Pharmaceutical compositions comprising WRN helicase inhibitors

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] This invention relates to compounds that are inhibitors of Werner syndrome helicase (WRN helicase), pharmaceutical compositions containing such inhibitors, and methods of treatment using such inhibitors. [0001.1] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy, created on August 23, 2023, is named 036844-109326_P38040_SL.xml and is 8,062 bytes in size. [Background technology]

[0002] RECQ helicases are DNA-dependent ATPases that unwind DNA from 3' to 5'. Altered or absent expression of three RECQ helicases, BLM, Werner (WRN), and RECQL4, causes overlapping yet distinct human syndromes (de Renty C, Ellis N A. Ageing Res Rev 2017;33:36-51). In 2019, multiple groups independently identified WRN as a potential synthetic lethal target for cancers expressing high levels of microsatellite instability (MSI-H cancers) (Chan, EM et al., Nature 2019, 568, 551-556; Behan, FM et al., Nature 2019, 568, 511-516; Lieb et al. eLife 2019, 8, e43333). Several reports have described the identification of small molecules that inhibit WRN helicase activity through 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 novel inhibitors of WRN helicase for the treatment of MSI-H cancers. Summary of the Invention

[0004] Some embodiments described herein include a compound of formula (I): TIFF0007818138000001.tif38170 or a pharmaceutically acceptable salt or solvate thereof [In the formula, 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 10 aryl), -O-(optionally substituted 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- or 6-membered heterocyclyl. R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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, 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or R 4 taken together with the carbon atom to which it is shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4 are optionally substituted C6-C, together with the carbon atoms to which they are shown attached. 10 forms an aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an 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 for W 1 , W 2 , W 3 , W 4 , or W 5 and; W 1teeth: TIFF0007818138000002.tif32170In formula, TIFF0007818138000003.tif24170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000004.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5-6 membered heterocyclyl; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 and R 7a together with the carbon atoms to which they are shown attached form an azetidinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , and R 8 together with the carbon atoms to which they are shown attached form an azetidinyl or pyrrolodinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , R 8 , and R 9 together with the carbon atoms to which they are shown attached to form a dihydropyrrolyl ring; Or R 7, R 7a , R 8 , R 9 , and R 10 taken together with the carbon atoms to which they are shown attached form a 2,3-dihydrothiophene 1,1-dioxide ring; or R 8 , R 9 , and R 10 together with the carbon atoms to which they are shown attached to form a 1,1-dioxido-2H-thiethyl ring; W 2 teeth: TIFF0007818138000005.tif32170In formula, TIFF0007818138000006.tif26170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000007.tif10170R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are H, respectively; Or R 11 together with the nitrogen atom to which it is shown attached, and R 12 , R 12a , and R 13 taken together with the carbon atoms to which they are shown attached form an optionally substituted azetidinyl ring; W 3 teeth: TIFF0007818138000008.tif32170In formula, TIFF0007818138000009.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W4 teeth: TIFF0007818138000010.tif43170In formula, TIFF0007818138000011.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; Each R a are independently optionally substituted C1-C6 alkyl; W 5 teeth: TIFF0007818138000012.tif22170In formula, TIFF0007818138000013.tif22170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000014.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and —O—(C1-C6 alkyl)] Regarding.

[0005] Some embodiments described herein include a compound of formula (II): TIFF0007818138000015.tif38170 or a pharmaceutically acceptable salt or solvate thereof [In the formula, 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 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 taken together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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); Or R 3 together with the carbon atom to which it is attached and Y, 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or R 4 taken together with the carbon atom to which they are shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4 are optionally substituted C6-C, together with the carbon atoms to which they are shown attached. 10 forms an aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an 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; 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. Regarding.

[0006]

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

[0007]

[0007] Some embodiments described herein also provide a method for treating a disease (such as a proliferative disease, e.g., cancer) in a patient, 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 the embodiments thereof described herein), and / or a pharmaceutically acceptable salt thereof.

[0008]

[0008] Some embodiments described herein also provide 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 of formula (I) or formula (II) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt or solvate thereof.

[0009]

[0009] Some embodiments described herein also provide a method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase), comprising effecting 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 electrophile and cysteine ​​727 as set forth in SEQ ID NO: 1 or a variant thereof, and the sulfur atom of the cysteine ​​residue undergoes reaction with the electrophile.

[0010] Some embodiments described herein also provide a modified WRN helicase protein comprising a non-naturally occurring small molecule fragment having a covalent bond to cysteine ​​727 of a WRN helicase protein, the small molecule fragment comprising SEQ ID NO:1 or a variant thereof as described herein, and having the structure of formula (III): TIFF0007818138000016.tif66170[In formula: S is the sulfur atom of cysteine ​​727 of SEQ ID NO: 1 or a variant thereof; TIFF0007818138000017.tif8170 representing amino acid positions 1 to 726 and 7288 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 and; Q 1 teeth: TIFF0007818138000018.tif31170In formula, TIFF0007818138000019.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5-6 membered heterocyclyl; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 and R 7a together with the carbon atoms to which they are shown attached form an azetidinyl ring; Or R 6 together with the carbon atom to which they are shown attached, and R 7 , R 7a , and R 8 together with the carbon atoms to which they are shown attached form an azetidinyl or pyrrolodinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , R 8 , and R 9 together with the carbon atoms to which they are shown attached to 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 shown attached to form 2,3-dihydrothiophene 1,1-dioxide; Or R 8 , R 9 , and R 10 together with the carbon atoms to which they are shown attached to form a 1,1-dioxido-2H-thienyl ring; Q 2 teeth: TIFF0007818138000020.tif28170In formula, TIFF0007818138000021.tif10170R 11is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are H, respectively; Or R 11 together with the nitrogen atom to which it is shown attached, and R 12 , R 12a , and R 13 taken together with the carbon atoms to which they are shown attached form an optionally substituted azetidinyl ring; Q 3 teeth: TIFF0007818138000022.tif34170In formula, TIFF0007818138000023.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; Q 4 teeth: TIFF0007818138000024.tif35170In formula, TIFF0007818138000025.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; Each R a are independently optionally substituted C1-C6 alkyl; Q 5 teeth: TIFF0007818138000026.tif26170In formula, TIFF0007818138000027.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and —O—(C1-C6 alkyl); U: TIFF0007818138000028.tif33170In formula, TIFF0007818138000029.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 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 taken together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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, 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or R 4 taken together with the carbon atom to which it is shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4 are optionally substituted C6-C, together with the carbon atoms to which they are shown attached. 10 forms an aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an 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 an optionally substituted C1-C6 alkyl. The present invention provides a modified WRN helicase protein having the following structure:

[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, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications 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 restrictive.

[0012] Incorporation by Reference

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over such conflicting material. DETAILED DESCRIPTION OF THE INVENTION

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

[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. Therefore, the terms "a" (or "an"), "one or more," or "at least one" can be used interchangeably herein.

[0015]

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

[0016]

[0016] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" (or "C1-C6 alkyl") means 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] "Alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1-20 In some embodiments, the alkyl group has 1 to 15 carbon atoms ("C 1-15 In some embodiments, the alkyl group has 1 to 14 carbon atoms ("C 1-14 In some embodiments, the alkyl group has 1 to 13 carbon atoms ("C 1-13 In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, the alkyl group has 1 to 11 carbon atoms ("C 1-11 In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 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-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like.

[0018] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (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. 2-6 Examples of alkenyl groups include those listed above. 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0019] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 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 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 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. 2-6 Examples of alkenyl groups are C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc.

[0020] "Carbocyclyl," "cycloalkyl," or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 Carbocyclyl groups include, but are not limited to, those listed above. 3-6 Included are carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, those listed above for C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples illustrate, in certain embodiments, carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as bicyclic systems ("bicyclic carbocyclyl") or tricyclic systems ("tricyclic carbocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, the points of attachment being on the carbocyclyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system.

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

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

[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 independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), saturated, or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, the points of attachment being on either the carbocyclyl ring or the heterocyclyl ring, or to one or more aryl or heteroaryl groups, the points of attachment being on the heterocyclyl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.

[0024] In some embodiments, a 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, a 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, a 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, a 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]

[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 pyrrolyl-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] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an 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, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system.

[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 (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur) provided to the aromatic ring system ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. The term "heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the 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 to 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 to 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 to 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, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, 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] "Saturated" refers to a ring moiety that does not contain any double or triple bonds, ie, the ring contains all single bonds.

[0031] Alkyl, alkenyl, cycloalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups can be optionally substituted. "Optionally substituted" refers to a group that can be substituted or unsubstituted. Typically, the term "substituted" means that at least one hydrogen present on the group is replaced with a non-hydrogen substituent, and the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfur can have hydrogen and / or non-hydrogen substituents that satisfy the valence of the heteroatom and form a stable compound.

[0032] Exemplary non-hydrogen substituents are halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —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, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or two geminal hydrogens on the carbon atom are replaced by =O groups;

[0033] R aa Each instance of 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-14 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0034] R bb Each instance of 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 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0035] R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-14 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0036] R dd Each example 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 Carbocyclyl, C 6-10aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; or two geminal R on a carbon atom dd The substituents may be joined to form =O.

[0033]

[0037] In a preferred embodiment, the optional substituents are 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 In a more preferred embodiment, the optional substituents are selected from the group consisting of fluoro, chloro, trifluoromethyl, cyano, hydroxyl, amino, deutorio, methoxy, methyl, ethyl, phenyl, oxo, methylsulfanyl, dimethylamino, phenoxy, tert-butoxy, cyclopropoxy, difluoromethoxy, cyclopropyl, and cyclohexyl. In a preferred embodiment, the optional substituents are selected from the group consisting of fluoro, trifluoromethyl, hydroxyl, deutorio, methyl, phenyl, and cyclopropyl.

[0034]

[0038] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or an element (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 an 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: In TIFF0007818138000030.tif21170, carbons 2 and 5 do not have -OH directly bonded to them.

[0036]

[0040] Also, for example, the site: It should also be noted that tautomeric forms such as TIFF0007818138000031.tif18170 are considered equivalent unless otherwise specified.

[0037]

[0041] As used herein, the term "composition" is intended to encompass not only a product containing the specified ingredients in the specified amounts, but also any product that results directly or indirectly 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 often participate in Michael addition reactions, in which a nucleophile adds to an α,β-unsaturated carbonyl compound containing an electron-withdrawing group. This reaction belongs to the 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, resulting in the formation of a new covalent bond between a portion of the Michael acceptor moiety and a donor moiety. The Michael acceptor moiety is the electrophile, and the "donor moiety" is the nucleophile.

[0039]

[0043] "Effective amount" or "therapeutically effective amount" is meant to describe an amount of a compound or composition described herein that is effective to inhibit the enzyme, disease, or condition described above, and thus results in the desired therapeutic, ameliorative, inhibitory, and / or preventative effect.

[0040]

[0044] The term "salt" includes any salt. A "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of 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, lanthanide, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and ammonium salts. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0041]

[0045] "Solvate" includes all solvates. As used herein, the term "pharmaceutically acceptable solvate" refers to 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 (where 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 a repeat unit, resulting in a novel length allele in tumor DNA when compared with normal / germline DNA from the same individual. Tumors with an "MSI-High" (MSI-H) phenotype are tumors that have DNA sequence length alterations in at least two evaluated mononucleotide or dinucleotide microsatellite loci (e.g., BAT25, BAT26, D2S123, D5S346, and D175250). Methods for identifying MSI-H tumor status are well known in the art and include, for example, polymerase chain reaction (PCR) testing for MSI status. Mononucleotide or dinucleotide markers used to characterize MSI status 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 therefore may exist in various stereoisomeric forms, e.g., 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, asymmetric carbon atoms (chiral carbon atoms) may 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 may be in the form of mixtures of various isomers.

[0044]

[0048] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium; 19 F 18 F, replacing carbon 13 C or 14 Replacing C-enriched carbon and / or oxygen atoms 18 Compounds having the present structures except for the replacement with O 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 with such isotopically enriched atoms are useful, for example, as analytical tools and probes in biological assays.

[0045] Certain isotopically labeled compounds of formula (I) (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays.3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically labeled compounds of formula (I) may be useful for medical imaging purposes. For example, 11 C or 18 Those labeled with positron-emitting isotopes such as F may be useful for positron emission tomography (PET) applications, 123 Those labeled with gamma-ray-emitting isotopes such as I may be useful for single-photon emission computed tomography (SPECT) applications. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. Furthermore, isotope substitution at sites where epimerization occurs may slow or reduce the epimerization process, thereby retaining a more active or potent form of the compound for a longer period of time. Isotopically labeled compounds of formula (I), particularly those with longer half-lives (t 1 / 2 Compounds containing isotopes with a .alpha.-methyl group (>1 day) can generally be prepared by substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent following procedures similar to those disclosed in the following schemes and / or examples herein.

[0046]

[0050] The present invention provides a series of potent and selective WRN inhibitors that engage cysteine ​​727 (C727) of WRN through irreversible covalent attachment of an electrophilic group. In one embodiment, these inhibitors exhibit potent helicase inhibition, reducing viability exclusively in MSI cell lines but not in MSS cell lines, and completely inhibiting tumor growth in xenograft mouse models of MSI cell lines. In one embodiment, the ATP cooperativity of these inhibitors (enhanced potency in the presence of ATP or ADP; i.e., cellular assays or lysates supplemented with ATP) is a surprising and unexpected feature of these compounds.

[0047]

[0051] The compounds described herein can 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 are methods 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. The administration can be in vivo. For example, WRN helicase can be inhibited in vivo. The administration can be to a subject. The administration can be to a cell. The administration can be in vitro. For example, WRN helicase can be inhibited in vitro.

