Pharmaceutical compositions comprising WRN helicase inhibitors

Abstract

Disclosed are compounds of Formula (I): # imgabs0 # or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R3, X, Y, Z and W are as defined herein. The compounds are inhibitors of, for example, WRN helicase and are useful in the treatment of proliferative diseases such as cancer.

Description

Technical Field

[0001] The present invention relates to compounds that are inhibitors of Werner syndrome helicase (WRN helicase), pharmaceutical compositions comprising the inhibitors, and methods of treatment using the inhibitors. Background Art

[0002] RECQ helicase is a DNA-dependent ATPase that unwinds DNA from 3' to 5' DNA. Three RECQ helicases (BLM, Werner (WRN) and RECQL4) cause overlapping but different human syndromes when their expression is altered or lost (de Renty C, Ellis N A. Aging Res Rev 2017; 33: 36-51). In 2019, WRN was independently identified by multiple research groups as a potential synthetic lethal target for cancers expressing high levels of microsatellite instability (MSI-H cancer) (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). There are several reports describing the identification of small molecules that inhibit WRN helicase activity by unknown mechanisms (Aggarwal et al., Cancer Res. 2013, 73, 5497; Aggarwal et al., PNAS 2011, 108, 4, 1525-1530; Sommers et al., PLoS ONE 2019, 14(1), e0210525).

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

[0004] Some embodiments described herein relate to a compound of formula (I):

[0005]

[0006] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0007] X is CR 2 or N;

[0008] Y is CR 4 or N;

[0009] Z is CR 5 or N;

[0010] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[0011] The condition is that X, Y and Z are not N at the same time;

[0012] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0013] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[0014] to six-membered heterocyclic group;

[0015] R 2 is H, optionally substituted C1-C6 alkyl or halo;

[0016] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[0017] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[0018] C 10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0019] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0020] R 4 is H, C1-C6 alkyl, cyano or halo,

[0021] or R 4 Together with the carbon atom to which it is attached and Z, form an optionally substituted five-membered

[0022] to six-membered heteroaryl;

[0023] or R 3 and R 4Together with the carbon atom to which they are attached, they form an optionally substituted C6-

[0024] C 10 Aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0025] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0026] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl);

[0027] Each R is independently H or an optionally substituted C1-C6 alkyl group;

[0028] W for W 1 、W 2 、W 3 、W 4 or W 5 ;

[0029] W 1 for:

[0030]

[0031] in:

[0032] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0033] R 6 is H;

[0034] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0035] R 7a is H or deuterium;

[0036] R 8 is H;

[0037] R 9 is H; and

[0038] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group;

[0039] or R 6 Together with the nitrogen atom to which it is attached and R 7 and R 7aConnect with them as shown

[0040] The connected carbon atoms form an azetidinyl ring;

[0041] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a and R 8 With them

[0042] The carbon atoms shown are joined together to form an azetidinyl or pyrrolidinyl ring;

[0043] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a 、R 8 and R 9 With it

[0044] The carbon atoms shown are connected together to form a dihydropyrrolyl ring;

[0045] or R 7 、R 7a 、R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached, they form a 2,3-dihydrothiophene 1,1-dioxide ring; or

[0046] R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form a 1,1-dioxido-2H-thietidenyl ring;

[0047] W 2 for:

[0048]

[0049] in:

[0050] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0051] R 11 is H;

[0052] R 12 is H or an optionally substituted C1-C6 alkyl group;

[0053] R 12a is H; and

[0054] R 13 and R14 Each is H;

[0055] or R 11 Together with the nitrogen atom to which it is attached and R 12 、R 12a and R 13 With them

[0056] The carbon atoms shown are joined together to form an optionally substituted azetidinyl ring;

[0057] W 3 for:

[0058]

[0059] in:

[0060] Indicates the connection point;

[0061] R 15 is H;

[0062] R 16 is H or an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group;

[0063] W 4 for:

[0064]

[0065] in:

[0066] Indicates the connection point;

[0067] R 17 is H;

[0068] R 18 is H or optionally substituted C1-C6 alkyl; and

[0069] Each R a are independently optionally substituted C1-C6 alkyl;

[0070] W 5 for:

[0071]

[0072] in:

[0073] Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicates the connection point;

[0074] m is 1, 2, or 3; and

[0075] R 19 Selected from the group consisting of: C1-C6 alkyl and -O-(C1-C6 alkyl).

[0076] Some embodiments described herein relate to a compound of formula (II):

[0077]

[0078] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0079] X is CR 2 or N;

[0080] Y is CR 4 or N;

[0081] Z is CR 5 or N;

[0082] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[0083] The condition is that X, Y and Z are not N at the same time;

[0084] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0085] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[0086] to six-membered heterocyclic group;

[0087] R 2 is H, optionally substituted C1-C6 alkyl or halo;

[0088] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[0089] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[0090] C 10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0091] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0092] R 4 is H, C1-C6 alkyl, cyano or halo;

[0093] or R 4 Together with the carbon atom to which it is attached and Z, form an optionally substituted five-membered

[0094] to six-membered heteroaryl;

[0095] or R 3 and R 4 Together with the carbon atoms to which they are attached as shown and R 3 To form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted penta

[0096] 1- to 6-membered heterocyclic group or heterocycloalkenyl group;

[0097] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl);

[0098] Each R is independently H or optionally substituted C1-C6 alkyl; and

[0099] V comprises an electrophile that reacts with the sulfur atom at cysteine ​​727 shown in SEQ ID NO: 1 or a variant thereof and forms a covalent bond.

[0100] Some embodiments described herein also provide a pharmaceutical composition 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.

[0101] Some embodiments described herein also provide a method of treating a disease in a patient (such as a proliferative disease, e.g., cancer), comprising administering to a patient in need thereof 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.

[0102] Some embodiments described herein also provide a method of inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a subject in need of such inhibition, 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.

[0103] Some embodiments described herein also provide a method of inhibiting WRN helicase (Werner syndrome ATP-dependent helicase), the method comprising effecting a non-naturally occurring covalent modification at cysteine ​​727 as shown in SEQ ID NO: 1 or a variant thereof, the modification resulting from a bond-forming reaction between an electrophile and cysteine ​​727 as shown in SEQ ID NO: 1 or a variant thereof, wherein the sulfur atom at the cysteine ​​residue undergoes reaction with the electrophile.

[0104] 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 the WRN helicase protein, wherein the modified WRN helicase protein comprises SEQ ID NO: 1 or a variant thereof as shown herein; and has a structure of Formula (III):

[0105]

[0106] in:

[0107] S is the sulfur atom of cysteine ​​727 in SEQ ID NO: 1 or a variant thereof;

[0108] and represents amino acid positions 1 to 726 and 7288 to 1432 of SEQ ID NO: 1 or a variant thereof, respectively; and

[0109] Q for Q 1 , Q 2 , Q 3 , Q 4 or Q 5 ;in:

[0110] Q 1 for:

[0111]

[0112] in:

[0113] Indicates the connection point;

[0114] R 6 is H;

[0115] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0116] R 7a is H or deuterium;

[0117] R 8 is H;

[0118] R 9 is H; and

[0119] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group;

[0120] or R 6 Together with the nitrogen atom to which it is attached and R 7 and R 7a Connect with them as shown

[0121] The connected carbon atoms form an azetidinyl ring;

[0122] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a and R 8 With them

[0123] The carbon atoms shown are joined together to form an azetidinyl or pyrrolidinyl ring;

[0124] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a 、R 8 and R 9 With it

[0125] The carbon atoms shown are connected together to form a dihydropyrrolyl ring;

[0126] or R 7 、R 7a 、R 8 、R 9 and R 10Together with the carbon atoms to which they are attached as shown, they form 2,3-dihydrothiophene 1,1-dioxide;

[0127] or R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form a 1,1-dioxido-2H-thietidenyl ring;

[0128] Q 2 for:

[0129]

[0130] in:

[0131] Indicates the connection point;

[0132] R 11 is H;

[0133] R 12 is H or an optionally substituted C1-C6 alkyl group;

[0134] R 12a is H; and

[0135] R 13 and R 14 Each is H;

[0136] or R 11 Together with the nitrogen atom to which it is attached and R 12 、R 12a and R 13 With them

[0137] The carbon atoms shown are joined together to form an optionally substituted azetidinyl ring;

[0138] Q 3 for:

[0139]

[0140] in:

[0141] Indicates the connection point;

[0142] R 15 is H; and

[0143] R 16 is H or an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group;

[0144] Q 4 for:

[0145]

[0146] in:

[0147] Indicates the connection point;

[0148] R 17 is H;

[0149] R 18 is H or optionally substituted C1-C6 alkyl; and

[0150] Each R a are independently optionally substituted C1-C6 alkyl;

[0151] Q 5 for:

[0152]

[0153] in:

[0154] Indicates the connection point;

[0155] m is 1, 2, or 3; and

[0156] R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl); and

[0157] U is:

[0158]

[0159] in:

[0160] Indicates the connection point;

[0161] X is CR 2 or N;

[0162] Y is CR 4 or N;

[0163] Z is CR 5 or N;

[0164] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[0165] The condition is that X, Y and Z are not N at the same time;

[0166] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0167] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[0168] to six-membered heterocyclic group;

[0169] R 2 is H, optionally substituted C1-C6 alkyl or halo;

[0170] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[0171] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[0172] C 10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0173] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0174] R 4 is H, C1-C6 alkyl, cyano or halo,

[0175] or R 4 Together with the carbon atom to which it is attached and Z, form an optionally substituted five-membered

[0176] to six-membered heteroaryl;

[0177] or R 3 and R 4 Together with the carbon atom to which they are attached, they form an optionally substituted C6-

[0178] C 10 Aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0179] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0180] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl); and

[0181] Each R is independently H or optionally substituted C1-C6 alkyl.

[0182] Additional aspects and advantages of the present disclosure will become 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 appreciated, the present disclosure supports other different embodiments, and its several details are capable of modification in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative and not restrictive.

[0183] Incorporated by reference

[0184] 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 a publication, patent, or patent application incorporated by reference conflicts with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0185] definition

[0186] Unless otherwise indicated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings. All undefined technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0187] Unless otherwise indicated, as used herein, "a / 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. Thus, the terms "a / an," "one or more," and "at least one" can be used interchangeably herein.

[0188] "Patient" includes both humans and animals. "Patient" and "subject" are used interchangeably herein.

[0189] When a range of values ​​is listed, it is intended to include every value and subrange within that range. For example, “C 1–6 Alkyl) (or "C1-C6 alkyl") is intended to encompass: 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.

[0190] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 15 carbon atoms ("C 1-15 In some embodiments, an alkyl group has 1 to 14 carbon atoms ("C 1-14 In some embodiments, an alkyl group has 1 to 13 carbon atoms ("C 1-13 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 11 carbon atoms ("C 1-11 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butane (C5), tert-pentyl (C5) and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like.

[0191] "Alkenyl" refers to a straight or branched chain hydrocarbon radical 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, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 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 the above-mentioned C 2-4 Alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0192] "Alkynyl" refers to a straight or branched chain hydrocarbon radical ("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 2-8In some embodiments, an 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, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has 2 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 include the above-mentioned C 2-4 Alkynyl groups as well as pentynyl (C5), hexynyl (C6), etc. Further examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0193] "Carbocyclyl," "cycloalkyl," or "carbocyclic" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, the 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, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a 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 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8Carbocyclyl groups include but are not limited to the above C 3-6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclyl groups include but are not limited to the above C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As shown in the above examples, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged, or spirocyclic ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")), and may be saturated or may 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, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbon atoms still refers to the number of carbon atoms in the carbocyclic ring system.

[0194] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-14 In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-10 In some embodiments, a 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 the cycloalkyl group include the above-mentioned C 5-6 Cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the cycloalkyl group include the above-mentioned C 3-6Cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).

[0195] "Cycloalkenyl" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, the cycloalkenyl group is a non-aromatic cyclic hydrocarbon group consisting of a "cycloalkyl" ("cycloalkyl") and zero heteroatoms, wherein at least two of the carbon atoms have a carbon-carbon double bond. In some embodiments, the cycloalkenyl group has 3 to 14 ring carbon atoms and at least one double bond. In some embodiments, the cycloalkenyl group has 3 to 10 ring atoms and at least one double bond. In some embodiments, the cycloalkenyl group has 3 to 6 ring atoms and at least one double bond. In some embodiments, the cycloalkenyl group has two double bonds.

[0196] "Heterocyclyl" or "heterocyclic" refers to a radical or free radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is 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 a carbon or nitrogen atom, if valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spirocyclic ring systems, such as bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may include 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, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members still refers to the number of ring members in the heterocyclyl ring system.

[0197] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl group has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl group has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0198] Exemplary 3-membered heterocyclic groups containing 1 heteroatom include but are not limited to aziridinyl, oxiranyl, and thiranyl. Exemplary 4-membered heterocyclic groups containing 1 heteroatom include but are not limited to azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing 1 heteroatom include but are not limited to tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include but are not limited to dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthylimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepanyl, 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, etc.

[0199] "Aryl" refers to a radical ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 "Aryl"; for example, 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" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system.

[0200] "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 π electrons shared in the cyclic array) having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom if valence permits. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members still refers to 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, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members refers 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 heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0201] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is 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 provided in the aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is 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 provided in the aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl group has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0202] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, aza Azepinyl, oxa Oxepinyl and thia Thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0203] "Saturated" means that the ring portion does not contain double or triple bonds, ie, the ring contains single bonds throughout.

[0204] Alkyl, alkenyl, cycloalkenyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl groups can be optionally substituted. "Optionally substituted" means that the group can be substituted or unsubstituted. Generally speaking, the term "substituted" means that at least one hydrogen present on the group is replaced by a non-hydrogen substituent, and it produces a stable compound after replacement, for example, a compound that will not spontaneously undergo conversion (such as by rearrangement, cyclization, elimination or other reactions). Heteroatoms (such as nitrogen, oxygen and sulfur) can have hydrogen substituents and / or non-hydrogen substituents that satisfy the valence of the heteroatoms and cause the formation of stable compounds.

[0205] Exemplary non-hydrogen substituents may be selected from the group consisting of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa ,–N(R bb )2、–N(OR cc )R bb,–SH,–SR aa 、–C(=O)R aa , –CO2H, –CHO, –CO2R aa 、–OC(=O)R aa ,–OCO2R aa 、–C(=O)N(R bb )2、–OC(=O)N(R bb )2. –NR bb C(=O)R aa ,–NR bb CO2R aa ,–NR bb C(=O)N(R bb )2、–C(=NR bb )R aa 、–C(=NR bb )OR aa 、–OC(=NR bb )R aa 、–OC(=NR bb )OR aa 、–C(=NR bb )N(R bb )2、–OC(=NR bb )N(R bb )2. –NR bb C(=NR bb )N(R bb )2, –C(=O)NR bb SO2R aa ,–NR bb SO2R aa 、–SO2N(R bb )2. –SO2R aa 、–S(=O)R aa 、–OS(=O)R aa 、-B(OR cc )2、C 1–10 Alkyl, C 2–10 Alkenyl, C 2–10 Alkynyl, C 3–14 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6–14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R dd Group substitution, or two geminal hydrogen atoms on the carbon atom are replaced by a group =O;

[0206] R aa Each instance of is independently selected from the group consisting of: C 1-10 Alkyl, C1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-14 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 Aryl, and a group consisting of 5- to 14-membered heteroaryl, or two R aa The groups are connected to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0207] R bb Each instance of is independently selected from the group consisting of hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. –CO2R aa ,–SO2R aa 、–SO2N(R cc )2. –SOR aa 、C 1–10 Alkyl, C 1–10 Perhalogenated alkyl, C 2–10 Alkenyl, C 2–10 Alkynyl, C 3–14 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 Aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are connected to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0208] R cc Each instance of is independently selected from the group consisting of: hydrogen, C 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-14 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 Aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are connected to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution; and

[0209] R dd Each instance of is independently selected from the group consisting of: halo, –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)(C 1–6 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 Perhalogenated alkyl, C2–6 Alkenyl, C 2–6 Alkynyl, C 3–10 Carbocyclic group, C 6–10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; or two geminal R dd The substituents may be linked to form =0.

[0210] In a preferred embodiment, the optional substituents are selected from the group consisting of halo, cyano, hydroxy, amino, deuterated, -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 Cycloalkyl. In a more preferred embodiment, the optional substituent is selected from the group consisting of fluoro, chloro, trifluoromethyl, cyano, hydroxy, amino, deuterated, methoxy, methyl, ethyl, phenyl, oxo, methylthio, dimethylamino, phenoxy, tert-butoxy, cyclopropyloxy, difluoromethoxy, cyclopropyl and cyclohexyl. In a preferred embodiment, the optional substituent is selected from the group consisting of fluoro, trifluoromethyl, hydroxy, deuterated, methyl, phenyl and cyclopropyl.

[0211] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0212] It should be noted that in the heteroatom-containing ring systems described herein, there are no hydroxyl groups on carbon atoms adjacent to a N, O, or S, and there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

[0213]

[0214] There is no -OH group directly attached to the carbons labeled 2 and 5.

[0215] It should also be noted that tautomeric forms, such as, for example, the following moieties:

[0216]

[0217] are deemed equivalent unless otherwise stated.

[0218] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0219] An "electrophile" is a chemical species that forms a bond with a nucleophile by accepting an electron pair. Such electrophiles typically participate in Michael addition reactions, which involve the nucleophilic addition of a nucleophile to an α,β-unsaturated carbonyl compound containing an electron-withdrawing group. This reaction belongs to the larger class of conjugate additions and is widely used for the mild formation of C-C bonds. The term "Michael acceptor moiety" refers to a functional group capable of participating in a Michael reaction, in which a new covalent bond is formed 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.

[0220] "Effective amount" or "therapeutically effective amount" is intended to describe an amount of a compound or composition described herein that is effective to inhibit the aforementioned enzymes, diseases, or conditions and thereby produce the desired therapeutic, ameliorative, inhibitory, and / or preventative effect.

[0221] "Salts" include any and all salts. "Pharmaceutically acceptable salts" refer to salts that are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutical salts in detail in the following document: 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 formed by amino groups 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, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional 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 alkyl sulfonates, and aryl sulfonates.

[0222] "Solvate" includes any and all solvates. As used herein, the term "pharmaceutically acceptable solvate" is a solvate formed by the association of one or more solvent molecules with one or more molecules of a compound disclosed herein. The term "solvate" includes hydrates (wherein the solvent molecule is water) (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

[0223] As used herein, "microsatellite instability" or "MSI" is defined as an alteration in microsatellite length due to the generation of new length alleles in tumor DNA due to deletions or insertions of repeat units compared to normal / germline DNA from the same individual. A tumor with a "high MSI" (MSI-H) phenotype is a tumor that has DNA sequence length alterations in at least two of the assessed single-nucleotide 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. Single-nucleotide or dinucleotide markers used to characterize MSI status include, but are not limited to, BAT25, BAT26, D2S123, D5S346, and D17S250; also known as the Bethesda panel.

[0224] The compounds described herein may contain one or more asymmetric centers and are therefore capable of existing in a variety of stereoisomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers (including a racemic mixture and a mixture enriched in one or more stereoisomers). According to the Cahn-Ingold Prelog Convention, an asymmetric carbon atom (chiral carbon atom) may have an "R" or "S" configuration. Isomers can be separated from a mixture 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 a single isomer substantially free of other isomers, and alternatively, may be a mixture of multiple isomers.

[0225] 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, compounds having the structures of the present invention except for the replacement of hydrogen by deuterium or tritium, 19 F Sutra 18 F replacement, carbon 13 C or 14 C-enriched carbon substitution, and / or oxygen atoms 18 O substitution) are within the scope of the present disclosure. Other examples of isotopes include 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F. 36 Cl and 123 I. Compounds having such isotopically enriched atoms are useful as analytical tools or probes, for example, in biological assays.

[0226] Certain isotopically labeled compounds of formula (I) (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. Particularly preferred are tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes, because they are easy to prepare and detect. Certain isotopically labeled compounds of formula (I) may be used for medical imaging purposes, for example, using positron emitting isotopes such as 11 C or 18 Those labeled with F are useful in applications in positron emission tomography (PET), and gamma-ray emitting isotopes such as 123 Those labeled with I can be used for applications in single photon emission computed tomography (SPECT). In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. In addition, isotopic substitution at sites where epimerization occurs may slow or reduce the epimerization process, thereby retaining the more active or potent form of the compound for a longer period of time. Isotopically labeled compounds of formula (I), particularly those containing compounds with longer half-lives (t 1 / 2 >1 day) can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

[0227] The present invention provides a series of potent, selective WRN inhibitors that bind to cysteine ​​727 (C727) of WRN via irreversible covalent binding of an electrophilic group. In one embodiment, these inhibitors exhibit potent helicase inhibition, reduced viability of only MSI cell lines, but not MSS cell lines, and complete tumor growth inhibition in a xenograft mouse model of MSI cell lines. In one embodiment, the ATP synergy of these inhibitors (improved efficacy in the presence of ATP or ADP: i.e., cell assays or lysates supplemented with ATP) is a surprising and unexpected feature of these compounds.

[0228] The compounds described herein may also be used in combination with one or more additional therapeutic and / or prophylactic agents (see "Combination Therapies" below).

[0229] In other embodiments, disclosed herein are methods for inhibiting WRN helicase. In some embodiments, the methods comprise administering a compound disclosed herein. In some embodiments, the methods comprise administering ATP. In some embodiments, the methods comprise administering a compound disclosed herein and ATP. In some embodiments, the methods comprise administering ADP. In some embodiments, the methods comprise administering a compound disclosed herein and ADP. Administration can be in vivo. For example, WRN helicase can be inhibited in vivo. Administration can be to a subject. Administration can be to a cell. Administration can be in vitro. For example, WRN helicase can be inhibited in vitro.

[0230] In some embodiments, disclosed herein are methods for performing a WRN helicase activity assay. Some embodiments include methods for measuring WRN helicase activity. The method may include contacting a WRN helicase with a WRN helicase substrate. The method may include administering a WRN helicase substrate. The method may include contacting a WRN helicase with ATP. The method may include administering ATP. The method may include administering a WRN helicase substrate and ATP. The method may include contacting a WRN helicase with ADP. The method may include administering ADP. The method may include administering a WRN helicase substrate and ADP. Administration may be in vivo. For example, the WRN helicase activity assay may be performed in cultured cells. Administration may be directed to cells. Administration may be in vitro. For example, the WRN helicase activity assay may 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.

[0231] Example

[0232] Examples of embodiments of the present application include the following:

[0233] Example 1

[0234] A compound of formula (I):

[0235]

[0236] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0237] X is CR 2 or N;

[0238] Y is CR 4 or N;

[0239] Z is CR 5 or N;

[0240] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[0241] The condition is that X, Y and Z are not N at the same time;

[0242] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0243] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[0244] to six-membered heterocyclic group;

[0245] R 2 is H, optionally substituted C1-C6 alkyl or halo;

[0246] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[0247] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[0248] C10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0249] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0250] R 4 is H, C1-C6 alkyl, cyano or halo;

[0251] or R 4 Together with the carbon atom to which it is attached and Z, form an optionally substituted five-membered

[0252] to six-membered heteroaryl;

[0253] or R 3 and R 4 Together with the carbon atom to which they are attached, they form an optionally substituted C6-

[0254] C 10 Aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0255] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0256] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl);

[0257] Each R is independently H or an optionally substituted C1-C6 alkyl group;

[0258] W for W 1 、W 2 、W 3 、W 4 or W 5 ;

[0259] W 1 for:

[0260]

[0261] in:

[0262] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0263] R 6 is H;

[0264] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0265] R 7a is H or deuterium;

[0266] R 8 is H;

[0267] R 9 is H; and

[0268] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group; or

[0269] R 6 Together with the nitrogen atom to which it is attached and R 7 and R 7a together with the carbon atoms to which they are attached as shown, form an azetidinyl ring;

[0270] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a and R 8 With them

[0271] The carbon atoms shown are joined together to form an azetidinyl or pyrrolidinyl ring;

[0272] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a 、R 8 and R 9 together with the carbon atoms to which they are attached, form a dihydropyrrolyl ring; or

[0273] R 7 、R 7a 、R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form 2,3-dihydrothiophene 1,1-dioxide;

[0274] or R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form a 1,1-dioxido-2H-thietidenyl ring;

[0275] W 2 for:

[0276]

[0277] in:

[0278] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0279] R 11 is H;

[0280] R 12 is H or an optionally substituted C1-C6 alkyl group;

[0281] R 12a is H; and

[0282] R 13 and R 14 Each is H;

[0283] or R 11 Together with the nitrogen atom to which it is attached and R 12 、R 12a and R 13 With them

[0284] The carbon atoms shown are joined together to form an optionally substituted azetidinyl ring;

[0285] W 3 for:

[0286]

[0287] in:

[0288] Indicates the connection point;

[0289] R 15 is H;

[0290] R 16 is H or an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group;

[0291] W 4 for:

[0292]

[0293] in:

[0294] Indicates the connection point;

[0295] R 17 is H;

[0296] R 18 is H or optionally substituted C1-C6 alkyl; and

[0297] Each R a are independently optionally substituted C1-C6 alkyl; and

[0298] W 5 for:

[0299]

[0300] in:

[0301] Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicates the connection point;

[0302] m is 1, 2, or 3; and

[0303] R 19 Selected from the group consisting of: C1-C6 alkyl and -O-(C1-C6 alkyl).

