Substituted oxoisoindolinyl piperidine-2,6-dione compounds and methods of degrading proteins

Abstract

Disclosed are compounds of Formula (I): or stereoisomers, tautomers, or salts thereof, wherein X, Y, W, Z, L, R3, R4, R5, R6, R7, m, n, and p are defined herein. Also disclosed are methods of using such compounds to decrease the level Cyclin E1; and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of proliferative disorders, such as cancer.

Description

[0001] SUBSTITUTED OXOISOINDOLINYE PIPERIDINE-2, 6-DIONE

[0002] COMPOUNDS AND METHODS OF DEGRADING PROTEINS

[0003] CROSS REFERENCE

[0004] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 723,622 filed November 22, 2024, which is incorporated herein in its entirety.

[0005] DESCRIPTION

[0006] The present invention generally relates to substituted oxoisoindolinyl piperidine- 2, 6-dione compounds useful for decreasing the levels of the Cyclin El protein. Provided herein are substituted oxoisoindolinyl piperidine-2, 6-dione compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions comprising at least one compound according to the invention that are useful for the treatment of proliferative disorders, such as cancer.

[0007] REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA PATENT CENTER

[0008] Incorporated herein by reference in its entirety is a Sequence Listing entitled, “20241121 SEQ 14897USPSP” comprising SEQ ID NO: 1 through SEQ ID NO: 9, which include nucleic acid and / or amino acid sequences disclosed herein. The Sequence Listing has been submitted herein in XML format via Patent Center, and thus constitutes both the paper and computer readable form thereof. The Sequence Listing was first created using WIPO Sequence on November 21, 2024, and is 11,524 Bytes.

[0009] BACKGROUND OF THE INVENTION

[0010] Cyclin El is a member of the E-type cyclin family encoded by the CCNE1 gene. Cyclin El regulates various cellular processes, including cell cycle progression, DNA replication, histone biosynthesis, and transcriptional regulation. During the G1 phase of the cell cycle, Cyclin El binds and activates Cyclin-dependent kinases (CDKs), particularly CDK2, to form an active Cyclin E1 / CDK2 complex. This complex phosphorylates RBI and other RB family proteins, leading to the activation of E2F family transcriptional factor proteins and subsequent progression of the cell cycle (Asghar et al., Nat. Rev. Drug. Dis. 14: 130-146 (2015); Otto & Sicinski, Nat. Rev. Can. 17:93-115 (2017)).

[0011] Dysregulation of the cell cycle is a hallmark of cancer. Cyclin El is frequently overexpressed and amplified in cancers and is associated with cell cycle dysregulation (Witkiewicz et al., Trends in Cancer Vol 8(9) 711-725 (2022)). Amplification of the CCNE1 gene has been linked to poor clinical outcomes in various cancers, including gynecologic cancers (breast, ovarian, endometrial), gastrointestinal cancers (e.g. gastric, bladder), and other cancers of either solid or hematological origins (Keyomarsi et al., NEJM 347(20): 1566-1575 (2002), Macheret et al., Nature 555: 112-116 (2018), Etemadmoghadam et al., PLos One 5(1 l):el5498 pages 1-14 (2010); Au-Yeung et al., Clin. Can. Res. 23(7): 1862-1874 (2017)). Depletion of Cyclin El protein is a potential therapeutic strategy for the treatment of such cancers.

[0012] Cyclin El overexpression has been implicated in resistance to several anti-cancer agents such as CDK4 / 6 inhibitors, endocrine therapies, Her2 -targeting agents, PARP inhibitors and chemotherapeutic agents, suggesting that depletion of Cyclin El protein could help overcome or prevent resistance to such agents, either as a single agent or in combination with other therapies (Turner et al. J. Clin. Oncol. 37(14): 1169-1178 (2019); Herrera-Abreu et al., Cancer Res. 76(8):2301-2313 (2016); Scaltriti et al., PNAS 108(9): 3761-3766 (2011); Freeman-Cook et al., Cancer Cell 39, 1-18 (2021)).

[0013] There remains a need for therapies that can target Cyclin El directly to decrease the levels of Cyclin El protein in cancers. There remains a need for therapies that can selectively decrease the levels of Cyclin El protein in cancer cells while minimizing the degradation of GSPT1 (translation termination factor G1 to S phase transition proteins 1) in the normal tissues to maximize therapeutic index and facilitate efficacious responses in the clinic. Reduction of GSPT1 protein in normal human tissues is reportedly associated with dose-limiting and on-target toxicities (Uy et al., Blood 13 November 2019, http: / / doi.org / 10.1182 / blood-2019-123966).

[0014] There remains a need for therapies that can decrease the levels of Cyclin El protein.

[0015] Further, there remains a need for therapies that can decrease the levels of Cyclin El protein and minimize degradation of GSPT1.

[0016] The present invention fills the foregoing need by providing compounds that are useful to decrease the level of Cyclin E. Additionally, provided are compounds that are useful to decrease the level of Cyclin El and are selective against degradation of GSPT1.

[0017] SUMMARY OF THE INVENTION

[0018] The present invention provides substituted oxoisoindolinyl piperidine-2, 6-dione compounds of Formula (I), including stereoisomers, tautomers, salts, and prodrugs thereof, which are useful to decrease the levels of the Cyclin El.

[0019] The present invention also provides pharmaceutical compositions comprising a compound of Formula (I), stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs thereof; and a pharmaceutically acceptable carrier.

[0020] The present invention also provides a method of treating a disease or disorder by decreasing the levels of the Cyclin El, the method comprising administering to a patient a compound of Formula (I), stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs thereof.

[0021] The present invention also provides processes and intermediates for making the compounds of Formula (I), stereoisomers, tautomers, or salts thereof.

[0022] The present invention also provides the use of the compounds of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs thereof, for the manufacture of a medicament to decrease Cyclin El protein levels, for the treatment of certain diseases, including cancer.

[0023] The compounds of Formula (I) and compositions comprising the compounds of Formula (I) may be used in treating, preventing, or curing various proliferative disorders, such as cancer. Pharmaceutical compositions comprising these compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as cancer.

[0024] These and other features of the invention will be set forth in expanded form as the disclosure continues.

[0025] DETAILED DESCRIPTION

[0026] Applicants have found substituted oxoisoindolinyl piperidine-2, 6-dione compounds that decrease the levels of Cyclin El protein. The substituted oxoisoindolinyl piperidine-2, 6-dione compounds are believed to facilitate the interaction of Cyclin El protein with the corresponding E3 ubiquitin ligase complex (Culhn4-Cereblon, CUL4- CRBN), with concomitant degradation of the Cyclin El protein. These compounds are useful for the treatment of certain diseases, including cancer. The compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

[0027] The first aspect of the present invention provides at least one compound of Formula (I): or stereoisomers, tautomers, or salts thereof, wherein:

[0028] (i) X is CRi and Y is CR2 or N; or

[0029] (ii) X is N and Y is CR2; one of W and Z is CH, CRe, or N and the other of W and Z is CRe or CH;

[0030] Ri is hydrogen, F, Cl, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -0CHF2, -OCH2CHF2, -0CH2CN, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -N(CH3)(CH2CH3), -CH2(oxetanyl), -OCH2(cyclopropyl), -O(cyclopropyl), -O(cyclobutyl), -O(cyclopentyl), -O(tetrahydropyranyl), -N(CH3)2, cyclopropyl, cyclopentyl, azetidinyl, fluoroazetidinyl, or pyrrolidinyl;

[0031] R2 is hydrogen, F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, or cyclopropyl;

[0032] R3is hydrogen or F;

[0033] R4 is hydrogen or -CH3;

[0034] Rs is F or -CH3;

[0035] Re is F or Cl; each R7 is independently F, Cl, -CH3, -CHF2, or -OCH3; m is zero or 1; n is zero or 1; and p is zero, 1, 2, or 3.

[0036] The second aspect of the present invention provides at least one compound of Formula (II): or stereoisomers, tautomers, or salts thereof, wherein:

[0037] (i) X is CRi and Y is CR2 or N; or

[0038] (ii) X is N and Y is CR2;

[0039] Ri is hydrogen, F, Cl, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -OCHF2, -OCH2CHF2, -OCH2(cyclopropyl), -O(cyclopropyl), -O(cyclobutyl), -O(cyclopentyl), -O(tetrahydropyranyl), -N(CH3)2, cyclopropyl, or azetidinyl;

[0040] R2 is hydrogen, F, or -OCH3;

[0041] R3is hydrogen or F;

[0042] R4 is hydrogen or -CH3;

[0043] R5is -CH3;

[0044] Re is F or Cl; each R7 is independently F, Cl, -CH3, -CHF2, or -OCH3; m is zero or 1; n is zero or 1; and p is zero, 1, 2, or 3.

[0045] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0046] One embodiment provides a compound of Formula (I), or stereoisomers or tautomers thereof. One embodiment provides a salt of the compound of Formula (I), or stereoisomers or tautomers thereof.

[0047] One embodiment provides a pharmaceutically acceptable salt of the compound of Formula (I), or stereoisomers or tautomers thereof.

[0048] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein W is CH or CRe and Z is CRe or CH.

[0049] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein W is N and Z is CRe or CH.

[0050] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein W is CH or CRe and Z is N.

[0051] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is CR2. The compounds of this embodiment have the structure of Formula (la):

[0052] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is N. The compounds of this embodiment have the structure of Formula (lb):

[0053] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein X is N and Y is CR2. The compounds of this embodiment have the structure of Formula (Ic):

[0054] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CRi,Y is CR2, W is CH, and Z is CH. The compounds of this embodiment have the structure of Formula (Ila):

[0055] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CRi, Y is N, W is CH, and Z is CH. The compounds of this embodiment have the structure of Formula (lib):

[0056] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is N, Y is CR2, W is CH, and Z is CH. The compounds of this embodiment have the structure of Formula (lie):

[0057] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is CR2 or N.

[0058] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein W is CH and Z is CH. The compounds of this embodiment have the structure of Formula (Id):

[0059] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein W is N and Z is CH. The compounds of this embodiment have the structure of Formula (le):

[0060] One embodiment provides at least one compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein W is CH and Z is N. The compounds of this embodiment have the structure of Formula (If):

[0061] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein L is -O-, -CH2-, .

[0062] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein L is -O- or .

[0063] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein L is -O-.

[0064] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein L is -CH2-, -CF2-, or .

[0065] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen, F, Cl, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -0CHF2, -OCH2CHF2, -0CH2CN, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -N(CH3)(CH2CH3), -CH2(oxetanyl), -OCH2(cyclopropyl), -O(cyclopropyl), -O(cyclobutyl), -O(cyclopentyl), -O(tetrahydropyranyl), -N(CH3)2, cyclopropyl, cyclopentyl, azetidinyl, or pyrrolidinyl.

[0066] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen, F, Cl, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -0CHF2, -OCH2CHF2, -OCH2CN, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)2, cyclopropyl, or cyclopentyl.

[0067] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen, F, Cl, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2.

[0068] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen, F, -OCH3, or -OCD3.

[0069] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen or F.

[0070] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen, -OCH3, or -OCD3.

[0071] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen.

[0072] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is F, -OCH3, or -OCD3.

[0073] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R2is hydrogen, F, -CH3, -CH2CH3, -OCH3, or -OCH2CH3.

[0074] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R2is hydrogen, F, -CH3, or -CH2CH3.

[0075] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R2is hydrogen, F, -CH3, or -OCH3.

[0076] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R2is hydrogen, F, or -CH3.

[0077] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R2 is hydrogen or F.

[0078] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R2 is hydrogen.

[0079] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R2 is F.

[0080] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R3 is hydrogen.

[0081] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R3 is F.

[0082] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R4 is hydrogen.

[0083] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R4 is -CH3.

[0084] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R5 is F.

[0085] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R5 is -CH3.

[0086] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein m is zero.

[0087] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein m is 1.

[0088] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein n is zero.

[0089] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein n is 1.

[0090] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein n is i and Re is F.

[0091] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 1, 2, or 3.

[0092] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 1 or 2.

[0093] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is zero, 1, or 2.

[0094] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is zero or 1.

[0095] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 0.

[0096] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 1.

[0097] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 2.

[0098] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 3.

[0099] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 1, 2, or 3; and each R7 is independently F, Cl, -CH3, or -OCH3.

[0100] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 1, 2, or 3; and each R7 is independently F, -CH3, or -OCH3.

[0101] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein p is 1, 2, or 3; and each R7 is F. Included in this embodiment are compounds in which p is 1 or 2 and each R7 is F. Also, included in this embodiment are compounds in which p is 1 and R7 is F. Further, included in this embodiment are compounds in which p is 2 and each R7 is F.

[0102] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, having the structure of Formula (Ila):

[0103] Ri is hydrogen, F, Cl, -OH, -CH3, -CH(CH3)2, -CF3, -CH2OCH3, -CH2CH2OCH3,

[0104] -OCH3, -OCD3, -OCH2CH3, -OCH2CH2OCH3, -OCHF2, -OCH2CHF2,

[0105] -OCH2(cyclopropyl), -O(cyclopropyl), -O(cyclobutyl), -O(tetrahydropyranyl), or cyclopropyl;

[0106] R2 is hydrogen, F, or -OCH3;

[0107] R3is hydrogen or F;

[0108] R4 is hydrogen or -CH3;

[0109] R5is -CH3;

[0110] Rs is F or Cl; each R7 is independently F, Cl, -CH3, -CHF2, or -OCH3; m is zero or 1; n is zero or 1; and p is zero, 1, 2, or 3.

[0111] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, having the structure of Formula (lib): wherein:

[0112] L is -O-;

[0113] Ri is hydrogen, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -N(CH3)2, cyclopropyl, or azetidinyl;

[0114] R3 is hydrogen;

[0115] R4 is hydrogen or -CH3;

[0116] R5is -CH3;

[0117] Re is F; each R7 is independently F, Cl, -CH3, -CHF2, or -OCH3; m is zero or 1; n is zero or 1; and p is 1, 2, or 3.

[0118] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, having the structure of Formula (Ic): wherein:

[0119] L is -O-;

[0120] R2 is hydrogen or -OCH3;

[0121] R3 is hydrogen;

[0122] R4 is hydrogen or -CH3;

[0123] Re is F; each R7 is independently F or -CHF2; m is zero; n is zero or 1; and p is 1, 2, or 3.

[0124] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; and m is zero.

[0125] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen; R2 is F; R3 is hydrogen; R4 is hydrogen; and m is zero. One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen; R2 is hydrogen; R3 is F; R4 is hydrogen; and m is zero.

[0126] One embodiment provides a compound of Formula (I) having the following structure: or stereoisomers, tautomers, or salts thereof, wherein:

[0127] (i) X is CRi and Y is CH;

[0128] (ii) X is N and Y is CH; or

[0129] (iii) X is CH and Y is N;

[0130] Ri is hydrogen or -OCH3; and

[0131] R2 is hydrogen or F.

[0132] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is CH. Included in this embodiment, are compounds having the structure:

[0133] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is N and Y is CH. Included in this embodiment are compounds having the structure: One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CH and Y is N. Included in this embodiment are compounds having the structure:

[0134] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is CH; and Ri is hydrogen.

[0135] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is CH; and Ri is -OCH3.

[0136] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure:

[0137] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure: wherein:

[0138] (i) X is CRi and Y is CR2 or N; or

[0139] (ii) X is N and Y is CR2;

[0140] Ri is hydrogen or -OCH3;

[0141] R2 is hydrogen; and

[0142] Re is hydrogen or F. Included in this embodiment are compounds in which Ri is -OCH3 and Re is F.

[0143] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure: wherein:

[0144] (i) X is CRi and Y is CR2 or N; or

[0145] (ii) X is N and Y is CR2;

[0146] Ri is hydrogen or -OCH3;

[0147] R2 is hydrogen; and

[0148] Re is hydrogen or F.

[0149] Included in this embodiment are compounds in which Ri is -OCH3 and Re is F.

[0150] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure:

[0151] Included in this embodiment are compounds in which Ri is hydrogen. Also included in this embodiment are compounds in which Ri is -OCH3.

[0152] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure:

[0153] Included in this embodiment are compounds in which Ri is hydrogen. Also included in this embodiment are compounds in which Ri is -OCH3.

[0154] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure: One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure:

[0155] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure:

[0156] One embodiment provides a compound of Formula (I) or tautomers or salts thereof, wherein said compound has the structure:

[0157] One embodiment provides a compound of Formula (I), wherein the compound has the structure: or stereoisomers, tautomers, or salts thereof. Included in this embodiment are compounds having the structures: or tautomers, or salts thereof.

[0158] One embodiment provides a compound of Formula (I), wherein the compound has the structure: or stereoisomers, tautomers, or salts thereof. Included in this embodiment are compounds having the structures: or tautomers, or salts thereof.

[0159] One embodiment provides a compound of Formula (I), wherein the compound has the structure: or stereoisomers, tautomers, or salts thereof. Included in this embodiment are compounds having the structures: or tautomers, or salts thereof.

[0160] One embodiment provides a compound of Formula (I), wherein the compound has the structure: or stereoisomers, tautomers, or salts thereof. Included in this embodiment are compounds having the structures: or tautomers, or salts thereof.

[0161] One embodiment provides a compound of Formula (I), wherein the compound has the structure: or stereoisomers, tautomers, or salts thereof.

[0162] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0163] (3 S)-3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (1);

[0164] 3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (2);

[0165] (3 S)-3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-m ethoxy - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (3);

[0166] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (4);

[0167] (3 S)-3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (5); (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-l- oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (6);

[0168] 3 -(3 - { 4- [4-(3 , 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo-5H, 6H,7H- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (7); or

[0169] 3 -(3 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (8).

[0170] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0171] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (1);

[0172] 3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (2);

[0173] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (3 );

[0174] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (4);

[0175] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (5);

[0176] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (6);

[0177] (3 S)-3 -(3 - { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (7);

[0178] 3 -(3 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (8);

[0179] (3 S)-3 -(6- { 4- [4 - (3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (9);

[0180] (3 S)-3 -(6- { 4- [4 - ( 5 -chloro-2-fluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (10);

[0181] (3 S)-3 -(6- { 4- [4-(2-methoxyphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (11);

[0182] (3 S)-3 - [6 - (4 - { 4- [2-(difluoromethyl)phenoxy ]phenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (12); 3-[6-(4-{4-[(3,4-difluorophenyl)methyl]phenyl}-3-oxopiperazin-l-yl)-l-oxo-2,3- dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (13);

[0183] 3-[6-(4-{4-[difluoro(phenyl)methyl]phenyl}-3-oxopiperazin-l-yl)-l-oxo-2,3-dihydro- lH-isoindol-2-yl]piperidine-2, 6-dione (14);

[0184] (3S)-3-(6-{4-[4-(2,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-l-oxo-

[0185] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (15);

[0186] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-

[0187] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (16);

[0188] (3 S)-3 -(6- { 4- [4 - (3 ,4-difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-

[0189] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (17);

[0190] (3S)-3-(l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l-yl}-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (18);

[0191] (3 S)-3 -(6- { 4- [2-fluoro-4-(2,4, 5 -trifluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (19);

[0192] (3 S)-3 -(6- { 4- [4 - (3 -fluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (20);

[0193] (3S)-3-(6-{4-[2-fluoro-4-(2,3,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (21);

[0194] 3 -(6- { 4- [4-(2,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (22);

[0195] 3 -(6-{4-[4-(2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1H- isoindol-2-yl)piperidine-2, 6-dione (23);

[0196] 3 -(6- { 4- [4-(2-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (24);

[0197] 3 -(6- { 4- [4-(2-chlorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (25);

[0198] 3 -(6- { 4- [4-(2,6-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (26);

[0199] 3 - { 6- [4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2, 3 -dihydro- 1 H- isoindol-2-yl}piperidine-2, 6-dione (27);

[0200] 3 - { 6- [4-(4-benzylphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2, 3 -dihy dro- 1 H-i soindol-2- yl}piperidine-2, 6-dione (28); 3-(6-{4-[4-(2,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3-dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (29);

[0201] 3 -(6- { 4- [4-(3 ,4-difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (30);

[0202] 3 -(6- { 4- [4-(4-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (31);

[0203] 3 -(6- { 4- [4-(4-fluoro-2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (32);

[0204] 3 -(6- { 4- [4 -( 5 -fluoro-2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (33);

[0205] 3 -( 1 -oxo-6- { 3 -oxo-4- [4-(2, 4, 5 -trifluorophenoxy )phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (34);

[0206] 3 -( 1 -oxo-6- { 3 -oxo-4- [4 - (2 , 3 , 5 -trifluorophenoxy )phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- IH-isoindol -2 -yl)piperidine-2, 6-dione (35);

[0207] 3 -( 1 -oxo-6- { 3 -oxo-4- [4 - (2 , 3 ,4-trifluorophenoxy)phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (36);

[0208] 3 -( 1 -oxo-6- { 3 -oxo-4- [4-(3 ,4,5 -trifluorophenoxy )phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (37);

[0209] 3 -(6- { 4- [4 - (2 , 3 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (38);

[0210] 3 -(6- { 4- [2-fluoro-4-(2-fluorophenoxy)phenyl ] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (39);

[0211] 3 -(6- { 4- [4-(3 -fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (40);

[0212] 3 -(6- { 4- [4-(2,4-difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (41);

[0213] 3 - [ 6 -(4 - { 4 - [ (3 , 5 -difluorophenyl)methyl]phenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo-2, 3 - dihy dro- IH-isoindol -2 -yl]piperidine-2, 6-dione (42);

