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide TIFF2025522911000372.tif36170

[0788] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and (1R,3s,5S)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 434.2 [M+1].

[0390] Example 161

[0789] (S,E)-2-(tert-Butyl)-4-((1-cyanocyclopentyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000373.tif30170

[0790] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-dimethylpropanamidine hydrochloride was used in Step 3, and 1-hydroxycyclopentane-1-carbonitrile / LiHMDS / THF was used in Step 5 to obtain the title compound. LC-MS m / z: 421.0 [M+1].

[0391] Example 162

[0791] (S,E)-2-Cyclopentyl-4-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide TIFF2025522911000374.tif32170

[0792] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and ethyl (2Z)-2-(ethoxymethylene)-3-oxo-butanoate was used in Step 3 to obtain the title compound. LC-MS m / z: 430.2 [M+1].

[0392] Example 163

[0793] (S,E)-5-Cyano-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide TIFF2025522911000375.tif38170

[0794] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and (E)-3-amino-3-cyclopentyl-prop-2-enenitrile was used in Step 3 to obtain the title compound. LC-MS m / z: 440.2 [M+1].

[0393] Example 164

[0795] (S,E)-2-(Cyclopentylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000376.tif32170

[0394]

[0796] Procedure B

[0797] Step 1 TIFF2025522911000377.tif29170

[0798] To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1 g, 4.32 mmol) and phenol (0.50 g, 5.31 mmol) in DMF (10 mL, 0.432 M) was added K2CO3 (900 mg), and then the mixture was stirred at 25 °C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1) to give ethyl 2-methylsulfanyl-4-phenoxypyrimidine-5-carboxylate as a brown oil (800 mg, yield 64%).

[0395]

[0799] Step 2 TIFF2025522911000378.tif32170

[0800] To a solution of ethyl 2-methylsulfanyl-4-phenoxypyrimidine-5-carboxylate (300 mg, 1.03 mmol) in chloroform (5 mL, 0.207 M) was added 3-chloroperbenzoic acid (250 mg, 1.23 mmol) all at once, and the mixture was stirred at 0 °C for 2 hours. The mixture was diluted with DCM (15 ml) and washed with NaHCO3 (3 × 10 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude ethyl 2-methylsulfonyl-4-phenoxypyrimidine-5-carboxylate as a white solid (300 mg).

[0396]

[0801] Step 3 TIFF2025522911000379.tif32170

[0802] Ethyl 2-methylsulfonyl-4-phenoxy-pyrimidine-5-carboxylate (300 mg, 0.9307 mmol) and cyclopentylamine (150 mg, 1.76 mmol) were added to a solution of THF (5 mL, 0.186 M), and DIPEA (400 mg) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain ethyl 2-(cyclopentylamino)-4-phenoxy-pyrimidine-5-carboxylate as a colorless oil (100 mg, yield 33%).

[0397]

[0803] According to Steps 6 and 7 of Procedure A, using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid, the title compound was obtained. LC-MS m / z: 431.1 [M+1].

[0398] Example 165

[0804] (S,E)-2-(Cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000380.tif28170

[0805] In Procedure B, in Step 3, using cyclopentanol / LiHMDS, the title compound was obtained. LC-MS m / z: 432.2 [M+1].

[0399] Example 166

[0806] (S,E)-2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000381.tif32170

[0807] In Procedure B, in Step 3, using 7-azabicyclo[2.2.1]heptane hydrochloride, the title compound was obtained. LC-MS m / z: 443.2 [M+1].

[0400] Example 167

[0808] (E)-N-(3-(Methylsulfonyl)allyl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide TIFF2025522911000382.tif34170

[0401]

[0809] Procedure C

[0810] Step 1 TIFF2025522911000383.tif28170

[0811] To a mixture of ethyl 2-methylsulfanyl-4-phenoxy-pyrimidine-5-carboxylate (30 g, 103.33 mmol) in MeCN (200 mL, 0.517 M), DCM (200 ml) and SO2Cl2 (125 ml) were added at 0 °C. The resulting mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into ice-cooled saturated NaHCO3 solution (100 ml). The aqueous phase was extracted with EtOAc (3 × 150 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain ethyl 2-chloro-4-phenoxy-pyrimidine-5-carboxylate as a white solid (13.0 g, yield 45%).

[0402]

[0812] Step 2 TIFF2025522911000384.tif34170

[0813] To a solution of ethyl 2-chloro-4-phenoxy-pyrimidine-5-carboxylate (400 mg, 1.44 mmol) and pyrrolidine (112 mg, 1.59 mmol) in MeCN (7 mL, 0.205 M), DIPEA (694 mg, 5.37 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain ethyl 4-phenoxy-2-pyrrolidin-1-yl-pyrimidine-5-carboxylate as a white solid (130 mg, yield 29%).

[0403]

[0814] According to Steps 6 and 7 of Procedure A, the title compound was obtained. LC-MS m / z: 403.1 [M+1].

[0404] Example 168

[0815] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide TIFF2025522911000385.tif34170

[0816] In Procedure C, in the last step, [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used to obtain the title compound. LC-MS m / z: 417.2 [M+1].

[0405] Example 169

[0817] (S,E)-2-(3-Methoxyazetidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000386.tif34170

[0818] In Procedure C, in Step 2, 3-methoxyazetidine was used, and in the last step, [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used to obtain the title compound. LC-MS m / z: 433.2 [M+1].

[0406] Example 170

[0819] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2-azaspiro[3.3]heptan-2-yl)pyrimidine-5-carboxamide TIFF2025522911000387.tif36170

[0820] In Procedure C, in Step 2, 2-azaspiro[3.3]heptane was used, and in the last step, [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used to obtain the title compound. LC-MS m / z: 443.2 [M+1].

[0407] Example 171

[0821] 2-((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000388.tif36170

[0822] In Procedure C, (2R,5S)-2,5-dimethylpyrrolidine hydrochloride was used in Step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 445.0 [M+1].

[0408] Example 172

[0823] 2-((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000389.tif36170

[0824] In Procedure C, (2R,5R)-2,5-dimethylpyrrolidine hydrochloride was used in Step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 445.2 [M+1].

[0409] Example 173

[0825] (S,E)-2-(3,3-Difluoropyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000390.tif34170

[0826] In Procedure C, 3,3-difluoropyrrolidine hydrochloride / LiHMDS was used in Step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 453.0 [M+1].

[0410] Example 174

[0827] (S,E)-2-(2,2-Dimethylpyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000391.tif34170

[0828] In Procedure C, 2,2-dimethylpyrrolidine was used in Step 2, and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 445.2 [M+1].

[0411] Example 175

[0829] 2-((S)-2-Methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000392.tif36170

[0830] In Procedure C, (S)-2-methylpyrrolidine was used in Step 2, and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 431.2 [M+1].

[0412] Example 176

[0831] 2-((R)-2-Methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000393.tif36170

[0832] In Procedure C, (R)-2-methylpyrrolidine was used in Step 2, and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 431.2 [M+1].

[0413] Example 177

[0833] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(dimethylamino)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000394.tif32170

[0834] In Procedure C, dimethylamine hydrochloride was used in Step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 417.1 [M+1].

[0414] Example 178

[0835] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(methylamino)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000395.tif32170

[0836] In Procedure C, methylamine hydrochloride was used in Step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 403.1 [M+1].

[0415] Example 179

[0837] (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(diethylamino)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000396.tif34170

[0838] In Procedure C, diethylamine was used in Step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 445.2 [M+1].

[0416] Example 180

[0839] (S,E)-2-(Cyclopropyl(methyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000397.tif32170

[0840] In Procedure C, N-methylcyclopropanamine hydrochloride was used in Step 2, and the title compound was obtained using [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the final step. LC-MS m / z: 443.3 [M+1].

[0417] Example 181

[0841] (S,E)-2-(Azetidin-1-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000398.tif32170

[0842] In Procedure C, azetidine hydrochloride was used in Step 2, and the title compound was obtained using [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the final step. LC-MS m / z: 429.3 [M+1].

[0418] Example 182

[0843] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3-fluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000399.tif34170

[0844] In Procedure C, 3-fluoroazetidine hydrochloride was used in Step 2, and the title compound was obtained using [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the final step. LC-MS m / z: 447.2 [M+1].

[0419] Example 183

[0845] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000400.tif36170

[0846] In Procedure C, 3,3-difluoroazetidine hydrochloride was used in Step 2, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 465.2 [M+1].

[0420] Example 184

[0847] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(methyl(2,2,2-trifluoroethyl)amino)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000401.tif32170

[0848] In Procedure C, 2,2,2-trifluoro-N-methyl-ethanamine hydrochloride was used in Step 2, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 485.2 [M+1].

[0421] Example 185

[0849] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(ethyl(methyl)amino)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000402.tif32170

[0850] In Procedure C, N-ethylmethylamine was used in Step 2, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the final step to obtain the title compound. LC-MS m / z: 431.2 [M+1].

[0422] Example 186

[0851] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(isopropyl(methyl)amino)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000403.tif32170

[0852] In Procedure C, N-methylisopropylamine was used in Step 2, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the last step to obtain the title compound. LC-MS m / z: 445.1 [M+1].