[0304] Example 1A

[0305] A compound of formula (I):

[0306]

[0307] or a pharmaceutically acceptable salt thereof, wherein:

[0308] X is CR 2 or N;

[0309] Y is CR 4 or N;

[0310] Z is CR 5 or N;

[0311] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[0312] The condition is that X, Y and Z are not N at the same time;

[0313] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0314] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[0315] to six-membered heterocyclic group;

[0316] R2 is H, optionally substituted C1-C6 alkyl or halo;

[0317] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[0318] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[0319] C 10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0320] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0321] R 4 is H, C1-C6 alkyl, cyano or halo;

[0322] or R 4 Together with the carbon atom to which it is attached and Z, form an optionally substituted five-membered

[0323] to six-membered heteroaryl;

[0324] or R 3 and R 4 Together with the carbon atom to which they are attached, they form an optionally substituted C6-

[0325] C 10 Aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0326] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0327] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl);

[0328] Each R is independently H or an optionally substituted C1-C6 alkyl group;

[0329] W for W 1 、W 2 、W 3 、W4 or W 5 ;

[0330] W 1 for:

[0331]

[0332] in:

[0333] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0334] R 6 is H;

[0335] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0336] R 7a is H or deuterium;

[0337] R 8 is H;

[0338] R 9 is H; and

[0339] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group; or

[0340] R 6 Together with the nitrogen atom to which it is attached and R 7 and R 7a together with the carbon atoms to which they are attached as shown, form an azetidinyl ring;

[0341] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a and R 8 With them

[0342] The carbon atoms shown are joined together to form an azetidinyl or pyrrolidinyl ring;

[0343] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a 、R 8 and R 9 together with the carbon atoms to which they are attached, form a dihydropyrrolyl ring; or

[0344] R 7 、R 7a 、R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form 2,3-dihydrothiophene 1,1-dioxide;

[0345] or R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form a 1,1-dioxido-2H-thietidenyl ring;

[0346] W 2 for:

[0347]

[0348] in:

[0349] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0350] R 11 is H;

[0351] R 12 is H or an optionally substituted C1-C6 alkyl group;

[0352] R 12a is H; and

[0353] R 13 and R 14 Each is H;

[0354] or R 11 Together with the nitrogen atom to which it is attached and R 12 、R 12a and R 13 With them

[0355] The carbon atoms shown are joined together to form an optionally substituted azetidinyl ring;

[0356] W 3 for:

[0357]

[0358] in:

[0359] Indicates the connection point;

[0360] R 15 is H;

[0361] R 16 is H or an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group;

[0362] W 4 for:

[0363]

[0364] in:

[0365] Indicates the connection point;

[0366] R 17 is H;

[0367] R 18 is H or optionally substituted C1-C6 alkyl; and

[0368] Each R a are independently optionally substituted C1-C6 alkyl; and

[0369] W 5 for:

[0370]

[0371] in:

[0372] Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicates the connection point;

[0373] m is 1, 2, or 3; and

[0374] R 19 Selected from the group consisting of: C1-C6 alkyl and -O-(C1-C6 alkyl).

[0375] Example 1B

[0376] A compound of formula (I):

[0377]

[0378] in:

[0379] X is CR 2 or N;

[0380] Y is CR 4 or N;

[0381] Z is CR 5 or N;

[0382] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[0383] The condition is that X, Y and Z are not N at the same time;

[0384] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0385] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[0386] to six-membered heterocyclic group;

[0387] R 2 is H, optionally substituted C1-C6 alkyl or halo;

[0388] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[0389] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[0390] C 10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0391] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0392] R 4 is H, C1-C6 alkyl, cyano or halo;

[0393] or R 4 Together with the carbon atom to which it is attached and Z, form an optionally substituted five-membered

[0394] to six-membered heteroaryl;

[0395] or R 3 and R 4 Together with the carbon atom to which they are attached, they form an optionally substituted C6-

[0396] C 10 Aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[0397] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[0398] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl);

[0399] Each R is independently H or an optionally substituted C1-C6 alkyl group;

[0400] W for W 1 、W 2 、W 3 、W 4 or W 5 ;

[0401] W 1 for:

[0402]

[0403] in:

[0404] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0405] R 6 is H;

[0406] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0407] R 7a is H or deuterium;

[0408] R 8 is H;

[0409] R 9 is H; and

[0410] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group; or

[0411] R 6Together with the nitrogen atom to which it is attached and R 7 and R 7a together with the carbon atoms to which they are attached as shown, form an azetidinyl ring;

[0412] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a and R 8 With them

[0413] The carbon atoms shown are joined together to form an azetidinyl or pyrrolidinyl ring;

[0414] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a 、R 8 and R 9 together with the carbon atoms to which they are attached, form a dihydropyrrolyl ring; or

[0415] R 7 、R 7a 、R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form 2,3-dihydrothiophene 1,1-dioxide;

[0416] or R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form a 1,1-dioxido-2H-thietidenyl ring;

[0417] W 2 for:

[0418]

[0419] in:

[0420] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0421] R 11 is H;

[0422] R 12 is H or an optionally substituted C1-C6 alkyl group;

[0423] R 12a is H; and

[0424] R 13 and R14 Each is H;

[0425] or R 11 Together with the nitrogen atom to which it is attached and R 12 、R 12a and R 13 With them

[0426] The carbon atoms shown are joined together to form an optionally substituted azetidinyl ring;

[0427] W 3 for:

[0428]

[0429] in:

[0430] Indicates the connection point;

[0431] R 15 is H;

[0432] R 16 is H or an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group;

[0433] W 4 for:

[0434]

[0435] in:

[0436] Indicates the connection point;

[0437] R 17 is H;

[0438] R 18 is H or optionally substituted C1-C6 alkyl; and

[0439] Each R a are independently optionally substituted C1-C6 alkyl; and

[0440] W 5 for:

[0441]

[0442] in:

[0443] Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicates the connection point;

[0444] m is 1, 2, or 3; and

[0445] R 19 Selected from the group consisting of: C1-C6 alkyl and -O-(C1-C6 alkyl).

[0446] Example 2

[0447] The compound according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0448] X is N;

[0449] Y is N; and

[0450] Z is CR 5 ;

[0451] Alternatively, Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl.

[0452] In other words, when X is N, Y is N, and Z is CR 5 When, formula (I) is represented by formula (IA):

[0453]

[0454] where R 1 、R 3 、R 5 and W are as defined for formula (I).

[0455] Example 2.1

[0456] The compound according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0457] X is N;

[0458] Y is N;

[0459] Z is CR 5 ;

[0460] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0461] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-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);

[0462] Each R is independently H or an optionally substituted C1-C6 alkyl group;

[0463] W for W 1 ;

[0464] W 1 for:

[0465]

[0466] in:

[0467] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0468] R 6 is H;

[0469] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0470] R 7a is H or deuterium;

[0471] R 8 is H;

[0472] R 9 is H; and

[0473] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted five-membered to six-membered heterocyclic group.

[0474] Example 2.1A

[0475] The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein:

[0476] X is N;

[0477] Y is N;

[0478] Z is CR 5 ;

[0479] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0480] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-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);

[0481] Each R is independently H or an optionally substituted C1-C6 alkyl group;

[0482] W for W 1 ;

[0483] W 1 for:

[0484]

[0485] in:

[0486] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0487] R 6 is H;

[0488] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0489] R 7a is H or deuterium;

[0490] R 8 is H;

[0491] R 9 is H; and

[0492] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted five-membered to six-membered heterocyclic group.

[0493] Example 2.1B

[0494] The compound according to embodiment 1, wherein:

[0495] X is N;

[0496] Y is N;

[0497] Z is CR 5 ;

[0498] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[0499] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-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);

[0500] Each R is independently H or an optionally substituted C1-C6 alkyl group;

[0501] W for W 1 ;

[0502] W 1 for:

[0503]

[0504] in:

[0505] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point;

[0506] R 6 is H;

[0507] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[0508] R 7a is H or deuterium;

[0509] R 8 is H;

[0510] R 9 is H; and

[0511] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted five-membered to six-membered heterocyclic group.

[0512] Example 2.2

[0513] The compound according to embodiment 2.1, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0514] R 1 -O-(C6-C 10 aryl);

[0515] R 3 is a fluorine-substituted C1-C6 alkyl group;

[0516] R 5 is H;

[0517] R 6 is H;

[0518] R 7 is a C3-C8 cycloalkyl group;

[0519] R 7a is H or deuterium;

[0520] R 8 is H;

[0521] R 9 is H; and

[0522] R 10 It is a C1-C6 alkyl group.

[0523] Example 2.2A

[0524] The compound according to embodiment 2.1 or a pharmaceutically acceptable salt thereof, wherein:

[0525] R 1 -O-(C6-C 10 aryl);

[0526] R 3 is a fluorine-substituted C1-C6 alkyl group;

[0527] R 5 is H;

[0528] R 6 is H;

[0529] R 7 is a C3-C8 cycloalkyl group;

[0530] R 7a is H or deuterium;

[0531] R 8 is H;

[0532] R 9 is H; and

[0533] R 10 It is a C1-C6 alkyl group.

[0534] Example 2.2B

[0535] A compound according to Embodiment 2.1, wherein:

[0536] R 1 -O-(C6-C 10 aryl);

[0537] R 3 is a fluorine-substituted C1-C6 alkyl group;

[0538] R 5 is H;

[0539] R 6 is H;

[0540] R 7 is a C3-C8 cycloalkyl group;

[0541] R 7a is H or deuterium;

[0542] R 8 is H;

[0543] R 9 is H; and

[0544] R 10 It is a C1-C6 alkyl group.

[0545] Example 3

[0546] The compound according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0547] X is CR 2 ;

[0548] Y is CR 4 ;and

[0549] Z is CR 5 ;

[0550] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heteroaryl;

[0551] or R 3 Together with the carbon atom to which it is shown attached and Y, it forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl.

[0552] In other words, when X is CR 2 、Y is CR 4 And Z is CR 5 When, formula (I) is represented by formula (IB):

[0553]

[0554] where R 1 、R 2 、R 3 、R 4 、R 5 and W are as defined for formula (I).

[0555] Example 4

[0556] The compound according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0557] X is CR 2 ;

[0558] Y is N; and

[0559] Z is CR 5 ;

[0560] or R 1 Together with the carbon atom to which it is shown attached and X, it forms an optionally substituted five- to six-membered heterocyclyl.

[0561] In other words, when X is CR 2 , Y is N and Z is CR5 When, formula (I) is represented by formula (IC):

[0562]

[0563] where R 1 、R 2 、R 3 、R 5 and W are as defined for formula (I).

[0564] Example 5

[0565] The compound according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0566] X is N;

[0567] Y is CR 4 ;and

[0568] Z is CR 5 ;

[0569] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[0570] C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl.

[0571] In other words, when X is N and Y is CR 4 And Z is CR 5 When, formula (I) is represented by formula (ID):

[0572]

[0573] where R 1 、R 3 、R 4 、R 5 and W are as defined for formula (I).

[0574] Example 6

[0575] The compound according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0576] X is N;

[0577] Y is CR 4 ;and

[0578] Z is N.

[0579] In other words, when X is N and Y is CR 4When Z is N, formula (I) is represented by formula (IE):

[0580]

[0581] where R 1 、R 3 、R 4 and W are as defined for formula (I).

[0582] Example 7

[0583] The compound according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0584] X is CR 2 ;

[0585] Y is CR 4 ;and

[0586] Z is N.

[0587] In other words, when X is CR 2 、Y is CR 4 When Z is N, formula (I) is represented by formula (IF):

[0588]

[0589] where R 1 、R 2 、R 3 、R 4 and W are as defined for formula (I).

[0590] Example 8

[0591] A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0592] In R 1 middle:

[0593] The optional substituents of the -O-(optionally substituted C3-C8 cycloalkyl) are 1 to 3 substituents selected from the group consisting of halo, cyano and hydroxy; or when there are two substituents on the same ring carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl;

[0594] The -O-(optionally substituted C6-C 10aryl) are 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, cyano, hydroxyl and -NH2, or 1 to 5 deuterium atoms;

[0595] Or when R 1 When taken together with the carbon atom to which it is attached and X form an optionally substituted five- to six-membered heterocyclyl, two substituents on the same ring carbon atom of the five- to six-membered heterocyclyl, together with the ring carbon atom to which they are attached, form a five- to six-membered cycloalkyl;

[0596] In R 3 middle:

[0597] The optional substituents of the optionally substituted C3-C8 cycloalkyl group are 1 to 3 substituents selected from the group consisting of hydroxy, halo, C1-C6 alkyl and C6-C 10 or when there are two substituents on the same carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C6-C 10 aryl;

[0598] Or when R 3 When taken together with the carbon atom to which it is 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 hydrogen atoms on the ring carbon atoms of the C3-C8 cycloalkyl or cycloalkenyl may be replaced by a group =0;

[0599] Or when R 3 When taken together with the carbon atom to which it is attached and Y to form an optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl, the optional substituents are 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl;

[0600] The optionally substituted C6-C 10 The optional substituents of the aryl group are 1 to 3 substituents selected from the group consisting of halo;

[0601] The optional substituents of 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, wherein the optional substituents of the C3-C6 cycloalkyl are 1 to 3 substituents selected from the group consisting of C1-C6 alkyl;

[0602] - NR2, wherein the optional substituents of the C1-C6 alkyl group of R are 1 to 3 substituents selected from the group consisting of halogen; and

[0603] The optional substituents of the optionally substituted four- to six-membered heterocyclic group are 1 to 3 substituents selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, and halo; or when there are two substituents on the same carbon atom of the optionally substituted four- to six-membered heterocyclic group, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl group.

[0604] Example 9

[0605] A compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0606] By R 1 The optionally substituted five- to six-membered heterocyclic group formed together with the carbon atom to which it is attached is

[0607] The double bond shown in the figure is in the 1 between the carbon of the group and X;

[0608] By R 3 The optionally substituted C6-C 10 Aryl

[0609]

[0610] By R 3 The optionally substituted five- to six-membered heterocycloalkenyl group formed together with the carbon atom to which it is attached and Y is

[0611] Among them with The carbon-carbon double bond between the two carbon atoms of the group is shown in the case of an R 3 between the carbon of the group and Y;

[0612] When R 3 When taken together with the carbon atom to which it is attached and Y to form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl is The carbon-carbon double bond shown in the figure is 3 between a carbon of the group and Y; and

[0613] Among them, R 4 The optionally substituted five- to six-membered heteroaryl group formed together with the carbon atom to which it is attached and Z is

[0614] In each structure, Indicates a connection point.

[0615] Example 10

[0616] A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0617] In R 1 middle:

[0618] The -O-(optionally substituted C3-C8 cycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexane-5-yl), -O-(spiro[3.3]heptane-2-yl), -O-(3-chlorocyclobutyl), -O-(bicyclo[3.1.0]hexane-3-yl), -O-(bicyclo[2.2.1]heptane-1-yl), -O-(1-cyanocyclopentyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl) or -O-(2,2-difluorocyclopentyl),

[0619] The -O-(optionally substituted C1-C6 alkyl) is ethoxy, isopropoxy or cyclopropylmethyloxy;

[0620] The -O-(optionally substituted C6-C 10 Aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalen-1-yl or phenoxy-d5;

[0621] The -O-(optionally substituted five- to six-membered heteroaryl) is pyridin-2-yloxy or pyridin-3-yloxy;

[0622] The -O-(optionally substituted five- to six-membered heterocyclyl) is tetrahydro-2H-pyran-4-yl or tetrahydro-2H-pyran-3-yl; and

[0623] The optionally substituted C3-C8 cycloalkyl group is a cyclohexyl group;

[0624] In R 2 middle:

[0625] The optionally substituted C1-C6 alkyl group is methyl; and

[0626] In R 3 middle:

[0627] The 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]hexane-5-yl;

[0628] The optionally substituted C3-C8 cycloalkenyl group is a cyclopentenyl group;

[0629] The optionally substituted C6-C 10 Aryl is phenyl;

[0630] The optionally substituted C1-C6 alkyl group is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl or cyclopropyldifluoromethyl;

[0631] The optionally substituted C1-C6 alkenyl group is 2-methylprop-1-en-1-yl;

[0632] NR2 is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl)2, or -N(methyl)(trifluoroethyl);

[0633] The -N(R)(optionally substituted C3-C8 cycloalkyl) is N(methyl)(cyclopropyl);

[0634] The -S-(optionally substituted C1-C6 alkyl) is methyl mercaptan;

[0635] The -O-(optionally substituted C1-C6 alkyl) is trifluoroethoxy or methoxy;

[0636] The -O-(optionally substituted C3-C8 cycloalkyl) is cyclopentyloxy or cyclopropyloxy; and

[0637] The optionally substituted four- to six-membered heterocyclic group or heterocycloalkenyl group is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptane-7-yl, bicyclo[1.1.1]pentane-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptane-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H -pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl or 3,3-difluoro-azetidin-1-yl;

[0638] In R 5 middle:

[0639] The C1-C6 alkyl group is a methyl group;

[0640] The -NR2 is -NH2; and

[0641] The -N(R)-C(=O)-(C1-C6 alkyl) is -N(H)-C(=O)-CH3.

[0642] Example 11

[0643] A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 1 , that is, W is

[0644]

[0645] where R 6 、R 7 、R 7a 、R 8 、R 9 and R 10 As defined in Example 1; and by The key representation Can exist as (Z)- or (E)-geometric isomers, wherein Indicates a connection point.

[0646] Example 12

[0647] The compound according to embodiment 11 or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0648] R 7The 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;

[0649] R 7 The optionally substituted C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, or difluorocyclohexyl;

[0650] R 7 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[0651] R 10 The optionally substituted C1-C6 alkyl is methyl;

[0652] R 10 The optionally substituted C3-C8 cycloalkyl is cyclopropyl;

[0653] R 10 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[0654] or where W 1 for:

[0655]

[0656] In each of the above structures, Indicates a connection point.

[0657] Example 13

[0658] A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 2 , that is, W is

[0659]

[0660] in:

[0661] Depend on Key indication Can exist as (Z)- or (E)-geometric isomers, wherein Indicate the connection point; and

[0662] R 11 、R 12 、R 12a 、R 13 and R14 As defined in Example 1.

[0663] Example 14

[0664] The compound according to embodiment 13 or a pharmaceutically acceptable salt or solvate thereof, wherein W 2 for:

[0665]

[0666] in:

[0667] R 21 is H or C1-C6 alkyl;

[0668] Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicates a connection point.

[0669] Example 15

[0670] A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 3 , that is, W is

[0671]

[0672] in:

[0673] Indicate the connection point; and

[0674] R 15 and R 16 As defined in Example 1.

[0675] Example 16

[0676] The compound according to embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0677] R 16 The optionally substituted C1-C6 alkyl is methyl; and

[0678] R 16 The optionally substituted C3-C8 cycloalkyl group is cyclopropyl.

[0679] Example 17

[0680] A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 4 , that is, W is

[0681]

[0682] in:

[0683] Indicate the connection point; and

[0684] R 17 、R 18 and R a As defined in Example 1.

[0685] Example 18

[0686] The compound according to embodiment 17, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0687] R 18 The optionally substituted C1-C6 alkyl is methyl; and

[0688] The optionally substituted C1-C6 alkyl group is methyl.

[0689] Example 19

[0690] A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein W is W 5 , that is, W is

[0691]

[0692] in:

[0693] Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicate the connection point; and

[0694] m and R 19 As defined in Example 1.

[0695] Example 20

[0696] The compound according to embodiment 19, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0697] R 19 The C1-C6 alkyl group is a methyl group; and

[0698] R 19 The -O-(C1-C6 alkyl) is a methoxy group.

[0699] Example 21

[0700] The compound according to any one of embodiments 2 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:

[0701] (E)-N-(3-(methylsulfonyl)allyl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide;

[0702] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-phenylpyrimidine-5-carboxamide;

[0703] (S,E)-2-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0704] (R,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0705] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0706] (S,E)-2-ethyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0707] (E)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0708] (E)-2-Isopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0709] (R,E)-2-cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0710] (S,E)-2-cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0711] (S,E)-2-cyclohexyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0712] (E)-2-ethyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0713] (S,E)-2-isopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0714] (S,E)-2-(cyclopentylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0715] (E)-2-cyclopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0716] (S,E)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0717] (E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0718] (R,Z)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0719] (S,Z)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0720] (E)-2-cyclobutyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0721] (E)-4-(4-chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide;

[0722] (S,E)-4-(4-chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0723] (E)-2-cyclopentyl-4-(3-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide;

[0724] (E)-2-cyclohexyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0725] (E)-N-(3-(methylsulfonyl)allyl)-2-(methylthio)-4-phenoxypyrimidine-5-carboxamide;

[0726] 2-cyclopropyl-N-((1,1-dioxido-2H-thietiden-3-yl)methyl)-4-phenoxypyrimidine-5-carboxamide;

[0727] 2-cyclopropyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0728] (E)-2-cyclopentyl-4-(4-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide;

[0729] (S,E)-2-cyclopentyl-4-(4-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0730] (S,E)-4-(2-chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0731] (S,E)-4-(3-chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0732] (S,E)-2-cyclopentyl-4-(3-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0733] (S,E)-2-cyclopentyl-4-(2-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0734] (S,E)-4-(cyclohexyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0735] (E)-2-cyclopentyl-N-methyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0736] (E)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-(p-tolyloxy)pyrimidine-5-carboxamide;

[0737] (E)-N-(3-(methylsulfonyl)allyl)-4-phenoxy-2-(1H-pyrazol-5-yl)pyrimidine-5-carboxamide;

[0738] (E)-4-(3-chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide;

[0739] (S,E)-2-cyclopentyl-4-(3,5-difluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0740] (S,E)-2-cyclopentyl-4-(4-fluoro-3-methylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0741] (S,E)-2-cyclopentyl-4-(3,5-dichlorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0742] (S,E)-2-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0743] (2-cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone;

[0744] (S,E)-2-cyclopentyl-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0745] (S,E)-4-(4-cyanophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0746] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-5-carboxamide;

[0747] (S,E)-2-cyclopentyl-4-(3,4-dimethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0748] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(m-tolyloxy)pyrimidine-5-carboxamide;

[0749] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0750] (S,E)-2-cyclopentyl-4-(4-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0751] (S,E)-2-cyclopentyl-4-(3-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0752] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(o-tolyloxy)pyrimidine-5-carboxamide;

[0753] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-5-carboxamide;

[0754] (S,E)-2-(cyclopropylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0755] (S,E)-4-cyclobutoxy-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0756] (S,E)-2-(1-hydroxycyclopentyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0757] (S,E)-2-cyclopentyl-N-(1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0758] N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-2-yl)pyrimidine-5-carboxamide;

[0759] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-2-yloxy)pyrimidine-5-carboxamide;

[0760] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-3-yloxy)pyrimidine-5-carboxamide;

[0761] (S,E)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[3.3]heptan-2-yloxy)pyrimidine-5-carboxamide;

[0762] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide;

[0763] (S,E)-2-(tert-Butyl)-4-(cyclohexyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0764] (S,E)-2-(tert-Butyl)-4-((4,4-difluorocyclohexyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0765] 2-cyclopentyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)oxy)pyrimidine-5-carboxamide;

[0766] (S,E)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[2.3]hexan-5-yloxy)pyrimidine-5-carboxamide;

[0767] (S,E)-2-cyclopropyl-4-(cyclopropylmethoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0768] 4-((1R,3S)-3-chlorocyclobutyloxy)-2-cyclopropyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0769] (S,E)-4-cyclohexyl-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0770] 4-[[(1S,5R)-3-Bicyclo[3.1.0]hexyl]oxy]-2-tert-butyl-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide;

[0771] (S,E)-2-(tert-Butyl)-4-((1-cyanocyclopentyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0772] (S,E)-2-(tert-Butyl)-4-(3,3-difluorocyclobutyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0773] (S,E)-2-cyclopentyl-4-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide;

[0774] (S,E)-2-(1-fluorocyclopentyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0775] (S,E)-2-cyclopentyl-4-(3-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0776] (S,E)-2-cyclopentyl-4-(4-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0777] (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone;

[0778] (S,E)-2-(tert-Butyl)-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0779] (S,E)-2-(cyclopentylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0780] (S,E)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0781] N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide;

[0782] (S,E)-4-(3-chloro-5-fluorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0783] (S,E)-2-(cyclohexylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0784] (S,E)-4-(3-aminophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0785] (S,E)-2-(cyclobutylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0786] (S,E)-2-cyclopropyl-N-(4-(cyclopropylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0787] (Z)-(2-cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone;

[0788] (E)-(2-cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone;

[0789] (S,E)-4-(cyclopentyloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0790] 2-cyclopentyl-4-(((1R,2R)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0791] (S,E)-4-amino-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide;

[0792] (S,E)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(naphthalen-1-yloxy)pyrimidine-5-carboxamide;

[0793] (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;

[0794] (S,E)-4-(cycloheptyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0795] 2-cyclopentyl-4-(((1S,2R)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0796] 2-cyclopentyl-4-(((1R,2S)-2-hydroxycyclohexyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0797] (S,E)-2-(bicyclo[1.1.1]pentan-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0798] 2-((1S,3R)-3-methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0799] 2-((1R,3S)-3-methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0800] (S,E)-2-(3-methoxyazetidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0801] 2-cyclopropyl-4-((3,3-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0802] 2-cyclopropyl-4-(((S)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0803] 2-cyclopropyl-4-(((R)-2,2-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0804] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2-azaspiro[3.3]heptane-2-yl)pyrimidine-5-carboxamide;

[0805] 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;

[0806] N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydro-2H-pyran-3-yl)pyrimidine-5-carboxamide;

[0807] (S,E)-2-(5,6-dihydro-2H-pyran-3-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0808] (S,E)-2-cyclopentyl-N-(4-methyl-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0809] (S,E)-2-(2-hydroxypropan-2-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0810] (S,E)-2-isobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0811] (S,E)-2-(2-methylprop-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0812] 2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0813] 2-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0814] (S,E)-4-(bicyclo[2.2.1]heptan-1-yloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide;

[0815] (S,E)-2-(3,3-difluoropyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0816] (S,E)-2-(2-methoxypropan-2-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0817] (S,E)-2-(1,1-difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0818] (S,E)-2-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0819] (S,E)-2-(1-methylcyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0820] (2-(1-methylcyclopropyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone;

[0821] (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methylene)azetidin-1-yl)methanone;

[0822] (2-((1S,3S)-3-methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone;

[0823] (2-((1r,3r)-3-methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone;

[0824] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide;

[0825] (S,E)-2-(2,2-dimethylpyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0826] 2-((S)-2-methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0827] 2-((R)-2-methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0828] 1-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one;

[0829] (S,E)-2-((1-methylcyclopropyl)methyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0830] (2-((1-methylcyclopropyl)methyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone;

[0831] (E)-(2-cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)pyrrolidin-1-yl)methanone;

[0832] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide;

[0833] (S,E)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide;