[0214] 3 - [6-(4- { 4- [(3 , 5-difluorophenyl)methyl]-2-fluorophenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (43);

[0215] 3 -(6- { 4- [4 -(2 , 3 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (44); 3-(l-oxo-6-{3-oxo-4-[4-(l-phenylcyclopropyl)phenyl]piperazin-l-yl}-2,3-dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (45);

[0216] 3 - { 1 -oxo-6- [3 -oxo-4-(6-phenoxypyri din-3 -yl)piperazin- 1 -yl] -2, 3 -dihydro- 1 H- isoindol -2 -yl}piperidine-2, 6-dione (46);

[0217] 3 -(6- { 4- [2-fluoro-4-(3 -fluorophenoxy )phenyl ] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (47);

[0218] 3-[6-(4-{4-[l-(3,4-difluorophenyl)cyclopropyl]phenyl}-3-oxopiperazin-l-yl)-l-oxo-

[0219] 2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (48);

[0220] 3 -(6- { 4- [3 -fluoro-4-(2-fluorophenoxy)phenyl ]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (49);

[0221] 3 -(6- { 4- [2-fluoro-4-(4-fluorophenoxy)phenyl ]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (50);

[0222] 3 -[6-(4- {4-[ 1 -(3 , 5-difluorophenyl)cy cl opropyl] phenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo-

[0223] 2.3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (51);

[0224] 3-(6-{4-[4-(2,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (52);

[0225] 3 -(6- { 4- [4 - (3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (53);

[0226] 3 -(6- { 4- [4-(2-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (54);

[0227] 3 -(4-m ethoxy-6- { 4-[4-(2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (55);

[0228] 3-(6-{4-[4-(2-chlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (56);

[0229] 3 - { 6- [4-(4-benzylphenyl)-3 -oxopiperazin- 1 -yl] -4-methoxy- 1 -oxo-2,3 -dihydro- 1 H- isoindol-2-yl}piperidine-2, 6-dione (57);

[0230] 3 -(6- { 4- [4-(4-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (58);

[0231] 3 -(4-methoxy- 1 -oxo-6- { 3 -oxo-4- [4-(2,4, 5 -trifluorophenoxy)phenyl]piperazin- 1 -yl } -

[0232] 2.3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (59);

[0233] 3-(6-{4-[2-fluoro-4-(2-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (60); 3 -(6- {4- [4-(2,4-difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (61);

[0234] 3 - [ 6 -(4 - { 4 - [ (3 , 5 -difluorophenyl)methyl]phenyl } -3 -oxopiperazin- 1 -yl)-4-methoxy- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (62);

[0235] 3-(4-methoxy-l-oxo-6-{3-oxo-4-[4-(l-phenylcyclopropyl)phenyl]piperazin-l-yl}-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (63);

[0236] 3 -(6- { 4- [6-(3 -fluorophenoxy)pyri din-3 -yl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (64);

[0237] 3-(6-{4-[3-fluoro-4-(2-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (65);

[0238] (3S)-3-(6-{4-[4-(2,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (66);

[0239] (3 S)-3-(6-{4-[4-(5-chloro-2-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl} -4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (67);

[0240] (3 S)-3 -(6- { 4- [4 - (2 , 3 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (68);

[0241] (3S)-3-(4-methoxy-l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l- yl}-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (69);

[0242] (3S)-3-(6-{4-[4-(3-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l-oxo-

[0243] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (70);

[0244] (3 S)-3 -(6- { 4- [4-(2,6-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (71);

[0245] (3 S)-3 - { 6-[4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl]-4-methoxy- 1 -oxo-2,3- dihydro- IH-isoindol -2 -yl}piperidine-2, 6-dione (72);

[0246] (3 S)-3 - [6 - (4 - { 4- [2-(difluoromethyl)phenoxy ]phenyl } -3 -oxopiperazin- 1 -yl)-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (73);

[0247] (3S)-3-(6-{4-[4-(2,3-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (74);

[0248] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (75);

[0249] (3 S)-3 -(6- { 4- [4 - (3 ,4-difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (76); (3S)-3-(6-{4-[2-fluoro-4-(2,4,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (77);

[0250] (3S)-3-(6-{4-[2-fluoro-4-(3-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (78);

[0251] (3S)-3-(6-{4-[4-(3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (79);

[0252] (3S)-3-(6-{4-[2-fluoro-4-(2,3,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (80);

[0253] (3 S)-3 -(6- { 4-[4-(2, 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (81);

[0254] (3 S)-3 -(6- { 4 - [4-(3 ,4-difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (82);

[0255] (3S)-3-(6-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-lH,2H,3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (83);

[0256] (3 S)-3 -(6- { 4 - [4-(3 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- 1H,2H,3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (84);

[0257] (3S)-3-(l-oxo-6-{3-oxo-4-[4-(2,4,5-trifluorophenoxy)phenyl]piperazin-l-yl}- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (85);

[0258] (3 S)-3 -(6- { 4 - [4 - (3 , 5 -difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (86);

[0259] (3S)-3-(6-{4-[4-(3,4-difluoro-2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (87);

[0260] (3 S)-3 -(1 -oxo-6- { 3 -oxo-4-[4-(2,3 , 5-trifluorophenoxy)phenyl]piperazin- 1 -y 1 } - lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (88);

[0261] (3S)-3-(6-{4-[2-fluoro-4-(2,4,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l- oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (89);

[0262] (3 S)-3 -(6- { 4-[4-(2, 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -y 1 } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (90);

[0263] (3S)-3-(3-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (91);

[0264] (3 S)-3 -(5 -oxo-3 - { 3 -oxo-4-[4-(2, 3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 -y 1 } - 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (92); (3S)-3-(3-{4-[4-(3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (93);

[0265] (3S)-3-(3-{4-[2-fluoro-4-(2,3,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5- oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (94);

[0266] (3S)-3-(6-{4-[4-(3-chloro-5-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (95);

[0267] 3 -(6- {4- [4-(3 -chi oro-5 -fluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (96);

[0268] (3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (97);

[0269] (3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (98);

[0270] (3S)-3-(6-{4-[2-chloro-4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (99);

[0271] (3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (100);

[0272] (3S)-3-(6-{4-[4-(3-chloro-5-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (101);

[0273] (3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (102);

[0274] (3S)-3-(6-{4-[4-(3-chloro-5-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-l- oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (103);

[0275] (3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (104);

[0276] (3 S)-3 -(6- { 4- [4-(3 -chi oro-5 -fluorophenoxy )-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (105);

[0277] 3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-lH,2H,3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (106);

[0278] 3 -(6- { 4- [4-(3 -chi oro-5 -fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (107);

[0279] (3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (108); (3S)-3-(6-{4-[5-(3,5-difluorophenoxy)-3-fluoropyridin-2-yl]-3-oxopiperazin-l-yl}-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (109);

[0280] 3 -[6-(4- {4-[ 1 -(3 , 5-difluorophenyl)cy cl opropyl] phenyl } -3 -oxopiperazin- 1 -yl)-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (110);

[0281] (3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -yl } -4-m ethoxy - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (111);

[0282] (3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)-3 -fluoropy ridin-2-yl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (112);

[0283] (3 S)-3 -[( lR)-5- {4- [4-(3 , 5-difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (113);

[0284] (3S)-3-[(lR)-5-{4-[4-(3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (114);

[0285] (3 S)-3 - [( 1 R)-5 - { 4- [4-(4-fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -methyl-3 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (115);

[0286] (3 S)-3 -[( lR)-5- {4- [4-(3 , 5-difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -methyl-3 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (116);

[0287] (3S)-3-[(lR)-5-{4-[4-(2,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (117);

[0288] (3S)-3-[(lR)-5-{4-[4-(3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-l- methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (118);

[0289] (3S)-3-[(lR)-l-methyl-3-oxo-5-{3-oxo-4-[4-(2,4,5- trifluorophenoxy)phenyl]piperazin-l-yl}-2,3-dihydro-lH-isoindol-2-yl]piperidine-2,6- di one (119);

[0290] (3 S)-3-[(lR)-5-{4-[4-(2-methoxyphenoxy)phenyl]-3-oxopiperazin-l-yl}-l -methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (120);

[0291] (3 S)-3 - [( 1 R)-5 - { 4- [4-(2, 3 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (121);

[0292] (3 S)-3 - [( 1 R)-5 - { 4- [4-(2, 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (122);

[0293] (3 S)-3 -[( lR)-5- {4- [2-fluoro-4-(3 -fluorophenoxy )phenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (123);

[0294] (3 S)-3 - [( 1 R)-5 - { 4- [4-(3 ,4-difluoro-2-m ethylphen oxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (124);

[0295] (3S)-3-[(lR)-l-methyl-3-oxo-5-{3-oxo-4-[4-(2,3,5- trifluorophenoxy)phenyl]piperazin-l-yl}-2,3-dihydro-lH-isoindol-2-yl]piperidine-2,6- dione (125);

[0296] (3 S)-3 - [( 1 S)-5 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (126);

[0297] (3S)-3-[(lS)-5-{4-[4-(4-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (127);

[0298] (3 S)-3 - [( 1 S)-5 - { 4- [4-(3 , 5 -difluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } - 1 -methyl-3 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (128);

[0299] (3 S)-3 - [(7R)-3 - { 4- [4-(3 , 5 -difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -7 -methyl-5 - oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (129);

[0300] (3 S)-3 - [(7R)-3 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 7 - methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (130);

[0301] (3 S)-3 - [(7 S)-3 - { 4- [4 - (3 , 5 -difluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } -7 -methyl-5 - oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (131);

[0302] (3S)-3-[(7S)-7-methyl-5-oxo-3-{3-oxo-4-[4-(2,3,5- trifluorophenoxy)phenyl]piperazin-l-yl}-5H,6H,7H-pyrrolo[3,4-b]pyridin-6- yl]piperidine-2, 6-dione (132);

[0303] (3S)-3-[(7R)-7-methyl-5-oxo-3-{3-oxo-4-[4-(2,3,5- trifluorophenoxy)phenyl]piperazin-l-yl}-5H,6H,7H-pyrrolo[3,4-b]pyridin-6- yl]piperidine-2, 6-dione (133);

[0304] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-3-methyl-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (134);

[0305] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-3- methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (135);

[0306] (3S)-3-(3-methyl-l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l- yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (136);

[0307] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-3-methyl-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (137);

[0308] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 3 - methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (138); (3 S)-3 -(3 -methyl- 1 -oxo-6- { 3 -oxo-4- [4-(2, 3 , 5 -trifluorophenoxy )phenyl ]piperazin- 1 - yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (139);

[0309] (3 S)-3 - [(7R)-3 - { 4- [4-(3 -chi oro-5 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -y 1 } - 7 - methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (140);

[0310] (3 S)-3 - [(7 S)-3 - { 4- [4 - (3 -chi oro-5 -fluorophenoxy )phenyl]-3 -oxopiperazin- 1 -y 1 } - 7 - methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (141);

[0311] (3 S)-3 - [(3R)-6- { 4- [4-(3 -chi oro-5 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -y 1 } - 3 - methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2, 6-dione (142);

[0312] (3 S)-3 -(6- { 4- [4 - (3 , 5 -di chlorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (143);

[0313] (3 S)-3 -(4-fluoro- 1 -oxo-6- { 3 -oxo-4- [4-(2,3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl } -2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione ( 144);

[0314] (3 S)-3 -(4-fluoro-6- { 4-[4-(2-fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (145);

[0315] (3S)-3-(4-fluoro-6-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (146);

[0316] (3S)-3-(6-{4-[4-(3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-l-oxo-

[0317] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (147);

[0318] (3 S)-3 - { 4-fluoro-6- [4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl}piperidine-2, 6-dione (148);

[0319] (3 S)-3 -(6- { 4- [4-(2, 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-fluoro- 1 -oxo-

[0320] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (149);

[0321] (3 S)-3 -(6- { 4- [4 - ( 5 -chloro-2-fluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } -4-fluoro- 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (150);

[0322] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-fluoro- 1 -oxo-

[0323] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (151);

[0324] (3S)-3-(6-{4-[4-(2,3-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (152);

[0325] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (153);

[0326] (3 S)-3 -(6- { 4- [4-(2, 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (154); (3 S)-3 -(4-fluoro-6- { 4 - [4-(3 -fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl }- 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (155);

[0327] (3 S)-3 -(4-fluoro-6- { 4- [2-fluoro-4-(3 -fluorophenoxy )phenyl] -3 -oxopiperazin- 1 -y 1 } - 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (156);

[0328] (3S)-3-(6-{4-[4-(3,5-difluoro-2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (157);

[0329] (3 S)-3 -(4-chl oro-6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-

[0330] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (158);

[0331] (3S)-3-(4-chloro-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } - 1 -oxo-2,3 -dihydro- 1 H-isoindol-2-yl)piperidine-2, 6-dione (159);

[0332] (3S)-3-(4-chloro-6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (160);

[0333] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methyl-l-oxo-

[0334] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (161);

[0335] 3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -4-methyl- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (162);

[0336] (3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -yl } -4-methyl- 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (163);

[0337] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-ethyl- 1 -oxo-

[0338] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (164);

[0339] 3-(4-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } - 1 -oxo-2,3 -dihydro- 1 H-isoindol-2-yl)piperidine-2, 6-dione (165);

[0340] (3 S)-3 -(4-cy cl opropyl-6- { 4- [4-(3 ,5 -difluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } - 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (166);

[0341] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-[(oxetan-3- yl)methyl]-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (167);

[0342] 3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-(methoxymethyl)-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (168);

[0343] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethyl)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (169);

[0344] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-hydroxy-l- oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (170); (3 S)-3 -(4-hydroxy-6-{4-[4-(2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-

[0345] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (171);

[0346] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-ethoxy-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (172);

[0347] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-propoxy -2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (173);

[0348] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethoxy)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (174);

[0349] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- ethoxy- 1 -oxo-2, 3 -dihydro- 1 H-i soindol-2-yl)piperi dine-2, 6-dione (175);

[0350] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-4- propoxy-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (176);

[0351] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(propan-2 -yloxy)-2, 3 -dihydro- IH-isoindol -2 -yl)piperi dine-2, 6-dione (177);

[0352] (3S)-3-(4-cyclopropoxy-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperi dine-2, 6-dione (178);

[0353] (3S)-3-[4-(cyclopentyloxy)-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H-i soindol -2 -y 1 ] pi p eri dine-2, 6-dione (179);

[0354] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4-(propan- 2 -yloxy)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (180);

[0355] (3 S)-3 -(4-cy clopropoxy-6- { 4 - [4 - (3 , 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 -y 1 } - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (181);

[0356] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- (2H3)methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (182);

[0357] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-

[0358] (2H3)methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (183);

[0359] (3 S)-3 - [4-(2,2-difluoroethoxy)-6- { 4- [4 - (3 , 5 -di fluor ophenoxy)phenyl ]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- IH-isoindol -2 -y 1 ]piperi dine-2, 6-dione ( 184);

[0360] (3 S)-3 - [4-(cy clopropylmethoxy)-6- { 4- [4-(3 , 5 -difluorophenoxy )phenyl ]-3 - oxopiperazin-l-yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (185);

[0361] 2-[(6- { 4 - [4 -(3 , 5 -difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -2-[(3 S)-2,6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindol-4-yl)oxy]acetonitrile (186); 2-[(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-2-[(3S)-2,6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindol-4-yl)oxy]acetonitrile (187);

[0362] (3S)-3-[4-(difluoromethoxy)-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l- yl } - 1 -oxo-2, 3 -dihydro- 1 H-isoindol -2 -yl]piperidine-2, 6-dione (188);

[0363] (3 S)-3 - [4-(difluoromethoxy)-6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl ]-3 - oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl]piperidine-2, 6-dione (189);

[0364] (3S)-3-[4-(difluoromethoxy)-6-{4-[6-(2-methylphenoxy)pyridin-3-yl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- IH-isoindol -2 -yl]piperidine-2, 6-dione (190);

[0365] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- (oxan-4-yloxy)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (191);

[0366] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(oxan-4- yloxy)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (192);

[0367] (3S)-3-(4-cyclobutoxy-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (193);

[0368] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4- (trifluoromethoxy)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (194);

[0369] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(trifluoromethoxy)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (195);

[0370] (3 S)-3 -(5 -fluoro- 1 -oxo-6- { 3 -oxo-4- [4 -(2 , 3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl } -2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (196);

[0371] (3 S)-3 -(6- { 4- [4 - (3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -5 -fluoro- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (197);

[0372] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -5 -fluoro- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (198);

[0373] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 5 - fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (199);

[0374] (3 S)-3 -(5 -fluoro-6- { 4 - [4 - (3 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (200);

[0375] (3 S)-3 -(5 -fluoro-6- { 4-[2-fluoro-4-(2, 3 , 5 -trifluorophenoxy)phenyl] -3 -oxopiperazin- 1 - yl } - 1 -oxo-2, 3 -dihydro- 1 H-isoindol-2-yl)piperidine-2, 6-dione (201 );

[0376] (3 S)-3 -(5 -fluoro-6- {4-[2-fluoro-4-(2, 4,5 -trifluorophenoxy)phenyl]-3 -oxopiperazin- 1 - yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (202); (3S)-3-(6-{4-[4-(2,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-fluoro-l-oxo-

[0377] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (203);

[0378] (3 S)-3 -(5 -fluoro- 1 -oxo-6- { 3 -oxo-4- [4-(2,4, 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl}-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (204);

[0379] (3S)-3-(6-{4-[4-(2,6-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-7-fluoro-l-oxo-

[0380] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (205);

[0381] (3 S)-3 -(6- { 4- [4-(2-chlorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -7-fluoro- 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (206);

[0382] (3 S)-3 -(7 -fluoro-6- { 4-[4-(2-fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (207);

[0383] (3 S)-3 -(6- { 4- [4 - (3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -7-fluoro- 1 -oxo-

[0384] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (208);

[0385] (3S)-3-(7-fluoro-6-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (209);

[0386] (3 S)-3 - { 7 -fluoro-6- [4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl}piperidine-2, 6-dione (210);

[0387] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-7-fluoro-l-oxo-

[0388] 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (211);

[0389] (3 S)-3 -(4-chl oro-6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -y 1 } - 5 - methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (212);

[0390] (3 S)-3 -(4-methoxy- 1 -oxo-6- { 3 -oxo-4- [4-(2, 3 ,4-trifluorophenoxy)phenyl]piperazin- 1 - yl } -2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (213);

[0391] (3 S)-3 -(6- { 4- [4-(2-chl oro-3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (214);

[0392] (3S)-3-(6-{4-[2-fluoro-4-(2,3,4-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (215);

[0393] (3S)-3-(6-{4-[4-(2-chloro-3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } -4-methoxy- 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (216);

[0394] (3S)-3-(6-{4-[4-(2-chloro-4,6-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (217);

[0395] (3S)-3-(6-{4-[4-(2-chloro-4,6-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } -4-methoxy- 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (218); (3S)-3-(4-fluoro-l-oxo-6-{3-oxo-4-[4-(2,3,4-trifluorophenoxy)phenyl]piperazin-l- yl } -2,3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (219);

[0396] (3S)-3-(6-{4-[4-(2-chloro-3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- fluoro- 1 -oxo-2, 3 -dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (220);

[0397] (3S)-3-(4-fluoro-6-{4-[2-fluoro-4-(2,3,4-trifluorophenoxy)phenyl]-3-oxopiperazin-l- yl } - 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (221 );

[0398] (3S)-3-(6-{4-[4-(2-chloro-3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl}-4-fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (222);

[0399] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (223);

[0400] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (224);

[0401] (3S)-3-(6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-5-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (225);

[0402] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4,5-dimethoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (226);

[0403] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } -4, 5 - dimethoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (227);

[0404] (3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -y 1 } -4, 5 - dimethoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (228);

[0405] (3S)-3-(4-chloro-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl}-5-methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (229);

[0406] (3S)-3-(4-chloro-6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (230);

[0407] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (231);

[0408] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- fluoro-5 -methoxy- 1 -oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (232);

[0409] (3S)-3-(6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-4-fluoro-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (233);

[0410] 3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -5 -methoxy - 4-methyl-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (234); 3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-methoxy-4-methyl-

[0411] 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (235);

[0412] 3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy )pyri din-2 -yl] -3 -oxopiperazin- 1 -yl } -5 -methoxy -4- methyl-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (236);

[0413] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4-(propan-

[0414] 2 -yl)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (237);

[0415] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(propan-2-yl)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (238);

[0416] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- (hydroxymethyl)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (239);

[0417] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- (hydroxymethyl)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (240);

[0418] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methyl-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (241);

[0419] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (242);

[0420] (3S)-3-(4-methyl-l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l- yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (243);

[0421] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-ethyl- 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (244);

[0422] 3-(4-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (245);

[0423] (3S)-3-(4-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3 ,4-c]pyri din-2 -yl)piperidine-2, 6-dione

[0424] (246);

[0425] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- (methoxymethyl)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione

[0426] (247);

[0427] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethyl)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (248);

[0428] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl }-4- methoxy-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (249); (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (250);

[0429] (3 S)-3 -(4-methoxy- 1 -oxo-6- { 3 -oxo-4- [4-(2, 3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (251);

[0430] (3 S)-3 -(6- { 4- [4 - (2 -fluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (252);

[0431] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-ethoxy-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (253);

[0432] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(propan-2-yloxy)-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (254);

[0433] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4-(propan- 2 -yloxy)-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (255);