[0423] Example 187

[0853] (E)-2-Cyclopentyl-N-methyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000404.tif32170

[0424]

[0854] Step 1 TIFF2025522911000405.tif34170

[0855] To a solution of 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylic acid (500 mg, 1.76 mmol) in DMF (2 mL, 0.879 M) were added methylaminoacetaldehyde dimethyl acetal (220 mg, 1.85 mmol), HATU (1.0 g), and DIPEA (0.91 ml). The mixture was stirred at 25 °C for 12 h under N2. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (using a 12 g Biotage Agela flash silica gel column, eluting with 0% to 15% ethyl acetate in petroleum ether) to give 2-cyclopentyl-N-(2,2-dimethoxyethyl)-N-methyl-4-phenoxy-pyrimidine-5-carboxamide as a white solid (600 mg, 89% yield).

[0425]

[0856] Step 2 TIFF2025522911000406.tif34170

[0857] 2-Cyclopentyl-N-(2,2-dimethoxyethyl)-N-methyl-4-phenoxy-pyrimidine-5-carboxamide (210 mg, 0.55 mmol) was added to TFA (25 ml). The mixture was stirred at 0 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 ml), and the aqueous phase was extracted with EtOAc (3 × 30 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-cyclopentyl-N-methyl-N-(2-oxoethyl)-4-phenoxy-pyrimidine-5-carboxamide (210 mg).

[0426]

[0858] In Procedure A, according to Step 1, using 2-cyclopentyl-N-methyl-N-(2-oxoethyl)-4-phenoxy-pyrimidine-5-carboxamide, the title compound was obtained. LC-MS m / z: 416.1 [M+1].

[0427] Example 188

[0859] (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone TIFF2025522911000407.tif32170

[0860] In Step 1 of the procedure for the compound of Example 187, using 2-cyclopropyl-4-phenoxy-pyrimidine-5-carboxylic acid / 3-azetidinone, 1-(2-cyclopropyl-4-phenoxy-pyrimidine-5-carbonyl)azetidin-3-one was obtained. According to Step 1 of Procedure A, n using BuLi as the base, the title compound was obtained. LC-MS m / z: 386.0 [M+1].

[0428] Example 189

[0861] (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone TIFF2025522911000408.tif32170

[0862] Using 2-tert-butyl-4-phenoxy-pyrimidine-5-carboxylic acid, the title compound was obtained according to the procedure for the compound of Example 188. LC-MS m / z: 402.0 [M+1].

[0429] Example 190

[0863] 1-(1-(2-(tert-Butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one TIFF2025522911000409.tif68170

[0864] A mixture of 1-(2-tert-butyl-4-phenoxy-pyrimidine-5-carbonyl)azetidin-3-one (63 mg, 0.19 mmol) and 1-(triphenyl-λ5-phosphanylidene)propan-2-one (108 mg, 0.34 mmol) in toluene (3 mL, 0.065 M) was stirred at 70 °C for 1.5 h. The mixture was concentrated and purified directly by preparative HPLC (reverse phase, MeCN / H2O (0.1% FA): 5~95%) to give the title compound as a white solid (2.8 mg, yield 4%). LC-MS m / z: 366.2 [M+1].

[0430] Example 191

[0865] Methyl 2-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetate TIFF2025522911000410.tif32170

[0866] Using methyl (triphenylphosphoranylidene)acetate as the starting material, the title compound was obtained according to the procedure for the compound of Example 190. LC-MS m / z: 382.2 [M+1].

[0431] Examples 192 and 193

[0867] (S,E)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide / (R,E)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000411.tif34170

[0868] Step 1 TIFF2025522911000412.tif23170

[0869] (3,3-Difluorocyclobutyl)methanol (1 g, 8.19 mmol) was added to a solution of Dess-Martin periodinane (4.86 g, 11.47 mmol) in DCM (30 mL, 0.273 M) at 25 °C, and the mixture was stirred for 14 h. The mixture was filtered through a filter, and the filter cake was washed with DCM (3 × 5 mL). Subsequently, the combined filtrate was washed with saturated Na2S2O3 solution (3 × 30 mL), saturated NaHCO3 solution (3 × 30 mL), and brine (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and crude 3,3-difluorocyclobutanecarbaldehyde (983 mg) was obtained.

[0432]

[0870] Step 2 TIFF2025522911000413.tif27170

[0871] 3,3-Difluorocyclobutanecarbaldehyde (713 mg, 5.94 mmol) and 2-methylpropan-2-sulfinamide (600 mg, 4.95 mmol) were added to a solution of copper sulfate (1.98 g, 12.38 mmol) in DCM (10 mL, 0.495 M). The mixture was stirred at 25 °C for 72 h. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with EtOAc (2×10 ml). The combined filtrates were concentrated to dryness to afford a residue. The residue was purified by flash chromatography (using a 20 g Biotage Agela flash silica gel column, eluting with 10% to 15% ethyl acetate in petroleum ether) to give (Z)-N-((3,3-difluorocyclobutyl)methylene)-2-methylpropan-2-sulfinamide as a pale yellow oil (770 mg, 70% yield).

[0433]

[0872] Step 3 TIFF2025522911000414.tif27170

[0873] (Z)-N-((3,3-Difluorocyclobutyl)methylene)-2-methylpropan-2-sulfinamide (1 g, 4.48 mmol) was added to a solution of vinylmagnesium bromide (13.4 mL, 13.44 mmol, 1 M in THF) at -50 °C in DCM (20 mL, 0.224 M). The solution was warmed to 25 °C over 16 h. The mixture was diluted with DCM (30 ml) and quenched slowly with water (10 ml). The mixture was then washed successively with saturated NaHCO3 (2×10 ml) and brine (2×10 ml). The organic phase was dried over Na2SO4, filtered, and concentrated to give crude N-(1-(3,3-difluorocyclobutyl)allyl)-2-methylpropan-2-sulfinamide as a 1:1 mixture of isomers (800 mg).

[0434]

[0874] Step 4 TIFF2025522911000415.tif27170

[0875] A solution of N-(1-(3,3-difluorocyclobutyl)allyl)-2-methylpropane-2-sulfinamide (300 mg, 1.19 mmol) in HCl / MeOH (10 mL) was stirred at 25 °C for 1 h under N2. The reaction mixture was concentrated under reduced pressure to afford crude 1-(3,3-difluorocyclobutyl)prop-2-en-1-amine HCl salt as a pale yellow oil (180 mg).

[0435]

[0876] Step 5 TIFF2025522911000416.tif36170

[0877] To a solution of 1-(3,3-difluorocyclobutyl)prop-2-en-1-amine HCl salt (50 mg, 0.34 mmol) in DMF (2 mL, 0.170 M) were added 2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxylic acid (95.2 mg, 0.34 mmol), HATU (194 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.85 mmol). The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (using a 12 g Agela flash silica gel column, eluting with 15% to 17% ethyl acetate in petroleum ether) to afford N-[1-(3,3-difluorocyclobutyl)allyl]-2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide as a white solid (100 mg, 72% yield).

[0436]

[0878] Step 6 TIFF2025522911000417.tif36170

[0879] N-[1-(3,3-Difluorocyclobutyl)allyl]-2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide (90 mg, 0.22 mmol) was added to a solution of potassium osmate(VI) dihydrate (6.8 mg, 0.022 mmol) and sodium periodate (94.9 mg, 0.44 mmol) in 1-propanol (2 mL, 0.055 M) and water (2 mL, 0.055 M). The mixture was stirred at 25 °C for 1 h under N2. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving crude N-[1-(3,3-difluorocyclobutyl)-2-oxo-ethyl]-2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide as a yellow solid (90 mg).

[0437]

[0880] Step 7 TIFF2025522911000418.tif36170

[0881] A solution of diethyl ((methylsulfonyl)methyl)phosphonate (92.3 mg, 0.40 mmol) in THF (5 mL, 0.052 M) was added with sodium hydride (11.7 mg, 0.29 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. Then, a solution of N-[1-(3,3-difluorocyclobutyl)-2-oxo-ethyl]-2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide (150 mg, 0.36 mmol) in THF (2 mL, 0.052 M) was added dropwise at 0 °C. After stirring at that temperature for 2.5 hours, the reaction mixture was poured into ice-cooled saturated NH4Cl solution (15 ml). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100*30mm*10uM, water (NH4HCO3) / MeCN = 35~55%B, flow rate = 25 mL / min) to obtain a mixture of the title compounds (50 mg, yield 28%). The mixture was separated by chiral SFC (column: Daicel ChiralPak AD (250mm*30mm*10um), neutral methanol) to obtain Peak 1 (LC-MS m / z: 488.1[M+1]) and Peak 2 (LC-MS m / z: 488.1[M+1]). The absolute stereochemistry of the title compounds was not confirmed.