[0834] (R,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0835] (S,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0836] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-phenylcyclopropyl)pyrimidine-5-carboxamide;

[0837] 2-((1R,3S)-3-methylcyclopentyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0838] (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0839] (S,E)-2-cyclopropyl-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0840] (S,E)-2-(3,3-difluorocyclobutyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0841] (R,E)-2-(1,1-difluoroethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0842] (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0843] (S,E)-2-(tert-Butyl)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0844] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide;

[0845] (S,E)-2-(tert-Butyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0846] (S,E)-2-cyclopropyl-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0847] (S,E)-2-(1-fluorocyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0848] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0849] (E)-2-(tert-Butyl)-N-(1-(2-(methylsulfonyl)vinyl)cyclopropyl)-4-phenoxypyrimidine-5-carboxamide;

[0850] (S,E)-4-Acetylamino-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide;

[0851] (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0852] (R,E)-2-cyclopropyl-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0853] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0854] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-4-phenoxypyrimidine-5-carboxamide;

[0855] (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0856] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(2-fluoropropan-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0857] N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((1S,3S)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide;

[0858] N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((1R,3R)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide;

[0859] (2-cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-1-yl)methanone;

[0860] (S,E)-2-cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0861] (S,Z)-2-cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0862] 2-(tert-Butyl)-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0863] (S,E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0864] 2-cyclopropyl-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0865] (S,E)-2-cyclopropyl-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0866] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylmethyl)-4-phenoxypyrimidine-5-carboxamide;

[0867] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0868] (S,Z)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0869] (R,E)-2-cyclopentyl-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0870] (S,E)-2-cyclobutyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0871] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide;

[0872] (S,E)-2-(cyclopropyldifluoromethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0873] (R,E)-2-(cyclopropyldifluoromethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0874] (S,E)-2-(1,1-difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)pent-1-en-3-yl)pyrimidine-5-carboxamide;

[0875] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide;

[0876] (E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0877] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide;

[0878] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0879] (S,E)-2-(tert-Butyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0880] (R,E)-2-(1,1-difluoroethyl)-4-phenoxy-N-(5,5,5-trifluoro-1-(methylsulfonyl)pent-1-en-3-yl)pyrimidine-5-carboxamide;

[0881] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0882] (R,E)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0883] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide;

[0884] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide;

[0885] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide;

[0886] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide;

[0887] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1-fluorocyclopropyl)-4-phenoxypyrimidine-5-carboxamide;

[0888] (S,E)-2-(tert-Butyl)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0889] (S,E)-2-(tert-Butyl)-N-(5,5-difluoro-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0890] (S,E)-N-(5,5-difluoro-1-(methylsulfonyl)pent-1-en-3-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0891] (S,E)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0892] (R,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide;

[0893] 4-(((1R,3S,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide;

[0894] 4-(((1R,3S,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-cyclopropyl-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide;

[0895] (R,E)-N-(1-(tert-Butoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0896] (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0897] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenoxybut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0898] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(spiro[2.3]hexan-5-yl)pyrimidine-5-carboxamide;

[0899] (R,E)-2-(1,1-difluoroethyl)-N-(1-(difluoromethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide;

[0900] (S,E)-2-(1,1-difluoroethyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0901] N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylfluoromethyl)-4-phenoxypyrimidine-5-carboxamide;

[0902] 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;

[0903] (S,E)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0904] (R,E)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0905] (S,E)-2-(cyclopropyldifluoromethyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0906] (R,E)-2-(cyclopropyldifluoromethyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0907] 2-(1,1-difluoroethyl)-N-((3R,4S,E)-4-methoxy-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide;

[0908] 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;

[0909] (R,E)-N-(1-cyclopropyloxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0910] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(dimethylamino)-4-phenoxypyrimidine-5-carboxamide;

[0911] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(methylamino)-4-phenoxypyrimidine-5-carboxamide;

[0912] (S,E)-2-cyclopropyloxy-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0913] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carboxamide;

[0914] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(diethylamino)-4-phenoxypyrimidine-5-carboxamide;

[0915] (S,E)-2-(cyclopropyl(methyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0916] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-methoxy-4-phenoxypyrimidine-5-carboxamide;

[0917] (S,E)-2-(azetidin-1-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide;

[0918] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(methyl(2,2,2-trifluoroethyl)amino)-4-phenoxypyrimidine-5-carboxamide;

[0919] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3-fluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide;

[0920] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(ethyl(methyl)amino)-4-phenoxypyrimidine-5-carboxamide;

[0921] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

[0922] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide;

[0923] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoropropyl)-4-phenoxypyrimidine-5-carboxamide;

[0924] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[0925] (S)-N-(3-cyanobut-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide;

[0926] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-(phenoxy-d5)pyrimidine-5-carboxamide;

[0927] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl-1-d)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide; and

[0928] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-(phenoxy-d5)pyrimidine-5-carboxamide.

[0929] Example 21A

[0930] The compound according to embodiment 21, or a pharmaceutically acceptable salt or solvate thereof, wherein when an R or S stereochemical configuration at one or more chiral carbons is specified, the compound includes a mixture of R or S configurations at that carbon;

[0931] or a mixture of (E) or (Z) geometric isomers of the above compounds.

[0932] Example 21.1

[0933] The compound according to any one of embodiments 2 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

[0934] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide.

[0935] Example 21.1A

[0936] The compound according to 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 includes a mixture of R or S configurations at that carbon;

[0937] or a mixture of (E) or (Z) geometric isomers of the above compounds.

[0938] Example 21.2

[0939] The compound according to any one of embodiments 2 and 8 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0940] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide.

[0941] Example 21.2A

[0942] The compound or pharmaceutically acceptable salt thereof according to Embodiment 21.2, wherein when the R or S stereochemical configuration at one or more chiral carbons is specified, the compound includes a mixture of R or S configurations at that carbon;

[0943] or a mixture of (E) or (Z) geometric isomers of the above compounds.

[0944] Example 21.3

[0945] A compound according to any one of embodiments 2 and 8 to 12, wherein the compound is:

[0946] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide.

[0947] Example 21.3A

[0948] a compound according to Embodiment 21.3, wherein when an R or S stereochemical configuration is specified at one or more chiral carbons, the compound includes a mixture of R or S configurations at that carbon;

[0949] or a mixture of (E) or (Z) geometric isomers of the above compounds.

[0950] Example 22

[0951] The compound according to any one of embodiments 3 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:

[0952] (E)-2-cyclobutoxy-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)benzamide;

[0953] (E)-4-cyclopentyl-2-ethoxy-N-(3-(methylsulfonyl)allyl)benzamide;

[0954] (E)-4-cyclopentyl-2-isopropoxy-N-(3-(methylsulfonyl)allyl)benzamide;

[0955] (E)-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)-2-phenoxybenzamide;

[0956] (E)-4-cyclopentyl-2-cyclopropyloxy-N-(3-(methylsulfonyl)allyl)benzamide;

[0957] 4-cyclopentyl-2-cyclopropyloxy-N-((1,1-dioxido-2H-thietiden-3-yl)methyl)benzamide;

[0958] (E)-2-cyclobutoxy-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)benzamide;

[0959] (E)-4-cyclopentyl-2-ethoxy-N-(3-(methylsulfonyl)allyl)benzamide;

[0960] (E)-4-cyclopentyl-2-isopropoxy-N-(3-(methylsulfonyl)allyl)benzamide;

[0961] (E)-4-cyclopentyl-N-(3-(methylsulfonyl)allyl)-2-phenoxybenzamide;

[0962] (E)-4-cyclopentyl-2-cyclopropyloxy-N-(3-(methylsulfonyl)allyl)benzamide;

[0963] 4-cyclopentyl-2-cyclopropyloxy-N-((1,1-dioxido-2H-thietiden-3-yl)methyl)benzamide;

[0964] (S,E)-5-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)quinoline-8-carboxamide;

[0965] (S,E)-6-(cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide;

[0966] (E)-4-cyclopentyl-2-(cyclopentyloxy)-N-(3-(methylsulfonyl)allyl)benzamide;

[0967] rac-(R,E)-4-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxybenzamide;

[0968] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-oxo-6-phenoxy-2,3-dihydro-1H-indene-5-carboxamide;

[0969] (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

[0970] 2,2-Dimethyl-6-(3-((methylsulfonyl)methylene)azetidine-1-carbonyl)-5-phenoxy-2,3-dihydro-1H-inden-1-one.

[0971] Example 22A

[0972] The compound according to 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 specified, the compound includes a mixture of R or S configurations at those carbon atoms;

[0973] or a mixture of (E) or (Z) geometric isomers of the above compounds.

[0974] Example 23

[0975] The compound according to any one of embodiments 4 and 8 to 12, wherein the compound is selected from the group consisting of:

[0976] (S,E)-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide;

[0977] (S,E)-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0978] (S,E)-6-(cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide;

[0979] (S,E)-6-(cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0980] (S,E)-6-cyclopropyl-5-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide;

[0981] (S,E)-6-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide; and

[0982] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-4-phenoxynicotinamide.

[0983] Example 23A

[0984] The compound according to 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 specified, the compound includes a mixture of the (R) or (S) configuration at those carbon atoms;

[0985] or a mixture of (E) and (Z) geometric isomers of the above compounds.

[0986] Example 24

[0987] The compound according to any one of embodiments 5 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:

[0988] (S,E)-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0989] (S,E)-6-(cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0990] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxyquinoline-3-carboxamide;

[0991] (S,E)-5-cyano-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0992] (S,E)-6-(cyclopent-1-en-1-yl)-5-fluoro-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0993] (S,E)-6-cyclopropyl-5-fluoro-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxynicotinamide;

[0994] (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide;

[0995] (S,E)-6-cyclopentyl-5-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0996] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-2-phenoxynicotinamide;

[0997] (S,E)-6-(1,1-difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide;

[0998] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxamide;

[0999] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-1-methyl-6-phenoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

[1000] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(1,1-difluoroethyl)-5-fluoro-2-phenoxynicotinamide;

[1001] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-7,7-difluoro-2-phenoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide;

[1002] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-6-carboxamide; and

[1003] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(cyclopropyldifluoromethyl)-5-fluoro-2-phenoxynicotinamide.

[1004] Example 24A

[1005] The compound according to 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 specified, the compound includes a mixture of the R or S configuration at that carbon;

[1006] or a mixture of (E) or (Z) geometric isomers of the above compounds.

[1007] Example 25

[1008] The compound according to any one of embodiments 6 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

[1009] (S,E)-5-(Cyclopent-1-en-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-phenoxypyrazine-2-carboxamide.

[1010] Example 25A

[1011] The compound according to 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 specified, the compound includes a mixture of the (R) or (S) configuration at those carbon atoms;

[1012] or a mixture of E or Z geometric isomers of the above compounds.

[1013] Example 26

[1014] The compound according to any one of embodiments 7 and 8 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

[1015] (S,E)-5-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-3-phenoxypicolinamide.

[1016] Example 26A

[1017] The compound according to 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 specified, the compound includes a mixture of the (R) or (S) configuration at those carbon atoms;

[1018] or a mixture of E or Z geometric isomers of the above compounds.

[1019] Example 27

[1020] A compound according to any one of embodiments 2, 8 to 10, and 13 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:

[1021] 2-(1-(2-cyclopropyl-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetonitrile;

[1022] 2-(1-(2-cyclopropyl-4-phenoxypyrimidine-5-carbonyl)-2-methylazetidin-3-ylidene)acetonitrile;

[1023] (E)-N-(3-cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide; and

[1024] (Z)-N-(3-Cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide.

[1025] Example 27A

[1026] The compound according to embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the (E) or (Z) geometric isomer of the compound is specified, or a mixture of the (E) or (Z) geometric isomers of the compound.

[1027] Example 28

[1028] A compound according to any one of embodiments 2, 8 to 10, and 15 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:

[1029] N-(2-cyanoallyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide;

[1030] 2-(tert-Butyl)-N-(2-cyanoallyl)-4-phenoxypyrimidine-5-carboxamide;

[1031] N-(2-cyanoallyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[1032] N-(2-cyanoallyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide;

[1033] N-(2-cyanoallyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide;

[1034] (R)-N-(3-cyanobut-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[1035] (S)-N-(3-cyanobut-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide;

[1036] (S)-N-(3-cyanobut-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide; and

[1037] (S)-N-(2-cyano-1-cyclopropylallyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide.

[1038] Example 28A

[1039] 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 includes a mixture of the (R) or (S) configuration at those carbon atoms.

[1040] Example 29

[1041] A compound according to any one of embodiments 2, 8 to 10, and 17 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

[1042] (S)-2-(1,1-difluoroethyl)-N-(5-(dimethylamino)-5-oxopent-3-yn-2-yl)-4-phenoxypyrimidine-5-carboxamide.

[1043] Example 29A

[1044] 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 includes a mixture of the (R) or (S) configuration at those carbons.

[1045] Example 30

[1046] A compound according to any one of embodiments 2, 8 to 10, and 19 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:

[1047] 1-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one; and

[1048] Methyl 2-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetate.

[1049] Example 31

[1050] 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.

[1051] Example 31A

[1052] 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.

[1053] Example 31B

[1054] A compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, and a pharmaceutically acceptable carrier or excipient.

[1055] Example 31.1

[1056] A compound or pharmaceutically acceptable salt according to any one of Embodiments 1 to 30 and 21A to 29A.

[1057] Example 31.1A

[1058] A compound according to any one of Embodiments 1 to 30 and 21A to 29A.

[1059] Example 32

[1060] 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 1 to 30, 2.1, 2.2, 21.1, 21.1A, and 21A to 29A, or a pharmaceutically acceptable salt or solvate thereof.

[1061] Example 32A

[1062] According to the method of embodiment 32, the method comprises administering to the patient a therapeutically effective amount of a compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A and 21A to 29A, or a pharmaceutically acceptable salt thereof.

[1063] Example 32B

[1064] 36. The method of Embodiment 32, comprising administering to a patient a therapeutically effective amount of a compound of any one of Embodiments 1-30, 2.1, 2.2, 21.1, 21.1A, and 21A-29A.

[1065] Example 33

[1066] The method according to embodiment 32, wherein the proliferative disease is cancer.

[1067] Example 34

[1068] The method according to embodiment 33, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, skin cancer and MSI-H cancer.

[1069] Example 35

[1070] A method of inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of at least one compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, and 21A to 29A, or a pharmaceutically acceptable salt or solvate thereof.

[1071] Example 35A

[1072] A method of inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of at least one compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, and 21A to 29A, or a pharmaceutically acceptable salt thereof.

[1073] Example 35B

[1074] A method of inhibiting WRN helicase (Werner syndrome ATP-dependent helicase) in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of at least one compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, and 21A to 29A.

[1075] Example 36

[1076] A method for inhibiting WRN helicase (Werner syndrome ATP-dependent helicase), the method comprising effecting a non-naturally occurring covalent modification at cysteine ​​727 as shown in SEQ ID NO: 1 or a variant thereof, the modification resulting from a bond-forming reaction between an electrophile and cysteine ​​727 as shown in SEQ ID NO: 1 or a variant thereof, wherein the sulfur atom at the cysteine ​​residue undergoes reaction with the electrophile.

[1077] Example 37

[1078] 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, acetylenonitrile, enone, alkynone, alkenoate, and acetylenate.

[1079] Example 38

[1080] The method of embodiment 37, wherein:

[1081] The vinyl sulfone is represented by the following structure:

[1082]

[1083] The alkynyl sulfone is represented by the following structure:

[1084]

[1085] The alkenylsulfonamide is represented by the following structure:

[1086]

[1087] The vinyl sulfoxide is represented by the following structure:

[1088]

[1089] The alkynyl sulfoxide is represented by the following structure:

[1090] The vinyl sulfoximine is represented by the following structure:

[1091] The alkynyl sulfoximine is represented by the following structure:

[1092] The acrylamide is represented by the following formula:

[1093]

[1094] The acrylonitrile is represented by the following structure:

[1095]

[1096] The enone is represented by the following structure:

[1097]

[1098] The alkynone is represented by the following structure:

[1099]

[1100] The enoate is represented by the following structure: And the alkynoate is represented by the following structure:

[1101]

[1102] in:

[1103] represents a possible point of attachment of the chemical moiety to the rest of the electrophile.

[1104] Example 39

[1105] A compound of formula (II):

[1106]

[1107] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1108] X is CR 2 or N;

[1109] Y is CR4 or N;

[1110] Z is CR 5 or N;

[1111] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[1112] The condition is that X, Y and Z are not N at the same time;

[1113] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[1114] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[1115] to six-membered heterocyclic group;

[1116] R 2 is H, optionally substituted C1-C6 alkyl or halo;

[1117] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[1118] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-

[1119] C 10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[1120] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[1121] R 4 is H, C1-C6 alkyl, cyano or halo;

[1122] or R4 Together with the carbon atom to which it is attached and Z, form an optionally substituted five-membered

[1123] to six-membered heteroaryl;

[1124] or R 3 and R 4 Together with the carbon atoms to which they are attached as shown and R 3 To form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted penta

[1125] 1- to 6-membered heterocyclic group or heterocycloalkenyl group;

[1126] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl);

[1127] Each R is independently H or optionally substituted C1-C6 alkyl; and

[1128] V comprises an electrophile that reacts with the sulfur atom at cysteine ​​727 shown in SEQ ID NO: 1 or a variant thereof and forms a covalent bond.

[1129] Example 40

[1130] The compound according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein the electrophile comprises at least one chemical moiety selected from the group consisting of vinyl sulfone, alkynyl sulfone, vinyl sulfonamide, vinyl sulfoxide, alkynyl sulfoxide, vinyl sulfoximine, alkynyl sulfoximine, acrylamide, acrylonitrile, acetylenonitrile, enone, alkynone, alkenoate and acetylenate.

[1131] Example 41

[1132] The compound according to embodiment 40, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1133] The vinyl sulfone is represented by the following structure:

[1134]

[1135] The alkynyl sulfone is represented by the following structure:

[1136]

[1137] The alkenylsulfonamide is represented by the following structure:

[1138]

[1139] The vinyl sulfoxide is represented by the following structure:

[1140] The alkynyl sulfoxide is represented by the following structure:

[1141] The vinyl sulfoximine is represented by the following structure:

[1142] The alkynyl sulfoximine is represented by the following structure:

[1143] The acrylamide is represented by the following formula:

[1144]

[1145] The acrylonitrile is represented by the following structure:

[1146]

[1147] The enone is represented by the following structure:

[1148]

[1149] The alkynone is represented by the following structure:

[1150]

[1151] The enoate is represented by the following structure:

[1152] and

[1153] The alkynoate ester is represented by the following structure:

[1154]

[1155] in:

[1156] represents a possible point of attachment of the chemical moiety to the rest of the electrophile.

[1157] Example 42

[1158] 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.

[1159] Example 42A

[1160] A compound or pharmaceutically acceptable salt according to any one of Embodiments 39 to 41, and a pharmaceutically acceptable carrier or excipient.

[1161] Example 42B

[1162] A compound according to any one of embodiments 39 to 41, and a pharmaceutically acceptable carrier or excipient.

[1163] Example 42.1

[1164] A compound or pharmaceutically acceptable salt according to any one of Embodiments 39 to 41.

[1165] Example 42.1A

[1166] A compound according to any one of embodiments 39 to 41.

[1167] Example 43

[1168] 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 Examples 39 to 41, or a pharmaceutically acceptable salt or solvate thereof.

[1169] Example 43A

[1170] According to the method of embodiment 43, the method comprises administering to the patient a therapeutically effective amount of the compound according to any one of embodiments 39 to 41 or a pharmaceutically acceptable salt thereof.

[1171] Example 43B

[1172] 44. 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.

[1173] Example 44

[1174] The method according to embodiment 43, wherein the proliferative disease is cancer.

[1175] Example 45

[1176] The method according to embodiment 44, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, skin cancer and MSI-H cancer.

[1177] Example 46

[1178] 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, wherein the modified WRN helicase protein comprises SEQ ID NO: 1 or a variant thereof; and has the structure of formula (III):

[1179]

[1180] in:

[1181] S is the sulfur atom of cysteine ​​727 in SEQ ID NO: 1 or a variant thereof;

[1182] and represents amino acid positions 1 to 726 and 728 to 1432 of SEQ ID NO: 1 or a variant thereof, respectively; and

[1183] Q for Q 1 , Q 2 , Q 3 , Q 4 or Q 5 ;in:

[1184] Q 1 for:

[1185]

[1186] in:

[1187] Indicates the connection point;

[1188] R 6 is H;

[1189] R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or optionally substituted five- to six-membered heterocyclyl;

[1190] R 7a is H or deuterium;

[1191] R 8 is H;

[1192] R 9 is H; and

[1193] R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group;

[1194] or R 6 Together with the nitrogen atom to which it is attached and R 7 and R 7a Connect with them as shown

[1195] The connected carbon atoms form an azetidinyl ring;

[1196] or R 6Together with the nitrogen atom to which it is attached and R 7 、R 7a and R 8 With them

[1197] The carbon atoms shown are joined together to form an azetidinyl or pyrrolidinyl ring;

[1198] or R 6 Together with the nitrogen atom to which it is attached and R 7 、R 7a 、R 8 and R 9 With it

[1199] The carbon atoms shown are connected together to form a dihydropyrrolyl ring;

[1200] or R 7 、R 7a 、R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form 2,3-dihydrothiophene 1,1-dioxide;

[1201] or R 8 、R 9 and R 10 Together with the carbon atoms to which they are attached, they form 2,3-dihydrothiazole

[1202] Phenyl 1,1-dioxide;

[1203] Q 2 for:

[1204]

[1205] in:

[1206] Indicates the connection point;

[1207] R 11 is H;

[1208] R 12 is H or an optionally substituted C1-C6 alkyl group;

[1209] R 12a is H; and

[1210] R 13 and R 14 Each is H;

[1211] or R 11 Together with the nitrogen atom to which it is attached and R 12 、R 12a and R 13 With them

[1212] The carbon atoms shown are joined together to form an optionally substituted azetidinyl ring;

[1213] Q 3 for:

[1214]

[1215] in:

[1216] Indicates the connection point;

[1217] R 15 is H; and

[1218] R 16 is H or an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group;

[1219] Q 4 for:

[1220]

[1221] in:

[1222] Indicates the connection point;

[1223] R 17 is H;

[1224] R 18 is H or optionally substituted C1-C6 alkyl; and

[1225] Each R a are independently optionally substituted C1-C6 alkyl;

[1226] Q 5 for:

[1227]

[1228] in:

[1229] Indicates the connection point;

[1230] m is 1, 2, or 3; and

[1231] R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl); and

[1232] U is:

[1233]

[1234] in:

[1235] Indicates the connection point;

[1236] X is CR 2 or N;

[1237] Y is CR 4 or N;

[1238] Z is CR 5 or N;

[1239] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl;

[1240] The condition is that X, Y and Z are not N at the same time;

[1241] 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl;

[1242] or R 1 Together with the carbon atom to which it is attached and X, form an optionally substituted five-membered

[1243] to six-membered heterocyclic group;

[1244] R 2 is H, optionally substituted C1-C6 alkyl or halo;

[1245] 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl);

[1246] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-C 10 Aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[1247] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[1248] R 4 is H, C1-C6 alkyl, cyano, or halo;

[1249] or R 4 together with the carbon atom to which it is shown attached and Z, forms an optionally substituted five- to six-membered heteroaryl;

[1250] or R 3 and R 4 Together with the carbon atoms to which they are attached, they form an optionally substituted C6-C 10 Aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered

[1251] a 3-membered heterocyclic group or a heterocyclic alkenyl group;

[1252] R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl); and

[1253] Each R is independently H or optionally substituted C1-C6 alkyl.

[1254] Example 47

[1255] The modified WRN helicase protein of embodiment 46, wherein:

[1256] X is N;

[1257] Y is N; and

[1258] Z is CR 5 ;or

[1259] Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl.

[1260] In other words, when X is N, Y is N, and Z is CR 5 When U is

[1261]

[1262] where R 1 、R 3 and R 5 As defined in Example 46.

[1263] Example 48

[1264] The modified WRN helicase protein of embodiment 46, wherein:

[1265] X is CR2 ;

[1266] Y is CR 4 ;and

[1267] Z is CR 5 ;

[1268] or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heteroaryl;

[1269] or R 3 Together with the carbon atom to which it is shown attached and Y, it forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl.

[1270] In other words, when X is CR 2 、Y is CR 4 And Z is CR 5 When U is

[1271]

[1272] where R 1 、R 2 、R 3 、R 4 and R 5 As defined in Example 46.

[1273] Example 49

[1274] The modified WRN helicase protein of embodiment 46, wherein:

[1275] X is CR 2 ;

[1276] Y is N; and

[1277] Z is CR 5 ;

[1278] or R 1 Together with the carbon atom to which it is shown attached and X, it forms an optionally substituted five- to six-membered heterocyclyl.

[1279] In other words, when X is CR 2 , Y is N and Z is CR 5 When U is

[1280]

[1281] where R 1 、R 2 、R 3 and R 5 As defined in Example 46.

[1282] Example 50

[1283] The modified WRN helicase protein of embodiment 46, wherein:

[1284] X is N;

[1285] Y is CR 4 ;and

[1286] Z is CR 5 ;

[1287] or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl.

[1288] In other words, when X is N and Y is CR 4 And Z is CR 5 When U is

[1289]

[1290] where R 1 、R 3 、R 4 and R 5 As defined in Example 46.

[1291] Example 51

[1292] The modified WRN helicase protein of embodiment 46, wherein:

[1293] X is N;

[1294] Y is CR 4 ;and

[1295] Z is N.

[1296] In other words, when X is N and Y is CR 4 And when Z is N, U is

[1297]

[1298] where R 1 、R 3 and R 4 As defined in Example 46.

[1299] Example 52

[1300] The modified WRN helicase protein of embodiment 46, wherein:

[1301] X is CR 2 ;

[1302] Y is CR 4 ;and

[1303] Z is N.

[1304] In other words, when X is CR 2 、Y is CR 4 And when Z is N, U is

[1305]

[1306] where R 1 、R 2 、R 3 and R 4 As defined in Example 46.