[0434] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethoxy)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (256);

[0435] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4-(2- methoxyethoxy)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (257);

[0436] 3 -(3 - { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -2-methoxy-5 -oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (258);

[0437] (3 S)-3 -(3 - { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -2- methoxy-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (259);

[0438] (3 S)-3 -(3 - { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -2- ethoxy-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (260);

[0439] (3S)-3-(3-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-2-ethoxy-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (261);

[0440] (3S)-3-(3-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-2-methyl-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (262);

[0441] (3 S)-3 - [4-(azetidin- 1 -y 1 ) - 6 - { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 - oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3 ,4-c]pyri din-2 -yl]piperidine-2, 6-dione (263);

[0442] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl }-4- (dimethylamino)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (264);

[0443] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-4- (pyrrolidin-l-yl)-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (265);

[0444] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(3 - fluoroazetidin-l-yl)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione

[0445] (266);

[0446] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- [ethyl(methyl)amino]-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione

[0447] (267);

[0448] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(ethylamino)- l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (268);

[0449] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl }-4- (methylamino)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (269);

[0450] (3S)-3-[4-(cyclopropylamino)-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin- l-yl}-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2, 6-dione (270);

[0451] (3 S)-3 - [4-(difluoromethyl)-6- { 4 - [4 - (3 , 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 - yl}-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2, 6-dione (271);

[0452] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-4- (trifluoromethyl)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (272);

[0453] (3S)-3-[4-(difluoromethyl)-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l- yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (273);

[0454] 6- { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -2 - [ (3 S)-2, 6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindole-4-carbonitrile (274);

[0455] 6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-2-[(3S)-2,6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindole-4-carbonitrile (275);

[0456] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-methyl-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (276);

[0457] 3-(5-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (277);

[0458] 3 -(6- { 4- [4-(3 , 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } -5 -ethyl- 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (278);

[0459] (3S)-3-{6-[(2R)-4-[4-(2,4-difluorophenoxy)phenyl]-2-methyl-5-oxopiperazin-l-yl]-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (279);

[0460] (3S)-3-{6-[(2S)-4-[4-(2,4-difluorophenoxy)phenyl]-2-methyl-5-oxopiperazin-l-yl]-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (280);

[0461] 3-{6-[(2S)-4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-2-methyl-5-oxopiperazin-l- yl]-4-methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (281);

[0462] (3S)-3-{6-[(2S)-4-[4-(3,5-difluorophenoxy)phenyl]-2-methyl-5-oxopiperazin-l-yl]-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (282);

[0463] (3 S)-3 - { 6 - [ (3 S)-4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -methyl-5- oxopiperazin-l-yl]-4-fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione

[0464] (283);

[0465] (3 S)-3 - { 6-[(3R)-4-[4-(3 , 5-difluorophenoxy)-2-fluorophenyl]-3 -methyl-5- oxopiperazin-l-yl]-4-fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione

[0466] (284);

[0467] 3 - { 6- [(2 S)-4- [4 - (3 , 5 -difluorophenoxy)phenyl] -2-methyl-3 -oxopiperazin- 1 -y 1 ] -4 - methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (285); or

[0468] 3 - { 6- [(2R)-4-[4-(3 , 5 -difluorophenoxy )phenyl ]-2-methyl-3 -oxopiperazin- 1 -y 1 ] -4 - methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (286).

[0469] The compounds of Formula (I) or stereoisomers, tautomers, or salts thereof, are useful to decrease the level of Cyclin El protein.

[0470] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0471] The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0472] Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more.

[0473] As used herein, the phrase “compounds and / or salts thereof’ refers to at least one compound, at least one salt of the compounds, or a combination thereof. For example, compounds of Formula (I) and / or salts thereof includes a compound of Formula (I); two compounds of Formula (I); a salt of a compound of Formula (I); a compound of Formula (I) and one or more salts of the compound of Formula (I); and two or more salts of a compound of Formula (I).

[0474] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0475] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0476] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.

[0477] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.

[0478] In accordance with a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0479] The term “amino” refers to the group -NEU

[0480] The term "oxo" refers to the group =0.

[0481] The compounds of the present invention include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0482] As used herein, the term “tautomer” refers to each of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule. For example, one skilled in the art would readily understand that a 1,2, 3 -triazole exists in two tautomeric forms as defined above:

[0483] 1 H-1 ,2 , 3-triazole 2 / 7-1 ,2 ,3-triazole

[0484] Thus, this disclosure is intended to cover all possible tautomers even when a structure depicts only one of them. For example, the compounds of Formula (I) can exist in tautomer forms:

[0485] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0486] The compounds of Formula (I) can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to one or more salts thereof. The term “salt(s)” denotes acidic salt(s) formed with inorganic and / or organic acids. In addition, the term “salt(s) may include zwitterions (inner salts), e.g., when a compound of Formula (I) contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of the Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0487] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, maleates (formed with maleic acid), 2- hydroxy ethanesulfonates, lactates, methanesulfonates (formed with methanesulfonic acid), 2 -naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3- phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0488] The compounds of Formula (I) can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as a solid. It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (I) are also within the scope of the present invention. The term “solvate” means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0489] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0490] In addition, compounds of Formula (I), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) (“substantially pure”), which is then used or formulated as described herein. Such “substantially pure” compounds of Formula (I) are also contemplated herein as part of the present invention.

[0491] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

[0492] The term “Cyclin El degrader” refers to an agent capable of reducing the level of the Cyclin El protein by degradation and / or inactivation and / or inhibition and / or reducing the expression levels of the Cyclin El protein, or a combination thereof.

[0493] As used herein, “Cyclin El” protein is encoded by the CCNE1 gene. Cyclin El is also known as CCNE, cyclin E, El-type cyclin, Gl / S-specific cyclin El or pCCNEl. “Cyclin El” protein includes all human isoforms encoded by CCNE1 gene as listed below-

[0494] Isoform 1 (UniPort P24864-1)

[0495] MPRERRERDAI<ERDTMI<EDGGAEFSARSRI<RI<ANVTVFLQDPDEEMAI<IDRTA RDQCGSQPWDNNAVCADPCSLIPTPDKEDDDRVYPNSTCKPRIIAPSRGSPLPVLS WANREEVWI<IMLNI<EI<TYLRDQHFLEQHPLLQPI<MRAILLDWLMEVCEVYI<L HRETFYLAQDFFDRYMATQENVVKTLLQLIGISSLFIAAKLEEIYPPKLHQFAYVT DGACSGDEILTMELMIMKALKWRLSPLTIVSWLNVYMQVAYLNDLHEVLLPQY PQQIFIQIAELLDLCVLDVDCLEFPYGILAASALYHFSSSELMQKVSGYQWCDIEN CVKWMVPFAMVIRETGSSKLKHFRGVADEDAHNIQTHRDSLDLLDKARAKKAM LSEQNRASPLPSGLLTPPQSGKKQSSGPEMA (SEQ ID NO: 1)

[0496] Isoform 2 (UniProt P24864-2)

[0497] MPRERRERDAKERDTMKEDGGAEFSARSRKRKANVTVFLQDPDEEMAKIDRTA RDQCGSQPWDNNAVCADPCSLIPTPDKEDDDRVYPNSTCKPRIIAPSRGSPLPVLS

[0498] WANREEVWKIMLNKEKTYLRDQHFLEQHPLLQPKMRAILLDWLMFIAAKLEEIY PPKLHQFAYVTDGACSGDEILTMELMIMKALKWRLSPLTIVSWLNVYMQVAYL NDLHEVLLPQ YPQQIFIQIAELLDLC VLD VDCLEFP YGIL AAS AL YHF S S SELMQK VSGYQWCDIENCVKWMVPFAMVIRETGSSKLKHFRGVADEDAHNIQTHRDSLD LLDKARAKKAMLSEQNRASPLPSGLLTPPQSGKKQSSGPEMA (SEQ ID NO: 2)

[0499] Isoform 3 (UniProt P24864-3)

[0500] MKEDGGAEFSARSRKRKANVTVFLQDPDEEMAKIDRTARDQCGSQPWDNNAV CADPCSLIPTPDKEDDDRVYPNSTCKPRIIAPSRGSPLPVLSWANREEVWKIMLNK

[0501] EKTYLRDQHFLEQHPLLQPKMRAILLDWLMEVCEVYKLHRETFYLAQDFFDRY

[0502] MATQENVVKTLLQLIGISSLFIAAKLEEIYPPKLHQFAYVTDGACSGDEILTMELM IMKALKWRLSPLTIVSWLNVYMQVAYLNDLHEVLLPQYPQQIFIQIAELLDLCVL D VDCLEFP YGIL AAS ALYHF S S SELMQK VS GYQWCDIENC VKWMVPF AMVIRET GSSKLKHFRGVADEDAHNIQTHRDSLDLLDKARAKKAMLSEQNRASPLPSGLLT PPQSGKKQSSGPEMA (SEQ ID NO: 3)

[0503] Isoform 4 (UniProt C9J2U0)

[0504] MKEDGGAEFSARSRKRKANVTVFLQDPDEEMAKIDRTARDQCGSQPWD

[0505] NNAVCADPCSLIPTPDKEDDDRVYPNSTCKPRIIAPSRGSPLPVLSWANREEVWKI MLNKEKTYLRDQHFLEQHPLLQPKMRAILLDWLMEVCEVYKLHRETFYLAQDF FDRYMATQENVVKTLLQLIGIS SLFIAAKLEEIYPPKLHQF AYVTDGAC SGDEILT MELMIMKLLDLC VLD VDCLEFP YGIL AAS AL YHF S S SELMQK VS GYQWCDIENC VKWMVPF AMVIRETGSSKLKHFRGVADEDAHNIQTHRDSLDLLDKARAKKAML SEQNRASPLPSGLLTPPQSGKKQSSGPEMA (SEQ ID NO: 4)

[0506] Isoform 5 (UniProt I3L413)

[0507] DDRVYPNSTCKPRIIAPSRGSPLPVLSWANREEVWKIMLNKEKTYLRDQH FLEQHPLLQPKMRAILLDWLMEVCEVYKLHRETFYLAQDFFDRYMATQENVVK TLLQLIGISSLFIAAKLEEIYPPKLHQFAYVTDGACSGDEILTMELMIMKLLDLCVL D VDCLEFP YGIL AAS ALYHF S S SELMQK VS GYQWCDIENC VKWMVPF A M V I RET GSSKLKHFRGVADEDAHNIQTHRDSLDLLDKARAKKAMLSEQNRASPLPSGLLT PPQSGKKQSSGPEMA (SEQ ID NO: 5)

[0508] Isoform 6 (UniProt I3L1Q9)

[0509] MPRERRERDAI<ERDTMI<EDGGAEFSARSRI<RI<ANVTVDPDEEMAI<IDRT ARDQCGSQPWDNNAVC ADPC SLIPTPDKEDDDRVYPNSTCKPRIIAP SRGSPLPVL SWANREEVWKIMLNKEKTYLRDQHFLEQHPLLQPKMRAILLDWLMEVCEVYKL HRETFYLAQDFFDRYMATQENVVKTLLQLIGISSLFIAAKLEEIYPPKLHQFAYVT D (SEQ ID NO: 6)

[0510] Isoform 7 (UniProt I3L1Q9)

[0511] MPRERRERDAI<ERDTMI<EDGGAEFSARSRI<RI<ANVTVDPDEEMAI<IDRT ARDQCGSQPWDNNAVC ADPC SLIPTPDKEDDDRVYPNSTCKPRIIAP SRGSPLPVL SWANREEVWKILNKEKTYLRDQHFLEQHPLLQPKMRAILLDWLMEVCEVYKLH RETFYLAQDFFDRYMATQENVVKTLLQLIGISSLFIAAKLEEIYPPKLHQFAYVTD (SEQ ID NO: 7)

[0512] Isoform 8 (UniProt A0A0G3DHS8)

[0513] MPRERRERDAKERDTMKEDGGAEFSARSRKRKANVTVFLQDPDEEMAKI DRTARDQCGSQPWDNNAVCADPCSLIPTPDKEDDDRVYPNSTCKPRIIAPSRGSP LPVLSWANREEVWKIMLNKEKTYLRDQHFLEQHPLLQPKMRAILLDWLMEVCE VYKLHRETFYLAQDFFDRYMATQENVVKTLLQLIGISSLFIAAKLEEIYPPKLHQF AYVTDGAC SGDEILTMELMIMKLLDLC VLD VDCLEFP YGIL AAS ALYHF S S SELM QKVSGYQWCDIENCVKWMVPFAMVIRETGSSKLKHFRGVADEDAHNIQTHRDS LDLLDKARAKKAMLSEQNRASPLPSGLLTPPQSGKKQSSGPEMA (SEQ ID NO: 8) Isoform 9 (UniProt V5W5X2)

[0514] MPRERRERDAKERDTMKEDGGAEFSARSRKRKANVTVFLQDPDEEMAKI DRTARDQCGSQPWDNNAVCADPCSLIPTPDKEDDDRVYPNSTCKPRIIAPSRGSP LPVLSWANREEVWKIMLNKEKTYLRDQHFLEQHPLLQPKMRAILLDWLMEEIYP PKLHQFAYVTDGACSGDEILTMELMIMKALKWRLSPLTIVSWLNVYMQVAYLN DLHEVLLPQ YPQQIFIQIAELLDLC VLD VDCLEFP YGIL AAS AL YHF S S SELMQK V SGYQWCDIENCVKWMVPFAMVIRETGSSKLKHFRGVADEDAHNIQTHRDSLDL LDKARAKKAMLSEQNRASPLPSGLLTPPQSGKKQSSGPEMA (SEQ ID NO: 9)

[0515] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" Cyclin El protein with a compound of Formula (I) includes the administration of a compound of the present invention to an individual or patient, such as a human, having Cyclin El protein as, for example, introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing Cyclin El protein.

[0516] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease. In contrast, “prophylaxis” or “prevention” refers to administration to a subject who does not have a disease to prevent the disease from occurring. “Treat,” “treating,” and “treatment” does not encompass prophylaxis or prevention.

[0517] “Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to decrease the level of the Cyclin El protein in the cells, or effective to treat proliferative disorders, such as cancer.

[0518] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0519] The term “patient” includes human subjects.

[0520] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including, / .< ., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms; and not injurious to the patient.

[0521] The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier.

[0522] UTILITY

[0523] The compounds of Formula (I) are useful for the treatment of cancer.

[0524] In one embodiment, a method is provided for the treatment of cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0525] One aspect provides a method of treating a disease or disorder by decreasing the level of the Cyclin El protein, the method comprising administering to a patient a therapeutically effective amount of a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof to decrease the Cyclin El protein level. In one embodiment, the disease or disorder is cancer.

[0526] In one embodiment, a method is provided for the treatment of a disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein: the Cyclin El protein is the amino acid sequence encoded by SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, or 9. In one embodiment, the disease or disorder is cancer. In another embodiment, the agent is a small compound having a molecular weight of 1000 or less. In a further embodiment, the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. In an additional embodiment, the agent is a proteolysis targeting chimera molecule.

[0527] In Embodiment 1, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 30%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0528] In Embodiment 2, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 40%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0529] In Embodiment 3, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 50%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0530] In Embodiment 4, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 60%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0531] In Embodiment 5, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 70%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0532] In Embodiment 6, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 80%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0533] In Embodiment 7, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 90%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0534] In Embodiment 8, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 95%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0535] In Embodiment 9, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 98%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0536] In Embodiment 10, a method is provided for the treatment of disease or disorder in a patient comprising administering to said patient a therapeutically effective amount of an agent to decrease the Cyclin El protein level, wherein the Cyclin El protein level is decreased by at least 99%. Included in this embodiment is a method where the disease or disorder is cancer. Also included in this embodiment is a method wherein the agent is the compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0537] In Embodiments 1 to 10, the decrease in the protein levels of the Cyclin El protein can be measured using the Cyclin El Cellular Degradation assay described hereinbelow.

[0538] Types of cancers that may be treated with the compound of Formula (I) include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, anal cancer, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, nasopharyngeal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, thymic carcinoma, esophagogastric cancer, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, mesothelioma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma.

[0539] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer has amplification, overexpression, or detectable expression of the CCNE1 gene.

[0540] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is melanoma.

[0541] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0542] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is mesothelioma.

[0543] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is breast cancer, including ductal carcinoma, invasive ductal carcinoma metastatic breast cancer, triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, estrogen receptor (ER)-positive breast cancer, hormone receptor-positive breast cancer, and hormone receptor-negative breast cancer.

[0544] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is prostate cancer, including adenocarcinoma of the prostate and castration-resistant prostate cancer.

[0545] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is pancreatic cancer, including pancreatic adenocarcinoma, exocrine pancreatic cancer and neuroendocrine pancreatic cancer.

[0546] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is kidney cancer, including renal cell carcinoma, clear cell renal cell carcinoma, and non-clear cell renal cell carcinomas, papillary renal cell carcinoma, Wilms tumor, and renal sarcoma.

[0547] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is gastric cancer, including gastric carcinoma.

[0548] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is kidney cancer, including renal carcinoma and kidney parenchymal carcinoma.

[0549] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is liver cancer, including hepatocellular carcinoma.

[0550] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is ovarian cancer, including ovarian carcinoma.

[0551] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is lymphoma, including Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, and diffuse large B-cell lymphoma (DLBCL).

[0552] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is leukemia, including acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, and diffuse large B- cell lymphoma (DLBCL).

[0553] In one embodiment, a method is provided for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is multiple myeloma.

[0554] The compounds for Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) are useful in treating or preventing any diseases or conditions that are associated with the activity of Cyclin El proteins. Any method of administration may be used to deliver the compound or pharmaceutical composition to the patient. In certain embodiments, the compound of Formula (I) or pharmaceutical composition comprising at least compound of Formula (I) is administered orally. In other embodiments, the Formula (I) or pharmaceutical composition comprising at least compound of Formula (I) is administered parenterally.

[0555] In one embodiment, the present invention provides a combined preparation of a compound of Formula (I), and / or a pharmaceutically acceptable salt thereof; and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and / or prophylaxis of multiple diseases or disorders associated with the activity of Cyclin El protein. The combined preparation can be used to decrease the protein level, to decrease the protein activity level, and / or to inhibit the expression level of Cyclin El proteins.

[0556] In one aspect, the compound(s) of Formula (I) are sequentially administered prior to administration of the immuno-oncology agent. In another aspect, compound(s) of Formula (I) are administered concurrently with the immuno-oncology agent. In yet another aspect, compound(s) of Formula (I) are sequentially administered after administration of the immuno-oncology agent.

[0557] In another aspect, compounds of Formula (I) may be co-formulated with an immuno-oncology agent.

[0558] Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.

[0559] In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0560] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7- 1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co- stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, ED AR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI / TL I A, TRAMP / DR3, ED AR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a / TNFp, TNFR2, TNFa, LTpR, Lymphotoxin a 1 P2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0561] In one aspect, T cell responses can be stimulated by a combination of a compound of Formula (I) and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0562] Other agents that can be combined with compounds of Formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of Formula (I) can be combined with antagonists of KIR, such as lirilumab.

[0563] Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553, WO1 1 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0564] In another aspect, compounds of Formula (I) can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and / or inflammation at tumor sites.

[0565] In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), MED 1-0680 (AMP-514; WO2012 / 145493), LIBTAYO (cemiplimab), JEMPERLI (dostarlimab), and ZYNYZ (retifanlimab) The immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP -224.

[0566] In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (W0207 / 005874), MSB0010718C (WO2013 / 79174), TECENTRIQ (atezolizumab), and BAVENCIO (avelumab).

[0567] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, relatlimab (W010 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (W008 / 132601, WO09 / 44273).

[0568] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0569] In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, W009 / 009116) and MK-4166 (WO 11 / 028683).

[0570] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (W0206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (W009 / 73620, WO09 / 1156652, WO1 1 / 56652, WO12 / 142237).

[0571] In another aspect, the immuno-oncology agent is an 0X40 agonist, such as an agonistic 0X40 antibody. Suitable 0X40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0572] In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic 0X40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879). In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0573] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0574] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO 11 / 109400).

[0575] In another aspect, the immuno-oncology agent is an anti-TIGIT agent. Suitable anti-TIGIT agents include antibodies such as an BMS-986207, tiragolumab, or MK-7684.

[0576] In another aspect, the immuno-oncology agent is a KRAS G12C inhibitor. Suitable KRAS G12C inhibitors include LUMAKRAS (sotorasib) or KRAZ ATI (adagrasib).

[0577] The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0578] One or more additional pharmaceutical agents or treatment methods such as, for example, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor vaccines, cytokine therapy (e.g., IL-2 and GM-CSF), and / or tyrosine kinase inhibitors can be optionally used in combination with the compounds of Formula (I) for treatment of Cyclin El protein associated diseases, disorders or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0579] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0580] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.

[0581] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, vinorelbine (Vavelbene®), bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-alpha), etoposide, and teniposide.

[0582] Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme inhibitor; a topoisomerase inhibitor such as irinotecan (Camptosar®, CPT-11); procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; tegafur; capecitabine; and haematopoietic growth factors.

[0583] Other anti-cancer agents include antihormonal or endocrine therapeutic agents. Suitable endocrine therapeutic agents include, but are not limited to, aromatase inhibitors such as letrozole, anastrozole, and exemestane; selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, and droloxifene; and selective estrogen receptor degraders (SERDs) such as fulvestrant.

[0584] Other anti-cancer agents include antibody therapeutics such as pertuzumab, antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL- 10 or TGF-P).