[0438] Examples 194 and 195

[0882] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide / (R,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF2025522911000419.tif33170

[0439]

[0883] Step 1 TIFF2025522911000420.tif28170

[0884] A solution of methyl (S)-2-amino-2-cyclopropylacetate (0.8 g, 6.19 mmol) in DCE (20 mL, 0.310 M) was added with di(phenyl)methanimine (1.12 g, 6.19 mmol) at 25 °C under N2. The reaction mixture was stirred at 95 °C for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE:EA = 2:1, Rf = 0.8, UV = 254 nm) to obtain methyl (2S)-2-(benzhydrylideneamino)-2-cyclopropyl-acetate as a yellow oil (0.82 g, yield 45%).

[0440]

[0885] Step 2 TIFF2025522911000421.tif28170

[0886] To a solution of methyl (2S)-2-(benzhydrylideneamino)-2-cyclopropyl-acetate (300 mg, 1.02 mmol) in THF (10 mL, 0.102 M) was added lithium diisopropylamide solution (1.02 mL, 2.05 mmol, 2 M) at 0 °C over 2 h. D2O (20 ml) was added to the mixture, and it was warmed to 25 °C under N2. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude methyl 2-(benzhydrylideneamino)-2-cyclopropyl-2-deuterio-acetate as a yellow oil (100 mg).

[0441]

[0887] Step 3 TIFF2025522911000422.tif28170

[0888] A solution of methyl 2-(benzhydrylideneamino)-2-cyclopropyl-2-deuterio-acetate (100 mg, 0.34 mmol) in THF (5 mL, 0.068 M) was added with 2N HCl (2 ml) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, poured into H2O (5 mL), and extracted with EtOAc (3 × 10 mL). Then, the aqueous solution was filtered and concentrated under reduced pressure to obtain crude methyl 2-amino-2-cyclopropyl-2-deuterio-acetate hydrochloride as a colorless oil (25 mg).

[0442]

[0889] Step 4 TIFF2025522911000423.tif21170

[0890] To a solution of methyl 2-amino-2-cyclopropyl-2-deuterio-acetate hydrochloride (300 mg, 1.80 mmol) in DCM (10 mL, 0.180 M) were added di-tert-butyl dicarbonate (0.47 g, 2.161 mmol) and triethylamine (1.82 g, 18.01 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 hours. The mixture was quenched with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (PE:EtOAc = 1:1) to obtain methyl 2-(tert-butoxycarbonylamino)-2-cyclopropyl-2-deuterio-acetate as a colorless oil (0.35 g, yield 84%).

[0443]

[0891] Methyl 2-(tert-butoxycarbonylamino)-2-cyclopropyl-2-deuterio-acetate was converted to tert-butyl N-(1-cyclopropyl-1-deuterio-2-oxo-ethyl)carbamate via LAH reduction and DMP oxidation as described above. In Procedure A, in Step 1, tert-butyl N-(1-cyclopropyl-1-deuterio-2-oxo-ethyl)carbamate was used with 2,2-difluoropropaneamidine in Step 3 to obtain a mixture of the title compounds. The mixture was separated by chiral SFC to obtain Peak 1 (LC-MS m / z: 439.2 [M+1]) and Peak 2 (LC-MS m / z: 439.2 [M+1]). The absolute stereochemistry of the title compound was not confirmed.

[0444] Example 196

[0892] (S,E)-4-(Cyclohexyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000424.tif32170

[0445]

[0893] Step 1 TIFF2025522911000425.tif34170

[0894] To a solution of ethyl 2-cyclopentyl-4-hydroxy-pyrimidine-5-carboxylate (0.300 g, 1.27 mmol) in THF (6 mL, 0.212 M) was added PPh3 (0.4 g) and cyclohexanol (0.127 g, 1.27 mmol) at 0 °C. Then, DIAD (0.308 g) was added dropwise. The mixture was stirred at 40 °C for 2 hours. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1, Rf (product) = 0.5) to obtain ethyl 4-(cyclohexyloxy)-2-cyclopentyl-pyrimidine-5-carboxylate as a yellow oil (0.1 g, yield 25%).

[0446]

[0895] In Procedure A, according to Step 6, using ethyl 4-(cyclohexyloxy)-2-cyclopentyl-pyrimidine-5-carboxylate, and according to Step 7, using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid, the title compound was obtained. LC-MS m / z: 422.1 [M+1].

[0447] Example 197

[0896] (S,E)-2-Cyclopentyl-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide TIFF2025522911000426.tif32170

[0897] In the procedure for the compound of Example 196, using cyclopentanol in Step 1, the title compound was obtained. LC-MS m / z: 408.2 [M+1].

[0448] Example 198

[0898] (E)-4-Cyclopentyl-2-(cyclopentyloxy)-N-(3-(methylsulfonyl)allyl)benzamide TIFF2025522911000427.tif32170

[0899] In the procedure for the compound of Example 196, using cyclopentanol and methyl 4-cyclopentyl-2-hydroxy-benzoate in Step 1, and using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step, the title compound was obtained. LC-MS m / z: 392.2 [M+1].

[0449] Example 199

[0900] (S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide TIFF2025522911000428.tif34170

[0450]

[0901] Procedure D

[0902] Project 1 TIFF2025522911000429.tif25170

[0903] Pd(dppf)Cl2 (702 mg, 0.97 mmol) was added to a mixture of methyl 4,6-dichloronicotinate (2 g, 9.71 mmol), cyclopent-1-ylboronic acid (978 mg, 8.74 mmol) and K2CO3 (2.68 g, 19.42 mmol) in 1,4-dioxane (25 mL, 0.324 M) and water (5 mL, 0.324 M). The resulting mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0 - 4% ethyl acetate / petroleum ether, gradient: 100 mL / min) to give methyl 4-chloro-6-(cyclopent-1-yl)pyridine-3-carboxylate as a yellow oil (1.5 g, 65% yield).

[0451]

[0904] Following step 5 in procedure A, methyl 6-(cyclopent-1-yl)-4-phenoxy-pyridine-3-carboxylate was obtained using methyl 4-chloro-6-(cyclopent-1-yl)pyridine-3-carboxylate.

[0452]

[0905] Project 2 TIFF2025522911000430.tif34170

[0906] Pd / C (200 mg) was added to THF (7 mL, 0.150 M) containing methyl 6-(cyclopent-1-yl)-4-phenoxy-pyridine-3-carboxylate (310 mg, 1.05 mmol). The resulting mixture was stirred at 25 °C for 16 h under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated to give crude methyl 6-cyclopentyl-4-phenoxy-pyridine-3-carboxylate as a yellow oil (310 mg).

[0453]

[0907] In Procedure A, methyl 6-cyclopentyl-4-phenoxy-pyridine-3-carboxylate was obtained according to Step 6, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used according to Step 7 to obtain the title compound. LC-MS m / z: 415.0 [M+1].

[0454] Example 200

[0908] (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide TIFF2025522911000431.tif34170

[0909] In Procedure A, methyl 6-(cyclopenten-1-yl)-4-phenoxy-pyridine-3-carboxylate was obtained according to Step 6, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used according to Step 7 to obtain the title compound. LC-MS m / z: 413.1 [M+1].

[0455] Example 201

[0910] (S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide TIFF2025522911000432.tif34170

[0911] In Procedure D, ethyl 2,6-dichloropyridine-3-carboxylate was used in Step 1 to obtain the title compound. LC-MS m / z: 415.2 [M+1].

[0456] Example 202

[0912] (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide TIFF2025522911000433.tif34170

[0913] In Procedure A, ethyl 6-cyclopentyl-2-phenoxy-pyridine-3-carboxylate was obtained according to Step 6, and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used according to Step 7 to obtain the title compound. LC-MS m / z: 413.2 [M+1].

[0457] Example 203

[0914] (S,E)-5-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)quinoline-8-carboxamide TIFF2025522911000434.tif25170

[0915] Using ethyl 5-bromoquinoline-8-carboxylate as a starting material, methyl 5-cyclopentyl-1,2,3,4-tetrahydroquinoline-8-carboxylate was obtained according to Steps 1 and 2 of Procedure D. TIFF2025522911000435.tif25170

[0916] To a solution of methyl 5-cyclopentyl-1,2,3,4-tetrahydroquinoline-8-carboxylate (149 mg, 0.575 mmol) in toluene (6 mL, 0.096 M) was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (313 mg, 1.38 mmol) at RT. The reaction was stirred at this temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified via normal phase column chromatography using Biotage Isolera (0-10% MeOH / DCM) to obtain methyl 5-cyclopentylquinoline-8-carboxylate as a dark solid (140 mg, 95% yield).

[0458]

[0917] According to Steps 6 and 7 of Procedure A, [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used to obtain the title compound. LC-MS m / z: 373.2 [M+1].