[0049]

[0053] Disclosed herein, in some embodiments, are methods for performing a WRN helicase activity assay. Some embodiments include methods for measuring WRN helicase activity. The method can include contacting a WRN helicase with a WRN helicase substrate. The method can include administering a WRN helicase substrate. The method can include contacting a WRN helicase with ATP. The method can include administering ATP. The method can include administering a WRN helicase substrate and ATP. The method can include contacting a WRN helicase with ADP. The method can include administering ADP. The method can include administering a WRN helicase substrate and ADP. The administering can be in vivo. For example, the WRN helicase activity assay can be performed in cultured cells. The administering can be to a cell. The administering 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] Implementation

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

[0055] Embodiment 1

[0056] Compounds of formula (I): TIFF0007818138000032.tif38170 or a pharmaceutically acceptable salt or solvate thereof [In the formula, 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 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 taken together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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); Or R 3 together with the carbon atom to which it is attached and Y, 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or R 4 taken together with the carbon atom to which it is shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4 are optionally substituted C6-C, together with the carbon atoms to which they are shown attached. 10 forms an aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an 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 for W 1 , W 2 , W 3 , W 4 , or W 5 and; W 1 teeth: TIFF0007818138000033.tif32170In formula, TIFF0007818138000034.tif24170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000035.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5-6 membered heterocyclyl; or R 6 together with the nitrogen atom to which it is shown bonded, and R 7and R 7a together with the carbon atoms to which they are shown attached form an azetidinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , and R 8 together with the carbon atoms to which they are shown attached form an azetidinyl or pyrrolodinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , R 8 , and R 9 taken together with the carbon atoms to which they are shown 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 shown attached to form 2,3-dihydrothiophene 1,1-dioxide; or R 8 , R 9 , and R 10 together with the carbon atoms to which they are shown attached to form a 1,1-dioxido-2H-thiethyl ring; W 2 teeth: TIFF0007818138000036.tif32170In formula, TIFF0007818138000037.tif26170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000038.tif10170R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R14 are H, respectively; Or R 11 together with the nitrogen atom to which it is shown attached, and R 12 , R 12a , and R 13 taken together with the carbon atoms to which they are shown attached form an optionally substituted azetidinyl ring; W 3 teeth: TIFF0007818138000039.tif32170In formula, TIFF0007818138000040.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W 4 teeth: TIFF0007818138000041.tif43170In formula, TIFF0007818138000042.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; Each R a are independently optionally substituted C1-C6 alkyl; W 5 teeth: TIFF0007818138000043.tif22170In formula, TIFF0007818138000044.tif22170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000045.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] Compounds of formula (I): TIFF0007818138000046.tif38170 or a pharmaceutically acceptable salt thereof [In the formula, 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 10 aryl), -O-(optionally substituted 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 taken together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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, 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or R 4 taken together with the carbon atom to which it is shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4 are optionally substituted C6-C, together with the carbon atoms to which they are shown attached. 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 for W 1 , W 2 , W 3 , W 4 , or W 5 and; W 1 teeth,: TIFF0007818138000047.tif32170In formula, TIFF0007818138000048.tif24170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000049.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5-6 membered heterocyclyl; or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 and R 7a together with the carbon atoms to which they are shown attached form an azetidinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , and R 8 together with the carbon atoms to which they are shown attached form an azetidinyl or pyrrolodinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , R 8 , and R 9 taken together with the carbon atoms to which they are shown 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 shown attached to form 2,3-dihydrothiophene 1,1-dioxide; Or R 8 , R 9 , and R 10 together with the carbon atoms to which they are shown attached to form a 1,1-dioxido-2H-thiethyl ring; W 2 teeth: TIFF0007818138000050.tif32170In formula, TIFF0007818138000051.tif26170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000052.tif10170R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are H, respectively; Or R 11 together with the nitrogen atom to which it is shown attached, and R 12 , R 12a , and R 13 taken together with the carbon atoms to which they are shown attached form an optionally substituted azetidinyl ring; W 3 teeth: TIFF0007818138000053.tif32170In formula, TIFF0007818138000054.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W 4teeth: TIFF0007818138000055.tif43170In formula, TIFF0007818138000056.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; Each R a are independently optionally substituted C1-C6 alkyl; W 5 teeth: TIFF0007818138000057.tif22170In formula, TIFF0007818138000058.tif22170 indicates that it can exist as either the (Z)- or (E)-geometric isomer, TIFF0007818138000059.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] Compounds of formula (I): TIFF0007818138000060.tif38170[In the formula, 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 10aryl), -O-(optionally substituted 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 taken together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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); Or R 3 together with the carbon atom to which it is attached and Y, 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or R 4 taken together with the carbon atom to which it is shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4are optionally substituted C6-C, together with the carbon atoms to which they are shown attached. 10 forming an aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an 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 for W 1 , W 2 , W 3 , W 4 , or W 5 and; W 1 teeth: TIFF0007818138000061.tif32170In formula, TIFF0007818138000062.tif24170 indicates that it can exist as either the (Z)- or (E)-geometric isomer, TIFF0007818138000063.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5-6 membered heterocyclyl; or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 and R 7atogether with the carbon atoms to which they are shown attached form an azetidinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , and R 8 together with the carbon atoms to which they are shown attached form an azetidinyl or pyrrolodinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , R 8 , and R 9 taken together with the carbon atoms to which they are shown 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 shown attached to form 2,3-dihydrothiophene 1,1-dioxide; Or R 8 , R 9 , and R 10 together with the carbon atoms to which they are shown attached to form a 1,1-dioxido-2H-thiethyl ring; W 2 teeth: TIFF0007818138000064.tif32170In formula, TIFF0007818138000065.tif26170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000066.tif10170R 11 is H; R 12 is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14are H, respectively; Or R 11 together with the nitrogen atom to which it is shown attached, and R 12 , R 12a , and R 13 taken together with the carbon atoms to which they are shown attached form an optionally substituted azetidinyl ring; W 3 teeth: TIFF0007818138000067.tif32170In formula, TIFF0007818138000068.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; W 4 teeth: TIFF0007818138000069.tif43170In formula, TIFF0007818138000070.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; Each R a are independently optionally substituted C1-C6 alkyl; W 5 teeth: TIFF0007818138000071.tif22170In formula, TIFF0007818138000072.tif22170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000073.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 and; or Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl; 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0054]

[0064] In other words, X is N, Y is N, and Z is CR 5 then formula (I) corresponds to formula (IA): TIFF0007818138000074.tif38170, R 1 , R 3 , R 5 and W is as defined for formula (I).

[0055]

[0065] Embodiment 2.1

[0066] 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 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); 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 and; W 1 but: TIFF0007818138000075.tif32170In formula, TIFF0007818138000076.tif24170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000077.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5- to 6-membered heterocyclyl; 2. A 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 but: TIFF0007818138000078.tif32170In formula, TIFF0007818138000079.tif24170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000080.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5- to 6-membered heterocyclyl; 2. A 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 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 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); 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 but: TIFF0007818138000081.tif32170In formula, TIFF0007818138000082.tif24170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000083.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5- to 6-membered heterocyclyl; 2. The compound of embodiment 1.

[0058]

[0071] Embodiment 2.2

[0072] R 1 -O-(C6-C 10 aryl); R 3 is a 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; A compound according to embodiment 2.1, or a pharmaceutically acceptable salt or solvate thereof.

[0059]

[0073] Embodiment 2.2A

[0074] R 1 -O-(C6-C 10 aryl); R 3 is a 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; A compound according to embodiment 2.1, or a pharmaceutically acceptable salt thereof.

[0060]

[0075] Embodiment 2.2B

[0076] R 1-O-(C6-C 10 aryl); R 3 is a 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 and; Y is CR 4 and; Z is CR 5 and; 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 taken together with the carbon atom to which it is shown attached and Y form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl; 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0062]

[0079] In other words, X is CR 2 and Y is CR 4 and Z is CR 5 then formula (I) corresponds to formula (IB): TIFF0007818138000084.tif49170, 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 and; Y is N; Z is CR 5 and; Or R 1 taken together with the carbon atom to which it is shown attached and X form an optionally substituted 5- to 6-membered heterocyclyl; 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0064]

[0082] In other words, X is CR 2 and Y is N and Z is CR 5 then formula (I) corresponds to formula (IC): TIFF0007818138000085.tif38170, R 1 , R 2 , R 3 , R 5 and W are as defined for formula (I).

[0065]

[0083] Embodiment 5

[0084] 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof. X is N; Y is CR 4 and; Z is CR 5 and; Or R 3 together with the carbon atom to which it is shown attached and Y, an optionally substituted C6-C 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an 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 then formula (I) corresponds to formula (ID): TIFF0007818138000086.tif49170, 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, 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0068]

[0088] In other words, X is N and Y is CR 4 and when Z is N, formula (I) is formula (IE): TIFF0007818138000087.tif49170, 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, 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof.

[0070]

[0091] In other words, X is CR 2 and Y is CR 4 and when Z is N, formula (I) is formula (IF): TIFF0007818138000088.tif49170, R 1 , R2 , R 3 , R 4 and W are as defined for formula (I).

[0071]

[0092] EMBODIMENT 8

[0093] 8. A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof,

[0094] R 1 In:

[0095] The optional substituents of -O-(optionally substituted C3-C8 cycloalkyl) are 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 a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl;

[0096] -O-(optionally substituted C6-C 10 aryl), the optional substituents are 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 R 1 taken together with the carbon atom to which it is shown attached and X to form an optionally substituted 5- to 6-membered heterocyclyl, then two substituents on the same ring carbon atom of the 5- to 6-membered heterocyclyl taken together with the carbon atom to which they are attached form a 5- to 6-membered cycloalkyl;

[0098] R 3 In:

[0099] The optional substituents of the optionally substituted C3-C8 cycloalkyl are hydroxy, halo, C1-C6 alkyl, and C6-C 10aryl; or when two substituents are present on the same carbon atom of a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C6-C 10 Forming aryl;

[0100] Or R 3 taken together with the carbon atom to which it is shown attached and Y to form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the optional substituents are 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl; or two geminal hydrogens on ring carbon atoms of the C3-C8 cycloalkyl or cycloalkenyl may be replaced by groups =O;

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

[0102] Optionally substituted C6-C 10 The optional substituents on the aryl are 1 to 3 substituents selected from the group consisting of halo;

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

[0104] -NR2 R C1-C6 alkyl optional substituents are 1 to 3 substituents selected from the group consisting of halo;

[0105] The optional substituents of the optionally substituted 4-6-membered heterocyclyl are 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 4-6-membered heterocyclyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl. The compound, or a pharmaceutically acceptable salt or solvate thereof.

[0072]

[0106] EMBODIMENT 9

[0107] 9. A compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt or solvate thereof,

[0108] R 1 together with the carbon atom to which it is shown attached to form an optionally substituted 5- or 6-membered heterocyclyl. TIFF0007818138000089.tif37170The double bond shown is R 1 between the carbon bearing the group and X;

[0109] R 3 is taken together with the carbon atom to which it is shown attached and Y to form an optionally substituted C6-C 10 Aryl is TIFF0007818138000090.tif29170

[0110] R 3 is taken together with the carbon atom to which it is shown to be attached and Y to form an optionally substituted 5- to 6-membered heterocyclenyl, TIFF0007818138000091.tif29170The carbon-carbon double bond shown between the two carbons is R 3 between the carbon bearing the group and Y;

[0111] R 3taken together with the carbon atom to which it is shown attached and Y to form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl is TIFF0007818138000092.tif33170In the formula, the carbon-carbon double bond shown is R 3 between the carbon bearing the group and Y;

[0112] R 4 is taken together with the carbon atom to which it is shown attached and Z to form an optionally substituted 5- to 6-membered heteroaryl, TIFF0007818138000093.tif29170 compound, or a pharmaceutically acceptable salt or solvate thereof.

[0073]

[0113] EMBODIMENT 10

[0114] 10. A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt or solvate thereof,

[0115] R 1 In:

[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-chloro(chrloro)cyclobutyl), -O-(bicyclo[3.1.0]hexane-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(chloro)-5-fluorophenoxy, 3-aminophenoxy, naphthalen-1-oxy, 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] The optionally substituted C3-C8 cycloalkyl is cyclohexyl;

[0122] R 2 In:

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

[0124] R 3 In:

[0125] Optionally substituted C3-C8 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;

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

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

[0128] optionally substituted C1-C6 alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropanyl, fluoro(fluro)propanyl, methoxypropanyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl, or cyclopropyldifluoromethyl;

[0129] 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] The 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, methoxyazetadin-1-yl, 2-azaspiro[3.3]heptan-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydropyranyl, tetrahydrofuran-1-yl, tetrahydro-2H-pyran-4-yl, di ...-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl 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 In:

[0137] C1-C6 alkyl is methyl;

[0138] -NR2 is -NH2;

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

[0074]

[0140] EMBODIMENT 11

[0141] W is W 1 That is, W is TIFF0007818138000094.tif26170, R 6 , R 7 , R 7a , R 8 , R 9 , and R 10 is as defined in embodiment 1; TIFF0007818138000095.tif24170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000096.tif10170A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof.

[0075]

[0142] EMBODIMENT 12

[0143] 12. A compound according to embodiment 11, or a pharmaceutically acceptable salt or solvate thereof,

[0144] R 7 wherein the optionally substituted C1-C6 alkyl 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 The optionally substituted C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, difluorocyclohexyl;

[0146] R 7 The optionally substituted 5- to 6-membered heterocyclyl is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[0147] R 10 wherein the optionally substituted C1-C6 alkyl is methyl;

[0148] R 10 wherein the optionally substituted C3-C8 cycloalkyl is cyclopropyl;

[0149] R 10 wherein the optionally substituted 5- to 6-membered heterocyclyl is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[0150] Or W 1 but: TIFF0007818138000097.tif51170 compound, or a pharmaceutically acceptable salt or solvate thereof.

[0076]

[0151] EMBODIMENT 13

[0152] 11. A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, W is W 2 That is, W is TIFF0007818138000098.tif32170In formula, TIFF0007818138000099.tif26170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000100.tif10170R 11 , R 12 , R 12a , R 13 , and R 14 is as defined in embodiment 1. The compound, or a pharmaceutically acceptable salt or solvate thereof.

[0077]

[0153] EMBODIMENT 14

[0154] 14. A compound according to embodiment 13, or a pharmaceutically acceptable salt or solvate thereof, W 2 but: TIFF0007818138000101.tif31170In formula, R 21 is H or C1-C6 alkyl; TIFF0007818138000102.tif31170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000103.tif10170 compound, or a pharmaceutically acceptable salt or solvate thereof.