[1307] Example 53

[1308] The modified WRN helicase protein of any one of embodiments 46 to 52, wherein:

[1309] In R 1 middle:

[1310] The optional substituents of the -O-(optionally substituted C3-C8 cycloalkyl) are 1 to 3 substituents selected from the group consisting of halo, cyano and hydroxy; or when there are two substituents on the same ring carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl;

[1311] The -O-(optionally substituted C6-C 10 aryl) are 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, cyano, hydroxyl and -NH2, or 1 to 5 deuterium atoms;

[1312] Or when R 1 When taken together with the carbon atom to which it is attached and X form an optionally substituted five- to six-membered heterocyclyl, two substituents on the same ring carbon atom of the five- to six-membered heterocyclyl, together with the ring carbon atom to which they are attached, form a five- to six-membered cycloalkyl;

[1313] In R 3 middle:

[1314] The optional substituents of the optionally substituted C3-C8 cycloalkyl group are 1 to 3 substituents selected from the group consisting of hydroxy, halo, C1-C6 alkyl and C6-C 10 or when there are two substituents on the same carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C6-C 10 aryl;

[1315] Or when R 3 When taken together with the carbon atom to which it is 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 hydrogen atoms on the ring carbon atoms of the C3-C8 cycloalkyl or cycloalkenyl may be replaced by a group =0;

[1316] Or when R 3 When taken together with the carbon atom to which it is attached and Y to form an optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl, the optional substituents are 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl;

[1317] The optionally substituted C6-C 10 The optional substituents of the aryl group are 1 to 3 substituents selected from the group consisting of halo;

[1318] The optional substituents of 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, wherein the optional substituents of the C3-C6 cycloalkyl are 1 to 3 substituents selected from the group consisting of C1-C6 alkyl;

[1319] - NR2, wherein the optional substituents of the C1-C6 alkyl group of R are 1 to 3 substituents selected from the group consisting of halogen; and

[1320] The optional substituents of the optionally substituted four- to six-membered heterocyclic group are 1 to 3 substituents selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, and halo; or when there are two substituents on the same carbon atom of the optionally substituted four- to six-membered heterocyclic group, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl group.

[1321] Example 54

[1322] The modified WRN helicase protein of any one of embodiments 46 to 53, wherein:

[1323] By R 1 The optionally substituted five- to six-membered heterocyclic group formed together with the carbon atom to which it is attached is

[1324] The double bond shown in the figure is in the 1 between the carbon of the group and X;

[1325] By R 3 The optionally substituted C6-C 10 Aryl

[1326]

[1327] By R 3 The optionally substituted five- to six-membered heterocycloalkenyl group formed together with the carbon atom to which it is attached and Y is

[1328] Among them with The carbon-carbon double bond between the two carbon atoms of the group is shown in the case of an R 3 between the carbon of the group and Y;

[1329] When R 3 When taken together with the carbon atom to which it is attached and Y to form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl is The carbon-carbon double bond shown in the figure is 3 between a carbon of the group and Y; and

[1330] Among them, R 4 The optionally substituted five- to six-membered heteroaryl group formed together with the carbon atom to which it is attached and Z is

[1331] In each structure, Indicates a connection point.

[1332] Example 55

[1333] The modified WRN helicase protein of any one of embodiments 46 to 54, wherein:

[1334] In R 1 middle:

[1335] The -O-(optionally substituted C3-C8 cycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexane-5-yl), -O-(spiro[3.3]heptane-2-yl), -O-(3-chlorocyclobutyl), -O-(bicyclo[3.1.0]hexane-3-yl), -O-(bicyclo[2.2.1]heptane-1-yl), -O-(1-cyanocyclopentyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl) or -O-(2,2-difluorocyclopentyl),

[1336] The -O-(optionally substituted C1-C6 alkyl) is ethoxy, isopropoxy or cyclopropylmethyloxy;

[1337] The -O-(optionally substituted C6-C 10 Aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalen-1-yl or phenoxy-d5;

[1338] The -O-(optionally substituted five- to six-membered heteroaryl) is pyridin-2-yloxy or pyridin-3-yloxy;

[1339] The -O-(optionally substituted five- to six-membered heterocyclyl) is -O-tetrahydro-2H-pyran-4-yl or -O-tetrahydro-2H-pyran-3-yl; and

[1340] The optionally substituted C3-C8 cycloalkyl group is a cyclohexyl group;

[1341] In R 2 middle:

[1342] The optionally substituted C1-C6 alkyl group is methyl; and

[1343] In R 3 middle:

[1344] The 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]hexane-5-yl;

[1345] The optionally substituted C3-C8 cycloalkenyl group is a cyclopentenyl group;

[1346] The optionally substituted C6-C 10 Aryl is phenyl;

[1347] The optionally substituted C1-C6 alkyl group is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl or cyclopropyldifluoromethyl;

[1348] The optionally substituted C1-C6 alkenyl group is 2-methylprop-1-en-1-yl;

[1349] NR2 is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl)2, or -N(methyl)(trifluoroethyl);

[1350] The -N(R)(optionally substituted C3-C8 cycloalkyl) is N(methyl)(cyclopropyl);

[1351] The -S-(optionally substituted C1-C6 alkyl) is methyl mercaptan;

[1352] The -O-(optionally substituted C1-C6 alkyl) is trifluoroethoxy or methoxy;

[1353] The -O-(optionally substituted C3-C8 cycloalkyl) is cyclopentyloxy or cyclopropyloxy; and

[1354] The optionally substituted four- to six-membered heterocyclic group or heterocycloalkenyl group is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptane-7-yl, bicyclo[1.1.1]pentane-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptane-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H -pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl or 3,3-difluoro-azetidin-1-yl;

[1355] In R 5 middle:

[1356] The C1-C6 alkyl group is a methyl group;

[1357] The -NR2 is -NH2; and

[1358] The -N(R)-C(=O)-(C1-C6 alkyl) is -N(H)-C(=O)-CH3.

[1359] Example 56

[1360]

[1361] The modified WRN helicase protein according to any one of claims 46 to 55, wherein Q is Q 1 , that is, Q is:

[1362] in Indicates the connection point, and U, R 6 、R 7 、R 7a 、R 8 、R 9 and R 10 As defined in Example 46.

[1363] Example 57

[1364] The modified WRN helicase protein of embodiment 56, wherein:

[1365] R 7The 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;

[1366] R 7 The optionally substituted C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, or difluorocyclohexyl;

[1367] R 7 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[1368] R 10 The optionally substituted C1-C6 alkyl is methyl;

[1369] R 10 The optionally substituted C3-C8 cycloalkyl is cyclopropyl; and

[1370] R 10 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl;

[1371] or Q 1 for:

[1372]

[1373] In each structure, Indicates a connection point.

[1374] Example 58

[1375] The modified WRN helicase protein of any one of embodiments 46 to 55, wherein Q is Q 2 , that is, Q is:

[1376]

[1377] in Indicates the connection point, and U, R 11 、R 12 、R 12a 、R 13 and R 14 As defined in Example 46.

[1378] Example 59

[1379] The modified WRN helicase protein according to embodiment 58, wherein Q 2 for

[1380]

[1381] where R 21 is H or C1-C6 alkyl; wherein Indicates a connection point.

[1382] Example 60

[1383] The modified WRN helicase protein of any one of embodiments 46 to 55, wherein Q is Q 3 , that is, Q is:

[1384]

[1385] in Indicates the connection point, and U, R 15 and R 16 As defined in Example 46.

[1386] Example 61

[1387] The modified WRN helicase protein of embodiment 60, wherein:

[1388] R 16 The optionally substituted C1-C6 alkyl is methyl; and

[1389] R 16 The optionally substituted C3-C8 cycloalkyl group is cyclopropyl.

[1390] Example 62

[1391] The modified WRN helicase protein of any one of embodiments 46 to 55, wherein Q is Q 4 , that is, Q is:

[1392]

[1393] in Indicates the connection point, and U, R 17 、R 18 and R a As defined in Example 46.

[1394] Example 63

[1395] The modified WRN helicase protein of embodiment 62, wherein:

[1396] R18 The optionally substituted C1-C6 alkyl is methyl; and

[1397] The optionally substituted C1-C6 alkyl group is methyl.

[1398] Example 64

[1399] The modified WRN helicase protein according to any one of claims 46 to 55, wherein Q is Q 5 , that is, Q is:

[1400]

[1401] in Indicates the connection point, and U, m and R 19 As defined in Example 46.

[1402] Example 65

[1403] The modified WRN helicase protein of embodiment 64, wherein:

[1404] R 19 The C1-C6 alkyl group is a methyl group; and

[1405] R 19 The -O-(C1-C6 alkyl) is a methoxy group.

[1406] Example 66

[1407] 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 disease.

[1408] Example 66A

[1409] 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 disease.

[1410] Example 66B

[1411] A compound according to any one of Embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A and 39 to 41 for use in the treatment of a proliferative disease.

[1412] Example 67

[1413] A compound for use according to embodiment 66, or a pharmaceutically acceptable salt or solvate thereof, wherein the proliferative disease is cancer.

[1414] Example 67A

[1415] A compound or pharmaceutically acceptable salt for use according to embodiment 66, wherein the proliferative disease is cancer.

[1416] Example 67B

[1417] A compound for use according to embodiment 66, wherein the proliferative disease is cancer.

[1418] Example 68

[1419] A compound for use according to Example 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 tract cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

[1420] Example 68A

[1421] The compound or pharmaceutically acceptable salt thereof for use according to Example 67, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, skin cancer and MSI-H cancer.

[1422] Example 68B

[1423] A compound for use as described in Example 67, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

[1424] Example 69

[1425] A method of measuring WRN helicase activity in an assay comprising ATP and a compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A, and 39 to 41, 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.

[1426] Example 69A

[1427] A method of measuring WRN helicase activity in an assay comprising ATP and a compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A, and 39 to 41, 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.

[1428] Example 69B

[1429] A method of measuring WRN helicase activity in an assay comprising ATP and a compound according to any one of embodiments 1 to 30, 2.1, 2.2, 21.1, 21.1A, 21A to 29A, and 39 to 41. In some embodiments, the assay is an in vitro assay. In some embodiments, the assay is a WRN helicase activity assay.

[1430] Administration and pharmaceutical compositions

[1431] In general, the compounds described herein will be administered in a therapeutically effective amount by any acceptable mode of administration of a medicament with similar efficacy. The therapeutically effective amount of the compounds described herein can range from about 0.01 mg to about 500 mg per kg of patient body weight per day, which can be administered in a single dose or multiple doses. Suitable dosage levels can range from about 0.1 mg / kg to about 250 mg / kg per day, from about 0.05 mg / kg to about 100 mg / kg per day, or from about 0.1 mg / kg to about 50 mg / kg per day. Within this range, the dosage can be from about 0.05 mg / kg to about 0.5 mg / kg per day, from about 0.5 mg / kg to about 5 mg / kg, or from about 5 mg / kg to about 50 mg / kg per day. For oral administration, the composition can be provided in tablet form containing from about 1.0 mg to about 1000 mg 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 mg of active ingredient. The actual amount of compound (i.e., active ingredient) will depend on many factors, such as the severity of the disease to be treated, the age and relative health of the patient, the efficacy of the compound used, the route and form of administration, and other factors.

[1432] In general, the compounds described herein will be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or suppository), parenteral (e.g., intramuscular, intravenous, intrasternal, or subcutaneous), topical (e.g., applied to the skin), or via implant. The preferred route of administration is oral, using a convenient daily dosing regimen that can be adjusted based on the severity of the affliction. The composition can be in the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[1433] The choice of formulation depends on a variety of factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred, including enteric-coated or sustained-release tablets, pills, or capsules) and the bioavailability of the drug substance. Recently, based on the principle that bioavailability can be improved by increasing surface area (i.e., reducing particle size), pharmaceutical formulations have been developed, particularly for drugs that exhibit poor bioavailability. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles with a particle size range of 10 nm to 1,000 nm, wherein the active substance is loaded on a cross-linked macromolecular matrix. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation, wherein the drug substance is crushed into nanoparticles (average particle size of 400 nm) in the presence of a surface modifier, and then dispersed in a liquid medium to obtain a pharmaceutical formulation exhibiting very high bioavailability.

[1434] The compositions are generally composed of a compound described herein in combination with at least one pharmaceutically acceptable carrier / excipient. Acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic benefits of the compound. Such excipients can be any solid, liquid, semisolid, or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

[1435] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils (including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers (particularly for injectable solutions) include water, physiological saline, aqueous glucose solution and ethylene glycol.

[1436] Compressed gases can be used to disperse the compounds described herein in the form of an aerosol. Suitable inert gases for this purpose are nitrogen, carbon dioxide, and the like.

[1437] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th edition, 2000).

[1438] The level of the compound in the formulation can vary within the full range employed by those skilled in the art. Typically, in terms of weight percent (wt %), the formulation will contain from about 0.01 wt % to 99.99 wt % of the compound based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of from about 1 wt % to 80 wt %.

[1439] The compounds described herein can be used in combination with one or more other drugs to treat diseases or conditions for which the compounds described herein or other drugs may have utility, wherein the drug combination is safer or more effective than any drug alone. Such one or more other drugs can be administered simultaneously or sequentially with the compounds described herein by commonly used routes and commonly used amounts. When the compounds described herein are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compounds described herein is preferably used. However, combination therapy can also include a therapy in which the compounds described herein and one or more other drugs are administered according to different overlapping schedules. It is also envisioned that, when used in combination with one or more other active ingredients, the compounds described herein and other active ingredients can be used at lower doses than when each is used alone.

[1440] Therefore, the pharmaceutical compositions described herein may also include those containing one or more other active ingredients in addition to the compounds described herein. The subject that can be treated using the methods described herein is a subject suffering from a cancer characterized by an MSI-H phenotype. In some embodiments, the MSI-H phenotype is characterized by the presence of DNA sequence length changes in at least two of the 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 changes in at least two mononucleotide markers, the mononucleotide markers being selected from the group consisting of NR-21, NR-24, BAT-25, BAT-26, and NR-27 / Mono-27 in the MSI analysis system sold by Promega Corporation (Madison, Wisconsin, USA). In some embodiments, the cancer has mismatch repair deficiency (MMRd). In some embodiments, MMRd is caused by 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 additionally has a mutation that results in loss of ARID1A function. In some embodiments, MMRd is caused by a mutation or epigenetic silencing of the MMR gene promoter.

[1441] The types of cancer may include, for example, MSI-H cancer, adrenocortical carcinoma, bladder cancer, breast cancer, cervical squamous cell carcinoma, endocervical adenocarcinoma, bile duct cancer, chronic lymphocytic leukemia, colorectal cancer, colon adenocarcinoma, ovarian cancer, cutaneous T-cell lymphoma, lymphoma, diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, low-grade glioma, hepatocellular carcinoma In some embodiments, the subject is a patient with a high-risk liver cancer, such as hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, nasopharyngeal carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate cancer, rectal adenocarcinoma, sarcoma, skin melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, endometrial cancer, uterine carcinosarcoma, uveal melanoma, pediatric acute myeloid leukemia, pediatric neuroblastoma, pediatric high-risk Wilms' tumor, or any other type of cancer described herein. Cancer can be in the early or late stages (e.g., recurrent or metastatic cancer). In some embodiments, the subject has received previous anticancer therapy. In some embodiments, the subject has not received anticancer therapy treatment before. In some embodiments, cancer is resistant to immunotherapy (e.g., checkpoint inhibitors as described herein). In some embodiments, cancer is resistant to targeted therapy. In some embodiments, treatment resistance is driven by a defect in MMR, such as resistance to endocrine therapy in breast cancer and resistance to targeted therapy (e.g., temozolomide) in glioblastoma.

[1442] MSI-H can be found 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.

[1443] Combination therapy: The agents that reduce the level and / or activity of WRN in the cells of the subject as described herein can be administered alone or in combination with another anticancer therapy. Anticancer therapy can be another therapeutic agent (e.g., other agents for treating cancer or symptoms associated therewith) or in combination with other types of therapies for treating cancer (e.g., radiotherapy 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 dose of one or more of the therapeutic agents can be reduced from the standard dose when administered alone. For example, the dose can be determined empirically based on the drug combination and arrangement, or can be inferred by isoradiometric analysis (e.g., Black et al., Neurology 65: S3-S6 (2005)). In this case, the dose of the agent or compound in combination should provide a therapeutic effect.

[1444] In some embodiments, the anticancer 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 can be a humanized antibody or a fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, for example, an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA4 antibody or fusion protein, such as ipilimumab / In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / Pembrolizumab / or pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL1 (e.g., an inhibitory antibody or small molecule inhibitor) (e.g., MPDL3280A1RG7446 / atezolizumab; MED14736 / durvalumab; MSB0010718C / avelumab; BMS 936559 / cemiplimab). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224) (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor). 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, B-7 family ligand, or a combination thereof.

[1445] In some embodiments, the anti-cancer therapy is a biologic, such as a cytokine used in cancer treatment (e.g., an interferon or an interleukin (e.g., IL-2)). In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab. In some embodiments, the biologic is an immunoglobulin-based biologic, for example, a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen that is important for cancer. Such agents include: (Rituximab); (Daclizumab); (Basiliximab); (Palivizumab); (Infliximab); (Trastuzumab); MYLOTARG™ (Gemtuzumab ozogamicin); (Alemtuzumab); (Ibritumomab Tiuxetan); (Adalimumab); (Omalizumab); (Tositumomab-I-131); (Efalizumab); (Cetuximab); (bevacizumab); (Natalizumab); (Tocilizumab); (Panitumumab); (Ranibizumab); (Eculizumab); (Certolizumab pegol); (Golimumab); (Canakinumab); (ustekinumab); (Ofatumumab); (Denosumab); Numax (Motavizumab); ABThrax (Raxibacumab); (Belimumab); (ipilimumab); (Brentuximab vedotin); (Pertuzumab); (Ado-trastuzumab emtansine); and (Obinutuzumab). Also included are antibody-drug conjugates.

[1446] In certain embodiments, anticancer therapy is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful for 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, ureas substituted with anthracenediones, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogen, antiestrogen, androgen, antiandrogen and gonadal hormone-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), folinic acid, irinotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel. Non-limiting examples of chemotherapeutic agents include: alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines including hexamethylmelamine, triethylmelamine, triethylphosphoramide, triethylthiophosphoramide, and trimethylmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adolesin derivative); adozelesin), carzelesin, and bizelesin (synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; hyoscyamine; sarcodictyin; spongestatin; nitrogen mustards, such as chlorambucil, naphthyl mustard, chlorphosphamide, estramustine, ifosfamide, dichloromethyldiethylamine, methoxychlor hydrochloride, myfenamic acid, neomuscarin, phenesterine, prednimustine, trofosfamide, and uracil mustard;Nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma 11 and calicheamicin omega 11 (see, e.g., Agnew, Chem. Intl., ed. Engl. 33:183-186 (1994)); anthracyclines, including anthracycline A; bisphosphonates, such as clodronate; esperamicin; and neocarcinogens and related related chromophores of enediyne antibiotics), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid, nogalamycin, olive Olenomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptozocin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil; folic acid analogs such as leucovorin, methotrexate, trimetrexate; purine analogs such as fludarabine ), 6-mercaptopurine, thioguanine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauracil, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enocitabine, floxuridine; androgens such as kalutestosterone, drostanolone propionate, cyclothioandrostol, melastane, testolactone; antiadreners such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglucuronolactone; aldehydes Aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colcemid; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea;Lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-acetylhydrazine; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tricholonone; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; taxanes, for example, (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), Albumin-engineered nanoparticle formulation of paclitaxel without Cremophor (American Pharmaceutical Partners, Schaumberg, Ill.) and (docetaxel, Rhone-Poulenc Rorer, Antony, France); gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; and pharmaceutically acceptable salts, acids, and derivatives of any of the foregoing. Two or more chemotherapeutic agents can be administered in combination with the first therapeutic agent described herein as a mixture. 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).

[1447] In some embodiments, anticancer therapy is T cell adoptive transfer therapy. In some embodiments, T cells are activated T cells. T cells can be modified to express chimeric antigen receptors (CAR). CAR-modified T (CAR-T) cells can be produced by any method known in the art. For example, CAR-T cells can be produced by introducing a suitable expression vector encoding CAR into T cells. Before the amplification and genetic modification of T cells, the source of T cells is obtained from the subject. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue and tumor. In certain embodiments of the present invention, any number of T cell lines available in the art can be used. In some embodiments, T cells are autologous T cells. Whether before or after genetic modification of T cells to express a desired protein (e.g., CAR), T cells can generally be activated and expanded using methods such as those described in the following documents: 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.

[1448] Additional anti-cancer therapies may be non-drug therapies. For example, additional therapeutic agents are radiation therapy, cryotherapy, hyperthermia, and / or surgical resection of tumor tissue.

[1449] In any one of the combination embodiments described herein, the agent that reduces the level and / or activity of WRN in the cells of the subject and the additional therapeutic agent are administered simultaneously or sequentially in any order. The agent that reduces the level and / or activity of WRN in the cells of the subject can be administered immediately before or after the additional therapeutic agent (e.g., anticancer therapy) at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours to 24 hours, or at most 1 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 30 days.

[1450] Examples

[1451] abbreviation

[1452] % Percent

[1453] ℃ degrees Celsius

[1454] AcOH acetic acid

[1455] AcONa sodium acetate

[1456] aq. water-based

[1457] Boc tert-butyloxycarbonyl

[1458] BuLi butyl lithium

[1459] CDI 1,1'-Carbonyldiimidazole

[1460] cm centimeters

[1461] CO carbon monoxide

[1462] CO2 carbon dioxide

[1463] Cs2CO3 cesium carbonate

[1464] D2O Deuterium oxide, heavy water

[1465] DAST Diethylaminosulfur trifluoride

[1466] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[1467] DCE dichloroethane

[1468] DCM dichloromethane

[1469] DIAD Diisopropyl azodicarboxylate

[1470] DIBAL-H Diisobutylaluminum hydride

[1471] DIPEA N,N-Diisopropylethylamine

[1472] DMF dimethylformamide

[1473] DMP Dess-Martin iodine

[1474] DMSO dimethyl sulfoxide

[1475] dtbbpy 4,4'-di-tert-butyl-2,2'-bipyridine

[1476] EA Ethyl acetate

[1477] Et2O ether

[1478] EtOAc

[1479] EtOH

[1480] FA Formic acid

[1481] g grams

[1482] h hour

[1483] H2 Hydrogen

[1484] H2O water

[1485] HATU azabenzotriazole tetramethyl urea hexafluorophosphate

[1486] HBr hydrobromic acid

[1487] HCl

[1488] HPLC high-performance liquid chromatography

[1489] IBX 2-iodoacylbenzoic acid

[1490] IPA Isopropyl alcohol

[1491] K2CO3 potassium carbonate

[1492] L liter

[1493] LAH lithium aluminum hydride

[1494] LC-MS liquid chromatography-mass spectrometry

[1495] LED light-emitting diode

[1496] LiHMDS Lithium bis(trimethylsilyl)amide

[1497] M Moore

[1498] m / z mass-to-charge ratio

[1499] MeCN Acetonitrile

[1500] MeOH methanol

[1501] Mg milligrams

[1502] MgSO4 magnesium sulfate (anhydrous)

[1503] min

[1504] mL milliliters

[1505] mm millimeter

[1506] mmol millimole

[1507] MTBE methyl tert-butyl ether

[1508] N Normal

[1509] N2 nitrogen

[1510] Na2S2O3 sodium thiosulfate

[1511] Na2SO4 sodium sulfate (anhydrous)

[1512] NaClO2 sodium chlorite

[1513] NaH sodium hydride

[1514] NaHCO3 sodium bicarbonate

[1515] NaHMDS Sodium bis(trimethylsilyl)amide

[1516] NaOEt sodium ethoxide

[1517] NaOH sodium hydroxide

[1518] NaOMe sodium methoxide

[1519] NH4Cl ammonium chloride

[1520] NH4HCO3 ammonium bicarbonate

[1521] O2 oxygen

[1522] Pd(OH)2 Palladium Hydroxide

[1523] Pd / C Palladium on Carbon

[1524] PE petroleum ether

[1525] pH Hydrogen Index

[1526] POCl3 Phosphorus oxychloride

[1527] PPh3 triphenylphosphine

[1528] psi pounds per square inch

[1529] PTSA p-Toluenesulfonic acid

[1530] rac racemic

[1531] Rf blocker

[1532] rt room temperature

[1533] sat. saturated

[1534] SFC Supercritical Fluid Chromatography

[1535] SiO2 silicon dioxide, silica gel

[1536] SO2Cl2 sulfuryl chloride

[1537] tBuOK Potassium tert-butoxide

[1538] TEA triethylamine

[1539] TFA trifluoroacetic acid

[1540] THF Tetrahydrofuran

[1541] TLC thin layer chromatography

[1542] μm micrometer

[1543] W Watt

[1544] ZnCl2 zinc chloride

[1545] Example 1

[1546] (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1547]

[1548] Program A

[1549] Step 1

[1550]

[1551] A mixture of diethyl ((methylsulfonyl)methyl)phosphonate (6 g, 26.06 mmol), N-Boc-2-aminoacetaldehyde (4.56 g, 28.67 mmol) and potassium carbonate (9.00 g, 65.16 mmol) in THF (50 mL, 0.521 M) was stirred at 60 ° C for 3 hours. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 120g Purification by silica gel flash chromatography, 20% to 25% ethyl acetate / petroleum ether gradient elution, 100 mL / min) gave tert-butyl N-[(E)-3-methylsulfonylallyl]carbamate (5 g, 82% yield) as a white solid.

[1552] Step 2

[1553]

[1554] To a solution of tert-butyl N-[(E)-3-methylsulfonylallyl]carbamate (3 g, 12.75 mmol) in MeCN (40 mL, 0.319 M) was added p-toluenesulfonic acid monohydrate (2.91 g, 15.3 mmol). The mixture was stirred at 50 ° C for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give crude [(E)-3-methylsulfonylallyl]amine 4-methylbenzenesulfonic acid as a white solid (2.50 g, 64% yield).

[1555] Step 3

[1556]

[1557] 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 obtain 2-cyclopentyl-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester as a yellow solid (1.3 g, 62%).