[0459] Example 204

[0918] (S,E)-6-Cyclopropyl-5-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide TIFF2025522911000436.tif32170

[0919] In Procedure D, ethyl 4,6-dichloro-5-methylnicotinate / cyclopropylboronic acid / potassium phosphate (tribasic) was used in ...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof wherein, X is CR ２ or N; Y is CR ４ or N; Z is CR ５ or N; or, Y and Z together form an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R １ is H, -O-(optionally substituted C ３ -C ８ -cycloalkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ６ -C １０ -aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C ３ -C ８ -cycloalkyl; or R １ together with the carbon atom and X to which it is attached forms a 5- to 6-membered heterocyclyl which may be substituted R ２ is H, optionally substituted C １ -C ６ alkyl, or halo; R ３ is optionally substituted C ３ -C ８ -cycloalkyl, optionally substituted C ３ -C ８ -cycloalkenyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -alkenyl, -NR ２ , -N(R)(optionally substituted C ３ -C ８ -cycloalkyl), -S-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ３ -C ８ -cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C ３ -C ８ -cycloalkyl); or R ３ together with the carbon atom and Y to which it is attached forms an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R ４ is H, C １ -C ６ alkyl, cyano, or halo; or R ４ forms, together with the carbon atom and Z to which it is attached, an optionally substituted 5- or 6-membered heteroaryl; or R ３ and R ４ together with the carbon atom to which they are attached, form an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ４ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R ５ is H, C １ -C ６ alkyl, -NR ２ , or -N(R)-C(=O)-(C １ -C ６ alkyl); Each R is independently H or optionally substituted C １ -C ６ alkyl; W is W １ , W ２ , W ３ , W ４ , or W ５ ; W １ is: wherein, indicating that it may exist as either the (Z)- or (E)-geometric isomer, R ６ is H; R ７ is H, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R ７ａ is H or deuterium; R ８ is H; R ９ is H; R １０ is optionally substituted C １ -C ６ -alkyl, optionally substituted C ３ -C ８ -cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or R ６ together with the nitrogen atom to which it is shown as attached, and R ７ and R ７ａ together with the carbon atom to which they are shown as attached form an azetidinyl ring; or R ６ together with the nitrogen atom to which it is attached, and R ７ R ７ａ R ８ together with the carbon atoms to which they are attached form an azetidinyl or pyrrolidinyl ring; or R ６ together with the nitrogen atom to which it is attached, and R ７ R ７ａ R ８ R ９ together with the carbon atoms to which they are attached form a dihydropyrrolyl ring; or or, R ７ , R ７ａ , R ８ , R ９ , and R １０ together with the carbon atom to which they are attached form 2,3 - dihydrothiophene 1,1 - dioxide; or R ８ , R ９ , and R １０ together with the carbon atom to which they are attached form a 1,1-dioxide-2H-thiopyranyl ring; W ２ is: wherein, indicating that it may exist as either the (Z)- or (E)-geometric isomer, R １１ is H; R １２ is H or optionally substituted C １ -C ６ alkyl; R １２ａ is H; R １３ and R １４ are each H; Or, R １１ together with the nitrogen atom to which it is attached, and R １２ , R １２ａ , and R １３ together with the carbon atoms to which they are attached, form an optionally substituted azetidinyl ring; W ３ is: wherein, R １５ is H; R １６ is H or optionally substituted C １ -C ６ -alkyl, or optionally substituted C ３ -C ８ -cycloalkyl; W ４ is: wherein, R １７ is H; R １８ is H or optionally substituted C １ -C ６ alkyl; Each R ａ is, independently, optionally substituted C １ -C ６ alkyl; W ５ is: wherein, indicating that it may exist as either the (Z)- or (E)-geometric isomer, m is 1, 2, or 3; R １９ is selected from the group consisting of C １ -C ６ alkyl and -O-(C １ -C ６ alkyl).

2. X is N; Y is N; Z is CR ５ and; or, Y and Z together form an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered heterocyclyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. X is CR ２ and; Y is CR ４ and; Z is CR ５ and; or, Y and Z together form an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5- or 6-membered heteroaryl; or R ３ is combined with the carbon atom and Y to which it is attached to form an optionally substituted C ３ -C ８ cycloalkyl or cycloalkenyl The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. X is CR ２ and; Y is N; Z is CR ５ and; or R １ together with the carbon atom and X to which it is attached forms a 5- or 6-membered heterocyclyl which may be substituted The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. X is N; Y is CR ４ and; Z is CR ５ and; or R ３ together with the carbon atom and Y to which it is attached forms an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. X is N; Y is CR ４ and Z is N, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. X is CR ２ and; Y is CR ４ and; Z is N, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. X is N; Y is N; Z is CR ５ and; R １ is H, -O-(optionally substituted C ３ -C ８ -cycloalkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ６ -C １０ -aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C ３ -C ８ -cycloalkyl; R ３ is optionally substituted C ３ -C ８ -cycloalkyl, optionally substituted C ３ -C ８ -cycloalkenyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -alkenyl, -NR ２ , -N(R)-(optionally substituted C ３ -C ８ -cycloalkyl), -S-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ３ -C ８ -cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C ３ -C ８ -cycloalkyl); R ５ is H, C １ -C ６ -alkyl, -NR ２ , or -N(R)-C(=O)-(C １ -C ６ -alkyl); Each R is independently H or optionally substituted C １ -C ６ alkyl; W is W １ and; R ６ is H; R ７ is H, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R ７ａ is H or deuterium; R ８ is H; R ９ is H; R １０ is optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. R １ is -O-(C ６ -C １０ -aryl); R ３ is a fluoro-substituted C １ -C ６ alkyl; R ５ is H; R ６ is H; R ７ is C ３ -C ８ cycloalkyl; R ７ａ is H or deuterium; R ８ is H; R ９ is H; R １０ is C １ -C ６ alkyl, The compound according to claim 8, or a pharmaceutically acceptable salt thereof.

10. R １ wherein: -O-(optionally substituted C ３ -C ８ Any substituent of (cycloalkyl) is one to three substituents selected from the group consisting of halo, cyano, and hydroxy; or C ３ -C ８ When two substituents are present on the same ring carbon atom of cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C ３ -C ６ cycloalkyl; or C ３ -C ８ When two substituents are present on adjacent ring carbon atoms of cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C ３ -C ６ cycloalkyl; -O-(optionally substituted C ６ -C １０ aryl) any substituent is halo, C １ -C ６ alkyl, cyano, hydroxy, and -NH ２ 1 to 3 substituents selected from the group consisting of, or 1 to 5 deuterium atoms; or R １ when R, together with the carbon atom to which it is attached and X, forms an optionally substituted 5- or 6-membered heterocyclyl, two substituents on the same ring carbon atom of the 5- or 6-membered heterocyclyl, together with the ring carbon atom to which they are attached, form a 5- or 6-membered cycloalkyl; R ３ wherein: Optionally substituted C ３ -C ８ Any substituent of the cycloalkyl is 1 to 3 substituents selected from hydroxy, halo, C １ -C ６ alkyl, and C ６ -C １０ aryl; or when two substituents are present on the same carbon atom of C ３ -C ８ cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C ３ -C ６ cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of C ３ -C ８ cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C ６ -C １０ aryl; or R ３ is a carbon atom to which it is shown to be attached and Y together form an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, where any substituent is 1 to 3 substituents selected from the group consisting of halo and C １ -C ６ -alkyl; or two geminal hydrogens on the ring carbon atoms of C ３ -C ８ -cycloalkyl or cycloalkenyl can be replaced by the group =O; or R ３ is joined to the carbon atom to which it is attached and Y to form an optionally substituted 5- or 6-membered heterocyclyl or heteroaryl, and any substituent is selected from the group consisting of halo and C １ -C ６ alkyl, and is 1 to 3 substituents selected from the group consisting of; C which may be replaced ６ -C １０ Any substituent of the aryl is 1 to 3 substituents selected from the group consisting of halo; C which may be substituted １ -C ６ alkyl or C ６ any substituent of alkenyl is 1 to 5 substituents selected from the group consisting of halo, hydroxy, -O-(C １ -C ６ alkyl), and optionally substituted C ３ -C ６ cycloalkyl; any substituent of C ３ -C ６ cycloalkyl is 1 to 3 substituents selected from the group consisting of C １ -C ６ alkyl; -NR ２ wherein R of １ -C ６ any substituent of the alkyl is 1 to 3 substituents selected from the group consisting of halo; Any substituent of the 4- to 6-membered heterocyclyl which may be substituted is -O-(C １ -C ６ alkyl), C １ -C ６ alkyl, halo; or when two substituents are present on the same carbon atom of the 4- to 6-membered heterocyclyl which may be substituted, the substituents together with the ring carbon atom to which they are attached form C ３ -C ６ cycloalkyl, The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R １ forms, together with the carbon atom to which it is attached, an optionally substituted 5- to 6-membered heterocyclyl which is shown to be bonded thereto In the formula, the double bond shown is between the carbon having the R １ group and X; R ３ wherein R, together with the carbon atom to which it is attached and Y, forms an optionally substituted C ６ -C １０ aryl is R ３ a 5- or 6-membered optionally substituted heterocyclenyl formed together with the carbon atom to which it is attached and Y, in which The indicated carbon-carbon double bond between two carbons having it is between the carbon having the R ３ group and Y; R ３ When R, together with the carbon atom and Y to which it is attached, forms an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, the optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl is In the formula, the carbon-carbon double bond shown is between the carbon having the R ３ group and Y; R ４ A 5- or 6-membered heteroaryl which may be substituted and which is formed together with the carbon atom to which it is attached and Z is shown to be attached to In each structure, The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R １ wherein: -O-(optionally substituted C ３ -C ８ -cycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexan-5-yl), -O-(spiro[3.3]heptan-2-yl), -O-(3-chlorocyclobutyl), -O-(bicyclo[3.1.0]hexan-3-yl), -O-(bicyclo[2.2.1]heptan-1-yl), -O-(1-cyanocyclopentanyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl), or -O-(2,2-difluorocyclopentyl), and -O-(optionally substituted C １ -C ６ alkyl) is ethoxy, isopropoxy, or cyclopropylmethyloxy; -O-(optionally substituted C ６ -C １０ aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalen-1-oxy, or phenoxy-d5; -O-(optionally substituted 5- or 6-membered heteroaryl) is pyridin-2-yloxy, or pyridin-3-yloxy; -O-(optionally substituted 5- or 6-membered heterocyclyl) is tetrahydro-2H-pyran-4-yl, or tetrahydro-2H-pyran-3-yl; Optionally substituted C ３ -C ８ The cycloalkyl is cyclohexyl; R ２ wherein: C which may be replaced １ -C ６ the alkyl is methyl; R ３ wherein: Optionally substituted C ３ -C ８ The cycloalkyl is cyclopentyl, cyclobutyl, cyclohexyl, cyclopropyl, hydroxycyclopentyl, fluorocyclopentyl, methylcyclobutyl, methylcyclopropyl, phenylcyclopropyl, methylcyclopentyl, difluorocyclobutyl, fluorocyclopentyl, bicyclo[4.2.0]octa-1,3,5-trien-7-yl, or (trifluoromethyl)cyclopropyl, or spiro[2.3]hexan-5-yl; Optionally substituted C ３ -C ８ The cycloalkenyl is cyclopentenyl; Optionally substituted C ６ -C １０ aryl is phenyl; Optionally substituted C １ -C ６ wherein the alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl, or cyclopropyldifluoromethyl; C which may be replaced １ -C ６ The alkenyl is 2-methylprop-1-en-1-yl; NR ２ is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl) ２ or -N(methyl)(trifluoroethyl); -N(R)(optionally substituted C ３ -C ８ -cycloalkyl) is N(methyl)(cyclopropyl); -S-(optionally substituted C １ -C ６ -alkyl) is methylthiol; -O-(optionally substituted C １ -C ６ alkyl) is trifluoroethoxy or methoxy; -O-(optionally substituted C ３ -C ８ ycloalkyl) is cyclopentyloxy or cyclopropyloxy; The 4- to 6-membered heterocyclyl or heterocyclenyl which may be substituted is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptan-7-yl, bicyclo[1.1.1]pentan-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptan-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H-pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl, or 3,3-difluoro-azetidin-1-yl; R ５ wherein: C １ -C ６ The alkyl is methyl; -NR ２ is -NH ２ and; -N(R)-C(=O)-(C １ -C ６ -alkyl) is -N(H)-C(=O)-CH ３ is, The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. W is W １ The compound according to any one of claims 1 to 7 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein W is W