[0078]

[0155] EMBODIMENT 15

[0156] 11. A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, W is W 3 That is, W is TIFF0007818138000104.tif32170In formula, TIFF0007818138000105.tif10170R 15 and R 16 is as defined in embodiment 1. The compound, or a pharmaceutically acceptable salt or solvate thereof.

[0079]

[0157] EMBODIMENT 16

[0158] 16. A compound according to embodiment 15, or a pharmaceutically acceptable salt or solvate thereof,

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

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

[0080]

[0161] EMBODIMENT 17

[0162] 11. A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, W is W 4 That is, W is TIFF0007818138000106.tif43170In formula, TIFF0007818138000107.tif10170R 17 , R 18 , and R a is as defined in embodiment 1. The compound, or a pharmaceutically acceptable salt or solvate thereof.

[0081]

[0163] EMBODIMENT 18

[0164] 18. A compound according to embodiment 17, or a pharmaceutically acceptable salt or solvate thereof,

[0165] R 18 wherein 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] 11. A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, W is W 5 That is, W is TIFF0007818138000108.tif22170In formula, TIFF0007818138000109.tif22170 indicates that it can exist as either the (Z)- or (E)- geometric isomer, TIFF0007818138000110.tif10170m and R 19 is as defined in embodiment 1. The compound, or a pharmaceutically acceptable salt or solvate thereof.

[0083]

[0169] EMBODIMENT 20

[0170] 20. The compound of embodiment 19, or a pharmaceutically acceptable salt or solvate thereof.

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

[0172] R 19 -O-(C1-C6 alkyl) is methoxy;

[0084]

[0173] EMBODIMENT 21

[0174] 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; 2-Cyclopropyl-N-((1,1-dioxido-2H-thiet-3-yl)methyl)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-N-(1,1-dioxide-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)pent-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)pent-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)pent-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)pent-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)pent-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)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(5,5-difluoro-1-(methylsulfonyl)pent-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)pent-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 13. The 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] 22. The compound of embodiment 21, or a pharmaceutically acceptable salt or solvate thereof, wherein when the R or S stereochemical configuration at one or more chiral carbons is designated, the compound comprises a mixture of the R or S configuration at that carbon; or a mixture of the (E) or (Z) geometric isomers of said compound.

[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 13. The compound according to any one of embodiments 2 and 8 to 12, wherein:

[0087]

[0179] Embodiment 21.1A

[0180] The compound of embodiment 21.1, or a pharmaceutically acceptable salt or solvate thereof, wherein 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 the (E) or (Z) geometric isomers of said compound.

[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 13. The compound of any one of embodiments 2 and 8 to 12, wherein:

[0089]

[0183] Embodiment 21.2A

[0184] The compound of embodiment 21.2, or a pharmaceutically acceptable salt thereof, wherein 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 the (E) or (Z) geometric isomers of said compound.

[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 13. The compound of any one of embodiments 2 and 8 to 12, wherein

[0091]

[0187] Embodiment 21.3A

[0188] The compound of embodiment 21.3, wherein when the R or S stereochemical configuration at one or more chiral carbons is designated, the compound comprises a mixture of R or S configurations at that carbon; or a mixture of (E) or (Z) geometric isomers of said compound.

[0092]

[0189] EMBODIMENT 22

[0190] 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 13. The compound according to any one of embodiments 3 and 8 to 12, selected from the group consisting of:

[0093]

[0191] Embodiment 22A

[0192] The compound of embodiment 22, or a pharmaceutically acceptable salt or solvate thereof, wherein when the R or S stereochemical configuration at one or more chiral carbon atoms is designated, the compound comprises a mixture of the R or S configurations at those carbon atoms; or a mixture of the (E) or (Z) geometric isomers of said compound.

[0094]

[0193] EMBODIMENT 23

[0194] 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 13. The compound according to any one of embodiments 4 and 8 to 12, selected from the group consisting of:

[0095]

[0195] Embodiment 23A

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

[0096]

[0197] EMBODIMENT 24

[0198] 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 13. The compound according to any one of embodiments 5 and 8 to 12, selected from the group consisting of:

[0097]

[0199] Embodiment 24A

[0200] The compound of embodiment 24, or a pharmaceutically acceptable salt or solvate thereof, wherein when the R or S stereochemical configuration at one or more chiral carbon atoms is designated, the compound comprises a mixture of the R or S configuration at that carbon; or a mixture of the (E) or (Z) geometric isomers of said compound.

[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 13. The compound according to any one of embodiments 6 and 8 to 12, wherein:

[0099]

[0203] Embodiment 25A

[0204] The compound of embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, wherein when the R or S stereochemical configuration at one or more chiral carbon atoms is designated, the compound comprises a mixture of R or S configurations at those carbon atoms; or a mixture of E or Z geometric isomers of said compound.

[0100]

[0205] EMBODIMENT 26

[0206] The compound is: (S,E)-5-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-phenoxypicolinamide 13. The compound according to any one of embodiments 7 and 8 to 12, wherein:

[0101]

[0207] Embodiment 26A

[0208] 27. The compound of embodiment 26, or a pharmaceutically acceptable salt or solvate thereof, wherein when the R or S stereochemical configuration at one or more chiral carbon atoms is designated, the compound comprises a mixture of R or S configurations at those carbon atoms; or a mixture of E or Z geometric isomers of said compound.

[0102]

[0209] EMBODIMENT 27

[0210] 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 15. The compound of any one of embodiments 2, 8-10, and 13-14, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

[0103]

[0211] Embodiment 27A 28. The compound of embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein, when either the (E) or (Z) geometric isomer of the compound is specified, the compound is a mixture of the (E) or (Z) geometric isomers of said compound.

[0104]

[0212] EMBODIMENT 28

[0213] 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 17. The compound of any one of embodiments 2, 8-10, and 15-16, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

[0105]

[0214] Embodiment 28A

[0204] A compound according to embodiment 28, or a pharmaceutically acceptable salt or solvate 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.

[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 19. The compound of any one of embodiments 2, 8-10, and 17-18, wherein:

[0107]

[0217] Embodiment 29A

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

[0108]

[0218] EMBODIMENT 30

[0219] 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 21. The compound of any one of embodiments 2, 8-10, and 19-20, 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 excipient.

[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 excipient.

[0111]

[0224] Embodiment 31B

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

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

[0115]

[0232] Embodiment 32A

[0233] The method of embodiment 32, comprising administering to the patient a therapeutically effective amount of a compound of 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 of embodiment 32, comprising administering to the patient a therapeutically effective amount of a compound of any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, and 21A to 29A.

[0117]

[0236] EMBODIMENT 33

[0237] 33. The method of embodiment 32, wherein the proliferative disease is cancer.

[0118]

[0238] EMBODIMENT 34

[0239] 34. The method of 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 of embodiments 1-30, 2.1, 2.2, 21.1, 21.1A, and 21A-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, comprising administering to the subject a therapeutically effective amount of at least one compound according to any of embodiments 1-30, 2.1, 2.2, 21.1, 21.1A, and 21A-29A, or a pharmaceutically acceptable salt thereof.

[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, comprising administering to the subject a therapeutically effective amount of at least one compound described in any of embodiments 1-30, 2.1, 2.2, 21.1, 21.1A and 21A-29A.

[0122]

[0246] EMBODIMENT 36

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

[0123]

[0248] EMBODIMENT 37

[0249] 37. The method of embodiment 36, 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, ynone, enoate, and ynoate.

[0124]

[0250] EMBODIMENT 38

[0251] Vinyl sulfone has the structure TIFF0007818138000111.tif18170Alkynyl sulfone has the structure TIFF0007818138000112.tif20170Vinyl sulfonamide, structure TIFF0007818138000113.tif20170Vinyl sulfoxide has the structure TIFF0007818138000114.tif22170Alkynyl sulfoxide has the structure TIFF0007818138000115.tif12170Vinyl sulfoximine has the structure TIFF0007818138000116.tif18170Alkynyl sulfoximine has the structure TIFF0007818138000117.tif16170Acrylamide has the formula TIFF0007818138000118.tif22170Acrylonitrile has the structure TIFF0007818138000119.tif18170 Enone, structure TIFF0007818138000120.tif22170 Ynone, structure TIFF0007818138000121.tif14170 Enoate has the structure TIFF0007818138000122.tif22170Inoate, structure TIFF0007818138000123.tif12170 formula: TIFF0007818138000124.tif10170 represents a possible point of attachment of a chemical moiety to the rest of the electrophile, The method of embodiment 37.

[0125]

[0252] EMBODIMENT 39

[0253] Compounds of formula (II): TIFF0007818138000125.tif38170 or a pharmaceutically acceptable salt or solvate thereof [In the formula, 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- 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 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 taken together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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); Or R 3 together with the carbon atom to which it is attached and Y, 10forms an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, or halo; Or R 4 taken together with the carbon atom to which it is shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4 are optionally substituted C6-C, together with the carbon atoms to which they are attached. 10 forms an aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an 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; V comprises an electrophile that reacts with the sulfur atom of cysteine ​​727 according to SEQ ID NO: 1 or a variant thereof to form a covalent bond.

[0126]

[0254] EMBODIMENT 40

[0255] 40. The compound of 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, ynone, enoate, and ynoate.

[0127]

[0256] EMBODIMENT 41

[0257] 41. A compound according to embodiment 40, or a pharmaceutically acceptable salt or solvate thereof,

[0251] Vinyl sulfone has the structure TIFF0007818138000126.tif18170Alkynyl sulfone has the structure TIFF0007818138000127.tif20170Vinyl sulfonamide, structure TIFF0007818138000128.tif20170Vinyl sulfoxide has the structure TIFF0007818138000129.tif22170Alkynyl sulfoxide has the structure TIFF0007818138000130.tif12170Vinyl sulfoximine has the structure TIFF0007818138000131.tif18170Alkynyl sulfoximine has the structure TIFF0007818138000132.tif16170Acrylamide has the formula TIFF0007818138000133.tif22170Acrylonitrile has the structure TIFF0007818138000134.tif18170 Enone, structure TIFF0007818138000135.tif22170 Ynone, structure TIFF0007818138000136.tif14170 Enoate has the structure TIFF0007818138000137.tif22170Inoate, structure TIFF0007818138000138.tif12170 formula: TIFF0007818138000139.tif10170Represents a possible point of attachment of a chemical moiety to the rest of the electrophile, The compound, or a pharmaceutically acceptable salt or solvate thereof.

[0128]

[0258] EMBODIMENT 42

[0259] 42. A compound according to any one of embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0129]

[0260] Embodiment 42A

[0261] 42. A compound according to any one of embodiments 39 to 41, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0130]

[0262] Embodiment 42B

[0263] 42. A compound according to any one of embodiments 39 to 41, and a pharmaceutically acceptable carrier or excipient.

[0131]

[0264] Embodiment 42.1

[0265] 42. A compound according to any one of embodiments 39 to 41, or a pharmaceutically acceptable salt thereof.

[0132]

[0266] Embodiment 42.1A

[0267] 42. A compound according to any one of embodiments 39 to 41.

[0133]

[0268] EMBODIMENT 43

[0269] 42. A method of treating a proliferative disease in a patient in need thereof, 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 a patient a therapeutically effective amount of a compound according to any one of embodiments 39 to 41.

[0136]

[0274] EMBODIMENT 44

[0275] 44. The method of embodiment 43, wherein the proliferative disease is cancer.

[0137]

[0276] EMBODIMENT 45

[0277] 45. The method of embodiment 44, 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.

[0138]

[0278] EMBODIMENT 46

[0279] 1. A modified WRN helicase protein comprising a non-naturally occurring small molecule fragment having a covalent bond to cysteine ​​727 of a WRN helicase protein, comprising SEQ ID NO: 1 or a variant thereof, and having the structure of formula (III): TIFF0007818138000140.tif67170[In the formula, S is the sulfur atom of cysteine ​​727 of SEQ ID NO: 1 or a variant thereof; TIFF0007818138000141.tif8170 representing amino acid 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 and; Q 1 teeth: TIFF0007818138000142.tif28170In formula, TIFF0007818138000143.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 an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 cycloalkyl, or an optionally substituted 5-6 membered heterocyclyl; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 and R 7a together with the carbon atoms to which they are shown attached form an azetidinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , and R 8 together with the carbon atoms to which they are shown attached form an azetidinyl or pyrrolodinyl ring; Or R 6 together with the nitrogen atom to which it is shown bonded, and R 7 , R 7a , R 8 , and R 9 together with the carbon atoms to which they are shown attached to form a dihydropyrrolyl ring; Or R 7 , R 7a , R 8 , R 9 , and R 10 together with the carbon atoms to which they are shown attached to form 2,3-dihydrothiophene 1,1-dioxide; Or R 8 , R 9 , and R 10 together with the carbon atoms to which they are shown attached to form 2,3-dihydrothiophene 1,1-dioxide; Q 2 teeth: TIFF0007818138000144.tif24170In formula, TIFF0007818138000145.tif10170R 11 is H; R 12is H or optionally substituted C1-C6 alkyl; R 12a is H; R 13 and R 14 are H, respectively; Or R 11 together with the nitrogen atom to which it is shown attached, and R 12 , R 12a , and R 13 taken together with the carbon atoms to which they are shown attached form an optionally substituted azetidinyl ring; Q 3 teeth: TIFF0007818138000146.tif34170In formula, TIFF0007818138000147.tif10170R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl, or optionally substituted C3-C8 cycloalkyl; Q 4 teeth: TIFF0007818138000148.tif33170In formula, TIFF0007818138000149.tif10170R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; Each R a are independently optionally substituted C1-C6 alkyl; Q 5 teeth: TIFF0007818138000150.tif26170In formula, TIFF0007818138000151.tif10170m is 1, 2, or 3; R 19 is selected from the group consisting of C1-C6 alkyl and —O—(C1-C6 alkyl); U: TIFF0007818138000152.tif31170In formula, TIFF0007818138000153.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 5-6 membered heteroaryl), -O-(optionally substituted 5-6 membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; Or R 1 taken together with the carbon atom to which it is shown attached and X, form an optionally substituted 5- to 6-membered heterocyclyl; R 2 is H, optionally substituted C1-C6 alkyl, or halo; R 3 is an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkenyl, an 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, 10 forms an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl; R 4 is H, C1-C6 alkyl, cyano, halo; Or R 4 taken together with the carbon atom to which it is shown attached and Z, form an optionally substituted 5- to 6-membered heteroaryl; Or R 3 and R 4 are optionally substituted C6-C, together with the carbon atoms to which they are attached. 10 forms an aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or an 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 an 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 is; or Y and Z together form an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl; 47. A modified helicase protein according to embodiment 46.