[1558] Step 4

[1559]

[1560] To a solution of 2-cyclopentyl-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester (500 mg, 2.12 mmol) in phosphorus oxychloride (5 mL, 53.64 mmol, 1.645 g / ml) was added. The mixture was heated at 80 ° C for 2 hours. The mixture was concentrated to dryness under reduced pressure to give crude 4-chloro-2-cyclopentyl-pyrimidine-5-carboxylic acid ethyl ester as a brown oil (0.5 g).

[1561] Step 5

[1562]

[1563] To a solution of 4-chloro-2-cyclopentyl-pyrimidine-5-carboxylic acid ethyl ester (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 hours. 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 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester as a white solid (240 mg).

[1564] Step 6

[1565]

[1566] To a solution of 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (240 mg, 0.77 mmol) in THF (3 mL, 0.128 M) was added monohydrate lithium hydroxide (96.9 mg, 2.31 mmol). The mixture was stirred at 25 ° C for 3 hours. By gradually adding 2M HCl, the aqueous phase was adjusted to pH = 5 to 6. The precipitate was collected by filtration, washed with water and dried under reduced pressure to obtain crude 2-cyclopentyl-4-phenoxy-pyrimidine-5-carboxylic acid as a white solid (200 mg).

[1567] Step 7

[1568]

[1569] 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-methylsulfonylallyl]amine 4-methylbenzenesulfonic acid (113.5 mg, 0.37 mmol), HATU (200.6 mg, 0.53 mmol) and DIPEA (0.2 mL, 1.06 mmol) at 25 ° C. The mixture was stirred at 25 ° C. under N2 for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DMF (2 mL) and purified by preparative HPLC [column: Welch Xtimate C18 100×25 mm×3 μm, eluent: water (0.04% HCl) / MeCN=25% to 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].

[1570] Example 2

[1571] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1572]

[1573] Step 1

[1574]

[1575] To a solution of Boc-L-aminopropanol (10g, 57.07mmol) in MeCN (1L, 0.0571M) was added 1-hydroxy-1-oxo-1λ5,2-benzidoyl-3-one (40.0g, 142.67mmol) at 25°C. The reaction was stirred at 65°C for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain crude N-[(1S)-1-methyl-2-oxo-ethyl] tert-butyl carbamate, which was a yellow oil (10g).

[1576] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A. LC-MS m / z: 416.1 [M+1].

[1577] Example 3

[1578] (S,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1579]

[1580] The lower olefin isomer N-[(Z,1S)-1-methyl-3-methylsulfonyl-allyl]carbamic acid tert-butyl ester obtained in step 1 was used in the compound of Example 2 to obtain the title compound. LC-MS m / z: 416.2 [M+1].

[1581] Example 4

[1582] (R,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1583]

[1584] The title compound was obtained using tert-butyl N-[(1R)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A. LC-MS m / z: 416.1 [M+1].

[1585] Example 5

[1586] (R,Z)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1587]

[1588] The lower olefin isomer N-[(Z,1R)-1-methyl-3-methylsulfonyl-allyl]carbamic acid tert-butyl ester obtained in Step 1 was used in the compound of Example 4 to obtain the title compound. LC-MS m / z: 416.2 [M+1].

[1589] Example 6

[1590] (S,E)-2-Cyclopentyl-N-(1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1591]

[1592] 1-Hydroxy-1-oxo-1λ5,2-benzidoxin-3-one for Step 1 was prepared using tert-butyl N-[(1S)-1-(hydroxymethyl)propyl]carbamate / IBX / MeCN in Procedure A and NaH as the base in Step 1 to give the title compound. LC-MS m / z: 430.2 [M+1].

[1593] Example 7

[1594] (S,E)-2-Cyclopentyl-N-(4-methyl-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1595]

[1596] tert-Butyl N-[(1S)-1-formyl-2-methyl-propyl]carbamate for step 1 was prepared using Boc-D-valinol / IBX in procedure A and NaH as the base for step 1 to give the title compound. LC-MS m / z: 444.2 [M+1].

[1597] Example 8

[1598] (S,E)-2-Cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1599]

[1600] Step 1

[1601]

[1602] To a solution of tert-butyl N-[(1S)-1-cyclopropyl-2-hydroxy-ethyl]carbamate (500mg, 2.48mmol) in DCM (8mL, 0.311M) was added Dess-Martin periodinane (2.1g, 4.97mmol). The reaction mixture was stirred at 25°C for 1 hour under N2. The mixture was filtered and the filter cake was rinsed with DCM (3×15mL). The combined filtrate was then concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (Biotage, using 12g Agela rapid silica gel columns, eluted with petroleum ether containing 0% to 8% ethyl acetate) to obtain tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate, which was a colorless oil (300mg, 61% yield).

[1603] The title compound was obtained using N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A. LC-MS m / z: 442.1 [M+1].

[1604] Example 9

[1605] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopentyl-4-phenoxypyrimidine-5-carboxamide

[1606]

[1607] tert-Butyl N-[(1S)-1-cyclobutyl-2-oxo-ethyl]carbamate for step 1 was prepared using tert-butyl N-[(1S)-1-cyclobutyl-2-hydroxy-ethyl]carbamate / Dess-Martin periodinane / DCM in procedure A and NaH as the base in step 1 to give the title compound. LC-MS m / z: 456.1 [M+1].

[1608] Example 10

[1609] (R,E)-2-Cyclopentyl-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1610]

[1611] Step 1

[1612]

[1613] 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 minutes, and then DIBAL-H (47.9 mL, 47.90 mmol, 1.23 g / ml) was added dropwise to the mixture at -70 ° C. The mixture was quenched by adding saturated potassium sodium tartrate (100 mL) and stirred for 30 minutes, 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).

[1614] The title compound was obtained using tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH in step 1 of procedure A. LC-MS m / z: 446.1 [M+1].

[1615] Example 11

[1616] (S,E)-2-Methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1617]

[1618] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 4-hydroxy-2-methyl-pyrimidine-5-carboxylate in step 4. LC-MS m / z: 362.1 [M+1].

[1619] Example 12

[1620] (E)-2-Ethyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1621]

[1622] The title compound was obtained using propionamidine hydrochloride in step 3 of procedure A. LC-MS m / z: 362.2 [M+1].

[1623] Example 13

[1624] (S,E)-2-Ethyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1625]

[1626] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and propionamidine hydrochloride in step 3. LC-MS m / z: 376.2 [M+1].

[1627] Example 14

[1628] (E)-2-Isopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1629]

[1630] The title compound was obtained using 2-methylpropionamidine hydrochloride in step 3 of procedure A. LC-MS m / z: 376.1 [M+1].

[1631] Example 15

[1632] (S,E)-2-Isopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1633]

[1634] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 2-methylpropionamidine hydrochloride in step 3. LC-MS m / z: 390.1 [M+1].

[1635] Example 16

[1636] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-4-phenoxypyrimidine-5-carboxamide

[1637]

[1638] Using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in procedure A for step 1 and 2-methylpropionamidine hydrochloride in step 3, the title compound was obtained. LC-MS m / z: 416.1 [M+1].

[1639] Example 17

[1640] (E)-2-Cyclopropyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1641]

[1642] The title compound was obtained using cyclopropanecarboxamidine in step 3 of procedure A. LC-MS m / z: 374.0 [M+1].

[1643] Example 18

[1644] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1645]

[1646] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and cyclopropanecarboxamidine in step 3. LC-MS m / z: 388.0 [M+1].

[1647] Example 19

[1648] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(2-fluoropropan-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1649]

[1650] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH for step 1 and cyclopropanecarboxamidine for step 3 in procedure A. LC-MS m / z: 414.1 [M+1].

[1651] Examples 20 and 21

[1652] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 20)

[1653]

[1654] (S,Z)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 21)

[1655]

[1656] A mixture of the title compounds was obtained using tert-butyl N-[(1S)-1-benzyl-2-oxo-ethyl]carbamate / NaH for step 1 and cyclopropanecarboximidamide for step 3 in Procedure A. The mixture was separated by preparative HPLC (reverse phase, MeCN / H2O (0.1% FA) = 5% to 95%) to give 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]).

[1657] Example 22

[1658] (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone

[1659]

[1660] In Procedure A for Step 1, tert-butyl 3-formylazetidine-1-carboxylate was used. n BuLi and using cyclopropanecarboxamidine in step 3, the title compound was obtained as a mixture of olefin isomers (E:Z=1.6:1). LC-MS m / z: 400.2 [M+1].

[1661] Examples 23 and 24

[1662] (Z)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone (Example 23)

[1663]

[1664] (E)-(2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(2-(methylsulfonyl)vinyl)azetidin-1-yl)methanone (Example 24)

[1665]

[1666] The compound of Example 22 was separated by chiral SFC (column: Chiralpak AS-3) to obtain Peak 1 (Z isomer, LC-MS m / z: 400.2 [M+1]) and Peak 2 (E isomer, LC-MS m / z: 400.2 [M+1]).

[1667] Example 25

[1668] (S,E)-2-Cyclopropyl-N-(4-(cyclopropylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1669]

[1670] Step 1

[1671]

[1672] The solution of sodium cyclopropanesulfinate (922mg, 7.19mmol) in DMSO (6mL, 0.600M) was stirred at room temperature for 1 hour with complete dissolution of salt. Then diethyl iodomethylphosphonate (0.60mL, 3.60mmol) was added, and the mixture was heated at 80 ° C overnight. Additional sodium cyclopropanesulfinate (922mg, 7.19mmol) was added, and the mixture was heated at 100 ° C for 1 hour. The mixture was diluted with EtOAc, washed with 1M HCl and salt water, through Na2SO4 dried, and under reduced pressure concentrated to obtain residue. Residue was purified by Biotage Isolera (0% to 10% MeOH / DCM) via normal phase column chromatography, to obtain diethoxyphosphorylmethylsulfonylcyclopropane, which was a yellow oil (432mg, yield 47%).

[1673] The title compound was obtained using diethoxyphosphorylmethylsulfonylcyclopropane / tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and cyclopropanecarboxamidine in step 3. LC-MS m / z: 414.0 [M+1].

[1674] Example 26

[1675] (2-Cyclopropyl-4-phenoxy-pyrimidin-5-yl)-[(3Z)-3-(methylsulfonylmethylene)pyrrolidin-1-yl]methanone

[1676]

[1677] Using N-Boc-3-pyrrolidone / NaH for step 1 in procedure A and cyclopropanecarboxamidine for step 3, the title compound was obtained. LC-MS m / z: 400.0 [M+1].

[1678] Example 27

[1679] 2-Cyclopropyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1680]

[1681] The title compound was obtained following step 7 of procedure A using 2-cyclopropyl-4-phenoxy-pyrimidine-5-carboxylic acid and 3-amino-2,3-dihydrothiophene 1,1-dioxide. LC-MS m / z: 372.0 [M+1].

[1682] Example 28

[1683] (S,E)-2-Cyclopropyl-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1684]

[1685] Step 1

[1686]

[1687] CDI (592 mg, 3.65 mmol) was slowly added to a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propionic acid; N-cyclohexylcyclohexylamine (1.0 g, 2.44 mmol) in DCM and stirred at room temperature for 30 minutes until CO2 production 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 hours. 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 Na2SO4, 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).

[1688] Step 2

[1689]

[1690] DIBAL-H (0.86 mL, 4.8 mmol) was added dropwise to a solution of tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (356 mg, 1.31 mmol) in Et2O at -78°C. After 1 hour, the excess DIBAL-H was quenched by the addition of EtOAc, and the mixture was stirred at -78°C for another 15 minutes. The reaction mixture was poured into a mixture of citric acid and Et2O (15 mL), and the layers were gently shaken and then separated. The aqueous layer was then extracted with Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by normal phase chromatography (SiO 2 , EtOAc / heptane = 0% to 100%) to give tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (209.8 mg, 74% yield).

[1691] The title compound was obtained using tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate / Cs2CO3 in step 1 of procedure A and cyclopropanecarboxamidine in step 3. LC-MS m / z: 428.0 [M+1].

[1692] Example 29

[1693] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopropyl-4-phenoxypyrimidine-5-carboxamide

[1694]

[1695] The title compound was obtained using (2S)-2-(tert-butoxycarbonylamino)-2-cyclobutyl-acetic acid in step 1 and following the procedure for the compound of Example 28. LC-MS m / z: 428.0 [M+1].

[1696] Example 30

[1697] (S,E)-2-Cyclopropyl-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1698]

[1699] The title compound was obtained using (2S)-2-(tert-butoxycarbonylamino)-2-(3,3-difluorocyclobutyl)acetic acid in step 1 and following the procedure for the compound of Example 28. LC-MS m / z: 464.0 [M+1].

[1700] Example 31

[1701] (R,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1702]

[1703] The title compound was obtained using (2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propionic acid in step 1 and following the procedure for the compound of Example 28. LC-MS m / z: 434.0 [M+1].

[1704] Example 32

[1705] 2-Cyclopropyl-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1706]

[1707] The title compound was obtained by 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].

[1708] Example 33

[1709] (S,E)-2-Cyclopropyl-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1710]

[1711] The title compound was obtained by 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].

[1712] Example 34

[1713] (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-1-yl)methanone

[1714]

[1715] Step 1

[1716]

[1717] A mixture of tert-butyl 2,5-dihydro-1h-pyrrole-1-carboxylate (1g, 5.91mmol), sodium methanesulfinate (1.2g, 11.82mmol), iodine (1.65g, 6.50mmol) and sodium acetate (727mg, 8.86mmol) in ethyl acetate (15mL, 0.236M) and water (10mL, 0.236M) was stirred at 70°C (illuminated with a 1000W lamp) for 1 hour. The reaction mixture was poured into a saturated Na2S2O3 aqueous solution (15mL) and extracted with EtOAc (3×15mL). The combined organic layer was washed with brine (2×10mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 12g Purification by silica gel flash chromatography, 30% to 60% ethyl acetate / petroleum ether gradient elution, 100 mL / min) gave 3-iodo-4-methylsulfonyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (600 mg, 27% yield).

[1718] Step 2

[1719]

[1720] To a mixture 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 hours. The mixture was washed with aqueous HCl (1N, 3 mL), saturated NaHCO 3 (3 mL), and brine (3 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , PE: EtOAc = 1: 1) to give tert-butyl 3-methylsulfonyl-2,5-dihydropyrrole-1-carboxylate as a white solid (400 mg).

[1721] The title compound was obtained using tert-butyl 3-methylsulfonyl-2,5-dihydropyrrole-1-carboxylate in step 2 of procedure A and cyclopropanecarboxamidine in step 3. LC-MS m / z: 386.0 [M+1].

[1722] Example 35

[1723] (S,E)-2-(Cyclopropylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1724]

[1725] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 2-cyclopropylacetamidine in step 3 in procedure A. LC-MS m / z: 402.1 [M+1].

[1726] Example 36

[1727] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylmethyl)-4-phenoxypyrimidine-5-carboxamide

[1728]

[1729] Using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH for step 1 in procedure A and 2-cyclopropylacetamidine for step 3, the title compound was obtained. LC-MS m / z: 428.1 [M+1].

[1730] Example 37

[1731] N-((S,E)-1-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(cyclopropylfluoromethyl)-4-phenoxypyrimidine-5-carboxamide

[1732]

[1733] Step 1

[1734]

[1735] 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 at 75 ° C for 12 hours under N2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (8 mL), and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 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 μm, gradient of water (NH4HCO3)-MeCN: 30% to 50% B, 25 mL / min) to give 2-[cyclopropyl(fluoro)methyl]-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester as a yellow solid (10 mg, 9.4% yield).

[1736] In Procedure A, following step 6, using 2-[cyclopropyl(fluoro)methyl]-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester and following step 7, using [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid, the title compound was obtained. LC-MS m / z: 446.1 [M+1].

[1737] Example 38

[1738] (S,E)-2-(1-Methylcyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1739]

[1740] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 1-methylcyclopropanecarboximidamide hydrochloride in step 3. LC-MS m / z: 402.0 [M+1].

[1741] Example 39

[1742] (2-(1-Methylcyclopropyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone

[1743]

[1744] The title compound was obtained using tert-butyl 3-oxoazetidine-1-carboxylate / NaH in step 1 and 1-methylcyclopropanecarboximidamide hydrochloride in step 3 in procedure A. LC-MS m / z: 400.0 [M+1].

[1745] Example 40

[1746] (S,E)-2-((1-methylcyclopropyl)methyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1747]

[1748] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 2-(1-methylcyclopropyl)acetamidine in step 3 in procedure A. LC-MS m / z: 416.0 [M+1].

[1749] Example 41

[1750] (2-((1-Methylcyclopropyl)methyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone

[1751]

[1752] The title compound was obtained using tert-butyl 3-oxoazetidine-1-carboxylate / NaH in step 1 and 2-(1-methylcyclopropyl)acetamidine in step 3 in procedure A. LC-MS m / z: 414.0 [M+1].

[1753] Example 42

[1754] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-phenylcyclopropyl)pyrimidine-5-carboxamide

[1755]

[1756] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 1-phenylcyclopropanecarboximidamide in step 3 in procedure A. LC-MS m / z: 464.0 [M+1].

[1757] Example 43

[1758] (E)-2-Cyclobutyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1759]

[1760] The title compound was obtained using cyclobutanecarboximidamide in step 3 of procedure A. LC-MS m / z: 388.1 [M+1].

[1761] Example 44

[1762] (S,E)-2-Cyclobutyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1763]

[1764] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and cyclobutanecarboximidamide hydrochloride in step 3. LC-MS m / z: 402.1 [M+1].

[1765] Example 45

[1766] (S,E)-2-Cyclobutyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1767]

[1768] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH for step 1 and cyclobutanecarboximidamide hydrochloride for step 3 in procedure A. LC-MS m / z: 428.1 [M+1].

[1769] Examples 46 and 47

[1770] 2-((1s,3R)-3-methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 46)

[1771]

[1772] 2-((1r,3S)-3-methylcyclobutyl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 47)

[1773]

[1774] A mixture of the title compounds was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH for step 1 and 3-methylcyclobutanecarboximidamide for step 3 in Procedure A. The mixture was separated by chiral HPLC (column: Chiralpak AD-3) to give Peak 1 (compound of Example 46) (LC-MS m / z: 416.2 [M+1]) and Peak 2 (compound of Example 47) (LC-MS m / z: 416.2 [M+1]).

[1775] Examples 48 and 49

[1776] N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((1s,3R)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide (Example 48)

[1777]

[1778] N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((1r,3S)-3-methylcyclobutyl)-4-phenoxypyrimidine-5-carboxamide (Example 49)

[1779]

[1780] Using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH for step 1 and 3-methylcyclobutanecarboximidamide for step 3 in Procedure A, a mixture of the title compounds was obtained. The mixture was separated by chiral HPLC (column: Waters Xbridge BEH C18 (100×30 mm×10 μm), mobile phase: water (NH 4 HCO 3 )-MeCN, gradient from 30% to 65% B, flow rate: 60 mL / min) to give Peak 1 (compound of Example 48) (LC-MS m / z: 442.2 [M+1]) and Peak 2 (compound of Example 49).

[1781] (LC-MS m / z: 442.2 [M+1]).

[1782] Examples 50 and 51

[1783] (2-((1s,3s)-3-methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone (Example 50)

[1784]

[1785] (2-((1r,3r)-3-methylcyclobutyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone (Example 51)

[1786]

[1787] A mixture of the title compounds was obtained using tert-butyl 3-oxoazetidine-1-carboxylate / NaH for step 1 and 3-methylcyclobutanecarboximidamide for step 3 in Procedure A. The mixture was separated by chiral SFC (column: Daicel ChiralPak IC (250 mm×30 mm×10 μm), 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]).

[1788] Example 52

[1789] 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

[1790]

[1791] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and bicyclo[4.2.0]octa-1,3,5-triene-7-carboximidamide in step 3. LC-MS m / z: 450.0 [M+1].

[1792] Example 53

[1793] (S,E)-2-(Cyclobutylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1794]

[1795] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 2-cyclobutylacetamidine in step 3 in procedure A. LC-MS m / z: 416.2 [M+1].

[1796] Example 54

[1797] (S,E)-2-(Cyclopentylmethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1798]

[1799] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 2-cyclopentylacetamidine in step 3. LC-MS m / z: 430.2 [M+1].

[1800] Example 55

[1801] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(spiro[2.3]hexan-5-yl)pyrimidine-5-carboxamide

[1802]

[1803] Step 1

[1804]

[1805] 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 hours. 3-methylenecyclobutanecarbonitrile (3 g, 32.21 mmol) was then added dropwise to the mixture. The mixture was stirred at 80 ° C for 16 hours under N2. The reaction mixture was cooled to room temperature and slowly poured into a slurry of silica gel in DCM (15 mL) and stirred for 10 minutes. The silica gel was filtered and washed with MeOH (3 × 20 mL). The filtrate and washings were combined and concentrated under reduced pressure to obtain crude 3-methylenecyclobutanecarbonitrile as a white solid (2.35 g, 66% yield).

[1806] Step 2

[1807]

[1808] At 0 ° C, sodium methoxide (23.4 mL, 117.1 mmol, 5 M) was added to a solution of 3-methylenecyclobutanecarboximidamide (4.3 g, 39.03 mmol) in ethanol (40 mL, 0.781 M). A solution of diethyl ethoxymethylenemalonate (8.44 g, 39.03 mmol) in ethanol (10 mL, 0.781 M) was added dropwise to the mixture over 5 minutes. The mixture was stirred at 90 ° C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (5 mL) and the pH was adjusted to about 6 with saturated aqueous citric acid solution and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (15 mL). The resulting solid was collected by filtration, washed with MTBE (20 mL) and dried to give ethyl 4-hydroxy-2-(3-methylenecyclobutyl)pyrimidine-5-carboxylate as a light yellow solid (3.6 g, 39% yield).

[1809] Step 3

[1810]

[1811] Diiodomethane (1.7mL, 21.35mmol) was added to diethylzinc (21.4mL, 21.35mmol, 1M) at 0°C. The mixture was stirred at 0°C for 0.5 hours. Ethyl 4-hydroxy-2-(3-methylenecyclobutyl)pyrimidine-5-carboxylate (500mg, 2.13mmol) in DCM (1mL, 2.135M) was then slowly added to the mixture at 0°C. After stirring for 2 hours at this temperature, the mixture was warmed to room temperature and stirred at 25°C for 12 hours. The mixture was then filtered, and the filter cake was rinsed with EtOAc (3×5mL). The combined filtrate was concentrated under reduced pressure to obtain crude 4-hydroxy-2-spiro[2.3]hexane-5-yl-pyrimidine-5-carboxylate (160mg).

[1812] Using 4-hydroxy-2-spiro[2.3]hexan-5-yl-pyrimidine-5-carboxylic acid ethyl ester in Procedure A to follow Steps 4, 5, 6, and 7 (using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid), the title compound was obtained. LC-MS m / z: 428.2 [M+1].

[1813] Example 56

[1814] (E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1815]

[1816] The title compound was obtained using 2,2-dimethylpropionamidine hydrochloride in step 3 of procedure A. LC-MS m / z: 390.1 [M+1].

[1817] Example 57

[1818] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1819]

[1820] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 2,2-dimethylpropionamidine hydrochloride in step 3 in procedure A. LC-MS m / z: 404.2 [M+1].

[1821] Example 58

[1822] (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1823]

[1824] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH for step 1 and 2,2-dimethylpropionamidine hydrochloride for step 3 in procedure A. LC-MS m / z: 430.2 [M+1].

[1825] Example 59

[1826] 2-(tert-Butyl)-N-(1-(2-(methylsulfonyl)vinyl)cyclopropyl)-4-phenoxypyrimidine-5-carboxamide

[1827]

[1828] Procedure A was used to prepare tert-butyl (1-formyl-cyclopropyl)-carbamate using tert-butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate / Dess-Martin periodinane / DCM for step 1, and NaH as the base in step 1 and 2,2-dimethylpropionamidine hydrochloride in step 3 to obtain the title compound as a mixture of olefin isomers (E:Z=3.7:1). LC-MS m / z: 416.2 [M+1].

[1829] Examples 60 and 61

[1830] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 60)

[1831]

[1832] (S,Z)-2-(tert-butyl)-N-(4-(methylsulfonyl)-1-phenylbut-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Example 61)

[1833]

[1834] A mixture of the title compounds was obtained using tert-butyl N-[(1S)-1-benzyl-2-oxo-ethyl]carbamate / NaH for step 1 and 2,2-dimethylpropionamidine hydrochloride for step 3 in Procedure A. The mixture was separated by preparative HPLC (reverse phase, MeCN / H2O (0.1% FA) = 5% to 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]).

[1835] Example 62

[1836] (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methylene)azetidin-1-yl)methanone

[1837]

[1838] Step 1

[1839]

[1840] To a solution of 4-methylsulfonyltetrahydropyran (580 mg, 3.53 mmol) in THF (5 mL, 0.122 M) was added n-butyl lithium solution (3.1 mL, 7.77 mmol, 2.5 M) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hours, and then diphenyl chlorophosphate (948.8 mg, 3.53 mmol) was added. The mixture was stirred for 1 hour at 0 ° C. The reaction mixture was poured into a saturated NH4Cl aqueous solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (3×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 12g Purification by silica gel flash chromatography, 0% to 40% ethyl acetate / petroleum ether gradient elution, 100 mL / min) gave 4-(diphenoxyphosphorylmethylsulfonyl)tetrahydropyran as a yellow solid (1.0 g, 72% yield).

[1841] The title compound was obtained using 4-(diphenoxyphosphorylmethylsulfonyl)tetrahydropyran / tert-butyl 3-oxoazetidine-1-carboxylate / NaH in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3. LC-MS m / z: 472.1 [M+1].

[1842] Example 63

[1843] (R,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1844]

[1845] The title compound was obtained using tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3. LC-MS m / z: 434.2 [M+1].

[1846] Example 64

[1847] (S,E)-2-(tert-Butyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1848]

[1849] The title compound was obtained by 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].

[1850] Example 65

[1851] (S,E)-2-(tert-Butyl)-N-(1-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1852]

[1853] The title compound was obtained using tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate / Cs2CO3 in step 1 and 2,2-dimethylpropionamidine hydrochloride in step 3 in procedure A. LC-MS m / z: 444.2 [M+1].