14. R ７ optionally substituted C １ -C ６ alkyl is methyl, ethyl, isopropyl, methoxymethyl, cyclopropylmethyl, cyclopropyloxymethyl, tolyl, -CH(CH ３ )-OCH ３ , difluoroethyl, phenoxymethyl, -CH ２ -C(=O)-N(CH ３ ) ２ , or tert-butoxymethyl, difluoromethoxymethyl; R ７ Optionally substituted C ３ -C ８ The cycloalkyl is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH ２ -S-CH ３ , difluorocyclohexyl; R ７ The optionally substituted 5- or 6-membered heterocyclyl is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; R １０ optionally substituted C １ -C ６ alkyl is methyl; R １０ optionally substituted C ３ -C ８ the cycloalkyl is cyclopropyl; R １０ wherein the optionally substituted 5- or 6-membered heterocyclyl is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; Or, W １ is: In each of the above structures, The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. W is W ２ The compound according to any one of claims 1 to 7 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein W is W.

16. W ２ is: In the formula, R ２１ is H or C １ -C ６ alkyl; It shows that it may exist as either the (Z)- or (E)-geometric isomer, The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

17. W is W ３ The compound according to any one of claims 1 to 8 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein W is W

18. R １６ optionally substituted C １ -C ６ alkyl is methyl; R １６ Optionally substituted C ３ -C ８ wherein the cycloalkyl is cyclopropyl The compound according to claim 17, or a pharmaceutically acceptable salt thereof.

19. W is W ４ The compound according to any one of claims 1 to 8 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein W is W

20. R １８ Optionally substituted C １ -C ６ wherein the alkyl is methyl; Optionally substituted C １ -C ６ wherein the alkyl is methyl The compound according to claim 19, or a pharmaceutically acceptable salt thereof.

21. W is W ５ The compound according to any one of claims 1 to 8 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein W is W.

22. R １９ of C １ -C ６ the alkyl is methyl; R １９ in which -O-(C １ -C ６ -alkyl) is methoxy, The compound according to claim 21, or a pharmaceutically acceptable salt thereof.

23. The compound is: (E)-N-(3-(methylsulfonyl)allyl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-phenylpyrimidine-5-carboxamide; (S,E)-2-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Ethyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Isopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-Cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclohexyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Ethyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Isopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopentylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (R,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclobutyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-4-(4-Chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-4-(4-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (E)-2-Cyclohexyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-N-(3-(methylsulfonyl)allyl)-2-(methylthio)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopropyl-N-((1,1-dioxidido-2H-thiet-3-yl)methyl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopropyl-N-(1,1-dioxidido-2,3-dihydrothiophen-3-yl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(2-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(3-Chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(2-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(Cyclohexyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (E)-2-Cyclopentyl-N-methyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-(p-tolyloxy)pyrimidine-5-carboxamide; (E)-N-(3-(methylsulfonyl)allyl)-4-phenoxy-2-(1H-pyrazol-5-yl)pyrimidine-5-carboxamide; (E)-4-(3-Chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3,5-difluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-fluoro-3-methylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3,5-dichlorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (S,E)-2-Cyclopentyl-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(4-Cyanophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3,4-dimethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(m-tolyloxy)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(o-tolyloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-5-carboxamide; (S,E)-2-(Cyclopropylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-Cyclobutoxy-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(1-Hydroxycyclopentyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-2-yloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-3-yloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[3.3]heptan-2-yloxy)pyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-(cyclohexyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-((4,4-difluorocyclohexyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopentyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)oxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[2.3]hexan-5-yloxy)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-4-(cyclopropylmethoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 4-(((1R,3S)-3-Chlorocyclobutoxy))-2-cyclopropyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-Cyclohexyl-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 4-[[(1S,5R)-3-Bicyclo[3.1.0]hexanyl]oxy]-2-tert-butyl-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-((1-cyanocyclopentyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-4-(3,3-difluorocyclobutoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1-Fluorocyclopentyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(3-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(4-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (S,E)-2-(tert-Butyl)-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Cyclopentylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; (S,E)-4-(3-Chloro-5-fluorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Cyclohexylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-(3-Aminophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Cyclobutylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(cyclopropylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (Z)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone; (E)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone; (S,E)-4-(Cyclopentyloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(((1R,2R)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-Amino-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(naphthalen-1-yloxy)pyrimidine-5-carboxamide; (R,E)-2-(2-Fluorophenyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(2-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-(Cycloheptyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-4-(((1S,2R)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopentyl-4-(((1R,2S)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(Bicyclo[1.1.1]pentan-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((1S,3R)-3-Methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((1R,3S)-3-Methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(3-Methoxyazetidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-4-(((3,3-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopropyl-4-((((S)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; 2-Cyclopropyl-4-((((R)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2-azaspiro[3.3]heptan-2-yl)pyrimidine-5-carboxamide; 2-(Bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydro-2H-pyran-3-yl)pyrimidine-5-carboxamide; (S,E)-2-(5,6-Dihydro-2H-pyran-3-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(4-methyl-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(2-Hydroxypropan-2-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Isobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(2-Methylprop-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((2R,5R)-2,5-Dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-(Bicyclo[2.2.1]heptan-1-yloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-2-(3,3-Difluoropyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(2-Methoxypropan-2-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1,1-Difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1-Methylcyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (2-(1-Methylcyclopropyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methylene)azetidin-1-yl)methanone; (2-((1S,3S)-3-Methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (2-((1r,3r)-3-Methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide; (S,E)-2-(2,2-Dimethylpyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((S)-2-Methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-((R)-2-Methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 1-(1-(2-(tert-Butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one; (S,E)-2-((1-Methylcyclopropyl)methyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (2-((1-Methylcyclopropyl)methyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone; (E)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)pyrrolidin-1-yl)methanone; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide; (R,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-phenylcyclopropyl)pyrimidine-5-carboxamide; 2-((1R,3S)-3-Methylcyclopentyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(3,3-Difluorocyclobutyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(1,1-Difluoroethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1-Fluorocyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (E)-2-(tert-Butyl)-N-(1-(2-(methylsulfonyl)vinyl)cyclopropyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-4-Acetamido-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide; (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(2-fluoropropan-2-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-((1S,3S)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-((1R,3R)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide; (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-1-yl)methanone; (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,Z)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; 2-(tert-Butyl)-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropyl-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylmethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,Z)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-Cyclopentyl-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclobutyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopropyldifluoromethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(Cyclopropyldifluoromethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1,1-Difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide; (E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclobutyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(1,1-Difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)penta-1-en-3-yl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-N-(1-Methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(1-fluorocyclopropyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(5,5-difluoro-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(5,5-Difluoro-1-(methylsulfonyl)penta-1-en-3-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-(4,4-Difluorocyclohexyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide; 4-(((1R,3S,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; 4-(((1R,3S,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-cyclopropyl-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (R,E)-N-(1-(tert-Butoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(spiro[2.3]hexan-5-yl)pyrimidine-5-carboxamide; (R,E)-2-(1,1-difluoroethyl)-N-(1-(difluoromethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(1,1-difluoroethyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylfluoromethyl)-4-phenoxypyrimidine-5-carboxamide; 4-(((1R,3S,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-N-(1-(3,3-Difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-N-(1-(3,3-Difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopropyldifluoromethyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(Cyclopropyldifluoromethyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-2-(1,1-Difluoroethyl)-N-((3R,4S,E)-4-methoxy-1-(methylsulfonyl)penta-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (R,E)-N-((1R,3R,5S)-Bicyclo[3.1.0]hexan-3-yl)oxy)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)pyrimidine-5-carboxamide; (R,E)-N-(1-Cyclopropoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(dimethylamino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(methylamino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-Cyclopropoxy-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(diethylamino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Cyclopropyl(methyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-methoxy-4-phenoxypyrimidine-5-carboxamide; (S,E)-2-(Azetidin-1-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(methyl(2,2,2-trifluoroethyl)amino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3-fluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(ethyl(methyl)amino)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoropropyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S)-N-(3-cyanobut-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-(phenoxy-d5)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; and (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-(phenoxy-d5)pyrimidine-5-carboxamide The compound according to any one of claims 2 and 8 to 14, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