[0140]

[0282] In other words, X is N, Y is N, and Z is CR 5 When U is TIFF0007818138000154.tif34170[where, R 1 , R 3 , and R 5 is as defined in embodiment 46.

[0141]

[0283] EMBODIMENT 48

[0284] 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- to 6-membered heteroaryl or an optionally substituted 5- to 6-membered heteroaryl; Or R 3 taken together with the carbon atom to which it is shown attached and Y form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl; 47. A modified helicase protein according to embodiment 46.

[0142]

[0285] In other words, X is CR 2 and Y is CR 4 and Z is CR 5 When U is TIFF0007818138000155.tif41170, 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 taken together with the carbon atom to which it is shown attached and X form an optionally substituted 5- to 6-membered heterocyclyl; 47. A modified helicase protein according to embodiment 46.

[0144]

[0288] In other words, X is CR 2 and Y is N and Z is CR 5 When U is TIFF0007818138000156.tif31170, R 1 , R 2 , R 3 , and R 5 is 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 together with the carbon atom to which it is shown attached and Y, an optionally substituted C6-C 10 forming an aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted 5-6 membered heterocyclyl or heterocyclenyl, 47. A modified helicase protein according to embodiment 46.

[0146]

[0291] In other words, X is N and Y is CR 4and Z is CR 5 When U is TIFF0007818138000157.tif41170, R 1 , R 3 , R 4 , and R 5 is as defined in embodiment 46.

[0147]

[0292] EMBODIMENT 51

[0293] X is N; Y is CR 4 and Z is N, 47. A modified helicase protein according to embodiment 46.

[0148]

[0294] In other words, X is N and Y is CR 4 and when Z is N, U is TIFF0007818138000158.tif41170, R 1 , R 3 , and R 4 is as defined in embodiment 46.

[0149]

[0295] EMBODIMENT 52

[0296] X is CR 2 and; Y is CR 4 and; Z is N, 47. A modified helicase protein according to embodiment 46.

[0150]

[0297] X is CR 2 and Y is CR 4 and when Z is N, U is TIFF0007818138000159.tif41170, R 1 , R 2 , R 3 , and R 4 is as defined in embodiment 46.

[0151]

[0298] EMBODIMENT 53

[0299] 53. A modified helicase protein according to any one of embodiments 46 to 52, comprising

[0300] R 1 In:

[0301] The optional substituents of -O-(optionally substituted C3-C8 cycloalkyl) are 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 a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl;

[0302] -O-(optionally substituted C6-C 10 aryl) are 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 R 1 taken together with the carbon atom to which it is shown attached and X to form an optionally substituted 5- to 6-membered heterocyclyl, then two substituents on the same ring carbon atom of the 5- to 6-membered heterocyclyl taken together with the carbon atom to which they are attached form a 5- to 6-membered cycloalkyl;

[0304] R 3 In:

[0305] The optional substituents of the optionally substituted C3-C8 cycloalkyl are hydroxy, halo, C1-C6 alkyl, and C6-C 10aryl; or when two substituents are present on the same carbon atom of a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl; or when two substituents are present on adjacent ring carbon atoms of a C3-C8 cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C6-C 10 Do they form aryls;

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

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

[0308] Optionally substituted C6-C 10 The optional substituents on the aryl are 1 to 3 substituents selected from the group consisting of halo;

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

[0310] -NR2 R C1-C6 alkyl optional substituents are 1 to 3 substituents selected from the group consisting of halo;

[0311] The optional substituents of the optionally substituted 4-6-membered heterocyclyl are 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 4-6-membered heterocyclyl, the substituents, together with the ring carbon atoms to which they are attached, form a C3-C6 cycloalkyl. Modified helicase proteins.

[0152]

[0312] EMBODIMENT 54

[0313] 54. A modified helicase protein according to any one of embodiments 46 to 53, comprising:

[0314] R 1 together with the carbon atom to which it is shown attached to form an optionally substituted 5- or 6-membered heterocyclyl, TIFF0007818138000160.tif37170In the formula, the double bond shown is R 1 between the carbon bearing the group and X;

[0315] R 3 The carbon atom to which it is attached and Y together form an optionally substituted C6-C 10 The aryl is TIFF0007818138000161.tif25170

[0316] R 3 is an optionally substituted 5- to 6-membered heterocyclenyl formed by combining the carbon atom to which it is shown to be attached and Y, The double bond between the two carbons shown with TIFF0007818138000162.tif24170 is R 3 between the carbon bearing the group and Y;

[0317] R 3 taken together with the carbon atom to which it is shown attached and Y to form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl is TIFF0007818138000163.tif33170In the formula, the carbon-carbon double bond shown is R 3 between the carbon bearing the group and Y;

[0318] R 4 is taken together with the carbon atom to which it is shown attached and Z to form an optionally substituted 5- to 6-membered heteroaryl, TIFF0007818138000164.tif29170In the formula, in each structure, TIFF0007818138000165.tif10170Modified helicase protein.

[0153]

[0319] EMBODIMENT 55

[0320] 55. A modified helicase protein according to any one of embodiments 46 to 54, comprising: R 1 In: -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-chloro(chrloro)cyclobutyl), -O-(bicyclo[3.1.0]hexane-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-oxy, 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] The optionally substituted C3-C8 cycloalkyl is cyclohexyl;

[0326] R 2 In:

[0327] the optionally substituted C1-C6 alkyl is methyl;

[0328] R 3 In:

[0329] Optionally substituted C3-C8 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;

[0330] The optionally substituted C3-C8 cycloalkenyl is cyclopentenyl;

[0331] Optionally substituted C6-C 10 aryl is phenyl;

[0332] optionally substituted C1-C6 alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropanyl, fluoropropanyl, methoxypropanyl, 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] The 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, methoxyazetadin-1-yl, 2-azaspiro[3.3]heptan-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydropyranyl, tetrahydrofuran-1-yl, tetrahydro-2H-pyran-4-yl, di ...-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, tetrahydro-2H-pyran-4-yl 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 In:

[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 proteins.

[0154]

[0344] EMBODIMENT 56 TIFF0007818138000166.tif28170

[0345] 56. The modified WRN helicase protein of any one of claims 46 to 55, wherein Q is Q 1 That is, Q is: wherein: TIFF0007818138000167.tif10170U,R 6 , R 7 , R 7a , R 8 , R 9 , and R 10 A modified WRN helicase protein as defined in embodiment 46.

[0155]

[0346] EMBODIMENT 57

[0347] 57. A modified helicase protein according to embodiment 56, comprising:

[0348] R 7 wherein the optionally substituted C1-C6 alkyl 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 is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, difluorocyclohexyl;

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

[0351] R 10 wherein the optionally substituted C1-C6 alkyl is methyl;

[0352] R 10 wherein the optionally substituted C3-C8 cycloalkyl is cyclopropyl;

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

[0354] Or, Q 1 but: TIFF0007818138000168.tif60170In the formula, in each structure, TIFF0007818138000169.tif10170Modified helicase protein.

[0156]

[0355] EMBODIMENT 58

[0356] Q is Q 2 That is, Q is: TIFF0007818138000170.tif28170In formula, TIFF0007818138000171.tif10170U, R 11 , R 12 , R 12a , R 13 , and R 14 56. A modified WRN helicase protein according to any one of embodiments 46 to 55, wherein said modified WRN helicase protein is as defined in embodiment 46.

[0157]

[0357] EMBODIMENT 59

[0358] Q 2 but, TIFF0007818138000172.tif34170, R 21 is H or C1-C6 alkyl; TIFF0007818138000173.tif10170 A modified helicase protein described in embodiment 58.

[0158]

[0359] EMBODIMENT 60

[0360] Q is Q 3 That is, Q is: TIFF0007818138000174.tif32170In formula, TIFF0007818138000175.tif10170U, R 15 , and R 16 56. A modified WRN helicase protein according to any one of embodiments 46 to 55, wherein said modified WRN helicase protein is as defined in embodiment 46.

[0159]

[0361] EMBODIMENT 61

[0362] 61. A modified helicase protein according to embodiment 60, comprising:

[0363] R 16 wherein the optionally substituted C1-C6 alkyl is methyl;

[0364] R 16 wherein the optionally substituted C3-C8 cycloalkyl is cyclopropyl; Modified helicase proteins.

[0160]

[0365] EMBODIMENT 62

[0366] Q is Q 4 That is, Q is: TIFF0007818138000176.tif35170In formula, TIFF0007818138000177.tif10170U,R 17 , R 18 , and R a 56. A modified WRN helicase protein according to any one of embodiments 46 to 55, wherein said modified WRN helicase protein is as defined in embodiment 46.

[0161]

[0367] 63.

[0368] 63. A modified helicase protein according to embodiment 62, comprising:

[0369] R 18 wherein the optionally substituted C1-C6 alkyl is methyl;

[0370] The optionally substituted C1-C6 alkyl is methyl; Modified helicase proteins

[0162]

[0371] 64th embodiment

[0372] Q is Q 5 That is, Q is: TIFF0007818138000178.tif26170In formula, TIFF0007818138000179.tif10170U, m, and R 19 56. A modified WRN helicase protein according to any one of claims 46 to 55, wherein:

[0163]

[0373] EMBODIMENT 65

[0374] 65. A modified helicase protein according to embodiment 64, comprising:

[0375] R 19 wherein the C1-C6 alkyl is methyl;

[0376] R 19 -O-(C1-C6 alkyl) is methoxy; Modified helicase proteins

[0164]

[0377] 66. 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 1-30, 2.1, 2.2, 21.1, 21.1A, 21A-29A and 39-41 for use in the treatment of a proliferative disorder.

[0167]

[0383] 67. The method of claim 67,

[0384] 67. The compound, or a pharmaceutically acceptable salt or solvate thereof, for use according to embodiment 66, wherein the proliferative disease is cancer.

[0168]

[0385] Embodiment 67A

[0386] 67. The compound for use according to embodiment 66, or a pharmaceutically acceptable salt thereof, wherein the proliferative disease is cancer.

[0169]

[0387] Embodiment 67B

[0388] 67. The compound for use according to embodiment 66, wherein the proliferative disease is cancer.

[0170]

[0389] 68. The method of claim 68,

[0390] 68. The compound for use according to embodiment 67, 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] 68. The compound for use according to embodiment 67, 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] 68. The compound for use according to embodiment 67, 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] 69. The method of claim 69,

[0396] A method of measuring WRN helicase activity in an assay comprising ATP and a compound of 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 of measuring WRN helicase activity in an assay comprising ATP and a compound of 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 of measuring WRN helicase activity in an assay comprising ATP and a compound of any of embodiments 1-30, 2.1, 2.2, 21.1, 21.1A, 21A-29A, and 39-41. 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 Compositions

[0401] In general, the compounds described herein are administered in a therapeutically effective amount by any of the accepted modes of administration for agents that perform similar functions. The therapeutically effective amount of the compounds described herein is about 0.01 to about 500 mg per kg of patient body weight per day, and can be administered in single or multiple doses. Suitable dosage levels are about 0.1 to about 250 mg / kg, about 0.05 to about 100 mg / kg, or about 0.1 to about 50 mg / kg per day. Within this range, dosages can be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg per day. For oral administration, the composition may be provided in the form of a tablet containing from about 1.0 to about 1000 milligrams of 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 active ingredient. The actual amount of compound, i.e., active ingredient, will depend on many factors, including the severity of the condition being treated, the age and relative health of the patient, the potency of the compound utilized, and the route and form of administration.

[0177]

[0402] Generally, the compounds described herein are administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, nasal, or suppository), parenteral (e.g., intramuscular, intravenous, intrapleural, or subcutaneous), topical (e.g., applied to the skin), or via an implant. The preferred mode of administration is oral, using a convenient daily dosing regimen that can be adjusted according to the severity of the affliction. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or other suitable composition.

[0178]

[0403] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules containing enteric coatings or delayed-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 bioavailability can be increased by increasing the surface area, i.e., reducing the particle size, especially for drugs with low bioavailability. For example, U.S. Pat. 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 crosslinked polymer matrix. U.S. Pat. No. 5,145,684 describes a method for producing a pharmaceutical formulation in which the drug substance is milled into nanoparticles (average particle size 400 nm) in the presence of a surface modifier, which are then dispersed in a liquid medium to obtain a pharmaceutical formulation exhibiting significantly higher bioavailability.

[0179]

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

[0180]

[0405] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils including those of petroleum, animal, vegetable, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0181]

[0406] Compressed gases can be used to disperse the compounds described herein in the form of an aerosol. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like.

[0182]

[0407] Other suitable pharmaceutical excipients 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 range accepted by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01 to 99.99 wt% of the described compound based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. 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 be useful, where the drug combination is safer or more effective than either agent alone. Such other drugs may be administered simultaneously or sequentially with the compounds described herein, by a route and in an amount commonly used. 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 therapy in which the compounds described herein and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds described herein and the other active ingredients may be used in lower doses than when each is used alone.

[0185]

[0410] Thus, the pharmaceutical compositions described herein may include those that contain one or more other active ingredients in addition to the compounds described herein. Subjects that can be treated using the methods described herein are those with cancer characterized by an MSI-H phenotype. In some embodiments, the MSI-H phenotype is characterized by the presence of DNA sequence length alterations in at least two mononucleotide or dinucleotide markers selected from the group consisting of BAT25, BAT26, D25123, D55346, and D175250. In some embodiments, the MSI-H phenotype is characterized by the presence of DNA sequence length alterations 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 is mismatch repair deficient (MMRd). In some embodiments, MMRd is caused by a mutation in the MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2, and / or EPCAM genes. In some embodiments, MMRd is caused by a mutation in the MLH1, MSH2, MSH6, PMS2, and / or EPCAM genes. In some embodiments, MMRd is caused by a mutation in the MLH1 gene. In some embodiments, the cancer further has a mutation that results in loss of function of ARID1A. In some embodiments, MMRd is caused by a mutation or epigenetic silencing of an MMR gene promoter.