[1854] Example 66

[1855] (S,E)-2-(tert-Butyl)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1856]

[1857] The title compound was obtained using tert-butyl N-[(1S)-1-cyclobutyl-2-oxo-ethyl]carbamate / Cs2CO3 in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3. LC-MS m / z: 444.2 [M+1].

[1858] Example 67

[1859] (S,E)-2-(tert-Butyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1860]

[1861] The title compound was obtained using tert-butyl N-[(1S)-1-(3,3-difluorocyclobutyl)-2-oxo-ethyl]carbamate / Cs2CO3 in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3. LC-MS m / z: 480.2 [M+1].

[1862] Example 68

[1863] (R,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)-1-(methylthio)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1864]

[1865] The title compound was obtained using tert-butyl N-[(1R)-1-formyl-2-methylsulfanyl-ethyl]carbamate / Cs2CO3 in step 1 and 2,2-dimethylpropionamidine hydrochloride in step 3 in procedure A. LC-MS m / z: 450.0 [M+1].

[1866] Example 69

[1867] 2-(tert-Butyl)-N-((3R,4R,E)-4-methoxy-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1868]

[1869] The title compound was obtained using tert-butyl N-[(1S,2R)-1-formyl-2-methoxypropyl]carbamate / Cs2CO3 in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3. LC-MS m / z: 448.2 [M+1].

[1870] Example 70

[1871] (S,E)-2-(tert-Butyl)-N-(3-(methylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1872]

[1873] The title compound was obtained using tert-butyl N-[(1S)-2-oxo-1-tetrahydropyran-4-yl-ethyl]carbamate / Cs2CO3 in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3. LC-MS m / z: 474.2 [M+1].

[1874] Example 71

[1875] (S,E)-2-(tert-Butyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1876]

[1877] Using (2S)-2-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-oxo-butanoic acid in step 1 and following the procedure for the compound of Example 28 in step 2, 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 / Cs2CO3 in step 1 in procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3, the title compound was obtained. LC-MS m / z: 475.2 [M+1].

[1878] Example 72

[1879] (S,E)-2-(tert-Butyl)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1880]

[1881] Using (2S)-2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid in step 1 and following step 2 of the procedure for the compound of Example 28, 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 / Cs2CO3 in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3, the title compound was obtained. LC-MS m / z: 508.2 [M+1].

[1882] Example 73

[1883] (S,E)-2-(tert-Butyl)-N-(5,5-difluoro-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1884]

[1885] Using (2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro-butanoic acid in step 1 and following the procedure for the compound of Example 28, step 2, tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate was obtained. Using tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate / Cs2CO3 in step 1 of procedure A and 2,2-dimethylpropionamidine hydrochloride in step 3, the title compound was obtained. LC-MS m / z: 454.0 [M+1].

[1886] Examples 74 and 75

[1887] (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

[1888]

[1889] 2-(tert-Butoxycarbonylamino)-3-phenoxy-propionic acid is converted to tert-butyl N-(1-formyl-2-phenoxy-ethyl)carbamate via LiBH4 reduction and subsequent DMP oxidation. Using tert-butyl N-(1-formyl-2-phenoxy-ethyl)carbamate / NaH for step 1 in Procedure A, and 2,2-dimethylpropionamidine hydrochloride in step 3, a mixture of title compounds is obtained. The mixture is 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 is undetermined.

[1890] Example 76

[1891] (E)-2-Cyclohexyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[1892]

[1893] The title compound was obtained using cyclohexanecarboxamidine hydrochloride in step 3 of procedure A. LC-MS m / z: 416.1 [M+1].

[1894] Example 77

[1895] (S,E)-2-Cyclohexyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1896]

[1897] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and cyclohexanecarboxamidine hydrochloride in step 3. LC-MS m / z: 430.2 [M+1].

[1898] Example 78

[1899] N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-2-yl)pyrimidine-5-carboxamide

[1900]

[1901] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and tetrahydrofuran-2-carboximidamide in step 3. LC-MS m / z: 418.1 [M+1].

[1902] Example 79

[1903] N-((S,E)-4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide

[1904]

[1905] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and tetrahydrofuran-3-carboximidamide in step 3. LC-MS m / z: 418.1 [M+1].

[1906] Example 80

[1907] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-phenylpyrimidine-5-carboxamide

[1908]

[1909] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and benzamidine hydrochloride in step 3. LC-MS m / z: 424.1 [M+1].

[1910] Example 81

[1911] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide

[1912]

[1913] In Procedure A, starting with step 5, and 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].

[1914] Example 82

[1915] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(trifluoromethyl)pyrimidine-5-carboxamide

[1916]

[1917] In Procedure A, starting with step 5, and 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].

[1918] Example 83

[1919] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1920]

[1921] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 2,2,3,3,3-pentafluoropropionamidine in step 3 in procedure A. LC-MS m / z: 466.1 [M+1].

[1922] Example 84

[1923] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1924]

[1925] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in step 1 and 2,2,3,3,3-pentafluoropropionamidine in step 3 in procedure A. LC-MS m / z: 492.1 [M+1].

[1926] Example 85

[1927] (R,E)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1928]

[1929] The title compound was obtained using tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH in step 1 and 2,2,3,3,3-pentafluoropropionamidine in step 3 in procedure A. LC-MS m / z: 496.1 [M+1].

[1930] Example 86

[1931] (S,E)-2-(1,1-difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1932]

[1933] Step 1

[1934]

[1935] Under an argon atmosphere, ammonium chloride (3.87g, 72.41mmol) is suspended in toluene (40mL, 0.362M), and the mixture is cooled to 0°C. Hexane (41mL, 2M) containing triethylaluminum is added dropwise, and the reaction mixture is stirred at 25°C until it is observed that no more gas is produced. After adding ethyl 2,2-difluoropropionate (2g, 14.48mmol), the mixture is stirred at 80°C for 12 hours. It is then cooled to 0°C, methanol (80mL) is added, and then stirred at 25°C for 1 hour. After filtration, the solid is washed several times with methanol, and the solution is concentrated under reduced pressure to obtain crude 2,2-difluoropropionamidine as a white solid (1.40g, 89% yield).

[1936] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 2,2-difluoropropionamidine in step 3 in procedure A. LC-MS m / z: 412.1 [M+1].

[1937] Example 87

[1938] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1939]

[1940] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH for step 1 and 2,2-difluoropropionamidine in step 3 in procedure A. LC-MS m / z: 438.1 [M+1].

[1941] Example 88

[1942] (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1943]

[1944] The title compound was obtained using tert-butyl N-[(1S)-1-cyclobutyl-2-oxo-ethyl]carbamate / NaH for step 1 and 2,2-difluoropropionamidine in step 3 in procedure A. LC-MS m / z: 452.1 [M+1].

[1945] Example 89

[1946] (R,E)-2-(1,1-difluoroethyl)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1947]

[1948] The title compound was obtained using tert-butyl N-[(1S)-1-formyl-2-methoxy-ethyl]carbamate / NaH in step 1 of procedure A and 2,2-difluoropropionamidine in step 3. LC-MS m / z: 442.1 [M+1].

[1949] Example 90

[1950] (S,E)-N-(5,5-difluoro-1-(methylsulfonyl)pent-1-en-3-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1951]

[1952] The title compound was obtained using tert-butyl N-[(1S)-3,3-difluoro-1-formyl-propyl]carbamate / NaH in step 1 of procedure A and 2,2-difluoropropionamidine in step 3. LC-MS m / z: 462.0 [M+1].

[1953] Example 91

[1954] (S,E)-N-(1-(4,4-difluorocyclohexyl)-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1955]

[1956] The title compound was obtained using tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]carbamate / NaH in step 1 and 2,2-difluoropropionamidine in step 3 in procedure A. LC-MS m / z: 516.0 [M+1].

[1957] Example 92

[1958] (S,E)-2-(1,1-difluoroethyl)-N-(5-(dimethylamino)-1-(methylsulfonyl)-5-oxopent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1959]

[1960] The title compound was obtained using tert-butyl N-[(1S)-3-(dimethylamino)-1-formyl-3-oxopropyl]carbamate / Cs2CO3 in step 1 of procedure A and 2,2-difluoropropionamidine in step 3. LC-MS m / z: 483.0 [M+1].

[1961] Example 93

[1962] 2-(1,1-difluoroethyl)-N-((3R,4S,E)-4-methoxy-1-(methylsulfonyl)pent-1-en-3-yl)-4-phenoxypyrimidine-5-carboxamide

[1963]

[1964] The title compound was obtained by 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].

[1965] Examples 94 and 95

[1966] (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

[1967]

[1968] Step 1

[1969]

[1970] At 0 ° C, potassium tert-butoxide (25.8g, 23.02mmol) was added dropwise to a mixture of diethyl 2-acetamidomalonate (5.0g, 23.02mmol) in THF (50mL, 0.460M). Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (10.7g, 46.04mmol) was added. The resulting mixture was stirred at 75 ° C for 48 hours. The mixture was poured into a saturated NH4Cl aqueous solution (80mL) and extracted with EtOAc (2×100mL). The combined organic layer was washed with brine (100mL), filtered, concentrated under reduced pressure and purified by flash silica gel chromatography ( 20g Purification by silica gel flash chromatography, 0% to 70% ethyl acetate / petroleum ether gradient, 60 mL / min) gave diethyl 2-acetamido-2-(2,2,2-trifluoroethyl)malonate as a yellow oil (2.0 g, 29% yield).

[1971] Step 2

[1972]

[1973] A mixture of diethyl 2-acetamido-2-(2,2,2-trifluoroethyl)malonate (2.0 g, 6.68 mmol) in 6N HCl (10 mL) was stirred at 100 ° C for 15 hours. The mixture was adjusted to pH = 10 with NaOH (aqueous solution, 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 hours. The turbid reaction mixture was neutralized with 1.0 M HCl (pH = 4 to 5) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give crude 2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butyric acid as a yellow oil (400 mg).

[1974] Step 3

[1975]

[1976] To a solution of 2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butyric acid (100 mg, 0.39 mmol) in DCM (2 mL, 0.389 M) was added CDI (69 mg, 0.43 mmol) at 0 ° C. After stirring at 0 ° C for 1 hour, 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 hours. Potassium sodium tartrate (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 obtain crude tert-butyl N-(3,3,3-trifluoro-1-formyl-propyl)carbamate as a yellow oil (50 mg).

[1977] The title compound was obtained by using tert-butyl N-(3,3,3-trifluoro-1-formyl-propyl)carbamate in step 1 of Procedure A, followed by chiral HPLC separation (Phenomenex-Cellulose-2 column (250 mm × 30 mm × 5 μm)) and following the subsequent steps, respectively, while using 2,2-difluoropropionamidine in step 3. Both showed LC-MS m / z: 480.1 [M+1]. The absolute stereochemistry of the title compound was not determined.

[1978] Example 96

[1979] (R,E)-N-(1-(tert-Butoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1980]

[1981] Step 1

[1982]

[1983] At 0 DEG C, under N2, to N- (tert-butoxycarbonyl) -O- (tert-butyl) -L- serine (1g, 3.83mmol) in DCM (10mL, 0.348M) and methanol (1mL, 0.348M) solution in (trimethylsilyl) diazomethane (3.83mL, 7.65mmol, 2M) is added. The reaction mixture is stirred at 25 DEG C for 2 hours. The reaction mixture is quenched and concentrated under reduced pressure by adding saturated AcOH aqueous solution (10mL) to obtain crude (2S) -3- tert-butoxy -2- (tert-butoxycarbonyl amino) methyl propionate, which is a yellow oil (1.0g).

[1984] Step 2

[1985]

[1986] To a solution of (2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)methyl propionate (1g, 3.63mmol) in THF (10mL, 0.363M) was added lithium aluminum hydride solution (0.35g, 9.08mmol) at 0°C. The mixture was stirred at 25°C for 8 hours. The reaction mixture was quenched with Na2SO4.10H2O, filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1:0 to 3:1) to obtain tert-butyl N-[(1R)-1-(tert-butoxymethyl)-2-hydroxy-ethyl] carbamate, which was a colorless oil (900mg, 95% yield).

[1987] Tert-butyl N-[(1S)-1-(tert-butoxymethyl)-2-oxo-ethyl]carbamate was prepared using tert-butyl N-[(1R)-1-(tert-butoxymethyl)-2-hydroxy-ethyl]carbamate / Dess-Martin periodinane / DCM for step 1 in procedure A, and NaH as the base for step 1 and 2,2-difluoropropionamidine in step 3 to obtain the title compound. LC-MS m / z: 484.1 [M+1].

[1988] Example 97

[1989] (R,E)-N-(1-cyclopropyloxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide

[1990]

[1991] Step 1

[1992]

[1993] At 0 ° C, to a solution of (S)-aziridine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (800 mg, 3.98 mmol) was added boron trifluoride etherate (84.6 mg, 0.60 mmol) and DCM (15 mL, 0.265 M) containing cyclopropanol (461.8 mg, 7.95 mmol). The mixture was stirred at 0 ° C for 2 hours under N2. The reaction mixture was diluted with NaHCO3 (50 mL) and extracted with DCM (3 × 50 mL). The organic layer obtained was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (PE / EA=0 / 1 to 5 / 1) to obtain (2R)-2-(tert-butoxycarbonylamino)-3-(cyclopropyloxy)propionic acid methyl ester as a colorless oil (530 mg, 51% yield).

[1994] Methyl (2R)-2-(tert-butoxycarbonylamino)-3-(cyclopropyloxy)propanoate was converted to tert-butyl N-[(1S)-1-(cyclopropyloxymethyl)-2-oxo-ethyl]carbamate via LAH reduction and DMP oxidation as previously described. Using tert-butyl N-[(1S)-1-(cyclopropyloxymethyl)-2-oxo-ethyl]carbamate in NaH in step 1 and 2,2-difluoropropionamidine in step 3 in procedure A, the title compound was obtained. LC-MS m / z: 468.1 [M+1].

[1995] Example 98

[1996] (R,E)-2-(1,1-difluoroethyl)-N-(1-(difluoromethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[1997]

[1998] Step 1

[1999]

[2000] [Bromo(difluoro)methyl]trimethylsilane (4.5 g, 22.01 mmol) was added to a mixture of (S)-4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylic acid 3-tert-butyl ester (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 hours. The reaction mixture was poured into water (30 mL) and extracted with DCM (3×30 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 20g The reaction mixture was purified by flash chromatography on silica gel with a gradient of 0% to 5% ethyl acetate in petroleum ether at 100 mL / min to afford (4R)-4-(difluoromethoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow oil (1.20 g, 49% yield).

[2001] Step 2

[2002]

[2003] Toluenesulfonic acid monohydrate (162.29 mg, 0.85 mmol) was added to methanol (20 mL, 0.213 M) containing (4R)-4-(difluoromethoxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.2 g, 4.27 mmol). 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 layer was washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 12g The product was purified by flash chromatography on silica gel with a gradient of 0% to 20% ethyl acetate in petroleum ether at 100 mL / min to afford tert-butyl N-[(1R)-1-(difluoromethoxymethyl)-2-hydroxy-ethyl]carbamate as a colorless oil (800 mg, 78% yield).

[2004] Tert-butyl N-[(1S)-1-(difluoromethoxymethyl)-2-oxo-ethyl]carbamate was prepared using N-[(1R)-1-(difluoromethoxymethyl)-2-hydroxy-ethyl]carbamate / Dess-Martin periodinane / THF for step 1 in procedure A, and NaH as the base for step 1 and 2,2-difluoropropionamidine in step 3 to obtain the title compound. LC-MS m / z: 478.1 [M+1].

[2005] Example 99

[2006] (S,E)-2-(1-Fluorocyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2007]

[2008] In Procedure A, 1-fluorocyclopropanecarboximidamide was prepared according to the procedure for the compound of Example 86 using 1-fluorocyclopropanecarboxylic acid methyl ester and using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and 1-fluorocyclopropanecarboximidamide in Step 3 to obtain the title compound. LC-MS m / z: 406.1 [M+1].

[2009] Example 100

[2010] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1-fluorocyclopropyl)-4-phenoxypyrimidine-5-carboxamide

[2011]

[2012] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in step 1 and 1-fluorocyclopropanecarboximidamide in step 3 in procedure A. LC-MS m / z: 432.1 [M+1].

[2013] Example 101

[2014] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide

[2015]

[2016] In Procedure A, 1-(trifluoromethyl)cyclopropanecarboximidamide was prepared according to the procedure for the compound of Example 86 using ethyl 1-(trifluoromethyl)cyclopropanecarboxylate and tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in Step 1 and 1-(trifluoromethyl)cyclopropanecarboximidamide in Step 3 to give the title compound. LC-MS m / z: 456.1 [M+1].

[2017] Example 102

[2018] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide

[2019]

[2020] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in step 1 and 1-(trifluoromethyl)cyclopropanecarboximidamide in step 3 in procedure A. LC-MS m / z: 482.2 [M+1].

[2021] Example 103

[2022] (S,E)-2-(3,3-Difluorocyclobutyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2023]

[2024] Step 1

[2025]

[2026] At 0 ° C, diethylaminosulfur trifluoride (8.5 g, 52.58 mmol) was added to a solution of 3-oxo-cyclobutanecarbonitrile (2.5 g, 26.29 mmol) in DCM (100 mL, 0.263 M) over 0.5 hours. The mixture was stirred at 25 ° C for 12 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (20 mL), and the aqueous phase was extracted with DCM (3 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 3,3-difluorocyclobutanecarbonitrile, which was a brown oil (3.0 g).

[2027] Step 2

[2028]

[2029] To a solution of ammonium chloride (685mg, 12.81mmol) in toluene (15mL, 0.854M) was added triethylaluminum (923mg, 12.81mmol) at 0°C. The reaction was stirred at 25°C for 2 hours. 3,3-difluorocyclobutanecarbonitrile (1.5g, 12.81mmol) 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 (10mL) and stirred for 10min. The silica gel was filtered and washed with MeOH (3×15mL). The filtrate was concentrated under reduced pressure to obtain crude 3,3-difluorocyclobutanecarbonitrile, which was a light brown solid (1.0g).

[2030] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and 3,3-difluorocyclobutanecarboximidamide in step 3 in procedure A. LC-MS m / z: 438.1 [M+1].

[2031] Example 104

[2032] (E)-2-Cyclopentyl-N-(3-(methylsulfonyl)allyl)-4-(p-tolyloxy)pyrimidine-5-carboxamide

[2033]

[2034] The title compound was obtained using p-cresol in step 5 of procedure A. LC-MS m / z: 416.1 [M+1].

[2035] Example 105

[2036] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(m-tolyloxy)pyrimidine-5-carboxamide

[2037]

[2038] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and m-cresol in step 5. LC-MS m / z: 430.1 [M+1].

[2039] Example 106

[2040] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(o-tolyloxy)pyrimidine-5-carboxamide

[2041]

[2042] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and o-cresol in step 5. LC-MS m / z: 430.2 [M+1].

[2043] Example 107

[2044] (S,E)-2-Cyclopentyl-4-(4-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2045]

[2046] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 4-ethylphenol in step 5. LC-MS m / z: 444.2 [M+1].

[2047] Example 108

[2048] (S,E)-2-Cyclopentyl-4-(3-ethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2049]

[2050] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3-ethylphenol in step 5. LC-MS m / z: 444.2 [M+1].

[2051] Example 109

[2052] (S,E)-2-Cyclopentyl-4-(3,4-dimethylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2053]

[2054] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3,4-dimethylphenol in step 5. LC-MS m / z: 444.2 [M+1].

[2055] Example 110

[2056] (S,E)-2-Cyclopentyl-4-(4-fluoro-3-methylphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2057]

[2058] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3-fluoro-4-methylphenol in step 5. LC-MS m / z: 448.2 [M+1].

[2059] Example 111

[2060] (E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide

[2061]

[2062] The title compound was obtained using 3-fluorophenol in step 5 of procedure A. LC-MS m / z: 420.1 [M+1].

[2063] Example 112

[2064] (E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide

[2065]

[2066] The title compound was obtained using 4-fluorophenol in step 5 of procedure A. LC-MS m / z: 420.1 [M+1].

[2067] Example 113

[2068] (S,E)-2-Cyclopentyl-4-(4-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2069]

[2070] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 4-fluorophenol in step 5. LC-MS m / z: 434.1 [M+1].

[2071] Example 114

[2072] (S,E)-2-Cyclopentyl-4-(3-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2073]

[2074] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3-fluorophenol in step 5. LC-MS m / z: 434.1 [M+1].

[2075] Example 115

[2076] (S,E)-2-Cyclopentyl-4-(2-fluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2077]

[2078] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 2-fluorophenol in step 5. LC-MS m / z: 434.1 [M+1].

[2079] Example 116

[2080] (S,E)-2-Cyclopentyl-4-(3,5-difluorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2081]

[2082] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3,5-difluorophenol in step 5. LC-MS m / z: 452.1 [M+1].

[2083] Example 117

[2084] (E)-4-(3-chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide

[2085]

[2086] The title compound was obtained using 3-chlorophenol in step 5 of procedure A. LC-MS m / z: 436.1 [M+1].

[2087] Example 118

[2088] (S,E)-4-(3-chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2089]

[2090] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3-chlorophenol in step 5. LC-MS m / z: 450.1 [M+1].

[2091] Example 119

[2092] (S,E)-4-(2-chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2093]

[2094] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 2-chlorophenol in step 5. LC-MS m / z: 450.1 [M+1].

[2095] Example 120

[2096] (E)-4-(4-Chlorophenoxy)-2-cyclopentyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide

[2097]

[2098] The title compound was obtained using 4-chlorophenol in step 5 of procedure A. LC-MS m / z: 436.1 [M+1].

[2099] Example 121

[2100] (S,E)-4-(4-chlorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2101]

[2102] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 4-chlorophenol in step 5. LC-MS m / z: 450.1 [M+1].

[2103] Example 122

[2104] (S,E)-4-(3-chloro-5-fluorophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2105]

[2106] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3-chloro-5-fluorophenol in step 5. LC-MS m / z: 468.1 [M+1].

[2107] Example 123

[2108] (S,E)-2-Cyclopentyl-4-(3,5-dichlorophenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2109]

[2110] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3,5-dichlorophenol in step 5. LC-MS m / z: 484.1 [M+1].

[2111] Example 124

[2112] (S,E)-4-(4-Cyanophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2113]

[2114] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 4-hydroxybenzonitrile in step 5. LC-MS m / z: 441.2 [M+1].

[2115] Example 125

[2116] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-3-yloxy)pyrimidine-5-carboxamide

[2117]

[2118] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and 3-hydroxypyridine in step 5. LC-MS m / z: 417.1 [M+1].

[2119] Example 126

[2120] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(pyridin-2-yloxy)pyrimidine-5-carboxamide

[2121]

[2122] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and pyridin-2-ol in step 5. LC-MS m / z: 417.2 [M+1].

[2123] Example 127

[2124] (S,E)-4-Cyclobutoxy-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2125]

[2126] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and cyclobutanol / potassium tert-butoxide / THF in step 5. LC-MS m / z: 394.2 [M+1].

[2127] Example 128

[2128] (S,E)-4-(Cycloheptyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2129]

[2130] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and cycloheptanol / tBuOK / THF in step 5. LC-MS m / z: 436.2 [M+1].

[2131] Examples 129 and 130

[2132] 2-Cyclopentyl-4-[(1S,2R)-2-hydroxycyclohexyloxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 129)

[2133]

[2134] 2-Cyclopentyl-4-[(1R,2S)-2-hydroxycyclohexyloxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 130)

[2135]

[2136] 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 in Procedure A. The mixture was separated by preparative HPLC (neutral conditions) to give Peak 1 (compound of Example 129) (LC-MS m / z: 438.2 [M+1]) and Peak 2 (compound of Example 130) (LC-MS m / z: 438.2 [M+1]).

[2137] Examples 131 and 132

[2138] 2-Cyclopentyl-4-[(1S,2S)-2-hydroxycyclohexyloxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 131)

[2139]

[2140] 2-Cyclopentyl-4-[(1R,2R)-2-hydroxycyclohexyloxy]-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide (Example 132)

[2141]

[2142] 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-(1S,2S)-cyclohexane-1,2-diol / NaH / THF in step 5 in Procedure A. 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]).

[2143] Example 133

[2144] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-5-carboxamide

[2145]

[2146] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and tetrahydro-2H-pyran-4-ol / NaH / DMF in step 5 in procedure A. LC-MS m / z: 424.2 [M+1].

[2147] Example 134

[2148] 2-Cyclopentyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)oxy)pyrimidine-5-carboxamide

[2149]

[2150] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and (3S)-tetrahydropyran-3-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 424.2 [M+1].

[2151] Example 135

[2152] (S,E)-2-Cyclopentyl-4-(4-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2153]

[2154] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and hydroquinone in step 5 in procedure A. LC-MS m / z: 432.2 [M+1].

[2155] Example 136

[2156] (S,E)-2-Cyclopentyl-4-(3-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2157]

[2158] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and resorcinol in step 5. LC-MS m / z: 432.2 [M+1].

[2159] Example 137

[2160] (S,E)-2-Cyclopentyl-4-(2-hydroxyphenoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2161]

[2162] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and catechol in step 5. LC-MS m / z: 432.2 [M+1].

[2163] Example 138

[2164] (S,E)-4-(3-Aminophenoxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2165]

[2166] Using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate in NaH in step 1 of procedure A and tert-butyl 3-hydroxyphenylcarbamate in step 5, tert-butyl N-[3-[2-cyclopentyl-5-[[(E,1S)-1-methyl-3-methylsulfonyl-allyl]carbamoyl]pyrimidin-4-yl]oxyphenyl]carbamate was obtained as a yellow solid.

[2167]

[2168] 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 as a yellow solid (17.8 mg). LC-MS m / z: 431.2 [M+1].

[2169] Example 139

[2170] (S,E)-2-Cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(naphthalen-1-yloxy)pyrimidine-5-carboxamide

[2171]

[2172] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and naphthalen-1-ol in step 3. LC-MS m / z: 466.2 [M+1].

[2173] Example 140

[2174]

[2175] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and 1,2,3,4,5-pentadeutero-6-deuterooxy-benzene in step 5 in procedure A. LC-MS m / z: 393.2 [M+1].