[0585] Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0586] Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.

[0587] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0588] The pharmaceutical composition of the invention may optionally include at least one signal transduction modulator (STM). A "signal transduction modulator" is an agent that selectively modulates one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to growth arrest and / or apoptosis. Suitable STMs include, but are not limited to: (i) bcr / abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone: C225 [Goldstein et al., Clin. Cancer Res., 1 : 1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors such as, for example, trastuzumab (Herceptin®) and farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al., Nat. Med., l(8):792-797 (1995)); (iv) inhibitors of Akt family kinases or the Akt pathway, such as, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (200)); (v) cell cycle kinase inhibitors such as, for example, palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio®) (see, for example, Jhaveri et al., Expert Rev. Anticancer Ther., 21(10): 1105-1124 (2021)); and (vi) phosphatidyl inositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STM and at least one compound of Formula (I) may be in separate pharmaceutical compositions. In a specific embodiment of the present invention, at least one compound of Formula (I) and at least one STM may be administered to the patient concurrently or sequentially. In other words, at least one compound of Formula (I) may be administered first, at least one STM may be administered first, or at least one compound of Formula (I) and at least one STM may be administered at the same time. Additionally, when more than one compound of Formula (I) and / or STM is used, the compounds may be administered in any order.

[0589] In a specific embodiment of the present invention, at least one compound of Formula (I) and at least one chemotherapeutic agent are administered to the patient concurrently or sequentially. In other words, at least one compound of Formula (I) may be administered first, at least one chemotherapeutic agent may be administered first, or at least one compound of Formula (I) and the at least one STM may be administered at the same time. Additionally, when more than one compound of Formula (I) and / or chemotherapeutic agent is used, the compounds may be administered in any order. Similarly, any STM may also be administered at any point in comparison to the administration of the compound of Formula (I).

[0590] The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0591] PHARMACEUTICAL COMPOSITIONS

[0592] The invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of one or more of the compounds of Formula (I), formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally, one or more additional therapeutic agents described above.

[0593] The compounds of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the compound of Formula (I) can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrastemal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0594] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.

[0595] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.

[0596] A tablet can, for example, be prepared by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. Additionally, a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period. Exemplary water soluble taste masking materials, include, but are not limited to, hydroxypropyl -methyl cellulose and hydroxypropyl- cellulose. Exemplary time delay materials, include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0597] Hard gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) and / or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0598] Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[0599] An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

[0600] Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described hereinabove, and / or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.

[0601] Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.

[0602] An emulsion of at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof can, for example, be prepared as an oil-in-water emulsion. The oily phase of the emulsions comprising compounds of Formula (I) may be constituted from known ingredients in a known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and / or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.

[0603] The compounds of Formula (I) and / or at least one pharmaceutically acceptable salt thereof can, for example, also be delivered intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer’s solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[0604] Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e., Captisol), cosolvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e., Tween 80).

[0605] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Formula (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[0606] A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1,3 -butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.

[0607] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0608] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0609] The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[0610] For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.

[0611] The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and / or compositions of this invention depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.

[0612] Pharmaceutical compositions of this invention comprise at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Alternate compositions of this invention comprise a compound of the Formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0613] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of Cyclin El protein-associated diseases or disorders, and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0614] The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.

[0615] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. Compounds of Formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0616] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.

[0617] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 200 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0618] A typical capsule for oral administration contains at least one of the compounds of Formula (I) (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0619] A typical injectable preparation is produced by aseptically placing at least one of the compounds of Formula (I) (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

[0620] The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of Formula (I), alone or in combination with a pharmaceutical carrier. Optionally, compounds of Formula (I) can be used alone, in combination with other compounds of Formula (I), or in combination with one or more other therapeutic agent(s), e.g., an anticancer agent or other pharmaceutically active material.

[0621] Regardless of the route of administration selected, the compounds of Formula (I), which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0622] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0623] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of Formula (I) employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0624] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of Formula (I) employed in the pharmaceutical composition at levels lower than that required in order to achieve the therapeutic effect and gradually increase the dosage until the effect is achieved.

[0625] In general, a suitable daily dose of a compound of Formula (I) will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of Formula (I) for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.

[0626] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.

[0627] While it is possible for a compound of Formula (I) to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0628] The above other therapeutic agents, when employed in combination with the compounds of Formula (I), may be used, for example, in those amounts indicated in the Physicians’ Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.

[0629] METHODS OF PREPARATION

[0630] The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods know in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated by reference in their entirety.

[0631] The compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Wuts, P. G.; Greene, T. W. Greene ’s Protective Groups in Organic Synthesis, 4thed.; Wiley-Interscience: Hoboken, N.J., 2007.

[0632] EXAMPLES The following examples illustrate the particular embodiments of the present invention and do not limit the scope of the present invention. Chemical abbreviations and symbols as well as scientific abbreviations and symbols have their usual and customary meanings unless otherwise specified. Additional abbreviations employed in the Examples and elsewhere in this application are defined above. Common intermediates are generally useful for the preparation of more than one Example. Compounds of the Examples are identified by the example and step in which they were prepared (e.g., “1-A” denotes the Example 1, step A), or by the example only where the compound is the title compound of the example (for example, “1” denotes the title compound of Example 1). In some instances, alternate preparations of intermediates or examples are described. Frequently chemists skilled in the art of synthesis may devise alternative preparations which may be desirable based on one or more considerations such as shorter reaction time, less expensive starting materials, ease of operation or isolation, improved yield, amenable to catalysis, avoidance of toxic reagents, accessibility of specialized instrumentation, and decreased number of linear steps, etc. The intent of describing alternative preparations is to further enable the preparation of the examples of this invention. In some instances, some functional groups in the outlined examples and claims may be replaced by well-known bioisosteric replacements known in the art, for example, replacement of a carboxylic acid group with a tetrazole or a phosphate moiety.

[0633] ABBREVIATIONS

[0634] ACN acetonitrile

[0635] AIBN azobisiosbutyronitrile

[0636] Boc tert-butoxycarbonyl

[0637] CO2 carbon dioxide

[0638] CS2CO3 cesium carbonate

[0639] DAST diethylaminosulfur trifluoride

[0640] DBU l,8-diazabicyclo[5.4.0]undec-7-ene

[0641] DCE 1,2-di chloroethane

[0642] DCM dichloromethane

[0643] DIEA N,N-diisopropylethylamine

[0644] DMAc N,N-dimethylacetamide DMF N,N-dimethylformamide

[0645] DMSO dimethyl sulfoxide ee enantiomeric excess

[0646] EtOAc ethyl acetate

[0647] GCMS gas chromatography mass spectrometry h hour(s)

[0648] H2O water

[0649] HATU hexafluorophosphate azabenzotriazole tetramethyl uronium

[0650] Hex hexanes

[0651] HC1 hydrochloric acid

[0652] HPLC high performance liquid chromatography

[0653] IPA isopropyl alcohol

[0654] K2CO3 potassium carbonate

[0655] K2HPO4 potassium phosphate dibasic

[0656] K3PO4 potassium phosphate tribasic

[0657] LCMS liquid chromatography mass spectrometry

[0658] LiCl lithium chloride

[0659] MeOH methanol

[0660] MgSO4magnesium sulfate min minute(s) mL milliliter(s)

[0661] Na2SO4sodium sulfate

[0662] NBS N-bromosuccinimide

[0663] NCS N-chlorosuccinimide

[0664] PDA photodiode array

[0665] Pd-PEPPSI-IHept-Cl dichlorofl, 3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II)

[0666] Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)

[0667] PyBOP b enzotri azol e- 1 -y 1 -oxy -tri s-py rroli dino-phosphonium hexafluorophosphate

[0668] RuPhos 2-dicy clohexylphosphino-2 6 '- di i sopropoxybiphenyl

[0669] RuPhos Pd G2 second generation RuPhos palladacycle RuPhos Pd G3 third generation RuPhos palladacycle

[0670] SFC supercritical fluid chromatography

[0671] SiO2silica gel

[0672] TBS tert-butyldimethylsilyl

[0673] TEA triethylamine

[0674] TFA trifluoroacetic acid

[0675] Trixie Phos rac-2-(di-tert-butylphosphino)- 1 , 1 '-binaphthyl

[0676] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0677] XPhos 2-dicy clohexylphosphino-2 ',4 ', 6 ' -tri i sopropylbiphenyl

[0678] XPhos Pd G2 second generation XPhos palladacycle

[0679] XPhos Pd G3 third generation XPhos palladacycle

[0680] ANALYTICAL HPLC CONDITIONS

[0681] Method A: Column: Acquity UPLC BEH Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: acetonitrile / water (5:95) with 0.05% TFA; Mobile Phase B: acetonitrile / water (95:5) with 0.05% TFA; Temperature: 50 °C; Gradient: 0-100%B (0.0- 1.0 min), 100%B (1.0-1.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm and 254 nm) and MS (DUIS-ESI+APCI).

[0682] Method B: Column: Kinetex XB-C18, 3 mm x 75 mm, 2.6 pm particles; Mobile Phase A: acetonitrile / water (2:98) with 5 mM ammonium formate pH 3.3; Mobile Phase B: acetonitrile / water (98:2) with 5 mM ammonium formate pH 3.3; Gradient: 20-100%B (0.0-4.0 min), 100%B (4.0-4.6 min); Flow: 1.0 mL / min; Detection: UV (254 nm) and MS (DUIS-ESI+APCI).

[0683] Method C: Column: Kinetex XB-C18, 3 mm x 75 mm, 2.6 pm particles; Mobile Phase A: water with 0.1% TFA; Mobile Phase B: acetonitrile with 0.1% TFA; Temperature: 25 °C; Gradient: 5-95%B (0.0-2.5 min), 95%B (2.5-4.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (DUIS-ESI+APCI).

[0684] Method D: Column: Kinetex XB-C18, 3 mm x 75 mm, 2.6 pm particles; Mobile Phase A: acetonitrile / water (2:98) with 5 mM ammonium formate pH 3.3; Mobile Phase B: acetonitrile / water (98:2) with 5 mM ammonium formate pH 3.3; Temperature: 25 °C; Gradient: 20-100%B (0.0-4.0 min), 100%B (4.0-4.6 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (DUIS-ESI+APCI). Method E: Column: XB ridge Cl 8, 2.1 mm x 50 mm, 1.7 gm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -).

[0685] Method F: Column: XB ridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate; Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -).

[0686] Method G: Column: Acquity UPLC BEH Cl 8, 3.0 mm x 50 mm, 1.7 pm particles; Mobile Phase A: acetonitrile / water (2:98) with 5 mM ammonium formate (pH 3.3); Mobile Phase: B: acetonitrile / water (98:2) with 5 mM ammonium formate (pH 3.3); Temperature: 25 °C; Gradient: 20-98%B (0.0-1.5 min), 98%B (1.5-2.0 min); Flow: 0.7 mL / min; Detection: UV (220 nm) and MS (DUIS-ESI+APCI).

[0687] Method H: Column: Kinetex XB-C18, 3 mm x 75 mm, 2.6 pm particles; Mobile Phase A: water with 0.1% TFA; Mobile Phase B: acetonitrile with 0.1% TFA; Temperature: 25 °C; Gradient: 5-95%B (0.0-2.5 min), 95%B (2.5-4.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (DUIS-ESI+APCI).

[0688] Method I: Column: Acquity UPLC BEH Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: acetonitrile / water (5:95) with 10 mM ammonium acetate; Mobile Phase B: acetonitrile / water (95:5) with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100%B (0.0-1.0 min), 100%B (1.0-1.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm and 254 nm) and MS (DUIS-ESI+APCI).

[0689] Method J: Column: Kinetex XB-C18, 3 mm x 75 mm, 2.6 pm particles; Mobile Phase A: acetonitrile / water (2:98) with 5 mM ammonium formate pH 3.3; Mobile Phase B: acetonitrile / water (98:2) with 5 mM ammonium formate pH 3.3; Gradient: 40-100%B (0.0-3.5 min), 100%B (3.5-4.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (DUIS-ESI+APCI).

[0690] Method K: Column: Acquity UPLC BEH Cl 8, 3.0 mm x 50 mm, 1.7 pm particles; Mobile Phase A: acetonitrile / water (2:98) with 5 mM ammonium formate (pH 3.3); Mobile Phase: B: acetonitrile / water (98:2) with 5 mM ammonium formate (pH 3.3); Temperature: 25 °C; Gradient: 5-98%B (0.0-1.5 min), 98%B (1.5-2.0 min); Flow: 0.7 mL / min; Detection: UV (220 nm) and MS (DUIS-ESI+APCI). INTERMEDIATE 1-1

[0691] 1 -(4-(3 , 5 -difluorophenoxy )phenyl)piperazin-2-one

[0692] Intermediate I-1A: l-(4-bromophenoxy)-3,5-difluorobenzene

[0693] To a solution of 3, 5 -difluorophenol (20 g, 154 mmol) in DCM under oxygen atmosphere was added (4-bromophenyl)boronic acid (40.1 g, 200 mmol), copper (II) acetate (22.3 g, 123 mmol), 4A molecular sieves (30 g), and TEA (64 mL, 461 mmol). Two duplicate reactions were performed that were combined for workup and purification. The reaction mixtures were stirred at room temperature for 15 h. The mixtures were then filtered through a pad of Celite, which was rinsed with DCM, and the filtrate was concentrated under reduced pressure. The crude material was purified by reversed phase chromatography (0-65% acetonitrile / water with 0.1% ammonium formate) to afford l-(4- bromophenoxy)-3,5-difluorobenzene (30 g, 94 mmol, 31% yield) as a colorless liquid. GCMS (Column: HP-5MS 30 m x 0.25 mm, ID: 0.25 pm; Split Ratio: 1:20; Carrier Gas: Helium; Injection Volume: 1 mL; Oven Program: 120 °C (0.0-3.0 min), 120-300 °C (3.0- 7.5 min), 300 °C (7.5-15.0 min); Flow: 2 mL / min): retention time: 11.78 min, [M]+284.0, 286.0; 'HNMR (400 MHz, DMSO-d6) 8 = 7.61 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 7.03 (tt, J = 2.3, 9.4 Hz, 1H), 6.78 (dd, J = 2.3, 8.6 Hz, 2H).

[0694] Intermediate I-1B: tert-butyl 4-(4-(3, 5 -difluorophenoxy)phenyl)-3 -oxopiperazine- 1- carb oxy late

[0695] To a solution of l-(4-bromophenoxy)-3,5-difluorobenzene (940 mg, 3.30 mmol) and tert-butyl 3 -oxopiperazine- 1 -carboxylate (600 mg, 3.00 mmol) in 1,4-dioxane (10 mL) was added copper (I) iodide (57.1 mg, 0.300 mmol), (lA,2A)-N,N'-dimethyl-l,2- cyclohexanediamine (129 mg, 0.599 mmol), and potassium carbonate (828 mg, 5.99 mmol). The resulting mixture was stirred at 115 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined and concentrated. The crude material was purified by flash chromatography (SiCh, 24 g column, 0-50% EtOAc / hexanes) to afford tert-butyl 4-(4-(3,5-difluorophenoxy)phenyl)-3- oxopiperazine-1 -carboxylate (1.1 g, 2.72 mmol, 91% yield). LCMS (Method A): retention time 1.05 min, [M+H]+405.0; ' H NMR (500 MHz, METHANOL-d4) 8 7.43- 7.36 (m, 2H), 7.18-7.12 (m, 2H), 6.68 (tt, J = 9.1, 2.3 Hz, 1H), 6.64-6.56 (m, 2H), 4.21 (s, 2H), 3.88-3.73 (m, 4H), 1.51 (s, 9H).

[0696] Intermediate 1-1 :

[0697] To a solution of tert-butyl 4-(4-(3, 5 -difluorophenoxy )phenyl)-3 -oxopiperazine- 1- carboxylate (1.1 g, 2.72 mmol) in DCM (6 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature for 1 h. Volatiles were removed by rotary evaporation. The residue was dissolved in EtOAc, washed with water and 1 N NaOH. The organic layer was dried (Na2SO4), filtered, and concentrated to afford l-(4-(3,5- difluorophenoxy) phenyl)piperazin-2-one (710 mg, 2.33 mmol, 86% yield), which was used in the next step without further purification. LCMS (Method A): retention time 0.85 min, [M+H]+305.0;XHNMR (500 MHz, METHANOL-d4) 6 7.41-7.34 (m, 2H), 7.18- 7.12 (m, 2H), 6.68 (tt, J = 9.2, 2.3 Hz, 1H), 6.64-6.57 (m, 2H), 3.72 (t, J = 5.5 Hz, 2H), 3.57 (s, 2H), 3.19 (t, J = 5.5 Hz, 2H).

[0698] INTERMEDIATE 1-2

[0699] 1 -(4-(3 , 5 -difluorophenoxy)-2-fluorophenyl)piperazin-2-one

[0700] Intermediate I-2A: l-bromo-4-(3,5-difluorophenoxy)-2-fluorobenzene A mixture of 3, 5 -difluorophenol (10.0 g, 77.0 mmol) and copper (II) acetate (11.2 g, 61.5 mmol) in DCM (150 mL) was bubbled with oxygen for 2 minutes, then TEA (32.1 mL, 231 mmol), 4 A molecular sieves (5 g), and (4-bromo-3-fluorophenyl)boronic acid (20.2 g, 92.0 mmol) were added. The reaction mixture was stirred under oxygen atmosphere at room temperature for 16 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (SiCh, 40 g column, 0-2% EtOAc / petroleum ether) to afford l-bromo-4-(3,5-difluorophenoxy)-2-fluorobenzene (7.0 g, 21.9 mmol, 28% yield). GCMS (Column: HP-5MS 30 m x 0.25 mm, ID: 0.25 pm; Carrier Gas: Helium; Injection Volume: 1 mL; Oven Program: 70 °C (0.0-2.0 min), 70-300 °C (2.0-7.7 min), 300 °C (7.7-17.7 min); Flow: 2 mL / min): retention time 6.24 min, [M]+301.9, 303.9; 'HNMR (400 MHz, DMSO-d6): 8 7.78-7.72 (m, 1H), 7.28 (dd, J = 2.8, 9.9 Hz, 1H), 7.08 (tt, J = 2.3, 9.4 Hz, 1H), 6.95 (ddd, J = 1.1, 2.8, 8.9 Hz, 1H), 6.91-6.87 (m, 2H).

[0701] Intermediate I-2B: tert-butyl 4-(4-(3,5-difluorophenoxy)-2-fluorophenyl)-3- oxopiperazine-1 -carboxylate

[0702] To a solution of l-bromo-4-(3,5-difluorophenoxy)-2-fluorobenzene (10.0 g, 33.0 mmol) and tert-butyl 3 -oxopiperazine- 1 -carboxylate (9.91 g, 49.5 mmol) in 1,4-dioxane (100 mL) was added copper(I) iodide (3.14 g, 16.5 mmol), tripotassium phosphate (17.5 g, 82.0 mmol), and N,N'-dimethylethylenediamine (1.45 g, 16.5 mmol). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (TSfeSCh), filtered, and concentrated. The crude material was purified by flash chromatography (SiCh, 40-55% EtOAc / petroleum ether) to afford tert-butyl 4-(4-(3,5- difluorophenoxy)-2-fluorophenyl)-3 -oxopiperazine- 1 -carboxylate (6.5 g, 14.2 mmol, 43% yield) as an off-white solid. LCMS (Method B): retention time 3.35 min, [M-tBu-H]' 364.0.

[0703] Intermediate 1-2: To a cooled (0 °C) solution of tert-butyl 4-(4-(3,5-dmuorophenoxy)-2- fluorophenyl)-3 -oxopiperazine- 1 -carboxylate (6.5 g, 15.4 mmol) in 1,4-dioxane (50 mL) was added HC1 solution (4 N in 1,4-dioxane, 38.5 mL, 154 mmol). The resulting mixture was stirred at 0 °C for 16 h. The reaction mixture was diluted with diethyl ether and stirred for 10 min, resulting in the formation of a white solid. The mixture was filtered, and the solid was rinsed with diethyl ether. The solid was then dried under vacuum to afford l-(4-(3,5-difluorophenoxy)-2-fluorophenyl)piperazin-2-one HC1 salt (4.55 g, 11.4 mmol, 74% yield) as an off-white solid. LCMS (Method C): retention time 2.04 min; [M+H]+323.1; 'HNMR (400 MHz, DMSO-d6) 8 9.97 (br s, 2H), 7.46 (t, J = 8.7 Hz, 1H), 7.20 (dd, J = 11.1, 2.6 Hz, 1H), 7.10 (tt, J = 9.4, 2.3 Hz, 1H), 7.03 (ddd, J = 8.8, 2.6, 1.0 Hz, 1H), 6.93-6.84 (m, 2H), 3.92 (s, 2H), 3.88-3.80 (m, 2H), 3.60-3.49 (m, 2H).