[0186]

[0411] Cancer types include, for example, MSI-H cancer, adrenocortical carcinoma, bladder cancer, breast cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, bile duct carcinoma, chronic lymphocytic leukemia, colorectal cancer, colon adenocarcinoma, ovarian cancer, cutaneous T-cell lymphoma, lymphoid tumors diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, acute myeloid leukemia, low-grade glioma, and hepatocellular carcinoma The cancer may include lung adenocarcinoma, lung squamous 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 carcinoma, thymoma, uterine endometrial carcinoma, uterine carcinosarcoma, uveal melanoma, pediatric acute myeloid leukemia, pediatric neuroblastoma, high-risk pediatric Wilms' tumor, or any other type of cancer described herein. The cancer may be early-stage or advanced (e.g., recurrent or metastatic). In some embodiments, the subject has previously received anti-cancer therapy. In some embodiments, the subject has not previously been treated with anti-cancer therapy. In some embodiments, the cancer is resistant to immunotherapy (e.g., a checkpoint inhibitor described herein). In some embodiments, the cancer is resistant to targeted therapy. In some embodiments, the treatment resistance is caused by a defect in 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 seen in many types of cancer, including, but not limited to, colorectal cancer, endometrial cancer, bile duct cancer, bladder cancer, breast cancer, esophageal cancer, gastric or gastroesophageal junction cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, retroperitoneal adenocarcinoma, sarcoma, small cell lung cancer, small intestine cancer, and thyroid cancer.

[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 related condition) or can be combined with other types of therapy to treat cancer (e.g., radiation therapy or surgery). In some embodiments, the second therapeutic agent is selected based on the tumor type, tumor tissue of origin, tumor stage, or mutation status. In combination therapy, the dosage of one or more of the therapeutic agents can be reduced from the standard dosage when administered alone. For example, dosages can be empirically determined from drug combinations and permutations or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, the combined dosages of the agents or compounds should provide 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 (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion protein, such as ipilimumab / YERVOY® or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; or pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A1RG7446 / atezolizumab; MED14736 / durvalumab; MSB0010718C / avelumab; BMS 936559 / cemiplimab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein, e.g., AMP 224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAGS, VISTA, KIR, 2B4, CDi60, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.

[0190]

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

[0191]

[0416] In some embodiments, the anti-cancer 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, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin, irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. 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; ethylenimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan), bryostatin; kallistatin; CC-1065 (including its analogs adzelesin, carzelesin, and bizelesin). cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictine; spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, methiothamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma and calicheamicin omegal) (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins (including dynemicin A); bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin , 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin)), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycinolivomycin, peplomycin, potofilomycin, puromycin, chelamycin, rhodolubicin, streptomycin, Nigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil; folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; callus Androgens such as terone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole; elfomitin; elliptinium acetate; epothilone; etoglucide; gallium nitrate;Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerin; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; taxoids, such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, a cremophor-free albumin-processed paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (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 (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine;and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in cocktails and administered in combination with the first therapeutic agent described herein. Suitable 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 anti-cancer therapy is T cell adoptive 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 a CAR into T cells. Prior to T cell expansion and genetic modification, a source of 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, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art can be used. In some embodiments, the T cells are autologous T cells. Either before or after the T cells are genetically engineered to express a desired protein (e.g., a CAR), the T cells can be engineered using methods described in, e.g., 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.

[0193]

[0418] The additional anti-cancer therapy can be a non-drug treatment, for example, the additional therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and / or surgical removal of tumor tissue.

[0194]

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

[0195] TIFF0007818138000180.tif255170TIFF0007818138000181.tif255170TIFF0007818138000182.tif20170

[0196] Example 1

[0420] (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000183.tif34170

[0197]

[0421] Step A

[0422] Process 1 TIFF0007818138000184.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 h. 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 NaSO, 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 afford tert-butyl N-[(E)-3-methylsulfonylallyl]carbamate (5 g, 82% yield) as a white solid.

[0198]

[0424] Process 2 TIFF0007818138000185.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 h. 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] Process 3 TIFF0007818138000186.tif25170

[0427] To a solution of cyclopentanecarboxamidine (1.0 g, 8.92 mmol) in ethanol (15 mL, 0.594 M) was added 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 give ethyl 2-cyclopentyl-4-hydroxy-pyrimidine-5-carboxylate as a yellow solid (1.3 g, 62%).

[0200]

[0428] Process 4 TIFF0007818138000187.tif25170

[0429] To a solution of ethyl 2-cyclopentyl-4-hydroxy-pyrimidine-5-carboxylate (500 mg, 2.12 mmol) in 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 to dryness under reduced pressure to give crude ethyl 4-chloro-2-cyclopentyl-pyrimidine-5-carboxylate as a brown oil (0.5 g).

[0201]

[0430] Process 5 TIFF0007818138000188.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 KCO (326 mg, 2.36 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was extracted with EtOAc (2 × 10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude ethyl 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylate as a white solid (240 mg).

[0202]

[0432] Process 6 TIFF0007818138000189.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 pH 5–6 by slow addition of 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 (200 mg) as a white solid.

[0203]

[0434] Process 7 TIFF0007818138000190.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) was added [(E)-3-methylsulfonylyl]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 N 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 NaSO, 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*25 mm*3 μm, 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, 24% yield). 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 TIFF0007818138000191.tif34170

[0205]

[0437] Process 1 TIFF0007818138000192.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 was stirred at 65° C. for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to give crude tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate as a yellow oil (10 g).

[0206]

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

[0207] Example 3

[0440] (S,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000193.tif34170

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

[0208] Example 4

[0442] (R,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000194.tif34170

[0443] In Procedure A, tert-butyl N-[(1R)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 to give 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 TIFF0007818138000195.tif34170

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

[0210] Example 6

[0446] (S,E)-2-Cyclopentyl-N-(1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000196.tif32170

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

[0211] Example 7

[0448] (S,E)-2-Cyclopentyl-N-(4-methyl-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000197.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 give 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 TIFF0007818138000198.tif34170

[0213]

[0451] Process 1 TIFF0007818138000199.tif21170

[0452] To a solution of tert-butyl N-[(1S)-1-cyclopropyl-2-hydroxyethyl]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 under N at 25 °C for 1 h. The mixture was filtered, and the filter cake was rinsed with DCM (3 × 15 mL). The combined filtrate was then concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (Biotage using a 12 g Agela flash silica gel column, eluting with 0% to 8% ethyl acetate in petroleum ether) to give tert-butyl N-[(1S)-1-cyclopropyl-2-oxoethyl]carbamate as a colorless oil (300 mg, 61% yield).

[0214]

[0453] In Procedure A, N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 to give the title compound. 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 TIFF0007818138000200.tif34170

[0455] In Procedure A, tert-butyl N-[(1S)-1-cyclobutyl-2-oxo-ethyl]carbamate was prepared in Step 1 using tert-butyl N-[(1S)-1-cyclobutyl-2-hydroxy-ethyl]carbamate / Dess-Martin periodinane / DCM and NaH as the base in Step 1 to give 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 TIFF0007818138000201.tif34170

[0217]

[0457] Process 1 TIFF0007818138000202.tif21170

[0458] To a solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methoxypropanoic acid (5 g, 22.81 mmol) in THF (100 mL, 0.228 M) was added 1,1'-carbonyl-diimidazole (4.07 g, 25.09 mmol). The mixture was stirred at 20 °C for 30 min, 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 Sangiet's salt (100 mL), stirred for 30 min, and then extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate as a yellow oil (3.20 g).

[0218]

[0459] In Procedure A, tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH was used in Step 1 to give the title compound. 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 TIFF0007818138000203.tif28170

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

[0220] Example 12

[0462] (E)-2-Ethyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000204.tif28170

[0463] In Procedure A, propanamidine hydrochloride was used in step 3 to give the title compound. 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 TIFF0007818138000205.tif28170

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

[0222] Example 14

[0466] (E)-2-Isopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000206.tif32170

[0467] In Procedure A, 2-methylpropanamidine hydrochloride was used in step 3 to give the title compound. 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 TIFF0007818138000207.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 give 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 TIFF0007818138000208.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 give 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 TIFF0007818138000209.tif32170

[0473] In Procedure A, cyclopropanecarboxamidine was used in step 3 to give the title compound. 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 TIFF0007818138000210.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 give 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 TIFF0007818138000211.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 give 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) TIFF0007818138000212.tif32170

[0479] (S,Z)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 21) TIFF0007818138000213.tif32170

[0480] In Procedure A, tert-butyl N-[(1S)-1-benzyl-2-oxo-ethyl]carbamate / NaH was used for Step 1, and cyclopropanecarboxamidine was used for Step 3 to obtain a mixture of the title compounds. The mixture was separated by preparative HPLC (reverse phase, MeCN / HO (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 TIFF0007818138000214.tif32170

[0482] In step 1, tert-butyl 3-formylazetidine-1-carboxylate / n BuLi was used in step 3 with cyclopropanecarboxamidine to give 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) TIFF0007818138000215.tif32170

[0484] (E)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone (Example 24) TIFF0007818138000216.tif32170

[0485] The compound of Example 22 was separated by chiral SFC (column: Chiralpak AS-3) to give 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 TIFF0007818138000217.tif32170

[0232]

[0487] Process 1 TIFF0007818138000218.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 h to completely dissolve the salt. Diethyl iodomethylphosphonate (0.60 mL, 3.60 mmol) was then added, and the mixture was heated at 80 °C overnight. Additional sodium cyclopropanesulfonate (922 mg, 7.19 mmol) was added, and the mixture was heated at 100 °C for 1 h. The mixture was diluted with EtOAc, washed with 1 M HCl and brine, dried over NaSO, and concentrated under reduced pressure to give a residue. The residue was purified via normal-phase column chromatography using a 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 give 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 TIFF0007818138000219.tif32170

[0491] In Procedure A, N-Boc-3-pyrrolidinone / NaH was used for step 1 and cyclopropanecarboxamidine in step 3 to give 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 TIFF0007818138000220.tif32170

[0493] Following 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 TIFF0007818138000221.tif32170

[0237]

[0495] Process 1 TIFF0007818138000222.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 stirred at room temperature for 30 min until CO evolution ceased. DIPEA (0.64 mL, 3.65 mmol) was added dropwise to the reaction mixture, followed by solid N,O-dimethylhydroxylamine hydrochloride (356 mg, 3.65 mmol). After the addition was complete, the resulting mixture was stirred at room temperature for 16 h. The reaction was then quenched by the addition of water, and the resulting solution was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated to give crude tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (356 mg).

[0238]

[0497] Process 2 TIFF0007818138000223.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 EtO at −78 °C. After 1 h, excess DIBAL-H was quenched by adding EtOAc, and the mixture was stirred at −78 °C for an additional 15 min. The reaction mixture was poured into a mixture of citric acid and EtO (15 ml), and the layers were shaken briefly and then separated. The aqueous layer was then washed with EtO (3 × 20 ml). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified via normal phase chromatography (SiO2, EtOAc / heptane = 0-100%) to give tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (209.8 mg, 74% yield).

[0239]

[0499] In Procedure A, tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate / Cs2CO3 was used in Step 1 and cyclopropanecarboxamidine in Step 3 to give 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 TIFF0007818138000224.tif32170

[0501] The title compound was obtained following the procedure for the compound of Example 28, using (2S)-2-(tert-butoxycarbonylamino)-2-cyclobutyl-acetic acid in Step 1. 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 TIFF0007818138000225.tif33170

[0503] The title compound was obtained following the procedure for the compound of Example 28, using (2S)-2-(tert-butoxycarbonylamino)-2-(3,3-difluorocyclobutyl)acetic acid in Step 1. 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 TIFF0007818138000226.tif32170

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

[0243] Example 32

[0506] 2-Cyclopropyl-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000227.tif32170

[0507] The title compound was obtained following the procedure for the compound of Example 28, using (2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxy-butanoic acid in Step 1. 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 TIFF0007818138000228.tif33170

[0509] The title compound was obtained following the procedure for the compound of Example 28, using (2S)-2-(tert-butoxycarbonylamino)-2-tetrahydropyran-4-yl-acetic acid in Step 1. 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 TIFF0007818138000229.tif32170

[0246]

[0511] Process 1 TIFF0007818138000230.tif22170

[0512] A mixture of tert-butyl 2,5-dihydro-1h-pyrrole-1-carboxylate (1 g, 5.91 mmol), sodium methanesulfonate (1.2 g, 11.82 mmol), iodine (1.65 g, 6.50 mmol), and sodium acetate (727 mg, 8.86 mmol) in ethyl acetate (15 mL, 0.236 M) and water (10 mL, 0.236 M) was stirred at 70 °C (illuminated with a 1000 W lamp) for 1 h. The reaction mixture was poured into saturated aqueous NaSO (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, 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: 30-60% ethyl acetate / petroleum ether, gradient: 100 mL / min) to afford tert-butyl 3-iodo-4-methylsulfonyl-pyrrolidine-1-carboxylate as a yellow oil (600 mg, 27% yield).

[0247]

[0513] Process 2 TIFF0007818138000231.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) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (292.1 mg, 1.92 mmol) at 20 °C, and the mixture was stirred at 20 °C for 0.5 h. The mixture was washed with aqueous HCl (1 N, 3 mL), saturated NaHCO (3 mL), and brine (3 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, PE:EtOAc = 1:1) to give tert-butyl 3-methylsulfonyl-2,5-dihydropyrrole-1-carboxylate (400 mg) as a white solid.