[2176] Example 141

[2177] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[3.3]heptan-2-yloxy)pyrimidine-5-carboxamide

[2178]

[2179] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and spiro[3.3]heptan-2-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 406.2 [M+1].

[2180] Example 142

[2181] (S,E)-2-Cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(spiro[2.3]hexan-5-yloxy)pyrimidine-5-carboxamide

[2182]

[2183] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and spiro[2.3]hexan-5-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 392.0 [M+1].

[2184] Example 143

[2185] (S,E)-4-(Bicyclo[2.2.1]heptan-1-yloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2186]

[2187] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and norbornan-1-ol / LiHMDS / THF in step 5 in Procedure A. LC-MS m / z: 406.2 [M+1].

[2188] Example 144

[2189] (S,E)-4-(Cyclopentyloxy)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2190]

[2191] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and cyclopentanol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 380.2 [M+1].

[2192] Example 145

[2193] 4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide

[2194]

[2195] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and (1S,5R)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 378.0 [M+1].

[2196] Example 146

[2197] 2-Cyclopropyl-4-((3,3-difluorocyclopentyl)oxy)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2198]

[2199] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and 3,3-difluorocyclopentanol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 416.0 [M+1].

[2200] Examples 147 and 148

[2201] 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

[2202]

[2203] Using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of Procedure A, cyclopropanecarboximidamide in step 3, and 2,2-difluorocyclopentanol / LiHMDS / THF in step 5, a mixture of the title compounds was obtained. The mixture was separated by preparative HPLC (reverse phase, H2O / MeCN = 5% to 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 determined.

[2204] Example 149

[2205] 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

[2206]

[2207] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and rac-(1R,2R)-2-fluorocyclohexanol / LiHMDS / THF in step 5 in Procedure A. LC-MS m / z: 412.0 [M+1]. The absolute stereochemistry of these compounds was not determined.

[2208] Example 150

[2209] (S,E)-2-Cyclopropyl-4-(cyclopropylmethoxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2210]

[2211] 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 cyclopropanemethanol / LiHMDS / THF in step 5 in Procedure A. LC-MS m / z: 366.0 [M+1].

[2212] Example 151

[2213] 4-((1r,3S)-3-chlorocyclobutyloxy)-2-cyclopropyl-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2214]

[2215] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, cyclopropanecarboximidamide in step 3, and 3-chlorocyclobutanol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 400.2 [M+1].

[2216] Example 152

[2217] (S,E)-2-(tert-Butyl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-(phenoxy-d5)pyrimidine-5-carboxamide

[2218]

[2219] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and 1,2,3,4,5-pentadeutero-6-deuterooxy-benzene in step 5 in procedure A. LC-MS m / z: 409.2 [M+1].

[2220] Example 153

[2221] (S,E)-2-(tert-Butyl)-4-(cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2222]

[2223] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and cyclopentanol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 396.0 [M+1].

[2224] Example 154

[2225] (S,E)-2-(tert-Butyl)-4-(cyclohexyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2226]

[2227] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and cyclohexanol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 410.2 [M+1].

[2228] Example 155

[2229] (S,E)-2-(tert-Butyl)-4-((4,4-difluorocyclohexyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2230]

[2231] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and 4,4-difluorocyclohexanol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 446.2 [M+1].

[2232] Example 156

[2233] (S,E)-2-(tert-Butyl)-4-(3,3-difluorocyclobutyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2234]

[2235] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and 3,3-difluorocyclobutan-1-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 418.2 [M+1].

[2236] Example 157

[2237] 4-[[(1S,5R)-3-Bicyclo[3.1.0]hexyl]oxy]-2-tert-butyl-N-[(E,1S)-1-methyl-3-methylsulfonyl-allyl]pyrimidine-5-carboxamide

[2238]

[2239] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and (1S,5R)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 408.2 [M+1].

[2240] Example 158

[2241] 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

[2242]

[2243] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-difluoropropionamidine in step 3, and (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol / NaH / DMF in step 5 in procedure A. LC-MS m / z: 442.2 [M+1].

[2244] Example 159

[2245] 4-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-(tert-butyl)-N-((E)-3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide

[2246]

[2247] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and (1R,3s,5S)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 394.2 [M+1].

[2248] Example 160

[2249] 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

[2250]

[2251] The title compound was obtained using tert-butyl N-[(1S)-1-cyclopropyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and (1R,3s,5S)-bicyclo[3.1.0]hexan-3-ol / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 434.2 [M+1].

[2252] Example 161

[2253] (S,E)-2-(tert-Butyl)-4-((1-cyanocyclopentyl)oxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2254]

[2255] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1, 2,2-dimethylpropionamidine hydrochloride in step 3, and 1-hydroxycyclopentane-1-carbonitrile / LiHMDS / THF in step 5 in procedure A. LC-MS m / z: 421.0 [M+1].

[2256] Example 162

[2257] (S,E)-2-Cyclopentyl-4-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenoxypyrimidine-5-carboxamide

[2258]

[2259] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 of procedure A and ethyl (2Z)-2-(ethoxymethylene)-3-oxo-butyrate in step 3. LC-MS m / z: 430.2 [M+1].

[2260] Example 163

[2261] (S,E)-5-Cyano-6-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-phenoxynicotinamide

[2262]

[2263] The title compound was obtained using tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate / NaH in step 1 and (E)-3-amino-3-cyclopentyl-prop-2-enenitrile in step 3 in procedure A. LC-MS m / z: 440.2 [M+1].

[2264] Example 164

[2265] (S,E)-2-(Cyclopentylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2266]

[2267] Program B

[2268] Step 1

[2269]

[2270] To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (1g, 4.32mmol) and phenol (0.50g, 5.31mmol) in DMF (10mL, 0.432M) was added KCO (900mg), which was then stirred at 25°C for 12 hours. 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 2-methylthio-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester as a brown oil (800mg, 64% yield).

[2271] Step 2

[2272]

[2273] To a solution of 2-methylsulfanyl-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (300 mg, 1.03 mmol) in chloroform (5 mL, 0.207 M) was added 3-chloroperoxybenzoic acid (250 mg, 1.23 mmol) at one time and stirred at 0 ° C for 2 hours. The mixture was diluted with DCM (15 mL) and extracted with NaHCO (3 × 10 mL). The combined organic layer was washed with brine (20 mL), dried over Na SO, filtered and concentrated under reduced pressure to give crude 2-methylsulfonyl-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester as a white solid (300 mg).

[2274] Step 3

[2275]

[2276] To a solution of 2-methylsulfonyl-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (300 mg, 0.9307 mmol) and cyclopentylamine (150 mg, 1.76 mmol) in THF (5 mL, 0.186 M) was added DIPEA (400 mg), which was then stirred at 25 ° C for 2 hours. 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 2-(cyclopentylamino)-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester as a colorless oil (100 mg, 33% yield).

[2277] Following steps 6 and 7 of procedure A and using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid, the title compound was obtained. LC-MS m / z: 431.1 [M+1].

[2278] Example 165

[2279] (S,E)-2-(Cyclopentyloxy)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2280]

[2281] The title compound was obtained using cyclopentanol / LiHMDS in step 3 of procedure B. LC-MS m / z: 432.2 [M+1].

[2282] Example 166

[2283] (S,E)-2-(7-Azabicyclo[2.2.1]hept-7-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2284]

[2285] The title compound was obtained using 7-azabicyclo[2.2.1]heptane hydrochloride in step 3 of procedure B. LC-MS m / z: 443.2 [M+1].

[2286] Example 167

[2287] (E)-N-(3-(Methylsulfonyl)allyl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide

[2288]

[2289] Program C

[2290] Step 1

[2291]

[2292] To a mixture of 2-methylthio-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (30g, 103.33mmol) in MeCN (200mL, 0.517M) at 0°C, DCM (200mL) and SO2Cl2 (125mL) were added. The resulting mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into ice-saturated NaHCO3 solution (100mL). The aqueous phase was extracted with EtOAc (3x 150mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain 2-chloro-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester as a white solid (13.0g, 45% yield).

[2293] Step 2

[2294]

[2295] To a solution of 2-chloro-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester (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 hours. The reaction mixture was partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was dried over Na SO , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain 4-phenoxy-2-pyrrolidin-1-yl-pyrimidine-5-carboxylic acid ethyl ester as a white solid (130 mg, 29% yield).

[2296] The title compound was obtained following steps 6 and 7 of procedure A. LC-MS m / z: 403.1 [M+1].

[2297] Example 168

[2298] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide

[2299]

[2300] The title compound was obtained using [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step of Procedure C. LC-MS m / z: 417.2 [M+1].

[2301] Example 169

[2302] (S,E)-2-(3-methoxyazetidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2303]

[2304] The title compound was obtained using 3-methoxyazetidine in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 433.2 [M+1].

[2305] Example 170

[2306] (S,E)-N-(4-(Methylsulfonyl)but-3-en-2-yl)-4-phenoxy-2-(2-azaspiro[3.3]heptane-2-yl)pyrimidine-5-carboxamide

[2307]

[2308] The title compound was obtained using 2-azaspiro[3.3]heptane in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in procedure C. LC-MS m / z: 443.2 [M+1].

[2309] Example 171

[2310] 2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2311]

[2312] The title compound was obtained using (2R,5S)-2,5-dimethylpyrrolidine hydrochloride in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the final step in Procedure C. LC-MS m / z: 445.0 [M+1].

[2313] Example 172

[2314] 2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2315]

[2316] The title compound was obtained using (2R,5R)-2,5-dimethylpyrrolidine hydrochloride in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 445.2 [M+1].

[2317] Example 173

[2318] (S,E)-2-(3,3-difluoropyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2319]

[2320] The title compound was obtained using 3,3-difluoropyrrolidine hydrochloride / LiHMDS in step 2 of procedure C and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step. LC-MS m / z: 453.0 [M+1].

[2321] Example 174

[2322] (S,E)-2-(2,2-dimethylpyrrolidin-1-yl)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2323]

[2324] The title compound was obtained using 2,2-dimethylpyrrolidine in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 445.2 [M+1].

[2325] Example 175

[2326] 2-((S)-2-Methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2327]

[2328] The title compound was obtained using (S)-2-methylpyrrolidine in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 431.2 [M+1].

[2329] Example 176

[2330] 2-((R)-2-methylpyrrolidin-1-yl)-N-((S,E)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[2331]

[2332] The title compound was obtained using (R)-2-methylpyrrolidine in step 2 and [(E,1S)-1-methyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 431.2 [M+1].

[2333] Example 177

[2334] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(dimethylamino)-4-phenoxypyrimidine-5-carboxamide

[2335]

[2336] The title compound was obtained using dimethylamine hydrochloride in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 417.1 [M+1].

[2337] Example 178

[2338] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(methylamino)-4-phenoxypyrimidine-5-carboxamide

[2339]

[2340] The title compound was obtained using methylamine hydrochloride in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 403.1 [M+1].

[2341] Example 179

[2342] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(diethylamino)-4-phenoxypyrimidine-5-carboxamide

[2343]

[2344] The title compound was obtained using diethylamine in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 445.2 [M+1].

[2345] Example 180

[2346] (S,E)-2-(Cyclopropyl(methyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[2347]

[2348] The title compound was obtained using N-methylcyclopropylamine hydrochloride in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 443.3 [M+1].

[2349] Example 181

[2350] (S,E)-2-(azetidin-1-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[2351]

[2352] The title compound was obtained using azetidine hydrochloride in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 429.3 [M+1].

[2353] Example 182

[2354] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3-fluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide

[2355]

[2356] The title compound was obtained using 3-fluoroazetidine hydrochloride in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 447.2 [M+1].

[2357] Example 183

[2358] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluoroazetidin-1-yl)-4-phenoxypyrimidine-5-carboxamide

[2359]

[2360] The title compound was obtained using 3,3-difluoroazetidine hydrochloride in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 465.2 [M+1].

[2361] Example 184

[2362] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(methyl(2,2,2-trifluoroethyl)amino)-4-phenoxypyrimidine-5-carboxamide

[2363]

[2364] The title compound was obtained using 2,2,2-trifluoro-N-methyl-ethaneamine hydrochloride in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the final step in Procedure C. LC-MS m / z: 485.2 [M+1].

[2365] Example 185

[2366] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(ethyl(methyl)amino)-4-phenoxypyrimidine-5-carboxamide

[2367]

[2368] The title compound was obtained using N-ethylmethylamine in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 431.2 [M+1].

[2369] Example 186

[2370] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(isopropyl(methyl)amino)-4-phenoxypyrimidine-5-carboxamide

[2371]

[2372] The title compound was obtained using N-methylisopropylamine in step 2 and [(E,1S)-1-cyclopropyl-3-methylsulfonyl-allyl]amine 4-methylbenzenesulfonic acid in the last step in Procedure C. LC-MS m / z: 445.1 [M+1].

[2373] Example 187

[2374] (E)-2-Cyclopentyl-N-methyl-N-(3-(methylsulfonyl)allyl)-4-phenoxypyrimidine-5-carboxamide

[2375]

[2376] Step 1

[2377]

[2378] 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 at 25 ° C for 12 hours under N2. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (Biotage, using a 12 g Agela flash silica gel column, eluting with petroleum ether containing 0% to 15% ethyl acetate) to give 2-cyclopentyl-N-(2,2-dimethoxyethyl)-N-methyl-4-phenoxy-pyrimidine-5-carboxamide as a white solid (600 mg, 89% yield).

[2379] Step 2

[2380]

[2381] 2-Cyclopentyl-N-(2,2-dimethoxyethyl)-N-methyl-4-phenoxy-pyrimidine-5-carboxamide (210 mg, 0.55 mmol) was added to TFA (25 mL). The mixture was stirred at 0 ° C for 3 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (20 mL), and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 2-cyclopentyl-N-methyl-N-(2-oxoethyl)-4-phenoxy-pyrimidine-5-carboxamide (210 mg).

[2382] Following step 1 of procedure A using 2-cyclopentyl-N-methyl-N-(2-oxoethyl)-4-phenoxy-pyrimidine-5-carboxamide, the title compound was obtained. LC-MS m / z: 416.1 [M+1].

[2383] Example 188

[2384] (2-Cyclopropyl-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone

[2385]

[2386] 2-Cyclopropyl-4-phenoxy-pyrimidine-5-carboxylic acid / 3-azetidinone were used in step 1 of the procedure for the compound of Example 187 to obtain 1-(2-cyclopropyl-4-phenoxy-pyrimidine-5-carbonyl)azetidin-3-one. Following step 1 of procedure A, 1-(2-cyclopropyl-4-phenoxy-pyrimidine-5-carbonyl)azetidin-3-one was obtained using n BuLi was used as a base to obtain the title compound. LC-MS m / z: 386.0 [M+1].

[2387] Example 189

[2388] (2-(tert-Butyl)-4-phenoxypyrimidin-5-yl)(3-((methylsulfonyl)methylene)azetidin-1-yl)methanone

[2389]

[2390] The title compound was obtained using 2-tert-butyl-4-phenoxy-pyrimidine-5-carboxylic acid and following the procedure for the compound of Example 188. LC-MS m / z: 402.0 [M+1].

[2391] Example 190

[2392] 1-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)propan-2-one

[2393]

[2394] A mixture of 1-(2-tert-butyl-4-phenoxy-pyrimidine-5-carbonyl)azetidin-3-one (63 mg, 0.19 mmol) and 1-(triphenyl-λ5-phosphinyl)propan-2-one (108 mg, 0.34 mmol) in toluene (3 mL, 0.065 M) was heated at 70° C. for 1.5 hours. The mixture was concentrated and directly purified by preparative HPLC (reverse phase, MeCN / HO (0.1% FA): 5% to 95%) to give the title compound as a white solid (2.8 mg, 4%). LC-MS m / z: 366.2 [M+1].

[2395] Example 191

[2396] Methyl 2-(1-(2-(tert-butyl)-4-phenoxypyrimidine-5-carbonyl)azetidin-3-ylidene)acetate

[2397]

[2398] The title compound was obtained using methyl (triphenylphosphenyl)acetate as starting material and following the procedure for the compound of Example 190. LC-MS m / z: 382.2 [M+1].

[2399] Examples 192 and 193

[2400] (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

[2401]

[2402] Step 1

[2403]

[2404] 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 hours. The mixture was filtered, and the filter cake was rinsed with DCM (3 x 5 mL). The combined filtrate was then washed with saturated Na2S2O3 solution (3 x 30 mL), saturated NaHCO3 solution (3 x 30 mL), and brine (20 mL). The combined organic phases were dried over anhydrous Na2SO4 and filtered to give crude 3,3-difluorocyclobutanecarbaldehyde (983 mg).

[2405] Step 2

[2406]

[2407] To a mixture of 3,3-difluorocyclobutanecarboxaldehyde (713mg, 5.94mmol) and 2-methylpropane-2-sulfinamide (600mg, 4.95mmol) in DCM (10mL, 0.495M) was added copper sulfate (1.98g, 12.38mmol). The mixture was stirred at 25 ° C for 72 hours. The reaction mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (2×10mL). The combined filtrate was concentrated to dryness to obtain a residue. The residue was purified by flash chromatography (Biotage, using 20gAgela rapid silica gel column, eluted with petroleum ether containing 10% to 15% ethyl acetate) to obtain (Z)-N-((3,3-difluorocyclobutyl) methylene)-2-methylpropane-2-sulfinamide, which was a light yellow oil (770mg, 70% yield).

[2408] Step 3

[2409]

[2410] To a solution of (Z)-N-((3,3-difluorocyclobutyl)methylene)-2-methylpropane-2-sulfinamide (1g, 4.48mmol) in DCM (20mL, 0.224M) was added vinylmagnesium bromide (13.4mL, 13.44mmol, 1M in THF) at -50°C. The solution was allowed to warm to 25°C over 16 hours. The mixture was diluted with DCM (30mL) and slowly quenched with water (10mL). The mixture was then washed with saturated NaHCO (2×10mL) and brine (2×10mL) in sequence. The organic phase was dried over NaSO, filtered and concentrated to give crude N-(1-(3,3-difluorocyclobutyl)allyl)-2-methylpropane-2-sulfinamide, which was a 1:1 mixture (800mg) of isomers.

[2411] Step 4

[2412]

[2413] N-(1-(3,3-difluorocyclobutyl)allyl)-2-methylpropane-2-sulfinamide (300 mg, 1.19 mmol) was stirred in HCl / MeOH (10 mL) at 25° C. for 1 hour under N2. The reaction mixture was concentrated under reduced pressure to give crude 1-(3,3-difluorocyclobutyl)prop-2-en-1-amine hydrochloride as a light yellow oil (180 mg).

[2414] Step 5

[2415]

[2416] To a solution of 1-(3,3-difluorocyclobutyl)prop-2-ene-1-amine hydrochloride (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 at 25 ° C for 2 hours under N2. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (Biotage, using a 12 g Agela flash silica gel column, eluting with petroleum ether containing 15% to 17% ethyl acetate) 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).

[2417] Step 6

[2418]

[2419] 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 at 25 ° C for 1 hour under N2. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain crude N-[1-(3,3-difluorocyclobutyl)-2-oxo-ethyl]-2-(1,1-difluoroethyl)-4-phenoxy-pyrimidine-5-carboxamide as a yellow solid (90 mg).

[2420] Step 7

[2421]

[2422] 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 hour. 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 then added dropwise at 0 ° C. After stirring at this temperature for 2.5 hours, the reaction mixture was poured into an ice-saturated NH4Cl solution (15 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30 mm×10 μm, water (NH 4 HCO 3 ) / MeCN=35% to 55% B, flow rate=25 mL / min) to give a mixture of the title compounds (50 mg, 28% yield). The mixture was separated by chiral SFC (column: Daicel ChiralPak AD (250 mm×30 mm×10 μm), 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 compound was not determined.

[2423] Examples 194 and 195

[2424] (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

[2425]

[2426] Step 1

[2427]

[2428] To a solution of (S)-2-amino-2-cyclopropylacetic acid methyl ester (0.8 g, 6.19 mmol) in DCE (20 mL, 0.310 M) was added di(phenylmethylamine) (1.12 g, 6.19 mmol) under N at 25° C. The reaction mixture was stirred at 95° C. for 12 hours. 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 (2S)-2-(benzylideneamino)-2-cyclopropyl-acetic acid methyl ester as a yellow oil (0.82 g, 45% yield).

[2429] Step 2

[2430]

[2431] To a solution of (2S)-2-(benzylideneamino)-2-cyclopropyl-acetic acid methyl esters (300mg, 1.02mmol) in THF (10mL, 0.102M) was added lithium diisopropylamide solution (1.02mL, 2.05mmol, 2M) at 0°C for 2 hours. D o (20mL) was added to the mixture and allowed to warm to 25°C under N. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (5mL) and extracted with EtOAc (3 × 10mL). The combined organic layers were washed with salt water (2 × 10mL), dried over Na sO , filtered and concentrated under reduced pressure to obtain crude 2-(benzylideneamino)-2-cyclopropyl-2-deutero-acetic acid methyl esters, which were yellow oils (100mg).

[2432] Step 3

[2433]

[2434] Under N2, 2N HCl (2mL) is added to a solution of 2-(benzylideneamino)-2-cyclopropyl-2-dutero-acetic acid methyl esters (100mg, 0.34mmol) in THF (5mL, 0.068M) at 0°C. The reaction mixture is stirred for 1 hour at 25°C. The reaction mixture is concentrated under reduced pressure, and poured into H2O (5mL) and extracted with EtOAc (3 × 10mL). The aqueous solution is then filtered and concentrated under reduced pressure to obtain crude 2-amino-2-cyclopropyl-2-dutero-acetic acid methyl ester hydrochloride, which is a colorless oil (25mg).

[2435] Step 4

[2436]

[2437] To a mixture of 2-amino-2-cyclopropyl-2-deutero-acetic acid methyl ester hydrochloride (300mg, 1.80mmol) in DCM (10mL, 0.180M) was added di-tert-butyl dicarbonate (0.47g, 2.161mmol) and triethylamine (1.82g, 18.01mmol) at 20°C. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (5mL) and extracted with DCM (3×10mL). The combined organic layers were washed with brine (10mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (PE: EtOAc=1:1) to obtain 2-(tert-butoxycarbonylamino)-2-cyclopropyl-2-deutero-acetic acid methyl ester as a colorless oil (0.35g, 84% yield).

[2438] 2-(tert-Butoxycarbonylamino)-2-cyclopropyl-2-deutero-acetic acid methyl ester is converted to N-(1-cyclopropyl-1-deutero-2-oxo-ethyl)carbamic acid tert-butyl ester via LAH reduction and DMP oxidation as previously described. N-(1-cyclopropyl-1-deutero-2-oxo-ethyl)carbamic acid tert-butyl ester is used in step 1 of procedure A, and 2,2-difluoropropionamidine is used in step 3 to obtain a mixture of title compounds. The mixture is separated by chiral SFC to obtain peak 1 (LC-MS m / z: 439.2[M+1]) and peak 2 (LC-MS m / z: 439.2[M+1]). The absolute stereochemistry of the title compound is undetermined.

[2439] Example 196

[2440] (S,E)-4-(Cyclohexyloxy)-2-cyclopentyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide

[2441]

[2442] Step 1

[2443]

[2444] To a solution of 2-cyclopentyl-4-hydroxy-pyrimidine-5-ethyl formate (0.300g, 1.27mmol) in THF (6mL, 0.212M) was added PPh3 (0.4g) and cyclohexanol (0.127g, 1.27mmol) at 0°C. DIAD (0.308g) was then added dropwise. The mixture was stirred at 40°C for 2 hours. The reactant was diluted wit...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl; The condition is that X, Y and Z are not N at the same time; 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or R 1 Together with the carbon atom to which it is attached and X, it forms an optionally substituted five- to six-membered heterocyclic group; 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl; R 4 is H, C1-C6 alkyl, cyano or halo; or R 4 Together with the carbon atom to which it is attached and Z, it forms an optionally substituted five- to six-membered heteroaryl group; or R 3 and R 4 Together with the carbon atom to which they are attached, they form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five-membered to six-membered heterocyclyl or heterocycloalkenyl; 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 group; W is W 1 , W 2 , W 3 , W 4 or W 5 ; W 1 for: in: Depend on Key indication may exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point; R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl or optionally substituted five-membered to six-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; and R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group; or R 6 Together with the nitrogen atom to which it is attached and R 7 and R 7a together with the carbon atoms to which they are attached as shown, form an azetidinyl ring; or R 6 Together with the nitrogen atom to which it is attached and R 7 , R 7a and R 8 together with the carbon atom to which they are attached, form an azetidinyl or pyrrolidinyl ring; or R 6 Together with the nitrogen atom to which it is attached and R 7 , R 7a , R 8 and R 9 together with the carbon atoms to which they are attached, form a dihydropyrrolyl ring; or or R 7 , R 7a , R 8 , R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form 2,3-dihydrothiophene 1,1-dioxide; or R 8 , R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form a 1,1-dioxido-2H-thietidenyl ring; W 2 for: in: Depend on Key indication may exist as (Z)- or (E)-geometric isomers, wherein Indicates the connection point; R 11 is H; R 12 is H or an optionally substituted C1-C6 alkyl; R 12a is H; and R 13 and R 14 Each is H; or R 11 Together with the nitrogen atom to which it is attached and R 12 , R 12a and R 13 together with the carbon atoms to which they are shown attached, form an optionally substituted azetidinyl ring; W 3 for: in: Indicates the connection point; R 15 is H; R 16 is H or optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl; W 4 for: in: Indicates the connection point; R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; and Each R a are independently optionally substituted C1-C6 alkyl; and W 5 for: in: Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicates the connection point; m is 1, 2 or 3; and R 19 Selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl).

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

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X is CR 2 ; Y is CR 4 ;and Z is CR 5 ; or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heteroaryl; or R 3 Together with the carbon atom to which it is shown attached and Y, it forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X is CR 2 ; Y is N; and Z is CR 5 ; or R 1 Together with the carbon atom to which it is shown attached and X, it forms an optionally substituted five- to six-membered heterocyclic group.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X is N; Y is CR 4 ;and Z is CR 5 ; or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl.