[0704] INTERMEDIATE 1-3 tert-butyl (S)-5-amino-4-(6-bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate

[0705] Intermediate 1-3 A: methyl 5-bromo-2-(bromomethyl)benzoate

[0706] To a solution of methyl 5-bromo-2-methylbenzoate (50 g, 218 mmol) in 1,2- di chloroethane (500 mL) was added NBS (42.7 g, 240 mmol) and AIBN (10.75 g, 65.5 mmol). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and filtered through a Buchner funnel, which was rinsed with excess 5% EtOAc / petroleum ether (400 mL). The filtrate was concentrated under reduced pressure to afford crude methyl 5-bromo-2- (bromomethyl)benzoate (72 g, 194 mmol, 89 % yield) as a brown liquid. This material was used in the next step without further purification.1H NMR (400 MHz, DMSO-de) 6 7.99 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.3, 2.2 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 4.98 (s, 2H), 3.88 (s, 3H). Intermediate 1-3 :

[0707] A mixture of methyl 5-bromo-2-(bromomethyl)benzoate (154 g, 382 mmol), tertbutyl (S)-4,5-diamino-5-oxopentanoate (100 g, 497 mmol), and DIEA (267 mL, 1529 mmol) in DMF (300 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated by rotary evaporation, resulting in a thick, dark brown paste. The residue was shaken with ice cold water (300 mL), then DCM was added (500 mL), and the layers were separated. The organic phase was dried (ISfeSCh), filtered, and concentrated to give a thick, pale yellow paste. Cold petroleum ether (1000 mL) was added, and the mixture was allowed to stand for 1 h at 0 °C. The resulting fluffy solid was filtered through a Buchner funnel, washed with cold petroleum ether, and dried under vacuum to afford tertbutyl (S)-5-amino-4-(6-bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate (139 g, 302 mmol, 79% yield) as a pale yellow solid. The enantiomeric excess of this material was not determined. LCMS (Method D): retention time 2.25 min, [M+H]+397.0, 399.0; 'H NMR. (400 MHz, DMSO-d6) 8 7.86-7.76 (m, 2H), 7.64-7.53 (m, 2H), 7.20 (s, 1H), 4.77-4.68 (m, 1H), 4.63-4.53 (m, 1H), 4.50-4.40 (m, 1H), 2.22-2.09 (m, 3H), 2.05-1.92 (m, 1H), 1.33 (s, 9H).

[0708] EXAMPLE 1

[0709] (3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione

[0710] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-l-oxoisoindolin-2-yl)-5- oxopentanoate (350 mg, 0.881 mmol), l-(4-(3,5-difhiorophenoxy)phenyl)piperazin-2-one

[0711] (295 mg, 0.969 mmol), cesium carbonate (574 mg, 1.76 mmol), and Pd-PEPPSI-IHept-Cl (42.9 mg, 0.044 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude material was purified by flash chromatography (SiCh).

[0712] The resulting product was dissolved in acetonitrile (10 mL). Methanesulfonic acid (286 pL, 4.41 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SC>4), filtered, and concentrated by rotary evaporation. The crude material was purified via preparative SFC chromatography (Column: Chiralpak IB, 30 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Isocratic elution at 45%B over 40.0 min; Flow Rate: 90.5 mL / min; Column Temperature: 35 °C). The partially purified material was purified again via preparative SFC chromatography (Column: Whelk-Ol (R,R), 30 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Isocratic elution at 55%B over 15.0 min; Flow Rate: 89.5 mL / min; Column Temperature: 35 °C) to afford (3S)-3-(6-{4- [4-(3 , 5 -difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H-i soindol-2- yl)piperidine-2, 6-dione (56.9 mg, 0.103 mmol, 12% yield over two steps). SFC (Column: Whelk-Ol (R,R), 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN; Temperature: 25 °C; Isocratic elution at 55%B over 10.0 min; Flow: 2.0 mL / min; Detection: UV (220 nm)): retention time 5.70 min (99% ee); LCMS (Method E) retention time 1.77 min, [M+H]+547.2; 'HNMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 7.53-7.42 (m, 3H), 7.31 (dd, J = 8.5, 2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.20-7.14 (m, 2H), 7.02 (tt, J = 9.4, 2.3 Hz, 1H), 6.81-6.72 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.41-4.33 (m, 1H), 4.28-4.20 (m, 1H), 4.06 (s, 2H), 3.91-3.83 (m, 2H), 3.76-3.68 (m, 2H), 2.91 (ddd, J = 17.4, 13.6, 5.5 Hz, 1H), 2.66-2.56 (m, 1H), 2.45-2.33 (m, 1H), 2.05-1.96 (m, 1H).

[0713] EXAMPLE 2

[0714] 3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione

[0715] Intermediate 2 A: 3 -(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0716] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-l-oxoisoindolin-2-yl)-5- oxopentanoate (15 g, 37.8 mmol) and methanesulfonic acid (24.5 mL, 378 mmol) in acetonitrile (200 mL) was stirred at 80 °C for 2 h. Volatiles were removed, and the crude material was purified by flash chromatography (SiC>2, 50% EtOAc / petroleum ether) to afford 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (12 g, 36.3 mmol, 96% yield) as an off-white solid. The enantiomeric excess of this material and subsequent intermediates was not determined. LCMS (Method D): retention time = 1.32 min, [M+H]+323.0, 325.0; 'HNMR (400 MHz, DMSO-d6) 6 = 10.99 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 1.9, 8.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.48-4.27 (m, 2H), 2.91 (ddd, J = 5.4, 13.6, 17.5 Hz, 1H), 2.65-2.55 (m, 1H), 2.42-2.33 (m, 1H), 2.04-2.01 (m, 1H).

[0717] Example 2:

[0718] A mixture of 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (90 mg, 0.279 mmol), l-(4-(3,5-difluorophenoxy)-2-fluorophenyl)piperazin-2-one (146 mg, 0.334 mmol), cesium carbonate (272 mg, 0.836 mmol), and Pd-PEPPSI-IHept-Cl (27.1 mg, 0.028 mmol) in 1,4-dioxane (3 mL) was degassed and stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under a stream of nitrogen. The crude material was purified via reversed phase preparative HPLC (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 33-53%B (0.0- 30.0 min); Flow: 20 mL / min) to afford 3-(6-{4-[4-(3,5-difhiorophenoxy)-2- fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihydro- lH-isoindol-2-yl)piperidine-2,6- dione (27.1 mg, 0.048 mmol, 17%). LCMS (Method F): retention time 1.85 min, [M+H]+565.1; 'HNMR (600 MHz, DMSO-d6) 8 10.97 (s, 1H), 7.54-7.47 (m, 2H), 7.33 (dd, J = 2.3, 8.4 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.19 (dd, J = 2.6, 11.0 Hz, 1H), 7.08 (tt, J = 2.2, 9.4 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.94-6.77 (m, 2H), 5.11 (dd, J = 5.2, 13.4 Hz, 1H), 4.37 (d, J = 16.7 Hz, 1H), 4.27-4.22 (m, 1H), 4.07 (s, 2H), 3.77 (br d, J = 5.3 Hz, 2H), 3.74 (br d, J = 5.4 Hz, 2H), 2.91 (ddd, J = 5.4, 13.6, 17.5 Hz, 1H), 2.63-2.57 (m, 1H), 2.43-2.36 (m, 1H), 2.07-1.94 (m, 1H).

[0719] INTERMEDIATE 1-4 tert-butyl (S)-5-amino-4-(6-bromo-4-methoxy-l-oxoisoindolin-2-yl)-5-oxopentanoate

[0720] Intermediate I-4A: methyl 5-bromo-3-methoxy-2-methylbenzoate

[0721] To a cooled (0 °C) solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (19 g, 78 mmol) in acetone (200 mL) was added potassium carbonate (32.1 g, 233 mmol). The resulting mixture was stirred for 1 h at 0 °C, then iodomethane (12.1 mL, 194 mmol) was added. The reaction was stirred for 16 h, then the mixture was filtered through a bed of Celite, which was rinsed with DCM (200 mL). The filtrate was concentrated, and the resulting residue was purified by flash chromatography (SiC>2, 10-30% EtOAc / petroleum ether) to afford methyl 5-bromo-3-methoxy-2-methylbenzoate (19 g, 60.9 mmol, 79% yield. 'H NMR (400 MHz, DMSO-d6) 8 7.44 (d, J = 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 2.25 (s, 3H).

[0722] Intermediate I-4B: methyl 5-bromo-2-(bromomethyl)-3-methoxybenzoate

[0723] A mixture of methyl 5-bromo-3-methoxy-2-methylbenzoate (12 g, 46.3 mmol), NBS (12.36 g, 69.55 mmol), and AIBN (1.14 g, 6.95 mmol) in 1,2-di chloroethane (120 mL) was stirred at 85 °C for 1.5 h. The reaction mixture was then cooled to room temperature and concentrated. The residue was diluted with 50% ethyl acetate in petroleum ether and filtered to remove the solids. The filtrate was concentrated under reduced pressure to afford crude methyl 3-bromo-6-(bromomethyl)-2-ethoxybenzoate (18 g, 30.1 mmol, 65% yield). 'HNMR (400 MHz, DMSO-d6) 8 7.56 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 4.89 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H).

[0724] Intermediate 1-4:

[0725] A mixture of methyl 5-bromo-2-(bromomethyl)-3-methoxybenzoate (18 g, 53.3 mmol), tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (25.4 g, 107 mmol), and DIEA (27.9 mL, 160 mmol) in DMF (180 mL) was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and then concentrated to remove solvent. The crude residue was purified by flash chromatography (SiCh, 0-80% ethyl acetate / petroleum ether) to afford tert-butyl (S)-5-amino-4-(6-bromo-4-methoxy-l- oxoisoindolin-2-yl)-5-oxopentanoate (23 g, 49.5 mmol, 93% yield) as an off-white solid. The enantiomeric excess of this material was not determined. LCMS (Method D): retention time 2.40 min, [M+H]+427.0, 429.0;1H NMR (400 MHz, DMSO-d6) 6 7.56 (br s, 1H), 7.41-7.40 (m, 2H), 7.18 (br s, 1H), 4.70-4.67 (m, 1H), 4.52-4.29 (m, 2H), 3.92 (s, 3H), 2.19-2.10 (m, 3H), 2.04-1.97 (m, 1H), 1.33 (s, 9H).

[0726] EXAMPLE 3 (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l-oxo-

[0727] 2,3 -dihydro- 1 H-i soindol-2-yl)piperidine-2, 6-dione

[0728] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-l-oxoisoindolin-2-yl)-5- oxopentanoate (450 mg, 1.05 mmol), l-(4-(3,5-difluorophenoxy)phenyl)piperazin-2-one (353 mg, 1.16 mmol), cesium carbonate (686 mg, 2.11 mmol), and Pd-PEPPSI-IHept-Cl (51.2 mg, 0.053 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SC>4), filtered, and concentrated by rotary evaporation. The crude material was purified by flash chromatography (SiCh) to afford tert-butyl (S)-5-amino-4-(6-(4-(4-(3, 5 -difluorophenoxy) phenyl)-3 -oxopiperazin- l-yl)-4-m ethoxy- l-oxoisoindolin-2-yl)-5-oxopentanoate (360 mg).

[0729] Methanesulfonic acid (342 pL, 5.27 mmol) was added to tert-butyl (S)-5-amino-4- (6-(4-(4-(3, 5 -difluorophenoxy )phenyl)-3 -oxopiperazin- l-yl)-4-m ethoxy- 1-oxoisoindolin- 2-yl)-5-oxopentanoate (360 mg) in acetonitrile (6 mL). The resulting mixture was stirred at 55 °C for 3 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude material was purified via preparative SFC chromatography (Column: Greensep Pyridyl Amide, 30 mm x 150 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Isocratic elution at 25%B over 12.0 min; Flow Rate: 95.0 mL / min; Column Temperature: 35 °C) to afford (3S)-3-(6-{4-[4-(3,5- difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2, 3 -dihydro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (172 mg, 0.297 mmol, 28% yield over two steps). SFC (Column: Chiralpak IH, 4.6 mm x 150 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN; Temperature: 45 °C; Isocratic elution at 40%B over 20 min; Flow: 2.0 mL / min; Detection: UV (220 nm)): retention time 6.34 min (84% ee); LCMS (Method F) retention time 1.81 min, [M+H]+577.4; 'H NMR (400 MHz, DMSO-d6) 8 10.95 (s, IH), 7.51-7.43 (m, 2H), 7.22-7.13 (m, 2H), 7.02 (tt, J = 9.4, 2.3 Hz, IH), 6.83 (dd, J = 16.4, 1.8 Hz, 2H), 6.80-6.72 (m, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, IH), 4.34-4.23 (m, IH), 4.14 (d, J = 16.9 Hz, IH), 4.10 (s, 2H), 3.91 (s, 3H), 3.90-3.82 (m, 2H), 3.78- 3.69 (m, 2H), 2.98-2.83 (m, IH), 2.63-2.55 (m, IH), 2.42 (br dd, J = 13.6, 4.5 Hz, IH), 2.04-1.93 (m, IH).

[0730] EXAMPLE 4

[0731] (3 S)-3 -(6- { 4 - [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -y 1 } -4-methoxy- l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione

[0732] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-4-methoxy-l-oxoisoindolin-2- yl)-5-oxopentanoate (500 mg, 1.17 mmol), l-(4-(3,5-difluorophenoxy)-2-fluorophenyl) piperazin-2-one HC1 salt (462 mg, 1.29 mmol), cesium carbonate (1.14 g, 3.51 mmol), and Pd-PEPPSI-IHept-Cl (114 mg, 0.117 mmol) in 1,4-dioxane (10 mL) was degassed by sparging with nitrogen and stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through a Celite pad. The Celite was further rinsed with EtOAc, and the filtrate was concentrated by rotary evaporation. The residue was purified via flash chromatography (SiO2, 40 g column, 0-100% EtOAc / DCM) to afford tert-butyl (S)-5-amino-4-(6-(4-(4- (3 , 5 -difluorophenoxy )-2-fluorophenyl)-3 -oxopiperazin- 1 -yl)-4-methoxy- 1 -oxoi soindolin- 2-yl)-5-oxopentanoate (362 mg).

[0733] Methanesulfonic acid (228 pL, 3.51 mmol) was added to tert-butyl (S)-5-amino-4- (6-(4-(4-(3,5-difluorophenoxy)-2-fluorophenyl)-3-oxopiperazin-l-yl)-4-methoxy-l- oxoisoindolin-2-yl)-5-oxopentanoate (362 mg) in acetonitrile (6 mL). The resulting mixture was stirred at 60 °C overnight. Volatiles were removed under a stream of air, leaving behind a gummy solid, which was dissolved in EtOAc and washed carefully with water. The organic phase was then washed with brine, dried (Na2SO4), filtered, and concentrated by rotary evaporation with the bath temperature at 25 °C. The crude material was purified via preparative SFC chromatography (Column: Chiralpak H4, 30 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Isocratic elution at 40%B over 14.0 min; Flow Rate: 90 mL / min; Column Temperature: 35 °C) to afford (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (154.3 mg, 0.255 mmol, 22% yield over two steps). SFC (Column: Chiralpak AS-H, 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA with 0.1% diethylamine; Temperature: 25 °C; Isocratic elution at 30%B over 10.0 min; Flow: 2.0 mL / min; Detection: UV (220 nm)): retention time 6.22 mm (>99% ee); LCMS (Method F) retention time 1.91 min, [M+H]+595.0;XHNMR (400 MHz, DMSO-d6) 6 10.95 (s, 1H), 7.52 (t, J = 8.7 Hz, 1H), 7.20 (dd, J = 11.0, 2.6 Hz, 1H), 7.09 (tt, J = 9.4, 2.3 Hz, 1H), 7.02 (ddd, J = 8.7, 2.6, 1.0 Hz, 1H), 6.93-6.79 (m, 4H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.29 (d, J = 16.9 Hz, 1H), 4.20-4.06 (m, 3H), 3.91 (s, 3H), 3.84-3.70 (m, 4H), 2.98- 2.83 (m, 1H), 2.65-2.53 (m, 1H), 2.42 (qd, J = 13.2, 4.6 Hz, 1H), 2.04-1.93 (m, 1H).

[0734] INTERMEDIATE 1-5 tert-butyl (S)-5-amino-4-(6-chloro-l-oxo-l,3-dihydro-2H-pyrrolo[3,4-c] pyridin-2-yl)-5- oxopentanoate

[0735] Intermediate I-5A: methyl 2-chloro-5-methylisonicotinate

[0736] O

[0737] CL JL CH,

[0738] XA

[0739] CH3(I-5A)

[0740] Thionyl chloride (10.6 mL, 146 mmol) was added dropwise to a solution of 2- chloro-5-methylisonicotinic acid (10 g, 58.3 mmol) in methanol (150 mL). The resulting mixture was stirred at 75 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by flash chromatography (SiCh, 0- 20% ethyl acetate / petroleum ether) to afford methyl 2-chloro-5-methylisonicotinate (7.5 g, 40.4 mmol, 69% yield). LCMS (Method D): retention time 2.21 min, [M+H]+186.0; 'H NMR (400 MHz, CHLOROFORM-d) 8 8.36 (s, 1H), 7.76 (s, 1H), 3.96 (s, 3H), 2.55 (s, 3H).

[0741] Intermediate I-5B: methyl 5-(bromomethyl)-2-chloroisonicotinate

[0742] O clYyMH3

[0743] (I-5B)

[0744] A mixture of methyl 2-chloro-5-methylisonicotinate (7.0 g, 37.7 mmol), NBS (6.71 g, 37.7 mmol), and AIBN (1.239 g, 7.54 mmol) in 1,2-di chloroethane (70 mL) was stirred at 80 °C for 2 h. The reaction mixture was then concentrated under reduced pressure, diluted with ice cold water (250 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (150 mL), dried QSfeSCh), filtered, and concentrated under reduced pressure to afford methyl 5-(bromomethyl)-2- chloroisonicotinate (8.1 g, 20.8 mmol, 55% yield) as a pale brown liquid. LCMS (Method G): retention time 1.35 min, [M+H]+264.0, 266.0; 'H NMR (400 MHz, CHLOROFORM-d) 8 8.54 (s, 1H), 7.83 (s, 1H), 4.88 (s, 2H), 4.02 (s, 3H).

[0745] Intermediate 1-5:

[0746] A mixture of methyl 5-(bromomethyl)-2-chloroisonicotinate (8.0 g, 30.2 mmol), tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (10.8 g, 45.4 mmol), and DIEA (15.9 mL, 91 mmol) in DMF (30 mL) was stirred at 80 °C for 2 h. The reaction mixture was then diluted with ice cold water (500 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried QSfeSCh), and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiCh, 0-100% ethyl acetate / petroleum ether) to afford tert-butyl (S)-5- amino-4-(6-chloro-l-oxo-l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-5-oxopentanoate (7.05 g, 19.7 mmol, 65% yield) as an off-white solid. The enantiomeric excess of this material was not determined. LCMS (Method H): retention time 2.15 min, [M+H]+354.0; 'HNMR (400 MHz, DMSO-d6) 6 8.74 (d, J = 0.8 Hz, 1H), 7.79 (d, J = 1.0 Hz, 1H), 7.61 (br s, 1H), 7.25 (br s, 1H), 4.78-4.73 (m, 1H), 4.72-4.55 (m, 2H), 2.24-2.14 (m, 3H), 2.04-1.94 (m, 1H), 1.33 (s, 9H).

[0747] EXAMPLE 5

[0748] (3 S)-3 -(6- { 4 - [4 - (3 , 5 -difluorophenoxy)phenyl ]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 1 H,2H, 3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione A mixture of tert-butyl (S)-5-amino-4-(6-chloro-l-oxo-l,3-dihydro-2H- pyrrolo[3,4-c]pyridin-2-yl)-5-oxopentanoate (45 mg, 0.127 mmol), l-(4-(3,5- difluorophenoxy)phenyl)piperazin-2-one (42.6 mg, 0.140 mmol), cesium carbonate (83 mg, 0.254 mmol), and Pd-PEPPSI-IHept-Cl (6.19 mg, 6.36 pmol) in 1,4-dioxane (2.0 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was then filtered, followed by addition of methanesulfonic acid (83 pL, 1.27 mmol). The resulting mixture was stirred at 55 °C for 3 h. A few drops of water were added, then the crude reaction mixture was purified via preparative reversed phase chromatography (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA, Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 25 °C; Gradient: 30-60%B (0.0-20.0 min), 60-100%B (20.0-20.1 min), 100%B (20.1-24.0 min); Flow: 20 mL / min) to afford (3S)-3-(6-{4-[4-(3,5- difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3 ,4-c]pyri din-2 - yl)piperidine-2, 6-dione (24.6 mg, 42.9 pmol, 34% yield over two steps). SFC (Column: Chiralpak H4, 4.6 mm x 150 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN; Temperature: 45 °C; Isocratic elution at 40%B over 20 min; Flow: 2.0 mL / min; Detection: UV (220 nm)): retention time 18.33 min (38% ee); LCMS (Method F) retention time 1.76 min, [M+H]+547.9; 'H NMR (500 MHz, DMSO-d6) 8 8.47 (s, 1H), 7.45 (br d, J = 8.9 Hz, 2H), 7.16 (br d, J = 8.8 Hz, 2H), 7.12 (s, 1H), 7.00 (ddd, J = 9.3, 7.2, 2.1 Hz, 1H), 6.74 (dd, J = 8.5, 2.1 Hz, 2H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.49- 4.40 (m, 1H), 4.38-4.27 (m, 3H), 4.03-3.95 (m, 2H), 3.87 (br t, J = 5.0 Hz, 2H), 2.97-2.83 (m, 1H), 2.66-2.56 (m, 1H), 2.46-2.32 (m, 1H), 2.09-1.96 (m, 1H).