24. When the R or S stereochemical configuration at one or more chiral carbons is specified, the compound is a mixture of R or S configurations at that carbon; Or a mixture of E or Z geometric isomers of the aforementioned compound The compound according to claim 23, or a pharmaceutically acceptable salt thereof, comprising

25. The compound is: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide The compound according to any one of claims 2 and 8 to 14, or a pharmaceutically acceptable salt thereof.

26. The compound is: (E)-2-cyclobutoxy-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-2-ethoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-2-isopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)-2-phenoxybenzamide; (E)-4-cyclopentyl-2-cyclopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; 4-cyclopentyl-2-cyclopropoxy-N-((1,1-dioxide-2H-thiet-3-yl)methyl)benzamide; (E)-2-cyclobutoxy-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-2-ethoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-2-isopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)-2-phenoxybenzamide; (E)-4-cyclopentyl-2-cyclopropoxy-N-(3-(methylsulfonyl)allyl)benzamide; 4-cyclopentyl-2-cyclopropoxy-N-((1,1-dioxide-2H-thiet-3-yl)methyl)benzamide; (S,E)-5-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)quinoline-8-carboxamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (E)-4-Cyclopentyl-2-(cyclopentyloxy)-N-(3-(methylsulfonyl)allyl)benzamide; rac-(R,E)-4-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxybenzamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-oxo-6-phenoxy-2,3-dihydro-1H-indene-5-carboxamide; (S,E)-2,2-Dimethyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-oxo-6-phenoxy-2,3-dihydro-1H-indene-5-carboxamide; and 2,2-Dimethyl-6-(3-((methylsulfonyl)methylene)azetidine-1-carbonyl)-5-phenoxy-2,3-dihydro-1H-inden-1-one A compound according to any one of claims 3 and 10 to 14, or a pharmaceutically acceptable salt thereof, selected from the group consisting of [

27. ] When the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound is a mixture of (R) or (S) configurations at those carbon atoms; or a mixture of (E) or (Z) geometric isomers of the aforementioned compounds A compound according to claim 26, or a pharmaceutically acceptable salt thereof, comprising [

28. ] The compound is: (S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-Cyclopropyl-5-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-6-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; and (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-4-phenoxynicotinamide A compound according to any one of claims 4 and 10 to 14, or a pharmaceutically acceptable salt thereof, selected from the group consisting of. [

29. ] When the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound is a mixture of (R) or (S) configurations at those carbon atoms; or a mixture of (E) and (Z) geometric isomers of the aforementioned compounds A compound according to claim 28, or a pharmaceutically acceptable salt thereof, comprising. [

30. ] The compound is: (S,E)-6-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxyquinoline-3-carboxamide; (S,E)-5-Cyano-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-(Cyclopent-1-en-1-yl)-5-fluoro-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-6-Cyclopropyl-5-fluoro-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide; (S,E)-6-Cyclopentyl-5-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-N-(1-Cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxynicotinamide; (S,E)-6-(1,1-difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-5-fluoro-2-phenoxynicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-7,7-difluoro-2-phenoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-6-carboxamide; and (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(cyclopropyldifluoromethyl)-5-fluoro-2-phenoxynicotinamide The compound according to any one of claims 5 and 10 to 14, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

31. When the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound is a mixture of the R or S configuration at that carbon; Or a mixture of (E) or (Z) geometric isomers of the aforementioned compounds The compound according to claim 30, or a pharmaceutically acceptable salt thereof, comprising

32. The compound is: (S,E)-5-(cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-phenoxypyrazine-2-carboxamide The compound according to any one of claims 6 and 10 to 14, or a pharmaceutically acceptable salt thereof.

33. When the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound is a mixture of the (R) or (S) configuration at those carbon atoms; Or a mixture of E or Z geometric isomers of the aforementioned compounds The compound according to claim 32, or a pharmaceutically acceptable salt thereof, which comprises

34. The compound is: (S,E)-5-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-phenoxypicolinamide The compound according to any one of embodiments 7 and 10 to 14, or a pharmaceutically acceptable salt thereof.

35. When the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound is a mixture of (R) or (S) configurations at those carbon atoms; Or a mixture of E or Z geometric isomers of the aforementioned compound The compound according to claim 34, or a pharmaceutically acceptable salt thereof, which comprises

36. The compound is: 2-(1-(2-Cyclopropyl-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetonitrile; 2-(1-(2-Cyclopropyl-4-phenoxypyrimidine-5-carbonyl)-2-methylazetidin-3-ylidene)acetonitrile; (E)-N-(3-Cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide; and (Z)-N-(3-Cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide The compound according to any one of claims 2, 10 to 12 and 15 to 17, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

37. When the (E) or (Z) geometric isomer of the compound is specified, the compound according to claim 36, or a pharmaceutically acceptable salt thereof, which is a mixture of the (E) or (Z) geometric isomers of the said compound.

38. The compound is: N-(2-Cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide; 2-(tert-Butyl)-N-(2-cyanoallyl)-4-phenoxypyrimidine-5-carboxamide; N-(2-Cyanoallyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; N-(2-Cyanoallyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide; N-(2-Cyanoallyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; (R)-N-(3-cyanobut-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S)-N-(3-cyanobut-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; (S)-N-(3-cyanobut-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; and (S)-N-(2-cyano-1-cyclopropylallyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide A compound according to any one of claims 2, 10 to 12 and 17 to 18, or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

39. The compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein when the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of (R) or (S) configurations at those carbon atoms.

40. The compound is: (S)-2-(1,1-difluoroethyl)-N-(5-(dimethylamino)-5-oxopent-3-yn-2-yl)-4-phenoxypyrimidine-5-carboxamide A compound according to any one of claims 2, 10 to 12 and 19 to 20, or a pharmaceutically acceptable salt thereof.

41. The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein when the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of (R) or (S) configurations at those carbons.

42. The compound is: 1-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one; and Methyl 2-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetate A compound according to any one of claims 2, 10 to 12 and 21 to 22, or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

43. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

44. A method for treating a proliferative disorder in a patient in need of treatment for the proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

45. The method according to claim 44, wherein the proliferative disorder is cancer.

46. The method according to claim 45, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

47. A method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a patient in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

48. A method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase), comprising causing a non-naturally occurring covalent modification at cysteine 727 described in SEQ ID NO: 1 or a variant thereof, wherein the modification results from a bond-forming reaction between an electrophilic agent and cysteine 727 described in SEQ ID NO: 1 or a variant thereof, and the sulfur atom of the cysteine residue undergoes a reaction with the electrophilic agent.

49. The method according to claim 48, wherein the electrophilic agent comprises at least one chemical moiety selected from the group consisting of vinyl sulfone, alkynyl sulfone, vinyl sulfonamide, vinyl sulfoxide, alkynyl sulfoxide, vinyl sulfoximine, alkynyl sulfoximine, acrylamide, acrylonitrile, alkynenitrile, enone, inone, enoate, and inoate.

50. Vinyl sulfone has the structure Alkynyl sulfone has the structure Vinyl sulfonamide has the structure Vinyl sulfoxide has the structure Alkynyl sulfoxide has the structure Vinyl sulfoximine has the structure Alkynyl sulfoximine has the structure Acrylamide has the formula Acrylonitrile has the structure Enone has the structure Inone has the structure Enoate has the structure Inoate has the structure Wherein: Represents a possible bonding point of the chemical moiety to the remaining part of the electrophilic agent. The method according to claim 49.