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

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

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X is N; Y is N; Z is CR 5 ; R 1 is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C 10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-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 an optionally substituted C1-C6 alkyl group; W is W 1 ; R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl or optionally substituted five-membered to six-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; and R 10 It is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted five-membered to six-membered heterocyclic group.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein: R 1 -O-(C6-C 10 Aryl); R 3 is a fluorine-substituted C1-C6 alkyl group; R 5 is H; R 6 is H; R 7 is a C3-C8 cycloalkyl group; R 7a is H or deuterium; R 8 is H; R 9 is H; and R 10 It is a C1-C6 alkyl group.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: In R 1 middle: The optional substituents of the -O-(optionally substituted C3-C8 cycloalkyl) are 1 to 3 substituents selected from the group consisting of halo, cyano and hydroxy; or when there are two substituents on the same ring carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; The -O-(optionally substituted C6-C 10 The optional substituents of the aryl group are 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, cyano, hydroxyl and -NH2, or 1 to 5 deuterium atoms; Or when R 1 When together with the carbon atom to which it is attached and X form an optionally substituted five-membered to six-membered heterocyclic group, two substituents on the same ring carbon atom of the five-membered to six-membered heterocyclic group together with the ring carbon atom to which they are attached form a five-membered to six-membered cycloalkyl group; In R 3 middle: The optional substituents of the optionally substituted C3-C8 cycloalkyl group are 1 to 3 substituents selected from the group consisting of hydroxyl, halo, C1-C6 alkyl and C6-C 10 or when there are two substituents on the same carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C6-C 10 Aryl; Or when R 3 When it forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl group together with the carbon atom to which it is attached and Y, the optional substituents are 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl; or two geminal hydrogen atoms on the ring carbon atoms of the C3-C8 cycloalkyl or cycloalkenyl group may be replaced by a group =O; Or when R 3 When it is taken together with the carbon atom to which it is attached and Y to form an optionally substituted five-membered to six-membered heterocyclyl or heterocycloalkenyl, the optional substituents are 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl; The optionally substituted C6-C 10 The optional substituents of the aryl group are 1 to 3 substituents selected from the group consisting of halogen; The optional substituents of 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, wherein the optional substituents of the C3-C6 cycloalkyl are 1 to 3 substituents selected from the group consisting of C1-C6 alkyl; - The optional substituents of the C1-C6 alkyl group of R of NR2 are 1 to 3 substituents selected from the group consisting of halogen; and The optional substituents of the optionally substituted four-membered to six-membered heterocyclic group are 1 to 3 substituents selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, and halo; or when there are two substituents on the same carbon atom of the optionally substituted four-membered to six-membered heterocyclic group, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl group.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: By R 1 The optionally substituted five- to six-membered heterocyclic group formed together with the carbon atom to which it is attached is The double bond shown in the 1 Between the carbon of the group and X; 3 The optionally substituted C6-C 10 Aryl By R 3 The optionally substituted five- to six-membered heterocycloalkenyl group formed together with the carbon atom to which it is attached and Y is Among them with The carbon-carbon double bond between the two carbon atoms of the group is shown in the case of an R 3 Between the carbon of the group and Y; When R 3 When it is taken together with the carbon atom to which it is attached and Y to form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl group, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl group is The carbon-carbon double bond shown in 3 between a carbon of the group and Y; and Among them, R 4 The optionally substituted five- to six-membered heteroaryl group formed together with the carbon atom to which it is attached and Z is In each structure, Indicates the connection point.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: In R 1 middle: The -O-(optionally substituted C3-C8 cycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexane-5-yl), -O-(spiro[3.3]heptane-2-yl), -O-(3-chlorocyclobutyl), -O-(bicyclo[3.1.0]hexane-3-yl), -O-(bicyclo[2.2.1]heptane-1-yl), -O-(1-cyanocyclopentyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl) or -O-(2,2-difluorocyclopentyl), The -O-(optionally substituted C1-C6 alkyl) is ethoxy, isopropoxy or cyclopropylmethyloxy; The -O-(optionally substituted C6-C 10 Aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalene-1-oxy or phenoxy-d5; The -O-(optionally substituted five-membered to six-membered heteroaryl) is pyridin-2-yloxy or pyridin-3-yloxy; The -O-(optionally substituted five- to six-membered heterocyclyl) is tetrahydro-2H-pyran-4-yl or tetrahydro-2H-pyran-3-yl; and The optionally substituted C3-C8 cycloalkyl is cyclohexyl; In R 2 middle: The optionally substituted C1-C6 alkyl is methyl; and In R 3 middle: The 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]hexane-5-yl; The optionally substituted C3-C8 cycloalkenyl group is cyclopentenyl; The optionally substituted C6-C 10 Aryl is phenyl; The optionally substituted C1-C6 alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl or cyclopropyldifluoromethyl; The optionally substituted C1-C6 alkenyl is 2-methylprop-1-en-1-yl; NR2 is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl)2 or -N(methyl)(trifluoroethyl); The -N(R)(optionally substituted C3-C8 cycloalkyl) is N(methyl)(cyclopropyl); The -S-(optionally substituted C1-C6 alkyl) is methyl mercaptan; The -O-(optionally substituted C1-C6 alkyl) is trifluoroethoxy or methoxy; The -O-(optionally substituted C3-C8 cycloalkyl) is cyclopentyloxy or cyclopropyloxy; and The optionally substituted four- to six-membered heterocyclyl or heterocycloalkenyl is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptane-7-yl, bicyclo[1.1.1]pentane-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptane-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H -pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl or 3,3-difluoro-azetidin-1-yl; In R 5 middle: The C1-C6 alkyl group is a methyl group; The -NR2 is -NH2; and The -N(R)-C(=O)-(C1-C6 alkyl) is -N(H)-C(=O)-CH3.

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

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: R 7 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; R 7 The optionally substituted C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, difluorocyclohexyl; R 7 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; R 10 The optionally substituted C1-C6 alkyl is methyl; R 10 The optionally substituted C3-C8 cycloalkyl is cyclopropyl; R 10 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; or where W 1 for: In each of the above structures, Indicates the connection point.

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

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein W 2 for: in: R 21 is H or C1-C6 alkyl; Depend on Key indication may exist as (Z)- or (E)-geometric isomers, and wherein Indicates the connection point.

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

18. The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein: R 16 The optionally substituted C1-C6 alkyl is methyl; and R 16 The optionally substituted C3-C8 cycloalkyl is cyclopropyl.

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

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein: R 18 The optionally substituted C1-C6 alkyl is methyl; and The optionally substituted C1-C6 alkyl group is methyl.

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

22. The compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein: R 19 The C1-C6 alkyl group is a methyl group; and R 19 The -O-(C1-C6 alkyl) is a methoxy group.

23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 2 and 8 to 14, wherein the compound is selected from the group consisting of: (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-thietiden-3-yl)methyl)-4-phenoxypyrimidine-5-carboxamide; 2-Cyclopropyl-N-(1,1-dioxido-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]heptane-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-chlorocyclobutyloxy)-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]hexyl]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-difluorocyclobutyloxy)-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]heptane-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]heptane-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]heptane-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-acetylamino-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-cyclopropyloxy-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-Cyclopropyloxy-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.

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

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

26. The compound or pharmaceutically acceptable salt thereof according to any one of claims 3 and 10 to 14, wherein the compound is selected from the group consisting of: (E)-2-cyclobutyloxy-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-cyclopropyloxy-N-(3-(methylsulfonyl)allyl)benzamide; 4-Cyclopentyl-2-cyclopropyloxy-N-((1,1-dioxy-2H-thietiden-3-yl)methyl)benzamide; (E)-2-cyclobutyloxy-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-cyclopropyloxy-N-(3-(methylsulfonyl)allyl)benzamide; 4-Cyclopentyl-2-cyclopropyloxy-N-((1,1-dioxy-2H-thietiden-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.

27. The compound or pharmaceutically acceptable salt thereof according to claim 26, wherein when the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of the (R) or (S) configuration at those carbon atoms; or a mixture of (E) or (Z) geometric isomers of the above compounds.

28. The compound or pharmaceutically acceptable salt thereof according to any one of claims 4 and 10 to 14, wherein the compound is selected from the group consisting of: (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.

29. The compound or pharmaceutically acceptable salt thereof according to claim 28, wherein when the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of the (R) or (S) configuration at those carbon atoms; or a mixture of (E) and (Z) geometric isomers of the above compounds.

30. The compound or pharmaceutically acceptable salt thereof according to any one of claims 5 and 10 to 14, wherein the compound is selected from the group consisting of: (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.

31. The compound or pharmaceutically acceptable salt thereof of claim 30, 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 that carbon; or a mixture of (E) or (Z) geometric isomers of the above compounds.

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

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

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

35. The compound or pharmaceutically acceptable salt thereof of claim 34, wherein when the (R) or (S) stereochemical configuration at one or more chiral carbon atoms is specified, the compound comprises a mixture of the (R) or (S) configuration at those carbon atoms; or a mixture of E or Z geometric isomers of the above compounds.

36. A compound according to any one of claims 2, 10 to 12 and 15 to 17, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 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.

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

38. A compound according to any one of claims 2, 10 to 12 and 17 to 18, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 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.

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

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

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

42. A compound according to any one of claims 2, 10 to 12 and 21 to 22, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 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.

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

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

45. The method of claim 44, wherein the proliferative disease is cancer.

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

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

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

49. The method of claim 48, 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, acetylenonitrile, enone, acetylenone, alkynyl ester, and acetylenic ester.

50. The method of claim 49, wherein: The vinyl sulfone is represented by the following structure: The alkynyl sulfone is represented by the following structure: The alkenylsulfonamide is represented by the following structure: The vinyl sulfoxide is represented by the following structure: The alkynyl sulfoxide is represented by the following structure: The vinyl sulfoximine is represented by the following structure: The alkynyl sulfoximine is represented by the following structure: The acrylamide is represented by the following formula: The acrylonitrile is represented by the following structure: The enone is represented by the following structure: The alkynone is represented by the following structure: The enoate is represented by the following structure: and The alkynoate ester is represented by the following structure: in: Indicates a possible point of attachment of the chemical moiety to the rest of the electrophile.

51. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is CR 2 or N; Y is CR 4 or N; Z is CR 5 or N; or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl; The condition is that X, Y and Z are not N at the same time; 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or R 1 Together with the carbon atom to which it is attached and X, it forms an optionally substituted five- to six-membered heterocyclic group; 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl; R 4 is H, C1-C6 alkyl, cyano or halo; or R 4 Together with the carbon atom to which it is attached and Z, it forms an optionally substituted five- to six-membered heteroaryl group; or R 3 and R 4 The carbon atoms to which they are attached as shown and R 3 Together, they form an optionally substituted C6-C 10 aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five-membered to six-membered heterocyclyl or heterocycloalkenyl; 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; and V comprises an electrophile that reacts with the sulfur atom at cysteine ​​727 as shown in SEQ ID NO: 1 or a variant thereof and forms a covalent bond.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the electrophile comprises at least one chemical moiety selected from the group consisting of vinyl sulfone, alkynyl sulfone, vinyl sulfonamide, vinyl sulfoxide, alkynyl sulfoxide, vinyl sulfoximine, alkynyl sulfoximine, acrylamide, acrylonitrile, acetylenonitrile, enone, acetylenone, alkenoate, and acetylenate.

53. The compound according to claim 52 or a pharmaceutically acceptable salt thereof, wherein: The vinyl sulfone is represented by the following structure: The alkynyl sulfone is represented by the following structure: The alkenylsulfonamide is represented by the following structure: The vinyl sulfoxide is represented by the following structure: The alkynyl sulfoxide is represented by the following structure: The vinyl sulfoximine is represented by the following structure: The alkynyl sulfoximine is represented by the following structure: The acrylamide is represented by the following formula: The acrylonitrile is represented by the following structure: The enone is represented by the following structure: The alkynone is represented by the following structure: The enoate is represented by the following structure: and The alkynoate ester is represented by the following structure: in: Indicates a possible point of attachment of the chemical moiety to the rest of the electrophile.

54. A compound according to any one of claims 51 to 53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

55. A method of treating a proliferative disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 51 to 53, or a pharmaceutically acceptable salt thereof.

56. The method of claim 55, wherein the proliferative disease is cancer.

57. The method of claim 56, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, skin cancer, and MSI-H cancer.

58. 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, wherein the modified WRN helicase protein comprises SEQ ID NO: 1 or a variant thereof; and has a structure of formula (III): in: S is the sulfur atom of cysteine ​​727 in SEQ ID NO: 1 or a variant thereof; represents the amino acids at positions 1 to 726 and 728 to 1432 of SEQ ID NO: 1 or a variant thereof, respectively; and Q for Q 1 , Q 2 , Q 3 , Q 4 or Q 5 ; in: Q 1 for: in: Indicates the connection point; R 6 is H; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl or optionally substituted five-membered to six-membered heterocyclyl; R 7a is H or deuterium; R 8 is H; R 9 is H; and R 10 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted five-membered to six-membered heterocyclic group; or R 6 Together with the nitrogen atom to which it is attached and R 7 and R 7a together with the carbon atoms to which they are attached as shown, form an azetidinyl ring; or R 6 Together with the nitrogen atom to which it is attached and R 7 , R 7a and R 8 Together with the carbon atom to which they are attached, they form an azetidinyl or pyrrolidinyl ring; or R 6 Together with the nitrogen atom to which it is attached and R 7 , R 7a , R 8 and R 9 together with the carbon atoms to which they are attached as shown, 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 attached as shown, they form a 1,1-dioxy-2,3-dihydrothienyl ring; or R 8 , R 9 and R 10 Together with the carbon atoms to which they are attached as shown, they form a 1,1-dioxido-2H-thietidenyl ring; Q 2 for: in: Indicates the connection point; R 11 is H; R 12 is H or an optionally substituted C1-C6 alkyl; R 12a is H; and R 13 and R 14 Each is H; or R 11 Together with the nitrogen atom to which it is attached and R 12 , R 12a and R 13 together with the carbon atoms to which they are shown attached, form an optionally substituted azetidinyl ring; Q 3 for: in: Indicates the connection point; R 15 is H; and R 16 is H or optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl; Q 4 for: in: Indicates the connection point; R 17 is H; R 18 is H or optionally substituted C1-C6 alkyl; and Each R a are independently optionally substituted C1-C6 alkyl; Q 5 for: in: Indicates the connection point; m is 1, 2 or 3; and R 19 is selected from the group consisting of C1-C6 alkyl and -O-(C1-C6 alkyl); and U is: in: Indicates the connection point; 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 five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl; The condition is that X, Y and Z are not N at the same time; 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 five- to six-membered heteroaryl), -O-(optionally substituted five- to six-membered heterocyclyl), or optionally substituted C3-C8 cycloalkyl; or R 1 Together with the carbon atom to which it is attached and X, it forms an optionally substituted five- to six-membered heterocyclic group; 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 four- to six-membered heterocyclyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl; R 4 is H, C1-C6 alkyl, cyano, halo, or R 4 Together with the carbon atom to which it is attached and Z, it forms an optionally substituted five- to six-membered heteroaryl group; or R 3 and R 4 Together with the carbon atom to which they are attached, they form an optionally substituted C6-C 10 Aryl, optionally substituted C4-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl; R 5 is H, C1-C6 alkyl, -NR2 or -N(R)-C(=O)-(C1-C6 alkyl); and Each R is independently H or an optionally substituted C1-C6 alkyl group.

59. The modified WRN helicase protein of claim 58, wherein: X is N; Y is N; and Z is CR 5 ; Alternatively, Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heterocyclyl.

60. The modified WRN helicase protein of claim 58, wherein: X is CR 2 ; Y is CR 4 ;and Z is CR 5 ; or Y and Z together form an optionally substituted five- to six-membered heteroaryl or an optionally substituted five- to six-membered heteroaryl; or R 3 Together with the carbon atom to which it is shown attached and Y, it forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl.

61. The modified WRN helicase protein of claim 58, wherein: X is CR 2 ; Y is N; and Z is CR 5 ; or R 1 Together with the carbon atom to which it is shown attached and X, it forms an optionally substituted five- to six-membered heterocyclic group.

62. The modified WRN helicase protein of claim 58, wherein: X is N; Y is CR 4 ;and Z is CR 5 ; or R 3 Together with the carbon atom to which it is attached and Y, it forms an optionally substituted C6-C 10 aryl, optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl.

63. The modified WRN helicase protein of claim 58, wherein: X is N; Y is CR 4 ;and Z is N.

64. The modified WRN helicase protein of claim 58, wherein: X is CR 2 ; Y is CR 4 ;and Z is N.

65. The modified WRN helicase protein of any one of claims 58 to 64, wherein: In R 1 middle: The optional substituents of the -O-(optionally substituted C3-C8 cycloalkyl) are 1 to 3 substituents selected from the group consisting of halo, cyano and hydroxy; or when there are two substituents on the same ring carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; The -O-(optionally substituted C6-C 10 The optional substituents of the aryl group are 1 to 3 substituents selected from the group consisting of halo, C1-C6 alkyl, cyano, hydroxyl and -NH2, or 1 to 5 deuterium atoms; Or when R 1 When together with the carbon atom to which it is attached and X form an optionally substituted five-membered to six-membered heterocyclic group, two substituents on the same ring carbon atom of the five-membered to six-membered heterocyclic group together with the ring carbon atom to which they are attached form a five-membered to six-membered cycloalkyl group; In R 3 middle: The optional substituents of the optionally substituted C3-C8 cycloalkyl group are 1 to 3 substituents selected from the group consisting of hydroxyl, halo, C1-C6 alkyl and C6-C 10 or when there are two substituents on the same carbon atom of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl; or when there are two substituents on adjacent ring carbon atoms of the C3-C8 cycloalkyl, the substituents together with the ring carbon atoms to which they are attached form a C6-C 10 Aryl; Or when R 3 When it forms an optionally substituted C3-C8 cycloalkyl or cycloalkenyl group together with the carbon atom to which it is attached and Y, the optional substituents are 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl; or two geminal hydrogen atoms on the ring carbon atoms of the C3-C8 cycloalkyl or cycloalkenyl group may be replaced by a group =O; Or when R 3 When it is taken together with the carbon atom to which it is attached and Y to form an optionally substituted five-membered to six-membered heterocyclyl or heterocycloalkenyl, the optional substituents are 1 to 3 substituents selected from the group consisting of halo and C1-C6 alkyl; The optionally substituted C6-C 10 The optional substituents of the aryl group are 1 to 3 substituents selected from the group consisting of halogen; The optional substituents of 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, wherein the optional substituents of the C3-C6 cycloalkyl are 1 to 3 substituents selected from the group consisting of C1-C6 alkyl; - The optional substituents of the C1-C6 alkyl group of R of NR2 are 1 to 3 substituents selected from the group consisting of halogen; and The optional substituents of the optionally substituted four-membered to six-membered heterocyclic group are 1 to 3 substituents selected from the group consisting of -O-(C1-C6 alkyl), C1-C6 alkyl, and halo; or when there are two substituents on the same carbon atom of the optionally substituted four-membered to six-membered heterocyclic group, the substituents together with the ring carbon atoms to which they are attached form a C3-C6 cycloalkyl group.

66. The modified WRN helicase protein of any one of claims 58 to 65, wherein: By R 1 The optionally substituted five- to six-membered heterocyclic group formed together with the carbon atom to which it is attached is The double bond shown in the 1 Between the carbon of the group and X; By R 3 The optionally substituted C6-C 10 Aryl By R 3 The optionally substituted five- to six-membered heterocycloalkenyl group formed together with the carbon atom to which it is attached and Y is Among them with The carbon-carbon double bond between the two carbon atoms of the group is shown in the case of an R 3 Between the carbon of the group and Y; When R 3 When it is taken together with the carbon atom to which it is attached and Y to form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl group, the optionally substituted C3-C8 cycloalkyl or cycloalkenyl group is The carbon-carbon double bond shown in 3 between a carbon of the group and Y; and Among them, R 4 The optionally substituted five- to six-membered heteroaryl group formed together with the carbon atom to which it is attached and Z is In each structure, Indicates the connection point.

67. The modified WRN helicase protein of any one of claims 58 to 66, wherein: In R 1 middle: The -O-(optionally substituted C3-C8 cycloalkyl) is -O-cyclobutyl, -O-cyclopropyl, -O-cyclohexyl, -O-cyclopentyl, -O-(4,4-difluorocyclohexyl), -O-(spiro[2.3]hexane-5-yl), -O-(spiro[3.3]heptane-2-yl), -O-(3-chlorocyclobutyl), -O-(bicyclo[3.1.0]hexane-3-yl), -O-(bicyclo[2.2.1]heptane-1-yl), -O-(1-cyanocyclopentyl), -O-(3,3-difluorocyclobutyl), -O-(2-hydroxycyclohexyl), -O-cycloheptyl, -O-(2-fluorocyclohexyl), -O-(3,3-difluorocyclopentyl), -O-(2-fluorocyclohexyl) or -O-(2,2-difluorocyclopentyl), The -O-(optionally substituted C1-C6 alkyl) is ethoxy, isopropoxy or cyclopropylmethyloxy; The -O-(optionally substituted C6-C 10 Aryl) is phenoxy, 4-chlorophenoxy, 3-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 2-fluorophenoxy, p-tolyloxy, 3,5-difluorophenoxy, 4-fluoro-3-methylphenoxy, 3,5-dichlorophenoxy, 4-cyanophenoxy, 3,4-dimethylphenoxy, m-tolyloxy, 4-ethylphenoxy, 3-ethylphenoxy, o-tolyloxy, 2-hydroxyphenoxy, 3-hydroxyphenoxy, 4-hydroxyphenoxy, 3-chloro-5-fluorophenoxy, 3-aminophenoxy, naphthalene-1-oxy or phenoxy-d5; The -O-(optionally substituted five-membered to six-membered heteroaryl) is pyridin-2-yloxy or pyridin-3-yloxy; The -O-(optionally substituted five- to six-membered heterocyclyl) is -O-tetrahydro-2H-pyran-4-yl or -O-tetrahydro-2H-pyran-3-yl; and The optionally substituted C3-C8 cycloalkyl is cyclohexyl; In R 2 middle: The optionally substituted C1-C6 alkyl is methyl; and In R 3 middle: The 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]hexane-5-yl; The optionally substituted C3-C8 cycloalkenyl group is cyclopentenyl; The optionally substituted C6-C 10 Aryl is phenyl; The optionally substituted C1-C6 alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, fluoropropyl, methoxypropyl, difluoroethyl, difluoropropyl, (methylcyclopropyl)methyl, perfluoroethyl or cyclopropyldifluoromethyl; The optionally substituted C1-C6 alkenyl is 2-methylprop-1-en-1-yl; NR2 is -N(H)(cyclopentyl), -N(H)(methyl), -N(methyl)(ethyl), -N(methyl)(isopropyl), -N(ethyl)2 or -N(methyl)(trifluoroethyl); The -N(R)(optionally substituted C3-C8 cycloalkyl) is N(methyl)(cyclopropyl); The -S-(optionally substituted C1-C6 alkyl) is methyl mercaptan; The -O-(optionally substituted C1-C6 alkyl) is trifluoroethoxy or methoxy; The -O-(optionally substituted C3-C8 cycloalkyl) is cyclopentyloxy or cyclopropyloxy; and The optionally substituted four- to six-membered heterocyclyl or heterocycloalkenyl is tetrahydrofuranyl, 7-azabicyclo[2.2.1]heptane-7-yl, bicyclo[1.1.1]pentane-1-yl, methoxyazetidin-1-yl, 2-azaspiro[3.3]heptane-2-yl, tetrahydropyranyl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, dihydropyranyl, 5,6-dihydro-2H -pyran-3-yl, dimethylpyrrolidinyl, 2,2-dimethylpyrrolidin-1-yl, difluoropyrrolidinyl, methylcyclobutyl, pyrrolidinyl, pyrrolidin-1-yl, methylpyrrolidinyl, 2-methylpyrrolidin-1-yl, azetidinyl, azetidin-1-yl, fluoroazetidinyl, 3-fluoroazetidin-1-yl, difluoroazetidinyl or 3,3-difluoro-azetidin-1-yl; In R 5 middle: The C1-C6 alkyl group is a methyl group; The -NR2 is -NH2; and The -N(R)-C(=O)-(C1-C6 alkyl) is -N(H)-C(=O)-CH3.

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

69. The modified WRN helicase protein of claim 58, wherein: R 7 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; R 7 The optionally substituted C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, difluorocyclobutyl, -CH2-S-CH3, difluorocyclohexyl; R 7 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; R 10 The optionally substituted C1-C6 alkyl is methyl; R 10 The optionally substituted C3-C8 cycloalkyl is cyclopropyl; R 10 The optionally substituted five- to six-membered heterocyclic group is tetrahydropyranyl or tetrahydro-2H-pyran-4-yl; or where Q 1 for: In each structure, Indicates the connection point.

70. The modified WRN helicase protein of any one of claims 58 to 67, wherein Q is Q 2 .

71. The modified WRN helicase protein of claim 70, wherein Q 2 for Where R 21 is H or C1-C6 alkyl; wherein Indicates the connection point.

72. The modified WRN helicase protein of any one of claims 58 to 67, wherein Q is Q 3 .

73. The modified WRN helicase protein of claim 72, wherein: R 16 The optionally substituted C1-C6 alkyl is methyl; and R 16 The optionally substituted C3-C8 cycloalkyl is cyclopropyl.

74. The modified WRN helicase protein according to any one of claims 58 to 67, wherein Q is Q 4 .

75. The modified WRN helicase protein of claim 74, wherein: R 18 The optionally substituted C1-C6 alkyl is methyl; and The optionally substituted C1-C6 alkyl group is methyl.

76. The modified WRN helicase protein according to any one of claims 58 to 67, wherein Q is Q 5 .

77. The modified WRN helicase protein of claim 76, wherein: R 19 The C1-C6 alkyl group is a methyl group; and R 19 The -O-(C1-C6 alkyl) is a methoxy group.

78. A compound according to any one of claims 1 to 42 and 51 to 53, or a pharmaceutically acceptable salt thereof, for use in the treatment of a proliferative disease.

79. The compound for use according to claim 78, or a pharmaceutically acceptable salt thereof, wherein the proliferative disease is cancer.

80. The compound for use according to claim 79, 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.

Images