[0749] EXAMPLE 6

[0750] (3 S)-3 -(6- { 4 - [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -y 1 } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione

[0751] A mixture of tert-butyl (S)-5-amino-4-(6-chloro-l-oxo-l,3-dihydro-2H- pyrrolo[3,4-c]pyridin-2-yl)-5-oxopentanoate (375 mg, 1.06 mmol), l-(4-(3,5- difluorophenoxy)-2-fluorophenyl)piperazin-2-one HC1 salt (419 mg, 1.17 mmol), cesium carbonate (1.04 g, 3.18 mmol), and Pd-PEPPSI-IHept-Cl (61.9 mg, 0.064 mmol) in 1,4- di oxane (5.0 mL) was degassed by sparging with nitrogen and stirred at 100 °C for 5 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and eluted with EtOAc. The filtrate was concentrated to afford an oil, which was purified via flash chromatography (SiCh, 40 g column, 20-100% EtOAc / DCM) to afford a tan solid.

[0752] The resulting product was taken up in acetonitrile (5.0 mL). Methanesulfonic acid (344 pL, 5.30 mmol) was added, and the reaction mixture was stirred overnight at 60 °C. The mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified via preparative SFC chromatography (Column: Whelk-Ol (R,R), 30 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Isocratic elution at 50%B over 12.0 min; Flow Rate: 90 mL / min; Column Temperature: 35 °C) to afford (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2- fluorophenyl]-3-oxopiperazin-l-yl}-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl) piperidine-2, 6-dione (300 mg, 0.520 mmol, 49% yield over two steps). SFC (Column: Whelk-Ol (R,R), 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN; Temperature: 25 °C; Isocratic elution at 45%B over 10.0 min; Flow: 2.0 mL / min; Detection: UV (220 nm) and UV (254 nm)): retention time 5.6 min (99% ee); LCMS (Method F) retention time 1.83 min, [M+H]+566.1; 'HNMR (400 MHz, DMSO- d6) 6 11.01 (s, 1H), 8.47 (s, 1H), 7.51 (t, J = 8.7 Hz, 1H), 7.24-7.13 (m, 2H), 7.12-7.04 (m, 1H), 7.03-6.97 (m, 1H), 6.91-6.82 (m, 2H), 5.14 (dd, J = 13.1, 5.0 Hz, 1H), 4.51-4.41 (m, 1H), 4.39 (s, 2H), 4.36-4.28 (m, 1H), 4.04 (br t, J = 5.0 Hz, 2H), 3.78 (br t, J = 4.9 Hz, 2H), 3.00-2.81 (m, 1H), 2.61 (br d, J = 17.3 Hz, 1H), 2.41 (qd, J = 13.1, 4.3 Hz, 1H), 2.10-1.95 (m, 1H).

[0753] INTERMEDIATE 1-6 tert-butyl (S)-5-amino-4-(3-bromo-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b] pyridin-6-yl)-5- oxopentanoate

[0754] Intermediate I-6A: ethyl 5-bromo-2-(bromomethyl)nicotinate

[0755] A mixture of ethyl 5-bromo-2-methylnicotinate (6.0 g, 24.6 mmol), NBS (4.81 g, 27.0 mmol), and AIBN (1.21 g, 7.37 mmol) in 1,2-di chloroethane (50 mL) was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography (SiCh, 0-10% ethyl acetate / petroleum ether) to afford ethyl 5-bromo-2-(bromomethyl)nicotinate (6.5 g, 12.6 mmol, 51% yield) as a pale brown liquid. LCMS (Method H): retention time 2.70 min, [M+H]+323.8 (dibromo pattern); 'HNMR (400 MHz, DMSO-d6) 8 8.90 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 4.94 (s, 2H), 4.37 (q, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 5H).

[0756] Intermediate 1-6:

[0757] A mixture of methyl 5-bromo-2-(bromomethyl)nicotinate (6.5 g, 13.12 mmol), tert-butyl (S)-4,5-diamino-5-oxopentanoate (3.98 g, 19.7 mmol), and DIEA (9.17 mL, 52.5 mmol) in DMF (60 mL) was stirred at 90 °C for 12 h. The reaction mixture was then cooled to room temperature and concentrated. The crude residue was purified by flash chromatography (SiCh, 0-100% ethyl acetate / petroleum ether) to afford tert-butyl (S)-5-amino-4-(3-bromo-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5- oxopentanoate (4.62 g, 11.4 mmol, 87% yield) as a brown solid. The enantiomeric excess of this material was not determined. LCMS (Method D): retention time 1.71 min, [M+H]+398.2, 400.2; 'HNMR (400 MHz, DMSO-d6) 6 8.91 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.58 (br s, 1H), 7.23 (br s, 1H), 4.80-4.73 (m, 1H), 4.63-4.46 (m, 2H), 2.27-2.13 (m, 3H), 2.09-1.95 (m, 1H), 1.33 (s, 9H)

[0758] EXAMPLE 7 3 -(3 - { 4- [4-(3 , 5 -di fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo-5H, 6H, 7H- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione

[0759] A mixture of tert-butyl (S)-5-amino-4-(3-bromo-5-oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)-5-oxopentanoate (40 mg, 0.100 mmol), l-(4-(3,5- difluorophenoxy)phenyl)piperazin-2-one (39.7 mg, 0.131 mmol), cesium carbonate (65.4 mg, 0.201 mmol), and Pd-PEPPSI-IHept-Cl (4.89 mg, 5.02 pmol) in 1,4-dioxane (1.5 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layers were collected and concentrated. The crude residue was dissolved in acetonitrile (3 mL), followed by addition of methanesulfonic acid (33 pL, 0.502 mmol). The resulting mixture was stirred at 60 °C for 16 h. A few drops of water were added, then the crude reaction mixture was purified via preparative reversed phase chromatography (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 23-63%B (0.0-20.0 min), 63-100%B (20.0-20.1 min), 100%B (20.1-24.0 min); Flow: 20 mL / min) to afford 3-(3-{4-[4-(3,5-difluorophenoxy)phenyl]-3- oxopiperazin-l-yl}-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (12.9 mg, 23.3 pmol, 23% yield over two steps). The enantiomeric excess of this material was not determined. LCMS (Method E) retention time 1.68 min, [M+H]+548.3;!H NMR (500 MHz, DMSO-d6) 8 8.56 (d, J = 2.7 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.45 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 8.9 Hz, 2H), 7.03-6.93 (m, 1H), 6.74 (dd, J = 8.5, 2.1 Hz, 2H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J = 17.1 Hz, 1H), 4.31-4.22 (m, 1H), 4.13 (s, 2H), 3.93-3.83 (m, 2H), 3.81-3.71 (m, 2H), 2.96-2.82 (m, 1H), 2.66-2.57 (m, 1H), 2.47- 2.34 (m, 1H), 2.10-1.97 (m, 1H).

[0760] EXAMPLE 8

[0761] 3 -(3 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione

[0762] A mixture of tert-butyl (S)-5-amino-4-(3-bromo-5-oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)-5-oxopentanoate (80 mg, 0.201 mmol), l-(4-(3,5- difluorophenoxy)-2-fluorophenyl)piperazin-2-one (68.0 mg, 0.211 mmol), cesium carbonate (131 mg, 0.402 mmol), and Pd-PEPPSI-IHept-Cl (19.5 mg, 0.020 mmol) in

[0763] I,4-di oxane (3.0 mL) was degassed by sparging with nitrogen and stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through a Celite pad. The filtrate was washed with dilute HC1, followed by brine. The organic phase was dried (Na2SC>4), filtered, and concentrated by rotary evaporation. The residue was taken up in acetonitrile (2 mL), followed by addition of methanesulfonic acid (39 pL, 0.603 mmol). The reaction mixture was stirred at 60 °C overnight. The mixture was purified via preparative reversed phase chromatography (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 24-64%B (0.0-20.0 min), 64-100%B (20.0-20.1 min), 100%B (20.1-24.0 min); Flow: 20 mL / min) to afford 3-(3- {4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (12.6 mg, 21.8 pmol, 11% yield over two steps). The enantiomeric excess of this material was not determined. LCMS (Method E) retention time 1.72 min, [M+H]+566.3; ' H NMR (500 MHz, DMSO-d6) 8 10.99 (s, 1H), 8.58 (d, J = 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.52 (t, J = 8.7 Hz, 1H), 7.18 (dd, J =

[0764] I I.0, 2.6 Hz, 1H), 7.06 (tt, J = 9.4, 2.2 Hz, 1H), 7.01 (dd, J = 8.7, 1.8 Hz, 1H), 6.90-6.82 (m, 2H), 5.15 (dd, J = 13.3, 5.0 Hz, 1H), 4.42 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.1 Hz, 1H), 4.16 (s, 2H), 3.79 (apparent s, 4H), 2.97-2.83 (m, 1H), 2.66-2.57 (m, 1H), 2.48-2.35 (m, 1H), 2.09-1.96 (m, 1H).

[0765] EXAMPLES 9-21

[0766] The compounds in Table 1 were prepared according to the general procedures described for Example 1, using the appropriate aryl piperazinone bearing the desired R fragment:

[0767] TABLE 1

[0768] EXAMPLES 22-51

[0769] The compounds in Table 2 were prepared according to the general procedures described for Example 2, using the appropriate aryl piperazinone bearing the desired R fragment:

[0770] TABLE 2

[0771] EXAMPLES 52-65

[0772] The compounds in Table 3 were prepared according to the general procedures described for Example 2, using the appropriate aryl piperazinone bearing the desired R fragment:

[0773] EXAMPLES 66-70

[0774] The compounds in Table 4 were prepared according to the general procedures described for Example 3, using the appropriate aryl piperazinone bearing the desired R fragment:

[0775] EXAMPLES 71-80

[0776] The compounds in Table 5 were prepared according to the general procedures described for Example 4, using the appropriate aryl piperazinone bearing the desired R fragment:

[0777] EXAMPLES 81-85

[0778] The compounds in Table 6 were prepared according to the general procedures described for Example 5, using the appropriate aryl piperazinone bearing the desired R fragment:

[0779] TABLE 6

[0780] EXAMPLES 86-90

[0781] The compounds in Table 7 were prepared according to the general procedures described for Example 6, using the appropriate aryl piperazinone bearing the desired R fragment:

[0782] TABLE 7

[0783] EXAMPLES 91-92

[0784] The compounds in Table 8 were prepared according to the general procedures described for Example 7, using the appropriate aryl piperazinone bearing the desired R fragment:

[0785] TABLE S

[0786] EXAMPLES 93-94

[0787] The compounds in Table 9 were prepared according to the general procedures described for Example 8, using the appropriate aryl piperazinone bearing the desired R fragment:

[0788] TABLE 9

[0789] INTERMEDIATE 1-7 1 -(4-(3 -chloro-5-fluorophenoxy)phenyl)piperazin-2-one hydrochloride Intermediate I-7A: l-(4-bromophenoxy)-3-chloro-5-fluorobenzene

[0790] To a stirring mixture of 3-chloro-5-fluorophenol (2 g, 13.65 mmol) and molecular sieves (4 A, 2 g) in DCM (13.7 mL) was added copper (II) acetate (1.239 g, 6.82 mmol) and triethylamine (4.76 mL, 34.1 mmol). The resulting mixture was flushed with oxygen with vigorous stirring. To this was added (4-bromophenyl)boronic acid (3.01 g, 15.01 mmol). The resulting mixture was flushed with oxygen for 5 min and then stirred under a balloon of oxygen for 72 h. The reaction was diluted with diethyl ether and treated with Celite. The resulting mixture was filtered through Celite, rinsing with additional diethyl ether. The organics were washed with 1 M sodium hydroxide, then with a dilute solution of ammonia in water, then brine, dried over MgSCh, filtered, and concentrated. The residue was purified by silica gel chromatography (0% hold, then ramp to 10% EtOAc / Hex) to give 1.749 g (43% yield) as a colorless oil.!H NMR (500 MHz, CDCh) 8 7.55-7.50 (m, 2H), 6.98-6.94 (m, 2H), 6.86 (dt, J=8.3, 2.0 Hz, 1H), 6.78 (dd, J=3.1, 2.0 Hz, 1H), 6.62 (dt, J=9.7, 2.3 Hz, 1H);19F NMR (471 MHz, CDCh) 6 -109.02 (t, J=8.7 Hz, IF).

[0791] Intermediate I-7B: tert-butyl 4-(4-(3-chloro-5-fluorophenoxy)phenyl)-3-oxopiperazine-l- carb oxy late

[0792] A suspension of tert-butyl 3 -oxopiperazine- 1 -carboxylate (1.27 g, 6.34 mmol), 1- (4-bromophenoxy)-3-chloro-5-fluorobenzene (1.739 g, 5.77 mmol), trans-Nl,N2- dimethylcyclohexane-l,2-diamine (0.227 mL, 1.441 mmol), and K2CCh (1.753 g, 12.68 mmol) in 1,4-dioxane (32.9 mL) was bubbled with nitrogen for 5 min. To this was added copper(I) iodide (0.275 g, 1.441 mmol). The reaction was flushed with nitrogen, sealed, and warmed to 85 °C and held at that temperature for 16 h. The reaction was warmed to 90 °C and held at that temperature for 24 h. The reaction was diluted with diethyl ether and treated with Celite. The resulting mixture was filtered through a pad of Celite, rinsing with EtOAc and diethyl ether. The filtrate was washed with water, then with a solution of dilute aqueous ammonia, then brine, dried over MgSCh, filtered, and concentrated. The residue was purified by silica gel chromatography (20-80% EtOAc / Hex) to give 1.90 g (78% yield) as a white foam solid. LCMS (Method A): retention time 1.09 min, [M+H]+421.0; 'HNMR (500 MHz, CDC13) 8 7.36-7.30 (m, 2H), 7.12-7.07 (m, 2H), 6.86 (dt, J=8.3, 2.0 Hz, 1H), 6.82 (s, 1H), 6.66 (dt, J=9.7, 2.2 Hz, 1H), 4.29 (s, 2H), 3.86-3.74 (m, 4H), 1.53 (s, 9H);19F NMR (471 MHz, CDCI3) 6 -109.13 (t, J=8.7 Hz, IF).

[0793] Intermediate 1-7:

[0794] To a solution of tert-butyl 4-(4-(3-chloro-5-fluorophenoxy)phenyl)-3- oxopiperazine-1 -carboxylate (1.894 g, 4.50 mmol) in 1,4-dioxane (6 mL) was added HC1 (4 M in 1,4-dioxane, 12.4 mL, 49.5 mmol). The reaction was stirred for 1.5 h and concentrated under a stream of nitrogen. The resulting residue was triturated with diethyl ether (2X), removing the mother liquor with a pipette each time. The last traces of solvent were removed under vacuum to give 1.593 g (99% yield) as a white powder. LCMS (Method A): retention time 0.82 min, [M+H]+320.9.

[0795] INTERMEDIATE 1-8 l-(4-(3,4-dichlorophenoxy)phenyl)piperazin-2-one hydrochloride

[0796] Prepared according to the general procedures described for Intermediate 1-7, starting with 3, 4-di chlorophenol and (4-bromophenyl)boronic acid. LCMS (Method A): retention time 0.85 min, [M+H]+336.8.

[0797] INTERMEDIATE 1-9 l-(4-(3, 4-di chi orophenoxy)-2-fluorophenyl)piperazin-2-one hydrochloride Prepared according to the general procedures described for Intermediate 1-7, starting with 3, 4-di chlorophenol and (4-bromo-3-fluorophenyl)boronic acid. LCMS (Method A): retention time 0.82 min, [M+H]+354.8.

[0798] INTERMEDIATE I- 10 l-(4-(3 -chi oro-5 -fluorophenoxy)-2-fluorophenyl)piperazin-2-one hydrochloride

[0799] Prepared according to the general procedures described for Intermediate 1-7, starting with 3-chloro-5-fluorophenol and (4-bromo-3-fluorophenyl)boronic acid. LCMS (Method A): retention time 0.83 min, [M+H]+338.8.

[0800] INTERMEDIATE 1-11 l-(2-chloro-4-(3,5-difluorophenoxy)phenyl)piperazin-2-one hydrochloride

[0801] Prepared according to the general procedures described for Intermediate 1-7, starting with 3, 5 -difluorophenol and (4-bromo-3-chlorophenyl)boronic acid. LCMS (Method A): retention time 0.78 min, [M+H]+338.8.

[0802] INTERMEDIATE 1-12 l-(5-(3,5-difluorophenoxy)pyridin-2-yl)piperazin-2-one dihydrochloride

[0803] Prepared according to the general procedures described for Intermediate 1-7, starting with 6-brom opyri din-3 -ol and (3,5-difluorophenyl)boronic acid. LCMS (Method A): retention time 0.82 min, [M+H]+306.1.

[0804] INTERMEDIATE 1-13 l-(5-(3,5-difluorophenoxy)-3-fluoropyridin-2-yl)piperazin-2-one dihydrochloride

[0805] Intermediate 1-13 A: 2-chloro-5-(3,5-difluorophenoxy)-3-fluoropyridine

[0806] To a stirring mixture of (3,5-difluorophenyl)boronic acid (11.83 g, 74.9 mmol) and molecular sieves (4 A, 10.05 g) in DCM (68.1 mL) was added copper (II) acetate (4.95 g, 27.2 mmol) and TEA (23.74 mL, 170 mmol). The resulting mixture was flushed with oxygen with vigorous stirring. To this was added 6-chloro-5-fluoropyridin-3-ol (10.05 g, 68.1 mmol) and the reaction stirred under a balloon of oxygen for 72 h. The reaction was diluted with diethyl ether and treated with Celite. The resulting mixture was filtered through Celite, rinsing with additional diethyl ether. The organics were washed with 1 M NaOH (3X), then brine, dried over MgSCh, filtered and concentrated. The residue was purified by silica gel chromatography (0% hold, then ramp to 10% EtOAc / Hex) to give 4.32 g (24%) as a colorless oil. LCMS (Method A): retention time 1.09 min, [M+H]+259.9; 'HNMR (500 MHz, CDC13) 8 8.09 (d, J=2.5 Hz, 1H), 7.24 (dd, J=8.5, 2.5 Hz, 1H), 6.72-6.66 (m, 1H), 6.59 (dd, J=7.6, 2.2 Hz, 2H);19F NMR (471 MHz, CDCI3) 6 -106.53-106.66 (m, 2F), -114.61 (d, J=6.9 Hz, IF).

[0807] Intermediate I-13B: tert-butyl 4-(5-(3,5-difluorophenoxy)-3-fluoropyridin-2-yl)-3- oxopiperazine-1 -carboxylate

[0808] A dry vial was charged with tert-butyl 3 -oxopiperazine- 1 -carboxylate (2.005 g, 10.01 mmol), 2-chloro-5-(3,5-difluorophenoxy)-3-fluoropyridine (2 g, 7.70 mmol), and CS2CO3 (5.77 g, 17.72 mmol). The vial was flushed with nitrogen. To this was added 1,4-di oxane (25.7 mL), which was bubbled with nitrogen for 5 min. To this was added Xantphos (0.312 g, 0.539 mmol) and bis(dibenzylideneacetone)palladium(0) (0.310 g, 0.539 mmol). The reaction was flushed with nitrogen, sealed, and heated to 85 °C. The reaction was stirred vigorously at that temperature for 14 h. The mixture was cooled and poured into diethyl ether. The resulting mixture was filtered through a pad of Celite, rinsing with additional ether. The filtrate was washed with brine, dried over MgSCh, filtered, and concentrated. The crude reaction mixture was purified on a silica gel column (0-50% EtOAc / Hex) to give the product. Many fractions were contaminated with an impurity that eluted just after the desired material. Fractions that contained primarily product were combined and triturated with diethyl ether (2X) to give crop 1 (0.92 g). All of the mixed fractions were combined and concentrated. This material was triturated with diethyl ether (3X) to give a second less-pure crop of product (0.86 g). LCMS (Method A): retention time 1.04 min, [M+H]+424.1; 'H NMR (500 MHz, CDC13) 8 8.15 (d, J=2.5 Hz, 1H), 7.23 (dd, J=9.5, 2.4 Hz, 1H), 6.69 (tt, J=8.8, 2.2 Hz, 1H), 6.66-6.60 (m, 2H), 4.32 (s, 2H), 3.93-3.84 (m, 4H), 1.53 (s, 9H);19F NMR (471 MHz, CDC13-d) 6 -106.76 (br t, J=7.8 Hz, 2F), -117.47 (br s, IF).

[0809] Intermediate 1-13:

[0810] To a solution of tert-butyl 4-(5-(3,5-difluorophenoxy)-3-fluoropyridin-2-yl)-3- oxopiperazine-1 -carboxylate (3.68 g, 8.69 mmol) in 1,4-di oxane (11 mL) was added HC1 (4 M in 1,4-dioxane, 21.7 mL, 87 mmol). The reaction was warmed to 35 °C and held at that temperature for 2 h. The reaction was concentrated under a stream of nitrogen. The resulting residue was triturated with diethyl ether (2X), removing the mother liquor with a pipette each time. The last traces of solvent were removed under vacuum to give 3.388 g (quant.) as a white powder. LCMS (Method A): retention time 0.73 min, [M+H]+324.1.

[0811] INTERMEDIATE 1-14 di-tert-butyl (S)-2-(6-bromo-4-methoxy-l-oxoisoindolin-2-yl)pentanedioate Intermediate L14A: methyl 5-bromo-3-methoxy-2-methylbenzoate

[0812] To a solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (1.22 g, 4.98 mmol) in DMF (16 mL) was added cesium carbonate (3.24 g, 9.96 mmol). To this was added iodomethane (1.413 g, 9.96 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with ether, filtered, washed with water (2X), then brine, dried over MgSCh, filtered, and concentrated to give 1.296 g (100% yield). The crude material was taken into the next step without further purification.1H NMR (500 MHz, CDCI3) 6 7.57 (d, J=1.9 Hz, 1H), 7.10 (d, J=1.9 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.38 (s, 3H).