51. A compound of formula (II): Or a pharmaceutically acceptable salt thereof Wherein, X is CR ２ or N; Y is CR ４ or N; Z is CR ５ or N; Alternatively, Y and Z together form an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- or 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R １ is H, -O-(optionally substituted C ３ -C ８ -cycloalkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ６ -C １０ -aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C ３ -C ８ -cycloalkyl; or R １ together with the carbon atom and X to which it is attached forms a 5- or 6-membered heterocyclyl which may be substituted; R ２ is H, optionally substituted C １ -C ６ alkyl, or halo; R ３ is optionally substituted C ３ -C ８ -cycloalkyl, optionally substituted C ３ -C ８ -cycloalkenyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -alkenyl, -NR ２ , -N(R)(optionally substituted C ３ -C ８ -cycloalkyl), -S-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ３ -C ８ -cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C ３ -C ８ -cycloalkyl); Or, R ３ together with the carbon atom and Y to which it is shown to be attached forms an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R ４ is H, C １ -C ６ alkyl, cyano, or halo; or R ４ forms, together with the carbon atom and Z to which it is attached, an optionally substituted 5- to 6-membered heteroaryl; or R ３ and R ４ together with the carbon atom to which they are attached form an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ４ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R ５ is H, C １ -C ６ alkyl, -NR ２ , or -N(R)-C(=O)-(C １ -C ６ alkyl); Each R is independently H or optionally substituted C １ -C ６ alkyl; V comprises an electrophile that reacts with the sulfur atom of cysteine 727 set forth in SEQ ID NO: 1 or a variant thereof to form a covalent bond]. **Claim 52** The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein the electrophile comprises at least one chemical moiety selected from the group consisting of vinyl sulfone, alkynyl sulfone, vinyl sulfonamide, vinyl sulfoxide, alkynyl sulfoxide, vinyl sulfoximine, alkynyl sulfoximine, acrylamide, acrylonitrile, alkynenitrile, enone, inone, enoate, and inoate. **Claim 53** Vinyl sulfone has the structure Alkynyl sulfone has the structure Vinyl sulfonamide has the structure Vinyl sulfoxide has the structure Alkynyl sulfoxide has the structure Vinyl sulfoximine has the structure Alkynyl sulfoximine has the structure Acrylamide has the formula Acrylonitrile has the structure Enone has the structure Inone has the structure Enoate has the structure Inoate has the structure Wherein: Represents a possible point of attachment of the chemical moiety to the remainder of the electrophile The compound according to claim 52, or a pharmaceutically acceptable salt thereof. **Claim 54** The compound according to any one of claims 51 to 53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive. **Claim 55** A method of treating a proliferative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 51 to 53, or a pharmaceutically acceptable salt thereof. **Claim 56** The method according to claim 55, wherein the proliferative disease is cancer. **Claim 57** The method according to claim 56, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer. **Claim 58** A modified WRN helicase protein comprising a non-naturally occurring small molecule fragment having a covalent bond to cysteine 727 of the WRN helicase protein, comprising SEQ ID NO: 1 or a variant thereof, and having the structure of formula (III): [Wherein, S is the sulfur atom of cysteine 727 of SEQ ID NO: 1 or a variant thereof; represent the amino acids at positions 1 to 726 and 728 to 1432 of SEQ ID NO: 1 or a variant thereof, respectively; Q is Q １ , Q ２ , Q ３ , Q ４ , or Q ５ ; Q １ is: wherein, R ６ is H; R ７ is H, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; R ７ａ is H or deuterium; R ８ is H; R ９ is H; R １０ is optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ８ cycloalkyl, or optionally substituted 5- to 6-membered heterocyclyl; or R ６ together with the nitrogen atom to which it is attached, and R ７ and R ７ａ together with the carbon atoms to which they are attached form an azetidinyl ring; or, R ６ is, together with the nitrogen atom to which it is attached, also R ７ , R ７ａ , and R ８ is, together with the carbon atom to which it is attached, form an azetidinyl or pyrrolidinyl ring; or R ６ together with the nitrogen atom to which it is attached, and R ７ R ７ａ R ８ R ９ together with the carbon atoms to which they are attached form a dihydropyrrolyl ring; Or, R ７ R ７ａ R ８ R ９ and R １０ together with the carbon atom to which they are attached form a 1,1-dioxide-2,3-dihydrothiophenyl ring; or R ８ , R ９ , and R １０ together with the carbon atom to which they are attached form a 1,1-dioxide-2H-thiopyranyl ring; Q ２ is: wherein, R １１ is H; R １２ is H or optionally substituted C １ -C ６ alkyl; R １２ａ is H; R １３ and R １４ are each H; or R １１ together with the nitrogen atom to which it is attached, and R １２ , R １２ａ , and R １３ together with the carbon atoms to which they are attached form an optionally substituted azetidinyl ring; Q ３ is: wherein, R １５ is H; R １６ is H or optionally substituted C １ -C ６ -alkyl, or optionally substituted C ３ -C ８ -cycloalkyl; Q ４ is: wherein, R １７ is H; R １８ is H or optionally substituted C １ -C ６ alkyl; Each R ａ is, independently, optionally substituted C １ -C ６ alkyl; Q ５ is: wherein, m is 1, 2, or 3; R １９ is selected from the group consisting of C １ -C ６ alkyl and -O-(C １ -C ６ alkyl); U is: wherein, X is CR ２ or N; Y is CR ４ or N; Z is CR ５ or N; alternatively, Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl; provided that X, Y, and Z are not simultaneously N; R １ is H, -O-(optionally substituted C ３ -C ８ -cycloalkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ６ -C １０ -aryl), -O-(optionally substituted 5- to 6-membered heteroaryl), -O-(optionally substituted 5- to 6-membered heterocyclyl), or optionally substituted C ３ -C ８ -cycloalkyl; or R １ together with the carbon atom and X to which it is attached forms an optionally substituted 5- to 6-membered heterocyclyl R ２ is H, optionally substituted C １ -C ６ alkyl, or halo; R ３ is optionally substituted C ３ -C ８ -cycloalkyl, optionally substituted C ３ -C ８ -cycloalkenyl, optionally substituted C ６ -C １０ -aryl, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -alkenyl, -NR ２ , -N(R)(optionally substituted C ３ -C ８ -cycloalkyl), -S-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C １ -C ６ -alkyl), -O-(optionally substituted C ３ -C ８ -cycloalkyl), optionally substituted 4- to 6-membered heterocyclyl or heterocyclenyl, optionally substituted 5- to 6-membered heteroaryl, or -O-(optionally substituted C ３ -C ８ -cycloalkyl); Or, R ３ together with the carbon atom and Y to which it is shown to be attached, forms an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R ４ is H, C １ -C ６ alkyl, cyano, halo, and or R ４ together with the nitrogen atom and Z to which it is attached forms a 5- or 6-membered heteroaryl which may be substituted; Or, R ３ and R ４ together with the carbon atom to which they are attached form an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ４ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl; R ５ is H, C １ -C ６ alkyl, -NR ２ , or -N(R)-C(=O)-(C １ -C ６ alkyl); Each R is independently H or optionally substituted C １ -C ６ alkyl]] a modified WRN helicase protein having

59. X is N; Y is N; Z is CR ５ wherein; alternatively, Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl, the modified WRN helicase protein according to claim 58.

60. X is CR ２ and; Y is CR ４ wherein; Z is CR ５ and; alternatively, Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heteroaryl; or R ３ together with the carbon atom and Y to which it is attached forms an optionally substituted C ３ -C ８ cycloalkyl or cycloalkenyl the modified WRN helicase protein according to claim 58.

61. X is CR ２ and; Y is N; Z is CR ５ and; or R １ together with the carbon atom and X to which it is attached forms a 5- or 6-membered heterocyclyl which may be substituted the modified WRN helicase protein according to claim 58.

62. X is N; Y is CR ４ and; Z is CR ５ and; or R ３ together with the carbon atom and Y to which it is attached forms an optionally substituted C ６ -C １０ -aryl, an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, or an optionally substituted 5- to 6-membered heterocyclyl or heterocyclenyl, the modified WRN helicase protein according to claim 58.