[0248]

[0515] In Procedure A, tert-butyl 3-methylsulfonyl-2,5-dihydropyrrole-1-carboxylate was used in Step 2 and cyclopropanecarboxamidine in Step 3 to give 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 TIFF0007818138000232.tif28170

[0517] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2-cyclopropylacetamidine in Step 3 to give 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 TIFF0007818138000233.tif28170

[0519] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used for step 1 and 2-cyclopropylacetamidine in step 3 to give 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 TIFF0007818138000234.tif34170

[0252]

[0521] Process 1 TIFF0007818138000235.tif34170

[0522] To 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 lithium carbonate (127.6 mg, 1.68 mmol) and N-fluorobenzenesulfonimide (530.3 mg, 1.68 mmol). The mixture was stirred under N at 75 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (8 mL), and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, 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*30 mm*10 um, 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, using ethyl 2-[cyclopropyl(fluoro)methyl]-4-phenoxy-pyrimidine-5-carboxylate according to Step 6 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid according to Step 7, the title compound was obtained. 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 TIFF0007818138000236.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 in Step 3 to give 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 TIFF0007818138000237.tif32170

[0527] In Procedure A, t-butyl 3-oxoazetidine-1-carboxylate / NaH was used in Step 1 and 1-methylcyclopropanecarboxamidine hydrochloride in Step 3 to give 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 TIFF0007818138000238.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 in Step 3 to give 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 TIFF0007818138000239.tif30170

[0531] In Procedure A, t-butyl 3-oxoazetidine-1-carboxylate / NaH was used in Step 1 and 2-(1-methylcyclopropyl)acetamidine in Step 3 to give the title compound. 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 TIFF0007818138000240.tif32170

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

[0259] Example 43

[0534] (E)-2-Cyclobutyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000241.tif32170

[0535] In Procedure A, cyclobutanecarboxamidine was used in step 3 to give the title compound. 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 TIFF0007818138000242.tif32170

[0537] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and cyclobutanecarboxamidine hydrochloride in Step 3 to give the title compound. 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 TIFF0007818138000243.tif32170

[0539] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and cyclobutanecarboxamidine hydrochloride in Step 3 to give 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) TIFF0007818138000244.tif34170

[0541] 2-((1r,3S)-3-Methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 47) TIFF0007818138000245.tif34170

[0542] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH for Step 1 and 3-methylcyclobutanecarboxamidine for Step 3. The mixture was separated by chiral HPLC (column: Chiralpak AD-3) to give peak 1 (the compound of Example 46) (LC-MS m / z: 416.2 [M+1]) and peak 2 (the 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) TIFF0007818138000246.tif34170

[0544] N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-((1r,3S)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide (Example 49) TIFF0007818138000247.tif34170

[0545] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, and 3-methylcyclobutanecarboxamidine was used in Step 3 to obtain a mixture of the title compounds. The mixture was separated by chiral HPLC (column: Waters Xbridge BEH C18 (100*30 mm*10 um), 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) TIFF0007818138000248.tif34170

[0548] (2-((1r,3r)-3-Methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone (Example 51) TIFF0007818138000249.tif34170

[0549] In Procedure A, a mixture of the title compounds was obtained using t-butyl 3-oxoazetidine-1-carboxylate / NaH in Step 1 and 3-methylcyclobutanecarboxamidine in Step 3. The mixture was separated by chiral SFC (column: Daicel ChiralPak IC (250 mm * 30 mm * 10 um), mobile phase: neutral MeOH) to give 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 TIFF0007818138000250.tif32170

[0551] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamidine in Step 3 to give 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 TIFF0007818138000251.tif28170

[0553] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2-cyclobutylacetamidine in Step 3 to give 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 TIFF0007818138000252.tif28170

[0555] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2-cyclopentylacetamidine in Step 3 to give 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 TIFF0007818138000253.tif36170

[0269]

[0557] Process 1 TIFF0007818138000254.tif16170

[0558] To a solution of ammonium chloride (1.90 g, 35.43 mmol) in toluene (50 mL, 0.644 M) was added trimethylaluminum (16.1 mL, 32.21 mmol, 2 M) at 0 °C. The reaction was stirred at 25 °C for 2 h. 3-Methylenecyclobutanecarbonitrile (3 g, 32.21 mmol) was then added dropwise to the mixture. The mixture was stirred at 80 °C under N for 16 h. 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 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] Process 2 TIFF0007818138000255.tif25170

[0560] To a solution of 3-methylenecyclobutanecarboxamidine (4.3 g, 39.03 mmol) in ethanol (40 mL, 0.781 M) was added sodium methanolate (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 under N for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H O (5 mL), the pH was adjusted to approximately 6 with saturated aqueous citric acid, and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give 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 give ethyl 4-hydroxy-2-(3-methylenecyclobutyl)pyrimidine-5-carboxylate as a pale yellow solid (3.6 g, 39% yield).

[0271]

[0561] Process 3 TIFF0007818138000256.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 h. Then, 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 h, the mixture was warmed to rt and stirred at 25 °C for 12 h. Then, the mixture was filtered, and the filter cake was rinsed with EtOAc (3 × 5 mL). The combined filtrate was concentrated under reduced pressure to give crude ethyl 4-hydroxy-2-spiro[2.3]hexan-5-yl-pyrimidine-5-carboxylate (160 mg).

[0272]

[0563] In Procedure A, steps 4, 5, 6, and 7 (using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid) were followed using ethyl 4-hydroxy-2-spiro[2.3]hexan-5-yl-pyrimidine-5-carboxylate to give 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 TIFF0007818138000257.tif32170

[0565] In Procedure A, 2,2-dimethylpropanamidine hydrochloride was used in step 3 to give the title compound. 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 TIFF0007818138000258.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 in Step 3 to give 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 TIFF0007818138000259.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 in Step 3 to give 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 TIFF0007818138000260.tif32170

[0571] In Procedure A, using tert-butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate / Dess-Martin periodinane / DCM to prepare (1-formyl-cyclopropyl)-carbamic acid tert-butyl ester for step 1, and using NaH as the base in step 1 and 2,2-dimethylpropanamidine hydrochloride in step 3, the title compound was obtained 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) TIFF0007818138000261.tif32170

[0573] (S,Z)-2-(tert-butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 61) TIFF0007818138000262.tif32170

[0574] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-benzyl-2-oxo-ethyl]carbamate / NaH for Step 1 and 2,2-dimethylpropanamidine hydrochloride for Step 3. The mixture was separated by preparative HPLC (reverse phase, MeCN / HO (0.1% FA) = 5-95%) to give 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 TIFF0007818138000263.tif34170

[0279]

[0576] Process 1 TIFF0007818138000264.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 NH Cl (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na SO , 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 to 40% ethyl acetate / petroleum ether, gradient: 100 mL / min) to give 4-(diphenoxyphosphorylmethylsulfonyl)tetrahydropyran as a yellow solid (1.0 g, 72% yield).

[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 give 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 TIFF0007818138000265.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 in Step 3 to give 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 TIFF0007818138000266.tif32170

[0582] The title compound was obtained following the procedure for the compound of Example 63, using (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-methoxypropanoic acid in the first step. 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 TIFF0007818138000267.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 in Step 3 to give 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 TIFF0007818138000268.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 in Step 3 to give 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 TIFF0007818138000269.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 in Step 3 to give 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 TIFF0007818138000270.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 in Step 3 to give 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)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000271.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 in Step 3 to give 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 TIFF0007818138000272.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 in Step 3 to give 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 TIFF0007818138000273.tif32170

[0596] Following Step 2 of the procedure for the compound of Example 28, using (2S)-2-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-oxobutanoic acid in Step 1, tert-butyl N-[(1S)-3-(dimethylamino)-1-formyl-3-oxo-propyl]carbamate was obtained. Using tert-butyl N-[(1S)-3-(dimethylamino)-1-formyl-3-oxo-propyl]carbamate / CsCO in Step 1 and 2,2-dimethylpropanamidine hydrochloride in Step 3 in Procedure A, the title compound was obtained. 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 TIFF0007818138000274.tif38170

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

[0291] Example 73

[0599] (S,E)-2-(tert-butyl)-N-(5,5-difluoro-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000275.tif32170

[0600] Tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate was obtained according to step 2 of the procedure for the compound of Example 28, using (2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro-butanoic acid in step 1. In procedure A, tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate / CsCO in step 1 and 2,2-dimethylpropanamidine hydrochloride in step 3 were used to obtain the title compound. 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 TIFF0007818138000276.tif39170

[0602] 2-(tert-Butoxycarbonylamino)-3-phenoxypropanoic acid was converted to tert-butyl N-(1-formyl-2-phenoxyethyl)carbamate via LiBH reduction followed by DMP oxidation. In Procedure A, tert-butyl N-(1-formyl-2-phenoxyethyl)carbamate / NaH was used in Step 1 and 2,2-dimethylpropanamidine hydrochloride in Step 3 to give the title compound. The mixture was separated by chiral SFC (column: Chiralpak IG-3) to give 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 TIFF0007818138000277.tif34170

[0604] In Procedure A, cyclohexanecarboxamidine hydrochloride was used in step 3 to give 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 TIFF0007818138000278.tif34170

[0606] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and cyclohexanecarboxamidine hydrochloride in Step 3 to give 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 TIFF0007818138000279.tif32170

[0608] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and tetrahydrofuran-2-carboxamidine in Step 3 to give 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 TIFF0007818138000280.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 in Step 3 to give 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 TIFF0007818138000281.tif34170

[0612] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and benzamidine hydrochloride in Step 3 to give 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 TIFF0007818138000282.tif34170

[0614] In Procedure A, starting from step 5, using ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate in step 5 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in step 7, the title compound was obtained. 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 TIFF0007818138000283.tif34170

[0616] In Procedure A, starting from step 5, using ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate in step 5 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in step 7, the title compound was obtained. 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 TIFF0007818138000284.tif32170

[0618] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2,2,3,3,3-pentafluoropropanamidine in Step 3 to give the title compound. 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 TIFF0007818138000285.tif32170

[0620] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 1,2,2,3,3,3-pentafluoropropanamidine in Step 3 to give the title compound. 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 TIFF0007818138000286.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 in Step 3 to give 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 TIFF0007818138000287.tif32170

[0304]

[0624] Process 1 TIFF0007818138000288.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. Triethylaluminum in hexane (41 mL, 2 M) 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 h. It was then cooled to 0 °C, and methanol (80 mL) was added and stirred at 25 °C for 1 h. After filtration, the solid was washed several times with methanol, and the solution was concentrated under reduced pressure to give crude 2,2-difluoropropanamidine as a white solid (1.40 g, 89% yield).

[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 in Step 3 to give 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 TIFF0007818138000289.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 in Step 3 to give 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 TIFF0007818138000290.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 in Step 3 to give 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 TIFF0007818138000291.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 in Step 3 to give the title compound. LC-MS m / z: 442.1 [M+1].

[0309] Example 90

[0633] (S,E)-N-(5,5-difluoro-1-(methylsulfonyl)pent-1-en-3-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000292.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 in Step 3 to give 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 TIFF0007818138000293.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 in Step 3 to give 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 TIFF0007818138000294.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 in Step 3 to give 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)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000295.tif32170

[0640] The title compound was obtained following the procedure for the compound of Example 28, using (2S,3S)-2-(tert-butoxycarbonylamino)-3-methoxy-butanoic acid in Step 1. 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)pent-1-en-3-yl)pyrimidine-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 TIFF0007818138000296.tif33170

[0314]

[0642] Process 1 TIFF0007818138000297.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, 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, 29% yield).

[0315]

[0644] Process 2 TIFF0007818138000298.tif21170

[0645] A mixture of diethyl 2-acetamido-2-(2,2,2-trifluoroethyl)propanedioate (2.0 g, 6.68 mmol) in 6 N HCl (10 mL) was stirred at 100 °C for 15 min. The mixture was adjusted to pH = 10 with NaOH (aq, 6 M). 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 cloudy reaction mixture was neutralized with 1.0 M HCl (pH = 4-5) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated to give crude 2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (400 mg) as a yellow oil.

[0316]

[0646] Process 3 TIFF0007818138000299.tif21170

[0647] To a solution of 2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (100 mg, 0.39 mmol) in DCM (2 mL, 0.389 M) was added 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 was stirred at −70 °C for 0.5 h. Seniet's salt (0.8 mL, saturated) and EtOAc (0.8 mL) were added dropwise to the reaction 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 give crude tert-butyl N-(3,3,3-trifluoro-1-formyl-propyl)carbamate as a yellow oil (50 mg).

[0317]

[0648] In Procedure A, the following steps were carried out separately using tert-butyl N-(3,3,3-trifluoro-1-formyl-propyl)carbamate in step 1, followed by chiral HPLC separation (column: Phenomenex-Cellulose-2 (250 mm*30 mm*5 um)) and 2,2-difluoropropanamidine in step 3 to give 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 TIFF0007818138000300.tif34170

[0319]

[0650] Process 1 TIFF0007818138000301.tif30170

[0651] To a solution of N-(tert-butoxycarbonyl)-O-(tert-butyl)-L-serine (1 g, 3.83 mmol) in DCM (10 mL, 0.348 M) and methanol (1 mL, 0.348 M) was added (trimethylsilyl)diazomethane (3.83 mL, 7.65 mmol, 2 M) under N at 0 °C. 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] Process 2 TIFF0007818138000302.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 NaSO.10H0, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1:0 to 3:1) to give tert-butyl N-[(1R)-1-(tert-butoxymethyl)-2-hydroxyethyl]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-difluoropropanamidine was used in Step 3 to give 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 TIFF0007818138000303.tif34170

[0323]

[0656] Process 1 TIFF0007818138000304.tif28170

[0657] To 1-(tert-butyl) 2-methyl (S)-aziridine-1,2-dicarboxylate (800 mg, 3.98 mmol) was added boron trifluoride diethyl etherate (84.6 mg, 0.60 mmol) and cyclopropanol (461.8 mg, 7.95 mmol) in DCM (15 mL, 0.265 M) at 0 °C. The mixture was stirred under N at 0 °C for 2 h. The reaction mixture was diluted with NaHCO (50 mL) and extracted with DCM (3 × 50 mL). The resulting organic layer was dried over NaSO, 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, 51% yield).