[0813] Intermediate I-14B: methyl 5-bromo-2-(bromomethyl)-3-methoxybenzoate

[0814] To a solution of methyl 5 -bromo-3 -methoxy -2 -methylbenzoate (1.29 g, 4.98 mmol) and NBS (0.886 g, 4.98 mmol) in ACN (12.9 mL) was added AIBN (0.082 g, 0.498 mmol). The vial was sealed, warmed to 80 °C, and held at that temperature overnight. In the morning, the reaction was diluted with diethyl ether, washed with water, followed by a solution of sodium thiosulfate (0.787 g, 4.98 mmol) in water (100 mL), then brine, dried over MgSCh, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-10% EtOAc / Hex) to give 1.473 g (88% yield) as an oil. 'H NMR (500 MHz, CDC13) 8 7.70 (d, J=1.8 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 5.00 (s, 2H), 3.96 (s, 3H), 3.95 (s, 3H).

[0815] Intermediate 1-14:

[0816] To a solution of di-tert-butyl L-glutamate hydrochloride (1.202 g, 4.06 mmol) in ACN (10.2 mL) was added DIEA (1.77 mL, 10.16 mmol). After stirring briefly at room temperature, the reaction was treated with a solution of methyl 5-bromo-2- (bromomethyl)-3 -methoxybenzoate (1.373 g, 4.06 mmol) in ACN (10.2 mL). The vial was sealed, warmed to 70 °C, and held at that temperature overnight. In the morning, the reaction was concentrated and the resulting residue partitioned between diethyl ether and water and the layers separated. The organics were washed with 1.5 M K2HPO4, then brine, dried over MgSCh, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (5-30% EtOAc / Hex) to give 1.74 g (88 % yield) as a white solid. LCMS (Method I): retention time 1.14 min, [M+H]+483.9; 'HNMR (500 MHz, CDCI3) 8 7.62 (d, J=1.4 Hz, 1H), 7.15 (d, J=1.4 Hz, 1H), 4.95 (dd, J=10.9, 4.6 Hz, 1H), 4.55 (d, J=17.3 Hz, 1H), 4.28 (d, J=17.3 Hz, 1H), 3.92 (s, 3H), 2.44-2.29 (m, 2H), 2.26- 2.16 (m, 1H), 2.16-2.06 (m, 1H), 1.47 (s, 9H), 1.42 (s, 9H).

[0817] INTERMEDIATE 1-15 di-tert-butyl (S)-2-(6-bromo-4-methoxy-l-oxoisoindolin-2-yl)pentanedioate

[0818] To a well-stirred solution of methyl 5-bromo-2-(bromomethyl)benzoate (78 g, 180 mmol) in DMF (300 mL) was added di-tert-butyl L-glutamate (56.0 g, 216 mmol) and DIEA (157 mL, 899 mmol) at room temperature. The resulting mixture was heated at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered through a Celite pad and washed with excess EtOAc (600 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by recrystallization from 10% EtOAc / petroleum ether (500 mL). The solid was collected by filtration, rinsed with excess 10% EtOAc / petroleum ether (200 mL), and dried under high vacuum to afford di- tert-butyl (S)-2-(6-bromo-l-oxoisoindolin-2-yl)pentanedioate (43 g, 94 mmol, 52% yield) as a light brown solid. LCMS (Method J): retention time 2.77 min, [M+Na]+476.0;1H NMR (400 MHz, DMSO-d6) 6 7.82-7.85 (m, 2H), 7.61 (d, J = 8.40 Hz, 1H), 4.76-4.80 (m, 1H), 4.42-4.52 (m, 2H), 2.19-2.27 (m, 3H), 2.03-2.09 (m, 1H), 1.39 (s, 9H), 1.35 (s, 9H). INTERMEDIATE 1-16 di-tert-butyl (S)-2-(6-bromo-4-fluoro-l-oxoisoindolin-2-yl)pentanedioate Prepared according to the general procedures described for Intermediate 1-14, starting with methyl 5-bromo-3-fluoro-2 -methylbenzoate. LCMS (Method J): retention time 3.25 min, [M+Na]+494.0; 'H-NMR (400 MHz, DMSO-d6:D2O (~ 20: 1 v / v)) 8 7.85 (dd, J = 1.20, 8.80 Hz, 1H), 7.76 (d, J = 1.20 Hz, 1H), 4.75-4.79 (m, 1H), 4.60 (d, J = 17.60 Hz, 1H), 4.51 (d, J = 17.60 Hz, 1H), 2.36-2.50 (m, 3H), 2.22-2.26 (m, 1H), 1.40 (s, 9H), 1.3 (s, 9H);19F NMR (376 MHz, DMSO-d6) 6 -116.61 (s, IF).

[0819] EXAMPLE 95

[0820] (3 S)-3 -(6- { 4 - [4 - (3 -chi oro-5 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-m ethoxy- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione

[0821] Intermediate 95 A: di-tert-butyl (5)-2-(6-(4-(4-(3-chloro-5-fluorophenoxy)phenyl)-3- oxopiperazin- 1 -yl)-4-m ethoxy- 1 -oxoisoindolin-2-yl)pentanedioate A vial was charged with di- / c / 7-butyl (5)-2-(6-bromo-4-methoxy-l-oxoisoindolin- 2-yl)pentanedioate (120 mg, 0.248 mmol), l-(4-(3-chloro-5- fluorophenoxy)phenyl)piperazin-2-one hydrochloride (93 mg, 0.260 mmol), and CS2CO3 (242 mg, 0.743 mmol) and flushed with nitrogen. To this was added 1,4-dioxane (1.24 mL). The reaction mixture was stirred under a stream of nitrogen for 5 min and then treated with bis(dibenzylideneacetone)palladium(0) (7.12 mg, 0.012 mmol) and Xantphos (8.60 mg, 0.015 mmol). The reaction mixture was stirred under a stream of nitrogen for 2 min, sealed, and heated at 80 °C for 16 h. The reaction was diluted with 4 mL EtOAc, filtered through Celite, rinsing with additional EtOAc. The filtrate was concentrated and purified by silica gel chromatography (20%-100% EtOAc / Hex) to give 170.6 mg (95% yield) as a low melting solid. ' H NMR (500 MHz, CDCI3) 8 7.42-7.37 (m, 2H), 7.15- 7.10 (m, 2H), 7.06 (d, J=1.9 Hz, 1H), 6.87 (dt, J=8.3, 2.0 Hz, 1H), 6.84-6.83 (m, 1H), 6.73 (br d, J=0.6 Hz, 1H), 6.67 (dt, J=9.8, 2.2 Hz, 1H), 4.97 (dd, J=11.0, 4.7 Hz, 1H), 4.56 (d, J=16.8 Hz, 1H), 4.30 (d, J=16.9 Hz, 1H), 4.17 (s, 2H), 4.01-3.96 (m, 2H), 3.94 (s, 3H), 3.76-3.70 (m, 2H), 2.47-2.29 (m, 2H), 2.26-2.18 (m, 1H), 2.17-2.07 (m, 1H), 1.47 (s, 9H), 1.44 (s, 9H).19F NMR (471 MHz, CDCI3) 6 -109.08-109.16 (m, IF).

[0822] Intermediate 95B: (5)-2-(6-(4-(4-(3-chloro-5-fluorophenoxy)phenyl)-3-oxopiperazin-l- yl)-4-methoxy-l-oxoisoindolin-2-yl)pentanedioic acid

[0823] To a solution of di-ZcvV-butyl (5)-2-(6-(4-(4-(3-chloro-5-fluorophenoxy)phenyl)-3- oxopiperazin-l-yl)-4-methoxy-l-oxoisoindolin-2-yl)pentanedioate (168.6 mg, 0.233 mmol) in DCM (3 mL) was added anisole (0.051 mL, 0.466 mmol) and TFA (3 mL, 38.9 mmol). The reaction was stirred at room temperature for 1.5 h. The reaction was concentrated. The resulting residue was suspended in diethyl ether (6 mL) which gave a white precipitate. The solid was agitated with a spatula and the resulting suspension stirred vigorously for 5 min. The mother liquor was removed via pipette and discarded. The solid was again triturated with diethyl ether, removing the mother liquor with a pipette. The last traces of solvent were removed under vacuum to give 142 mg (100 % yield) as a white solid. LCMS (Method A): retention time 0.94 min, [M+H]+612.0.

[0824] Example 95:

[0825] To a suspension of (5)-2-(6-(4-(4-(3 -chi oro-5 -fluorophenoxy)phenyl)-3- oxopiperazin-l-yl)-4-methoxy-l-oxoisoindolin-2-yl)pentanedioic acid (142 mg, 0.232 mmol) in DCM (3867 pl) at room temperature was added HATU (181 mg, 0.476 mmol), followed by DIEA (243 pl, 1.392 mmol). The reaction was stirred at room temperature for 10 min. The reaction was placed in a 0 °C bath and treated with 2,2,2- trifluoroacetamide (27.5 mg, 0.244 mmol). The reaction was stirred at 0 °C for 1 h and quenched by addition of 1 M HC1. The lower layer was removed using a pipette. The aqueous phase was again extracted with DCM. The combined extracts were concentrated, dissolved in DMF (2.5 mL), treated with acetic acid (66.4 pl, 1.160 mmol), and filtered through a syringe filter. The crude material was purified via reversed phase preparative chromatography with the following conditions: Column: XBridge C18, 30 mm x 200 mm, 5 pm particles; Flow Rate: 50 mL / min; Column Temperature: 25 °C; ACN / H20 / 0.05% TFA. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative SFC (IPA / CO2) with the following conditions: Column: Chiralcel OJ-H, 30 mm x 250 mm, 5 pm particles; Flow Rate: 100 mL / min; Column Temperature: 50 °C. Fraction collection was triggered by PDA (220 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to give 24.0 mg (24% yield).XH NMR (500 MHz, DMSO-de) 8 10.96 (s, 1H), 7.47 (br d, J=8.9 Hz, 2H), 7.24-7.15 (m, 3H), 6.95-6.88 (m, 2H), 6.86-6.78 (m, 2H), 5.06 (br dd, J=13.1, 4.5 Hz, 1H), 4.36-4.25 (m, 1H), 4.16 (br d, J=16.9 Hz, 1H), 4.09 (s, 1H), 3.95-3.84 (m, 4H), 3.77-3.69 (m, 1H), 3.61-3.53 (m, 3H), 2.94-2.82 (m, 1H), 2.61 (br d, J=17.4 Hz, 1H), 2.46-2.34 (m, 1H), 2.07-1.95 (m, 1H); LCMS (Method E): retention time 2.01 min, [M+H]+593.0.

[0826] EXAMPLES 96-105

[0827] The compounds in Table 10 were prepared according to the general procedures described for Example 95, using the appropriate aryl piperazinone containing the desired R fragment and the appropriate aryl bromide bearing the desired Ri substituent:

[0828] TABLE 10

[0829] EXAMPLE 106

[0830] 3-(6-{4-[4-(3,4-di chlorophenoxy )phenyl]-3-oxopiperazin-l-yl}-l-oxo-lH,2H,3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione

[0831] Intermediate 106 A: di-tert-butyl 2-(6-(4-(4-(3,4-dichlorophenoxy)phenyl)-3- oxopiperazin- 1 -yl)- 1 -oxo- 1 ,3 -dihydro-2H-pyrrolo[3 ,4-c]pyridin-2-yl)pentanedioate

[0832] A vial was charged with di- / c / 7-butyl (5)-2-(6-chloro-l-oxo-l,3-dihydro-2H- pyrrolo[3,4-c]pyridin-2-yl)pentanedioate (60 mg, 0.146 mmol), l-(4-(3,4- dichlorophenoxy)phenyl)piperazin-2-one hydrochloride (57.3 mg, 0.153 mmol), and CS2CO3 (143 mg, 0.438 mmol) and flushed with nitrogen. To this was added 1,4-dioxane (973 pl). The reaction mixture was stirred under a stream of nitrogen for 5 min and then treated with bis(dibenzylideneacetone)palladium(0) (4.20 mg, 7.30 pmol) and Xantphos (5.07 mg, 8.76 pmol). The reaction mixture was stirred under a stream of nitrogen for 2 min, sealed, and heated at 80 °C for 16 h. The reaction was diluted with 4 mL EtOAc, filtered through Celite, rinsing with additional EtOAc. The filtrate was concentrated and purified by silica gel chromatography (25%-100% EtOAc / Hex) to give 70.0 mg (67% yield). LCMS (Method I): retention time 1.20 min, [M+H]+711.1; 'H NMR (500 MHz, CDCI3) 6 8.45 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.36-7.33 (m, 2H), 7.18 (s, 1H), 7.16 (d, . / =2,8 Hz, 1H), 7.09-7.06 (m, 2H), 6.92 (dd, J=8.9, 2.8 Hz, 1H), 4.99 (dd, J=10.7, 4.9 Hz, 1H), 4.73 (d, J=16.2 Hz, 1H), 4.44 (s, 2H), 4.24 (br s, 2H), 4.00-3.95 (m, 2H), 3.86 (br t, . / =2,8 Hz, 1H), 2.46-2.31 (m, 2H), 2.28-2.20 (m, 1H), 2.17-2.09 (m, 1H), 1.49 (s, 9H), 1.43 (s, 9H).

[0833] Intermediate 106B: 2-(6-(4-(4-(3,4-di chi orophenoxy)phenyl)-3 -oxopiperazin- l-yl)-l-oxo- l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pentanedioic acid

[0834] To a solution of di- / c / 7-butyl 2-(6-(4-(4-(3,4-dichlorophenoxy)phenyl)-3- oxopiperazin-l-yl)-l-oxo-l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pentanedioate (68.5 mg, 0.096 mmol) in DCM (1.25 mL) was added anisole (0.021 mL, 0.193 mmol) and

[0835] TFA (1.25 mL, 16.22 mmol). The reaction was stirred at room temperature for 1.33 h and then concentrated. The reaction was suspended in 4 mL of hexane and again concentrated. The residue was suspended in diethyl ether (6 mL), which gave an immediate precipitate of a white solid. The solid was agitated with a spatula and the resulting suspension stirred vigorously for 5 min. The mother liquor was removed via pipette and discarded. The solid was again suspended in diethyl ether, stirred vigorously, and the mother liquor removed via pipette. The last traces of solvent were removed under vacuum to give 61.9 mg (quant.) as a white solid which was used without additional purification. LCMS (Method I): retention time 0.81 min, [M+H]+599.0.

[0836] Example 106:

[0837] A vial was charged with 2-(6-(4-(4-(3,4-dichlorophenoxy)phenyl)-3-oxopiperazin- l-yl)-l-oxo-l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pentanedioic acid (61.9 mg, 0.103 mmol), 2,2,2-trifluoroacetamide (12.26 mg, 0.108 mmol), and HATU (118 mg, 0.310 mmol). To this was added DCM (1721 pl), followed by the dropwise addition of DIEA (108 pl, 0.620 mmol). After addition of DIEA, everything went into solution. The reaction was stirred at room temperature for 30 min The reaction was concentrated. The resulting residue was dissolved in DMF (2 mL), treated with acetic acid (29.6 pl, 0.516 mmol), and filtered through a syringe filter. The crude material was purified via reversed phase preparative chromatography with the following conditions: Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; ACN / H2O / IO mM NH4OAC. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via reversed phase preparative chromatography with the following conditions: Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; ACN / H20 / 0.05% TFA. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to give 12.3 mg (21% yield).!H NMR (500 MHz, DMSO-de) 6 11.01 (s, 1H), 8.47 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 2H), 7.30 (d, J=2.8 Hz, 1H), 7.14-7.09 (m, 3H), 7.03 (dd, J=8.9, 2.9 Hz, 1H), 5.10 (dd, J=13.0, 4.9 Hz, 1H), 4.49-4.42 (m, 1H), 4.49-4.41 (m, 1H), 4.37-4.30 (m, 2H), 4.03-3.95 (m, 1H), 3.86 (br t, J=5.1 Hz, 1H), 3.56 (br s, 2H), 2.94-2.83 (m, 1H), 2.66- 2.58 (m, 1H), 2.45-2.33 (m, 1H), 2.08-1.98 (m, 1H); LCMS (Method F): retention time 2.03 min, [M+H]+580.0.

[0838] EXAMPLES 107-112

[0839] The compounds in Table 11 were prepared according to the general procedures described for Example 106, using the appropriate aryl piperazinone containing the desired R fragment and the appropriate aryl or heteroaryl bromide bearing the desired Ri substituent:

[0840] TABLE 11

[0841] INTERMEDIATES 1-17 AND 1-18 tert-butyl (S)-5-amino-4-((R)-5-bromo-l-methyl-3-oxoisoindolin-2-yl)-5-oxopentanoate tert-butyl (S)-5-amino-4-((S)-5-bromo-l-methyl-3-oxoisoindolin-2-yl)-5-oxopentanoate

[0842] Intermediate I-17A: methyl 5-bromo-2-(l-bromoethyl)benzoate

[0843] A mixture of methyl 5-bromo-2-ethylbenzoate (25 g, 103 mmol), NBS (23.79 g, 134 mmol) and AIBN (5.07 g, 30.9 mmol) in 1,2-di chloroethane (250 mL) was stirred at 85 °C for 3 h. The reaction mixture was concentrated under reduced pressure and diluted with 5% ethyl acetate in petroleum ether. Solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford crude methyl 5-bromo-2-(l- bromoethyl)benzoate (40 g, 58%) as a pale red liquid.XH NMR (400 MHz, DMSO-de): 7.90 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.80 (s, 1H), 6.14 (q, J = 6.8 Hz, 1H), 2.56 (s, 3H), 1.99 (d, J= 6.9 Hz, 3H).

[0844] Intermediates 1-17 and 1-18:

[0845] A mixture of methyl 5-bromo-2-(l-bromoethyl)benzoate (40 g, 124 mmol), tertbutyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (38.6 g, 161 mmol), potassium carbonate (68.7 g, 497 mmol), and sodium iodide (24.21 g, 161 mmol) in acetonitrile (400 mL) was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiCh, 0-80% ethyl acetate in petroleum ether) to give tert-butyl (4S)-5-amino-4-(5-bromo-l- methyl-3-oxoisoindolin-2-yl)-5-oxopentanoate. The two diastereomers were separated by preparative SFC with the following conditions: Column: Chiralpak AD-H, 50 x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.1% ammonium hydroxide in methanol; Isocratic elution at 30%B; Flow Rate: 250 g / min; Temperature: 40 °C; UV: 220 nm.

[0846] Fractions containing the first peak were concentrated under reduced pressure to afford tert-butyl (S)-5-amino-4-((R)-5-bromo-l-methyl-3-oxoisoindolin-2-yl)-5- oxopentanoate (10.3 g, 20% yield). SFC (Column: Chiralpak AD-H, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.1% ammonium hydroxide in methanol; Temperature: 40 °C; Isocratic elution at 30%B; Flow: 3.0 mL / min): retention time 4.91 min; LCMS (Method D) retention time 2.59 min, [M+H]+411.0, 413.0; 'H NMR (400 MHz, DMSO-d6): 8 7.82-7.77 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.20 (br s, 1H), 7.15 (br s, 1H), 4.64 (q, J=6.7 Hz, 1H), 4.46-4.38 (m, 1H), 2.37-2.27 (m, 1H), 2.21- 2.10 (m, 3H), 1.40 (d, J=6.8 Hz, 3H), 1.36 (s, 9H).

[0847] Fractions containing the second peak were concentrated under reduced pressure to afford tert-butyl (S)-5-amino-4-((S)-5-bromo-l-methyl-3-oxoisoindolin-2-yl)-5- oxopentanoate (8.13 g, 15% yield). SFC (Column: Chiralpak AD-H, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.1% ammonium hydroxide in methanol; Temperature: 40 °C; Isocratic elution at 30%B; Flow: 3.0 mL / min): retention time 7.53 min; LCMS (Method D) retention time 2.58 min, [M+H]+411.0, 413.0; 'H NMR (400 MHz, DMSO-d6): 6 7.82-7.78 (m, 2H), 7.60 (d, J=7.8 Hz, 1H), 7.45 (br s, 1H), 7.21 (br s, 1H), 4.69 (q, J=6.6 Hz, 1H), 4.49-4.42 (m, 1H), 2.28-2.22 (m, 1H), 2.21- 2.09 (m, 3H), 1.48 (d, J=6.8 Hz, 3H), 1.37 (s, 9H).

[0848] The absolute configuration at Cl of the isoindolinone ring system of Intermediate 1-18 (peak 2) was assigned as (S) based on single-crystal x-ray diffraction data of a derivative of this compound. Inferring from this result, the Cl stereochemistry of Intermediate 1-17 (peak 1) was assigned as (R).