63. X is N; Y is CR ４ and Z is N, the modified WRN helicase protein according to claim 58.

64. X is CR ２ and; Y is CR ４ and; Z is N, the modified WRN helicase protein according to claim 58.

65. R １ wherein: -O-(optionally substituted C ３ -C ８ Any substituent of (cycloalkyl) is one to three substituents selected from the group consisting of halo, cyano, and hydroxy; or C ３ -C ８ When two substituents are present on the same ring carbon atom of cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C ３ -C ６ cycloalkyl; or C ３ -C ８ When two substituents are present on adjacent ring carbon atoms of cycloalkyl, the substituents, together with the ring carbon atom to which they are attached, form C ３ -C ６ cycloalkyl; -O-(optionally substituted C ６ -C １０ aryl) any substituent is halo, C １ -C ６ alkyl, cyano, hydroxy, and -NH ２ selected from the group consisting of 1 to 3 substituents or 1 to 5 deuterium atoms; or R １ when R is shown to be attached and together with the carbon atom and X forms an optionally substituted 5- to 6-membered heterocyclyl, two substituents on the same ring carbon atom of the 5- to 6-membered heterocyclyl together with the ring carbon atom to which they are attached form a 5- to 6-membered cycloalkyl; R ３ wherein: C which may be substituted ３ -C ８ Any substituent of the cycloalkyl is 1 to 3 substituents selected from hydroxy, halo, C １ -C ６ alkyl, and C ６ -C １０ aryl; or when there are two substituents on the same carbon atom of C ３ -C ８ cycloalkyl, the substituents together with the ring carbon atom to which they are attached form C ３ -C ６ cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of C ３ -C ８ cycloalkyl, the substituents together with the ring carbon atom to which they are attached form C ６ -C １０ aryl; or R ３ when taken together with the carbon atom and Y to which it is attached forms an optionally substituted C ３ -C ８ -cycloalkyl or cycloalkenyl, any substituent is one to three substituents selected from the group consisting of halo and C １ -C ６ -alkyl; or two geminal hydrogens on the ring carbon atoms of C ３ -C ８ -cycloalkyl or cycloalkenyl can be replaced by the group =O; or R ３ when the carbon atom to which it is attached and Y together form an optionally substituted 5- or 6-membered heterocyclyl or heteroarenyl, any substituent is selected from the group consisting of halo and C １ -C ６ alkyl and is one to three substituents; Optionally substituted C ６ -C １０ Any substituent of the aryl is 1 to 3 substituents selected from the group consisting of halo; C which may be substituted １ -C ６ alkyl or C ６ any substituent of alkenyl is 1 to 5 substituents selected from the group consisting of halo, hydroxy, -O-(C １ -C ６ alkyl), and optionally substituted C ３ -C ６ cycloalkyl; any substituent of C ３ -C ６ cycloalkyl is 1 to 3 substituents selected from the group consisting of C １ -C ６ alkyl; -NR ２ wherein R of １ -C ６ any substituent of the alkyl is 1 to 3 substituents selected from the group consisting of halo; Any substituent of the optionally substituted 4- to 6-membered heterocyclyl may be -O-(C １ -C ６ alkyl), C １ -C ６ alkyl, halo; or when two substituents are present on the same carbon atom of the optionally substituted 4- to 6-membered heterocyclyl, the substituents, together with the ring carbon atom to which they are attached, form C ３ -C ６ cycloalkyl, the modified WRN helicase protein according to any one of claims 58 to 64.

66. R １ together with the carbon atom to which it is attached forms an optionally substituted 5- to 6-membered heterocyclyl, In the formula, the double bond shown is between the carbon having the R １ group and X; R ３ a carbon atom to which it is attached and an optionally substituted C formed together with Y ６ -C １０ wherein aryl is R ３ A 5- or 6-membered optionally substituted heterocyclenyl formed together with the carbon atom to which it is attached and Y, wherein the heterocyclenyl is shown to be bonded thereto, wherein, The indicated carbon-carbon double bond between two carbons having it is the one between the carbon having the R ３ group and Y; R ３ When R, together with the carbon atom and Y to which it is attached, forms an optionally substituted C ３ -C ８ -cycloalkyl or -cycloalkenyl, the optionally substituted C ３ -C ８ -cycloalkyl or -cycloalkenyl is In the formula, the carbon-carbon double bond shown is between the carbon having the R ３ group and Y; R ４ A optionally substituted 5- or 6-membered heteroaryl formed together with the carbon atom to which it is attached and Z, provided that it is shown to be attached, in each structure, the modified WRN helicase protein according to any one of claims 58 to 65.

67. R １ wherein: -O-(optionally substituted C ３ -C ８ ycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexan-5-yl), -O-(spiro[3.3]heptan-2-yl), -O-(3-chloro cyclobutyl), -O-(bicyclo[3.1.0]hexan-3-yl), -O-(bicyclo[2.2.1]heptan-1-yl), -O-(1-cyanocyclopentanyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl), or -O-(2,2-difluorocyclopentyl), and -O-(optionally substituted C １ -C ６ alkyl) is ethoxy, isopropoxy, or cyclopropylmethyloxy; -O-(optionally substituted C ６ -C １０ aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalen-1-oxy, or phenoxy-d5; -O-(optionally substituted 5- to 6-membered heteroaryl) is pyridin-2-yloxy or pyridin-3-yloxy; -O-(optionally substituted 5- to 6-membered heterocyclyl) is -O-tetrahydro-2H-pyran-4-yl or -O-tetrahydro-2H-pyran-3-yl; C which may be replaced ３ -C ８ The cycloalkyl is cyclohexyl; R ２ wherein: Optionally substituted C １ -C ６ the alkyl is methyl; R ３ wherein: C which may be replaced ３ -C ８ The cycloalkyl is cyclopentyl, cyclobutyl, cyclohexyl, cyclopropyl, hydroxycyclopentyl, fluorocyclopentyl, methylcyclobutyl, methylcyclopropyl, phenylcyclopropyl, methylcyclopentyl, difluorocyclobutyl, fluorocyclopentyl, bicyclo[4.2.0]octa-1,3,5-trien-7-yl, or (trifluoromethyl)cyclopropyl, or spiro[2.3]hexan-5-yl; C which may be replaced ３ -C ８ The cycloalkenyl is cyclopentenyl; Optionally substituted C ６ -C １０ aryl is phenyl; Optionally substituted C １ -C ６ The alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl, or cyclopropyldifluoromethyl; C which may be replaced １ -C ６ the alkenyl is 2-methylprop-1-en-1-yl; NR ２ is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl) ２ , or -N(methyl)(trifluoroethyl); -N(R)(optionally substituted C ３ -C ８ -cycloalkyl) is N(methyl)(cyclopropyl); -S-(optionally substituted C １ -C ６ -alkyl) is methylthiol; -O-(optionally substituted C １ -C ６ alkyl) is trifluoroethoxy or methoxy; -O-(optionally substituted C ３ -C ８ ycloalkyl) is cyclopentyloxy or cyclopropyloxy; The 4- to 6-membered heterocyclyl or heterocyclenyl which may be substituted is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptan-7-yl, bicyclo[1.1.1]pentan-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptan-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H-pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl, or 3,3-difluoro-azetidin-1-yl; R ５ wherein: C １ -C ６ The alkyl is methyl; -NR ２ is -NH ２ and; -N(R)-C(=O)-(C １ -C ６ -alkyl) is -N(H)-C(=O)-CH ３ is, A modified WRN helicase protein according to any one of claims 58 to 66.

68. Q is Q １ The modified WRN helicase protein according to any one of claims 58 to 67, wherein Q is Q

69. R ７ optionally substituted C １ -C ６ alkyl is methyl, ethyl, isopropyl, methoxymethyl, cyclopropylmethyl, cyclopropyloxymethyl, tolyl, -CH(CH ３ )-OCH ３ , difluoroethyl, phenoxymethyl, -CH ２ -C(=O)-N(CH ３ ) ２ , or tert-butoxymethyl, difluoromethoxymethyl; R ７ Optionally substituted C ３ -C ８ The cycloalkyl is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH ２ -S-CH ３ , difluorocyclohexyl; R ７ The optionally substituted 5- to 6-membered heterocyclyl is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; R １０ Optionally substituted C １ -C ６ wherein the alkyl is methyl; R １０ optionally substituted C ３ -C ８ the cycloalkyl is cyclopropyl; R １０ The 5- to 6-membered heterocyclyl which may be substituted is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; Or, Q １ is: Wherein, in each structure, A modified WRN helicase protein according to claim 58.

70. Q is Q ２ The modified WRN helicase protein according to any one of claims 58 to 67, wherein Q is Q

71. Q ２ is wherein, R ２１ is H or C １ -C ６ alkyl; A modified WRN helicase protein according to claim 70.

72. Q is Q ３ The modified WRN helicase protein according to any one of claims 58 to 67, wherein Q is Q.

73. R １６ optionally substituted C １ -C ６ wherein the alkyl is methyl; R １６ optionally substituted C ３ -C ８ wherein the cycloalkyl is cyclopropyl A modified WRN helicase protein according to claim 72.

74. Q is Q ４ The modified WRN helicase protein according to any one of claims 58 to 67, wherein Q is Q.

75. R １８ optionally substituted C １ -C ６ alkyl is methyl; Optionally substituted C １ -C ６ wherein the alkyl is methyl A modified WRN helicase protein according to claim 74.

76. Q is Q ５ The modified WRN helicase protein according to any one of claims 58 to 67, wherein Q is Q

77. R １９ of C １ -C ６ the alkyl is methyl; R １９ in which -O-(C １ -C ６ -alkyl) is methoxy, A modified WRN helicase protein according to claim 76.

78. A compound according to any one of claims 1 to 42 and 51 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disorder.

79. A compound according to claim 78, or a pharmaceutically acceptable salt thereof, for use, wherein the proliferative disorder is cancer.

80. A compound according to claim 79, or a pharmaceutically acceptable salt thereof, for use, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

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