[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 previously described. In Procedure A, tert-butyl N-[(1S)-1-(cyclopropoxymethyl)-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2,2-difluoropropanamidine in Step 3 to give 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 TIFF0007818138000305.tif33170

[0660] Process 1 TIFF0007818138000306.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 bifluoride (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 NaSO, 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] Process 2 TIFF0007818138000307.tif29170

[0663] p-Toluenesulfonic acid monohydrate (162.29 mg, 0.85 mmol) was added to tert-butyl (4R)-4-(difluoromethoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylate (1.2 g, 4.27 mmol) in methanol (20 mL, 0.213 M). The mixture was stirred at 25° C. for 16 hours. 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 to 20% ethyl acetate / petroleum ether, gradient: 100 mL / min) to afford 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 TIFF0007818138000308.tif32170

[0666] Prepare 1-fluorocyclopropanecarboxamidine using methyl 1-fluorocyclopropanecarboxylate as in the procedure for the compound of Example 86, and use tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 1-fluorocyclopropanecarboxamidine in step 3 in Procedure A to give 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 TIFF0007818138000309.tif32170

[0668] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 1-fluorocyclopropanecarboxamidine in Step 3 to give 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 TIFF0007818138000310.tif32170

[0670] 1-(Trifluoromethyl)cyclopropanecarboxamidine was prepared using ethyl 1-(trifluoromethyl)cyclopropanecarboxylate as in the procedure for the compound of Example 86, and in Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 1-(trifluoromethyl)cyclopropanecarboxamidine in Step 3 to give 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 TIFF0007818138000311.tif32170

[0672] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 1-(trifluoromethyl)cyclopropanecarboxamidine in Step 3 to give the title compound. 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 TIFF0007818138000312.tif36170

[0333]

[0674] Process 1 TIFF0007818138000313.tif18170

[0675] To a solution of 3-oxo-cyclobutanecarbonitrile (2.5 g, 26.29 mmol) in DCM (100 mL, 0.263 M) was added diethylaminosulfur trifluoride (8.5 g, 52.58 mmol) over 0.5 h at 0 °C. The mixture was stirred under N at 25 °C for 12 h. 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 NaSO, filtered, and the filtrate was concentrated under reduced pressure to give crude 3,3-difluorocyclobutanecarbonitrile as a brown oil (3.0 g).

[0334]

[0676] Process 2 TIFF0007818138000314.tif21170

[0677] To a solution of ammonium chloride (685 mg, 12.81 mmol) in toluene (15 mL, 0.854 M) was added triethylaluminum (923 mg, 12.81 mmol) at 0°C. The reaction was stirred at 25°C for 2 hours. 3,3-Difluorocyclobutanecarbonitrile (1.5 g, 12.81 mmol) was added dropwise to the mixture. The mixture was stirred at 80°C for 16 hours. 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 minutes. The silica was filtered and washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure to give crude 3,3-difluorocyclobutanecarboxamidine (1.0 g) as a light brown solid.

[0335]

[0678] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 3,3-difluorocyclobutanecarboxamidine in Step 3 to give 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 TIFF0007818138000315.tif32170

[0680] In Procedure A, p-cresol was used in step 5 to give 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 TIFF0007818138000316.tif32170

[0682] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and m-cresol in Step 5 to give 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 TIFF0007818138000317.tif32170

[0684] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and o-cresol in Step 5 to give 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 TIFF0007818138000318.tif32170

[0686] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and 4-ethylphenol in Step 5. 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 TIFF0007818138000319.tif32170

[0688] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 3-ethylphenol in Step 5 to give 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 TIFF0007818138000320.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 in Step 5 to give 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 TIFF0007818138000321.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 in Step 5 to give 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 TIFF0007818138000322.tif32170

[0694] In Procedure A, 3-fluorophenol was used in step 5 to give 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 TIFF0007818138000323.tif33170

[0696] In Procedure A, 4-fluorophenol was used in step 5 to give 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 TIFF0007818138000324.tif33170

[0698] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 4-fluorophenol was used in Step 5 to give 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 TIFF0007818138000325.tif32170

[0700] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 3-fluorophenol was used in Step 5 to give 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 TIFF0007818138000326.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 give 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 TIFF0007818138000327.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 in Step 5 to give 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 TIFF0007818138000328.tif32170

[0706] In Procedure A, 3-chlorophenol was used in step 5 to give 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 TIFF0007818138000329.tif32170

[0708] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 3-chlorophenol in Step 5 to give 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 TIFF0007818138000330.tif33170

[0710] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 2-chlorophenol in Step 5 to give 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 TIFF0007818138000331.tif33170

[0712] In Procedure A, 4-chlorophenol was used in step 5 to give 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 TIFF0007818138000332.tif33170

[0714] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 4-chlorophenol in Step 5 to give 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 TIFF0007818138000333.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 in Step 5 to give 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 TIFF0007818138000334.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 in Step 5 to give 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 TIFF0007818138000335.tif33170

[0720] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 4-hydroxybenzonitrile in Step 5 to give 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 TIFF0007818138000336.tif32170

[0722] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and 3-hydroxypyridine in Step 5 to give 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 TIFF0007818138000337.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 in step 5 to give 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 TIFF0007818138000338.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 in Step 5 to give 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 TIFF0007818138000339.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 in Step 5 to give 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) TIFF0007818138000340.tif33170

[0730] 2-Cyclopentyl-4-[(1R,2S)-2-hydroxycyclohexoxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 130) TIFF0007818138000341.tif33170

[0731] In Procedure A, a mixture of the title compounds was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and rac-(1R,2S)-cyclohexane-1,2-diol / NaH / THF in Step 5. The mixture was separated by preparative HPLC (neutral conditions) to give 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) TIFF0007818138000342.tif33170

[0733] 2-Cyclopentyl-4-[(1R,2R)-2-hydroxycyclohexoxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 132) TIFF0007818138000343.tif33170

[0734] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and rac-(1S,2S)-cyclohexane-1,2-diol / NaH / THF in Step 5. The mixture was separated by preparative HPLC (neutral conditions) to give 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 TIFF0007818138000344.tif32170

[0736] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and tetrahydro-2H-pyran-4-ol / NaH / DMF in Step 5 to give 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 TIFF0007818138000345.tif32170

[0738] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1 and (3S)-tetrahydropyran-3-ol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000346.tif33170

[0740] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in step 1 and hydroquinone in step 5 to give 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 TIFF0007818138000347.tif32170

[0742] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in step 1 and resorcinol in step 5 to give 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 TIFF0007818138000348.tif33170

[0744] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in step 1 and catechol in step 5 to give 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 TIFF0007818138000349.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 in Step 5 to give tert-butyl N-[3-[2-cyclopentyl-5-[[(E,1S)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]pyrimidin-4-yl]oxyphenyl]carbamate as a yellow solid. TIFF0007818138000350.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 give a residue. The residue was dissolved in MeCN (1 mL), and the resulting solution was purified by preparative HPLC to give the title compound (17.8 mg) as a yellow solid. 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 TIFF0007818138000351.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 in Step 3 to give the title compound. LC-MS m / z: 466.2 [M+1].

[0370] Example 140 TIFF0007818138000352.tif38170

[0750] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and 1,2,3,4,5-pentadeuterio-6-deuteriooxy-benzene in Step 5 to give 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 TIFF0007818138000353.tif32170

[0752] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and spiro[3.3]heptan-2-ol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000354.tif31170

[0754] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and spiro[2.3]hexan-5-ol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000355.tif32170

[0756] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and norbornan-1-ol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000356.tif29170

[0758] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and cyclopentanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000357.tif36170

[0760] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and (1S,5R)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000358.tif30170

[0762] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and 3,3-difluorocyclopentanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000359.tif37170

[0764] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1, cyclopropanecarboxamidine in Step 3, and 2,2-difluorocyclopentanol / LiHMDS / THF in Step 5. The mixture was purified by preparative HPLC (reverse phase, HO / MeCN = 5-95%) to give 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 TIFF0007818138000360.tif32170

[0766] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and rac-(1R,2R)-2-fluorocyclohexanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000361.tif23170

[0768] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and cyclopropanemethanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000362.tif31170

[0770] In Procedure A, tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, cyclopropanecarboxamidine in Step 3, and 3-chlorocyclobutanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000363.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 in Step 3, and 1,2,3,4,5-pentadeuterio-6-deuteriooxy-benzene in Step 5 to give 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 TIFF0007818138000364.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 in Step 3, and cyclopentanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000365.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 in Step 3, and cyclohexanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000366.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 in Step 3, and 4,4-difluorocyclohexanol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000367.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 in Step 3, and 3,3-difluorocyclobutan-1-ol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000368.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 in Step 3, and (1S,5R)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000369.tif32170

[0784] In Procedure A, tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH was used in Step 1, 2,2-difluoropropanamidine in Step 3, and (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol / NaH / DMF in Step 5 to give 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 TIFF0007818138000370.tif36170

[0786] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1, 2,2-dimethylpropanamidine hydrochloride in Step 3, and (1R,3s,5S)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in Step 5. 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 TIFF0007818138000371.tif36170

[0788] In Procedure A, the title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in Step 1, 2,2-dimethylpropanamidine hydrochloride in Step 3, and (1R,3s,5S)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in Step 5. 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 TIFF0007818138000372.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 in Step 3, and 1-hydroxycyclopentane-1-carbonitrile / LiHMDS / THF in Step 5 to give 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 TIFF0007818138000373.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 in Step 3 to give 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 TIFF0007818138000374.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 in Step 3 to give 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 TIFF0007818138000375.tif32170

[0394]

[0796] Step B

[0797] Process 1 TIFF0007818138000376.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 KCO (900 mg) and then stirred at 25 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 2 / 1) to give ethyl 2-methylsulfanyl-4-phenoxy-pyrimidine-5-carboxylate as a brown oil (800 mg, 64% yield).

[0395]

[0799] Process 2 TIFF0007818138000377.tif32170

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

[0396]

[0801] Process 3 TIFF0007818138000378.tif32170

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

[0397]

[0803] Following 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: 431.1 [M+1].

[0398] Example 165

[0804] (S,E)-2-(Cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide TIFF0007818138000379.tif28170

[0805] In Procedure B, cyclopentanol / LiHMDS was used in step 3 to give the title compound. 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 TIFF0007818138000380.tif32170

[0807] In Procedure B, 7-azabicyclo[2.2.1]heptane hydrochloride was used in step 3 to give the title compound. 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 TIFF0007818138000381.tif34170

[0401]

[0809] Step C

[0810] Process 1 TIFF0007818138000382.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) was added DCM (200 mL) and SO2Cl2 (125 mL) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 12 h. The reaction mixture was poured into ice-cold 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 give a residue. The residue was purified by flash column (petroleum ether:ethyl acetate = 1:0 to 5:1) to give ethyl 2-chloro-4-phenoxy-pyrimidine-5-carboxylate as a white solid (13.0 g, 45% yield).

[0402]

[0812] Process 2 TIFF0007818138000383.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) was added DIPEA (694 mg, 5.37 mmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give ethyl 4-phenoxy-2-pyrrolidin-1-yl-pyrimidine-5-carboxylate as a white solid (130 mg, 29% yield).

[0403]

[0814] Steps 6 and 7 of Procedure A were followed to give the title compound. 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 TIFF0007818138000384.tif34170

[0816] In procedure C, [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the last step to give 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 TIFF0007818138000385.tif34170

[0818] In Procedure C, 3-methoxyazetidine was used in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give 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 TIFF0007818138000386.tif36170

[0820] In Procedure C, 2-azaspiro[3.3]heptane was used in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid was used in the last step to give 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 TIFF0007818138000387.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 last step to give 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 TIFF0007818138000388.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 last step to give 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 TIFF0007818138000389.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 last step to give 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 TIFF0007818138000390.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 last step to give 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 TIFF0007818138000391.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 in the last step to give 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 TIFF0007818138000392.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 in the last step to give 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 TIFF0007818138000393.tif32170

[0834] In Procedure C, dimethylamine hydrochloride was used in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give 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 TIFF0007818138000394.tif32170

[0836] In procedure C, methylamine hydrochloride was used in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give 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 TIFF0007818138000395.tif34170

[0838] In procedure C, using diethylamine in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step, the title compound was obtained. 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 TIFF0007818138000396.tif32170

[0840] In Procedure C, N-methylcyclopropanamine hydrochloride was used in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give the title compound. 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 TIFF0007818138000397.tif32170

[0842] In Procedure C, azetidine hydrochloride was used in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give the title compound. 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 TIFF0007818138000398.tif34170

[0844] In Procedure C, 3-fluoroazetidine hydrochloride was used in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give the title compound. 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 TIFF0007818138000399.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 last step to give 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 TIFF0007818138000400.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 last step to give 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 TIFF0007818138000401.tif32170

[0850] In procedure C, N-ethylmethylamine was used in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give 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 TIFF0007818138000402.tif32170

[0852] In Procedure C, N-methylisopropylamine was used in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step to give 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 TIFF0007818138000403.tif32170

[0424]

[0854] Process 1 TIFF0007818138000404.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) was added methylaminoacetaldehyde dimethyl acetal (220 mg, 1.85 mmol), HATU (1.0 g), and DIPEA (0.91 mL). The mixture was stirred under N at 25 °C for 12 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (Biotage using a 12 g 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] Process 2 TIFF0007818138000405.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 under N at 0 °C for 3 hours. 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 NaSO, 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, following Step 1, 2-cyclopentyl-N-methyl-N-(2-oxoethyl)-4-phenoxy-pyrimidine-5-carboxamide was used to give the title compound. 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 TIFF0007818138000406.tif32170

[0860] 2-Cyclopropyl-4-phenoxy-pyrimidine-5-carboxylic acid / 3-azetidinone was used in step 1 of the procedure for the compound of Example 187 to give 1-(2-cyclopropyl-4-phenoxy-pyrimidine-5-carbonyl)zetidin-3-one. Following step 1 of Procedure A, n BuLi was used as a base to give the title compound. 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 TIFF0007818138000407.tif32170

[0862] The title compound was obtained following the procedure for the compound of Example 188 using 2-tert-butyl-4-phenoxy-pyrimidine-5-carboxylic acid. 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 TIFF0007818138000408.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 directly purified by preparative HPLC (reverse-phase, MeCN / HO (0.1% FA): 5-95%) to give the title compound as a white solid (2.8 mg, 4% yield). 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 TIFF0007818138000409.tif32170

[0866] The title compound was obtained following the procedure of the compound of Example 190 using methyl (triphenylphosphoranylidene)acetate as the starting material. 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 TIFF0007818138000410.tif34170

[0868] Process 1 TIFF0007818138000411.tif23170

[0869] To a solution of (3,3-difluorocyclobutyl)methanol (1 g, 8.19 mmol) in DCM (30 mL, 0.273 M) was added Dess-Martin periodinane (4.86 g, 11.47 mmol) at 25 °C, and the mixture was stirred for 14 h. The mixture was filtered, and the filter cake was rinsed with DCM (3 × 5 mL). The combined filtrate was then washed with saturated NaSO solution (3 × 30 mL), saturated NaHCO solution (3 × 30 mL), and brine (20 mL). The combined organic layer was dried over anhydrous NaSO and filtered to give crude 3,3-difluorocyclobutanecarbaldehyde (983 mg).

[0432]

[0870] Process 2 TIFF0007818138000412.tif27170

[0871] To a solution of 3,3-difluorocyclobutanecarbaldehyde (713 mg, 5.94 mmol) and 2-methylpropane-2-sulfinamide (600 mg, 4.95 mmol) in DCM (10 mL, 0.495 M) was added copper sulfate (1.98 g, 12.38 mmol). 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 filtrate was concentrated to dryness to give a residue. The residue was purified by flash chromatography (Biotage using a 20 g Agela flash silica gel column, eluting with 10% to 15% ethyl acetate in petroleum ether) to give (Z)-N-((3,3-difluorocyclobutyl)methylene)-2-methylpropane-2-sulfinamide as a pale yellow oil (770 mg, 70% yield).

[0433]

[0872] Process 3 TIFF0007818138000413.tif27170

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

[0434]

[0874] Process 4 TIFF0007818138000414.tif27170

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

[0435]

[0876] Process 5 TIFF0007818138000415.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) was 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 under N at 25 °C for 2 h. 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (Biotage using a 12 g Agela flash silica gel column, eluting with 15% to 17% ethyl acetate in petroleum ether) to give 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] Process 6 TIFF0007818138000416.tif36170

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

[0437]

[0880] Process 7 TIFF0007818138000417.tif36170

[0881] To a solution of diethyl ((methylsulfonyl)methyl)phosphonate (92.3 mg, 0.40 mmol) in THF (5 mL, 0.052 M) was added sodium hydride (11.7 mg, 0.29 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. 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 h, the reaction mixture was poured into ice-cold 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 give a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100*30mm*10µM, water (NH4HCO3) / MeCN = 35-55% B, flow rate = 25mL / min) to give a mixture of the title compounds (50mg, 28% yield). The mixture was separated by chiral SFC (column: Daicel ChiralPak AD (250mm*30mm*10µm), neutral methanol) to give 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 TIFF0007818138000418.tif33170

[0439]

[0883] Process 1 TIFF0007818138000419.tif28170

[0884] To a solution of methyl (S)-2-amino-2-cyclopropyl acetate (0.8 g, 6.19 mmol) in DCE (20 mL, 0.310 M) was added di(phenyl)methanimine (1.12 g, 6.19 mmol) under N at 25 °C. 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 give methyl (2S)-2-(benzhydrylideneamino)-2-cyclopropyl-acetate as a yellow oil (0.82 g, 45% yield).

[0440]

[0885] Process 2 TIFF0007818138000420.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) over 2 h at 0 °C. DO (20 mL) was added to the mixture, which was warmed to 25 °C under N. 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 NaSO, filtered, and concentrated under reduced pressure to give crude methyl 2-(benzhydrylideneamino)-2-cyclopropyl-2-deuterio-acetate (100 mg) as a yellow oil.

[0441]

[0887] Process 3 TIFF0007818138000421.tif28170

[0888] To 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 2 N HCl (2 mL) under N at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, poured into HO (5 mL), and extracted with EtOAc (3 × 10 mL). The aqueous solution was then filtered and concentrated under reduced pressure to give crude methyl 2-amino-2-cyclopropyl-2-deuterio-acetate hydrochloride as a colorless oil (25 mg).

[0442]

[0889] Process 4 TIFF0007818138000422.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) was 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 h. 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 1:1) to give methyl 2-(tert-butoxycarbonylamino)-2-cyclopropyl-2-deuterio-acetate as a colorless oil (0.35 g, 84% yield).

[0443]

[0891] Methyl 2-(tert-butoxycarbonylamino)-2-cyclopropyl-2-deuterioacetate was converted to tert-butyl N-(1-cyclopropyl-1-deuterio-2-oxo-ethyl)carbamate via LAH reduction and DMP oxidation as previously described. In Procedure A, tert-butyl N-(1-cyclopropyl-1-deuterio-2-oxo-ethyl)carbamate was used in Step 1 and 2,2-difluoropropanamidine in Step 3 to give a mixture of the title compounds. The mixture was separated by chiral SFC to give 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 TIFF0007818138000423.tif32170

[0445]

[0893] Process 1 TIFF0007818138000424.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 h. The reaction mixture 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 give a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 10 / 1, Rf (product) = 0.5) to give ethyl 4-(cyclohexoxy)-2-cyclopentyl-pyrimidine-5-carboxylate as a yellow oil (0.1 g, 25% yield).

[0446]

[0895] In Procedure A, using ethyl 4-(cyclohexoxy)-2-cyclopentyl-pyrimidine-5-carboxylate according to step 6 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid according to step 7, 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 TIFF0007818138000425.tif32170

[0897] Using cyclopentanol in step 1 in the procedure for the compound of Example 196 gave the title compound. LC-MS m / z: 408.2 [M+1].

[0448] Example 198

[0898] (E)-4-Cyclopentyl-2-(cyclopentyloxy)-N-(3-(methylsulfonyl)allyl)benzamide TIFF0007818138000426.tif32170

[0899] Using the procedure for the compound of Example 196, using cyclopentanol and methyl 4-cyclopentyl-2-hydroxybenzoate in step 1 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonate 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 TIFF0007818138000427.tif34170

[0450]

[0901] Step D

[0902] Process 1 TIFF0007818138000428.tif25170

[0903] Pd(dppf)Cl (702 mg, 0.97 mmol) was added to a mixture of methyl 4,6-dichloronicotinate (2 g, 9.71 mmol), cyclopenten-1-ylboronic acid (978 mg, 8.74 mmol), and KCO (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 under N for 16 h. 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 NaSO, 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-(cyclopenten-1-yl)pyridine-3-carboxylate as a yellow oil (1.5 g, 65% yield).

[0451]

[0904] Following step 5 in Procedure A, methyl 4-chloro-6-(cyclopenten-1-yl)pyridine-3-carboxylate was used to give methyl 6-(cyclopenten-1-yl)-4-phenoxy-pyridine-3-carboxylate.

[0452]

[0905] Process 2 TIFF0007818138000429.tif34170

[0906] Pd / C (200 mg) was added to methyl 6-(cyclopenten-1-yl)-4-phenoxy-pyridine-3-carboxylate (310 mg, 1.05 mmol) in THF (7 mL, 0.150 M). The resulting mixture was stirred under H (15 psi) at 25 °C for 16 h. 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, using methyl 6-cyclopentyl-4-phenoxy-pyridine-3-carboxylate according to step 6 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid according to step 7, the title compound was obtained. 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 TIFF0007818138000430.tif34170

[0909] In Procedure A, using methyl 6-(cyclopenten-1-yl)-4-phenoxy-pyridine-3-carboxylate according to Step 6 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid according to Step 7, the title compound was obtained. 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 TIFF0007818138000431.tif34170

[0911] In procedure D, ethyl 2,6-dichloropyridine-3-carboxylate was used in step 1 to give 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 TIFF0007818138000432.tif34170

[0913] In Procedure A, using ethyl 6-cyclopentyl-2-phenoxy-pyridine-3-carboxylate according to step 6 and [(E,1S)-1-cyclop...

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof [In the formula, 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 is cycloalkyl; R ３ is an 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 C2-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 is alkyl; W is W １ , W ２ , W ３ , W ４ , or W ５ and W １ teeth: and During the ceremony, The bond represented by indicates that it can exist as either the (Z)- or (E)-geometric isomer; indicates the point of attachment; R ６ is H; R ７ is H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ８ cycloalkyl, or an optionally substituted 5- to 6-membered heterocyclyl; R ７ａ is H or deuterium; R ８ is H; R ９ is H; R １０ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ８ cycloalkyl, or an optionally substituted 5- to 6-membered heterocyclyl; Or, W 1 is where: The bond represented by indicates that it can exist as either the (Z)- or (E)-geometric isomer; indicates the point of attachment; W ２ teeth: and During the ceremony, The bond represented by may exist as either the (Z)- or (E)-geometric isomer; indicates the point of attachment; R １１ is H; R １２ is H or optionally substituted C １ -C ６ is alkyl; R １２ａ is H; R １３ and R １４ are each H; Or, W 2 is: and During the ceremony, R 21 is H or C 1 -C 6 alkyl; The bond represented by may exist as either the (Z)- or (E)-geometric isomer; indicates the point of attachment; W ３ teeth: and During the ceremony, indicates the point of attachment; R １５ is H; R １６ is H or optionally substituted C １ -C ６ Alkyl or optionally substituted C ３ -C ８ is cycloalkyl; W ４ teeth: and During the ceremony, indicates the point of attachment; R １７ is H; R １８ is H or optionally substituted C １ -C ６ is alkyl; Each R ａ are independently optionally substituted C １ -C ６ is alkyl; W ５ teeth: and During the ceremony, The bond represented by may exist as either the (Z)- or (E)-geometric isomer; indicates the point of attachment; m is 1, 2, or 3; R １９ is C １ -C ６ Alkyl and —O—(C １ -C ６ alkyl).

2. 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 is 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 C2-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 But 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 is 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 an 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; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ -O-(C ６ -C １０ aryl); R ３ is fluoro-substituted C １ -C ６ is alkyl; R ５ is H; R ６ is H; R ７ is C ３ -C ８ is cycloalkyl; R ７ａ is H or deuterium; R ８ is H; R ９ is H; R １０ is C １ -C ６ is alkyl, 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof.

4. R １ In: -O-(optionally substituted C ３ -C ８ the optional substituents of C are 1 to 3 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 a cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C ３ -C ６ forming a cycloalkyl; or C ３ -C ８ When two substituents are present on adjacent ring carbon atoms of a cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C ３ -C ６ Forming a cycloalkyl; -O-(optionally substituted C ６ -C １０ aryl) are optionally substituted with halo, C １ -C ６ Alkyl, cyano, hydroxy, and —NH ２ or 1 to 5 deuterium atoms; R ３ In: Optionally substituted C ３ -C ８ The optional substituents on the cycloalkyl are hydroxy, halo, C １ -C ６ Alkyl, and C ６ -C １０ aryl; or C ３ -C ８ When two substituents are present on the same carbon atom of a cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C ３ -C ６ forming a cycloalkyl; or C ３ -C ８ When two substituents are present on adjacent ring carbon atoms of a cycloalkyl, the substituents, together with the ring carbon atoms to which they are attached, form a C ６ -C １０ Forming an aryl; Optionally substituted C ６ -C １０ The optional substituents on the aryl are 1 to 3 substituents selected from the group consisting of halo; Optionally substituted C １ -C ６ Alkyl or C ６ The optional substituents on alkenyl are halo, hydroxy, —O—(C １ -C ６ alkyl), and optionally substituted C ３ -C ６ 1 to 5 substituents selected from the group consisting of cycloalkyl, C ３ -C ６ The optional substituents on the cycloalkyl are C １ -C ６ alkyl; -NR ２ C of R １ -C ６ The optional substituents on alkyl are 1 to 3 substituents selected from the group consisting of halo; Optional substituents of the optionally substituted 4- to 6-membered heterocyclyl are —O—(C １ -C ６ alkyl), C １ -C ６ and 1 to 3 substituents selected from the group consisting of alkyl, halo; or when two substituents are present on the same carbon atom of an optionally substituted 4- to 6-membered heterocyclyl, the substituents together with the ring carbon atoms to which they are attached form C ３ -C ６ forming a cycloalkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. W is W １ 2. The compound of claim 1, wherein:

6. W is W ２ 2. The compound of claim 1, wherein:

7. W ２ but: and During the ceremony, R ２１ is H or C １ -C ６ is alkyl; The bond represented by indicates that it can exist as either the (Z)- or (E)-geometric isomer; 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment.

8. W is W ３ 2. The compound of claim 1, wherein:

9. R １６ Optionally substituted C １ -C ６ alkyl is methyl; R １６ Optionally substituted C ３ -C ８ cycloalkyl is cyclopropyl; 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof.

10. W is W ４ 2. The compound of claim 1, wherein:

11. R １８ Optionally substituted C １ -C ６ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein alkyl is methyl.

12. W is W ５ 2. The compound of claim 1, wherein:

13. R １９ C １ -C ６ alkyl is methyl; R １９ -O-(C １ -C ６ alkyl) is methoxy; 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof.

14. 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; 2-cyclopropyl-N-((1,1-dioxide-2H-thiet-3-yl)methyl)-4-phenoxypyrimidine-5-carboxamide; 2-cyclopropyl-N-(1,1-dioxide-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)pent-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)pent-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; (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)pent-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)pent-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)pent-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)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide; (S,E)-N-(5,5-difluoro-1-(methylsulfonyl)pent-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)pent-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)-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 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

15. 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 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

16. 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 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. The compound is: (S)-2-(1,1-difluoroethyl)-N-(5-(dimethylamino)-5-oxopent-3-yn-2-yl)-4-phenoxypyrimidine-5-carboxamide 2. The compound of claim 1, wherein:

18. 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 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

20. formula: or a pharmaceutically acceptable salt thereof.

21. 21. A pharmaceutical composition comprising the compound of claim 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

22. formula: Compound.

23. 23. A pharmaceutical composition comprising a compound of claim 22 and a pharmaceutically acceptable carrier or excipient.

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