[0849] EXAMPLE 113 (3S)-3-[(lR)-5-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-l- methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione

[0850] A mixture of tert-butyl (S)-5-amino-4-((R)-5-bromo-l-methyl-3-oxoisoindolin-2- yl)-5-oxopentanoate (350 mg, 0.851 mmol), l-(4-(3,5-difluorophenoxy)-2- fluorophenyl)piperazin-2-one (336 mg, 0.936 mmol), cesium carbonate (832 mg, 2.55 mmol), and Pd-PEPPSI-IHept-Cl (83 mg, 0.085 mmol) in 1,4-dioxane (8 mL) was degassed by nitrogen sparging. The resulting mixture was blanketed under nitrogen and stirred at 100 °C for 3 h. The mixture was then cooled to room temperature, diluted with EtOAc, and filtered through a Celite pad. The filtrate was concentrated by rotary evaporation. The crude residue was taken up in ACN (10 mL), treated with methanesulfonic acid (166 pl, 2.55 mmol), and stirred overnight at 60 °C. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was separated and washed with brine, dried over Na2SO4, and concentrated to give a foam. The crude material was purified via preparative SFC chromatography with the following conditions: Column: Torus 2-PIC, 30 mm x 150 mm, 5 pm particles; Flow Rate: 90.49 mL / min; Column Temperature: 35 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (3S)-3- [( 1 R)-5 - { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -methyl-3 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (264 mg, 53% yield). SFC (Conditions: Column: Torus 2-PIC, 4.6 mm x 150 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IP A / ACN (50:50); Temperature: 45.0 °C; Isocratic elution at 25%B over 20.0 min; Flow: 2.0 mL / min; Detection: PDA (210 nm-400 nm)): retention time 6.62 min (94% ee); LCMS (Method F) retention time 1.91 min, [M+H]+579.2;!H NMR (400 MHz, DMSO-d6) 8 10.93 (s, 1H), 7.57-7.46 (m, 2H), 7.32 (dd, J= 8.4, 2.5 Hz, 1H), 7.22-7.15 (m, 2H), 7.08 (tt, J= 9.4, 2.3 Hz, 1H), 7.01 (ddd, J= 8.7, 2.7, 1.0 Hz, 1H), 6.93-6.82 (m, 2H), 4.74 (dd, J= 12.6, 5.3 Hz, 1H), 4.59 (q, J= 6.8 Hz, 1H), 4.07 (s, 2H), 3.82-3.68 (m, 4H), 2.90-2.75 (m, 1H), 2.72-2.55 (m, 2H), 2.04-1.93 (m, 1H), 1.39 (d, J = 6.6 Hz, 3H). EXAMPLES 114-125

[0851] The compounds in Table 12 were prepared according to the general procedures described for Example 113, using the appropriate aryl piperazinone containing the desired R fragment:

[0852] TABLE 12

[0853] EXAMPLES 126-128

[0854] The compounds in Table 13 were prepared according to the general procedures described for Example 113, using the appropriate aryl piperazinone containing the desired R fragment and tert-butyl (S)-5-amino-4-((S)-5-bromo-l-methyl-3-oxoisoindolin-2-yl)-5- oxopentanoate:

[0855] TABLE 13 INTERMEDIATES I- 19 AND 1-20 tert-butyl (S)-5-amino-4-((S)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)-5 -oxopentanoate tert-butyl (S)-5-amino-4-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)-5 -oxopentanoate

[0856] Intermediate I-19A: methyl 2,5-dibromonicotinate

[0857] To a stirred solution of 2,5-dibromonicotinic acid (20 g, 71.2 mmol) in DMF (250 mL) was added K2CO3 (49.2 g, 356 mmol). The mixture was stirred for 60 min under nitrogen atmosphere, then methyl iodide (5.79 mL, 93 mmol) was added at 0 °C. The mixture was then stirred at room temperature for 6 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude material was purified on SiO2 (120 g, eluted with 0-5% EtOAc in petroleum ether) to afford methyl 2,5-dibromonicotinate (20 g, 65.1 mmol, 91% yield) as an off-white solid. LCMS (Method H): retention time 2.50 min, [M+H]+293.9, 295.9;!H NMR (400 MHz, DMSOWr,) 8 ppm 8.74 (d, J= 2.50 Hz, 1H), 8.41 (d, J= 2.50 Hz, 1H), 3.89 (s, 3H).

[0858] Intermediate I-19B: methyl 5-bromo-2-ethylnicotinate

[0859] To a cooled (0 °C) solution of methyl 2,5-dibromonicotinate (20.0 g, 67.8 mmol) in THF (60 mL) under nitrogen atmosphere was added bis(dibenzylideneacetone)palladium(0) (1.948 g, 3.392 mmol), followed by diethylzinc in hexane (1.0 M, 74.6 mL, 74.6 mmol). The resulting mixture was stirred at room temperature for 6 h. The reaction was then quenched with saturated ammonium chloride solution (100 mL), stirred well for 15 min and extracted with EtOAc (2 x 250 mL). The layers were separated, and the organic phase was washed with brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on SiO2 (120 g, eluted with 0-1% EtOAc in petroleum ether) to obtain methyl 5- bromo-2-ethylnicotinate (15.5 g, 63.5 mmol, 93% yield) as an off-white semi solid.

[0860] LCMS (Method D): retention time 2.39 min, [M+H]+242.0, 244.0;1H NMR (400 MHz, DMSOA) 6 ppm 8.81 (d, = 2.38 Hz, 1H), 8.31 (d, = 2.38 Hz, 1H), 3.87 (s, 3H), 3.01 (q, J = 7.46 Hz, 2H), 1.20 (t, J = 7.44 Hz, 3H)

[0861] Intermediate I-19C: methyl 5-bromo-2-(l-bromoethyl)nicotinate

[0862] To a stirred solution of methyl 5-bromo-2-ethylnicotinate (15.5 g, 63.5 mmol) in

[0863] DCE under nitrogen atmosphere was added AIBN (4.17 g, 25.4 mmol) and NBS (13.56 g,

[0864] 76 mmol). The reaction was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (100 mL) and then extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on SiO2 (120 g, eluted with 3% EtOAc in petroleum ether) to afford methyl 5 -bromo-2-(l -bromoethyl) nicotinate (16.5 g, 49.6 mmol, 78% yield) as a pale yellow semi-solid. LCMS (Method H): retention time 2.73 min, [M+H]+321.9, 323.9. 325.9; 'HNMR (400 MHz, DMSOA) 8: 8.95 (d, J= 2.38 Hz, 1H), 8.40 (d, J= 2.38 Hz, 1H), 6.17 (q, J= 6.67 Hz, 1H), 3.90 (s, 3H), 2.00 (d, J = 6.75 Hz, 3H).

[0865] Intermediates 1-19 and 1-20:

[0866] To a solution of methyl 5-bromo-2-(l-bromoethyl)nicotinate (10 g, 31.0 mmol) and tert-butyl (S)-4,5-diamino-5-oxopentanoate (8.14 g, 40.2 mmol) in ACN (100 mL) was added K2CO3 (12.84 g, 93 mmol) and sodium iodide (6.96 g, 46.4 mmol). The reaction was heated at 75 °C for 16 h. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and washed with 50 mL EtOAc. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on SiC>2 (eluted with 0-76% EtOAc in petroleum ether) to afford tertbutyl (4S)-5-amino-4-(3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6- yl)-5-oxopentanoate as an off-white solid. The two diastereomers were separated by preparative SFC with the following conditions: Column: Lux i-Amylose-3, 50 x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: ACN / IPA (50:50); Gradient elution 40-100%B; Flow Rate: 250 g / min; Temperature : 40°C; UV: 220 nm.

[0867] Fractions containing the first peak were concentrated under reduced pressure to afford tert-butyl (S)-5-amino-4-((S)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)-5-oxopentanoate (6 g, 14.53 mmol, 47% yield). SFC (Column: Chiralpak IG, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: ACN / IPA (50:50); Temperature: 40 °C; Isocratic elution at 40%B; Flow: 3.0 mL / min): retention time 4.27 min; LCMS (Method D) retention time 2.04 min, [M+H]+412.0, 414.0; 'HNMR (400 MHz, DMSO-t / 6): 8 8.90 (d, J=2.13 Hz, 1H), 8.33 (d, J=2.13 Hz, 1H), 7.46 (br s, 1H), 7.23 (s, 1H), 4.68 (q, J=6.71 Hz, 1H), 4.43-4.53 (m, 1H), 2.27- 2.35 (m, 1H), 2.15-2.25 (m, 3H), 1.51 (d, J=6.75 Hz, 3H), 1.37 (s, 9H).

[0868] Fractions containing the second peak were concentrated under reduced pressure to afford tert-butyl (S)-5-amino-4-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)-5-oxopentanoate (6.8 g, 16.46 mmol, 53% yield). SFC (Column: Chiralpak IG, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: ACN / IPA (50:50); Temperature: 40 °C; Isocratic elution at 40%B; Flow: 3.0 mL / min): retention time 6.95 min; LCMS (Method D) retention time 2.17 min, [M+H]+412.0, 414.0; 'HNMR (400 MHz, DMSO-t / 6): 6 8.90 (d, J=2.25 Hz, 1H), 8.32 (d, J=2.25 Hz, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 4.67 (q, J=6.75 Hz, 1H), 4.39-4.51 (m, 1H), 2.30-2.41 (m, 1H), 2.11-2.26 (m, 3H), 1.44 (d, J=6.88 Hz, 3H), 1.36 (s, 9H).

[0869] The absolute configuration at C7 of the pyrrolopyridine ring system of Intermediate 1-19 (peak 1) was assigned as (S) based on single-crystal x-ray diffraction data for this compound. Inferring from this result, the C7 stereochemistry of Intermediate 1-20 (peak 2) was assigned as (R).

[0870] EXAMPLE 129

[0871] (3 S)-3 - [(7R)-3 - { 4- [4-(3 , 5 -difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -7 -methyl-5 - oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione

[0872] A mixture of tert-butyl (S)-5-amino-4-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro- 6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxopentanoate (50 mg, 0.121 mmol), l-(4-(3,5- difluorophenoxy)phenyl)piperazin-2-one (44.3 mg, 0.146 mmol), Pd-PEPPSI-IHept-Cl (5.90 mg, 6.06 pmol), and cesium carbonate (99 mg, 0.303 mmol) in 1,4-dioxane (2 mL) was degassed and stirred at 80 °C for 15 h under nitrogen atmosphere. The mixture was cooled to room temperature and purified via reversed phase preparative HPLC (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 30-100%B (0.0-30.0 min); Flow: 20 mL / min) to afford tert-butyl (S)-5 -amino-4-((R)-3 -(4-(4-(3 , 5 -difluorophenoxy )phenyl)-3 - oxopiperazin-l-yl)-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5- oxopentanoate (25 mg).

[0873] The resulting product was dissolved in acetonitrile (2 mL), followed by addition of methanesulfonic acid (47 pL, 0.728 mmol). The reaction mixture was stirred at 80 °C for 3 h. The mixture was purified via preparative reversed phase chromatography (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 24-64%B (0.0-20.0 min), 64-100%B (20.0-20.1 min), 100%B (20.1-24.0 min); Flow: 20 mL / min) to afford (3S)-3-[(7R)-3-{4- [4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-7-methyl-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (13.1 mg, 23.3 pmol, 19% yield over two steps). The enantiomeric excess of this material was not determined. LCMS (Method E) retention time 1.71 min, [M+H]+562.1; 'HNMR (500 MHz, DMSO-d6) 8 8.55 (br s, 1H), 7.55 (dd, J=7.9, 2.7 Hz, 1H), 7.46 (br d, J=8.7 Hz, 2H), 7.17 (br d, J=8.7 Hz, 2H), 7.03- 6.91 (m, 1H), 6.74 (dd, J=8.5, 2.1 Hz, 2H), 4.81-4.53 (m, 2H), 4.13 (d, J=1.5 Hz, 2H), 3.87 (br d, . / =4,7 Hz, 2H), 3.76 (br s, 2H), 2.90-2.70 (m, 1H), 2.66-2.60 (m, 2H), 2.13- 1.90 (m, 1H), 1.46-1.39 (m, 3H). EXAMPLE 130

[0874] (3 S)-3 - [(7R)-3 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 7 - methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione

[0875] Prepared according to the general procedures described for Example 129, starting with l-(4-(3,5-difluorophenoxy)-2-fluorophenyl)piperazin-2-one and tert-butyl (S)-5- amino-4-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5- oxopentanoate. LCMS (Method E): retention time 1.74 min, [M+H]+580.1.

[0876] EXAMPLE 131

[0877] (3 S)-3 -[(7 S)-3 - { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -7-methyl-5 - oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione

[0878] Prepared according to the general procedures described for Example 129, starting with l-(4-(3,5-difluorophenoxy)phenyl)piperazin-2-one and tert-butyl (S)-5-amino-4- ((S)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5- oxopentanoate. LCMS (Method E): retention time 1.72 min, [M+H]+562.1.

[0879] EXAMPLE 132 (3S)-3-[(7S)-7-methyl-5-oxo-3-{3-oxo-4-[4-(2,3,5-trifhiorophenoxy)phenyl]piperazin-l- yl}-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione

[0880] A mixture of tert-butyl (S)-5-amino-4-((S)-3-bromo-7-methyl-5-oxo-5,7-dihydro- 6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxopentanoate (60 mg, 0.146 mmol), l-(4-(2,3,5- trifluorophenoxy)phenyl)piperazin-2-one hydrochloride (62.7 mg, 0.175 mmol), potassium carbonate (60.3 mg, 0.437 mmol), and Pd-PEPPSI-IHept-Cl (5.90 mg, 6.06 pmol) in 1,4-di oxane (2 mL) was degassed and stirred at 100 °C for 15 h under nitrogen atmosphere. The mixture was cooled to room temperature and purified via reversed phase preparative HPLC (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 30- 100%B (0.0-30.0 min); Flow: 20 mL / min) to afford tert-butyl (S)-5-amino-4-((S)-7- methyl-5-oxo-3-(3-oxo-4-(4-(2,3,5-trifluorophenoxy)phenyl)piperazin-l-yl)-5,7-dihydro- 6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxopentanoate (30 mg).

[0881] The resulting product was dissolved in acetonitrile (2 mL), followed by addition of methanesulfonic acid (94 pL, 1.46 mmol). The reaction mixture was stirred at 80 °C for 3 h. The mixture was purified via preparative reversed phase chromatography (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 24-64%B (0.0-20.0 min), 64-100%B (20.0-20.1 min), 100%B (20.1-24.0 min); Flow: 20 mL / min) to afford (3 S)-3-[(7S)-7- methyl-5-oxo-3-{3-oxo-4-[4-(2, 3, 5-tri fluorophenoxy )phenyl]piperazin-l-yl}-5H,6H,7H- pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (3.5 mg, 6.04 pmol, 4% yield over two steps). The enantiomeric excess of this material was not determined. LCMS (Method E) retention time 1.67 min, [M+H]+580.2; 'HNMR (500 MHz, DMSO-d6) 8 8.55 (d, . / =2,4 Hz, 1H), 7.62-7.51 (m, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.39-7.31 (m, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.00-6.90 (m, 1H), 4.81-4.65 (m, 2H), 4.12 (s, 2H), 3.93-3.82 (m, 2H), 3.79-3.63 (m, 2H), 2.84-2.69 (m, 1H), 2.68-2.56 (m, 2H), 2.10-1.97 (m, 1H), 1.48-1.39 (m, 3H). EXAMPLE 133

[0882] (3S)-3-[(7R)-7-methyl-5-oxo-3-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l- yl}-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione

[0883] Prepared according to the general procedures described for Example 132, starting with l-(4-(2,3,5-trifluorophenoxy)phenyl)piperazin-2-one hydrochloride and tert-butyl (S)-5-amino-4-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6- yl)-5-oxopentanoate. LCMS (Method E): retention time 1.67 min, [M+H]+580.2.

[0884] INTERMEDIATES 1-21 AND 1-22 tert-butyl (4S)-5-amino-4-(6-chloro-3-methyl-l-oxo-l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)-5-oxopentanoate (Isomer 1) tert-butyl (4S)-5-amino-4-(6-chloro-3-methyl-l-oxo-l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)-5-oxopentanoate (Isomer 2)

[0885] Intermediate L21A: methyl 2-hydroxy-5-vinylisonicotinate

[0886] A solution of methyl 5-bromo-2-hydroxyisonicotinate (20 g, 86 mmol) and tributyl(vinyl)stannane (50.4 mL, 172 mmol) in 1,4 dioxane (150 mL) was purged with nitrogen for 5 minutes, then Pd(PPhs)4 (9.97 g, 8.62 mmol) was added. The reaction was stirred at 90 °C for 16 h. The reaction mixture was filtered through a Celite pad and washed with EtOAc (50 mL). The filtrate was concentrated to obtain crude methyl 2- hydroxy-5-vinylisonicotinate (10 g) as a yellow oil, which was carried into the next step without further purification. LCMS (Method K): retention time 0.694 min, [M+H]+

[0887] 180.0.

[0888] Intermediate 1-2 IB: methyl 5-ethyl-2-hydroxyisonicotinate

[0889] A mixture of methyl 2-hydroxy-5-vinylisonicotinate (10 g) and 10% palladium on carbon (5.94 g, 5.58 mmol) in THF (100 mL) was stirred under hydrogen bladder at room temperature for 16 h. The reaction mixture was filtered through a Celite pad, washed with methanol, and the filtrate was concentrated. The crude material was purified by column chromatography using SiCh (80 g, 15-100% EtOAc / petroleum ether) to afford methyl 5-ethyl-2-hydroxyisonicotinate (8.2 g, 42.5 mmol, 47% yield over two steps) as a yellow oil. LCMS (Method K): retention time 0.55 min, [M+H]+182.0; 'H NMR (400 MHz, DMSO-t / r,) 6 11.79 (br s, 1H), 7.31 (s, 1H), 6.60 (s, 1H), 3.83 (s, 3H), 3.33 (s, 3H), 2.25 (q, 2H, merged in DMSO peak), 1.03 (t, J = 7.44 Hz, 3H).

[0890] Intermediate I-21C: methyl 2-chloro-5-ethylisonicotinate

[0891] O CI\ / ^^O'CH3

[0892] J^CH3(i-2 IQ

[0893] To a stirred solution of methyl 5-ethyl-2-hydroxyisonicotinate (8.2 g, 45.3 mmol) in DMF (5 mL) was added phosphorus oxychloride (42.2 mL, 453 mmol). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered through a Celite pad, washed with methanol, and the filtrate was concentrated. The crude material was purified by SiC>2 (80 g, 5-100% EtOAc / petroleum ether) to afford methyl 2-chloro-5- ethylisonicotinate (7.2 g, 30.7 mmol, 68% yield) as a yellow oil. LCMS (Method K): retention time 1.270 min, 85%, [M+H]+200.0, 202.0; 'HNMR (400 MHz, DMSO-t / 6) 6 8.48 (s, 1H), 7.72 (s, 1H), 3.89 (s, 3H), 2.84 (q, J=7.50 Hz, 2H), 1.15 (t, J=7.50 Hz, 3H).

[0894] Intermediate I-21D: methyl 5-(l-bromoethyl)-2-chloroisonicotinate

[0895] To a stirred solution of methyl 2-chloro-5-ethylisonicotinate (6.6 g, 33.1 mmol) in DCE (100 mL) was added NBS (5.88 g, 33.1 mmol) and AIBN (0.543 g, 3.31 mmol). The resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched with water at 0 °C and extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford crude methyl 5-(l-bromoethyl)-2-chloroisonicotinate (9 g, 30.4 mmol, 92 % yield), which was carried into the next step without further purification. LCMS (Method K): retention time 1.38 min, [M+H]+277.8, 279.8; 'H NMR (400 MHz, DMSO- tZ6) 6 8.92 (s, 1H), 7.77 (s, 1H), 5.98 (q, J=6.92 Hz, 1H), 3.91 (s, 3H), 2.07 (d, . / =7.00 Hz, 3H).

[0896] Intermediates 1-21 and 1-22:

[0897] To a stirred solution of methyl 5-(l-bromoethyl)-2-chloroisonicotinate (9 g, 32.3 mmol) in DMF (60 mL) was added DIEA (28.2 mL, 162 mmol) and tert-butyl (S)-4,5- diamino-5-oxopentanoate hydrochloride (14.34 g, 60.1 mmol). The resulting mixture was stirred at 90 °C for 3 h. The reaction mixture was quenched with water (100 mL) at 0 °C and then extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude material was purified on SiC>2 (120 g, 15-100% EtOAc / petroleum ether) to afford tert-butyl (4S)-5- amino-4-(6-chl oro-3-methyl- 1-oxo- 1,3-dihy dro-2H-pyrrolo[3,4-c]pyri din-2 -yl)-5- oxopentanoate as a yellow oil. The two diastereomers were separated by preparative SFC with the following conditions: Column: Lux Cellulose-1, 30 x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.1% ammonium hydroxide in methanol; Isocratic elution at 30%B; Flow Rate: 100 g / min; Temperature.: 40°C; UV: 220 nm.

[0898] Fractions containing the first peak were concentrated under reduced pressure to afford tert-butyl (4S)-5-amino-4-(6-chloro-3-methyl-l-oxo-l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)-5-oxopentanoate (Isomer 1) (1.92 g, 5.11 mmol, 16% yield). SFC (Column: Chiralcel OD-H, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.1% ammonium hydroxide in methanol; Temperature: 40 °C; Isocratic elution at 30%B; Flow: 3.0 g / min): retention time 2.14 min; LCMS (Method H) retention time 2.25 min, [M+2H-tBu]+312.0;1H NMR (400 MHz, DMSO r,) 8 ppm 8.77 (s, 1H), 7.76 (d, J=0.88 Hz, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 4.84 (q, J=6.63 Hz, 1H), 4.42-4.49 (m, 1H), 2.14-2.31 (m, 4H), 1.54 (d, J=6.75 Hz, 3H), 1.37 (s, 9H).

[0899] Fractions containing the second peak were concentrated under reduced pressure to afford tert-butyl (4S)-5-amino-4-(6-chloro-3-methyl-l-oxo-l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)-5-oxopentanoate (Isomer 2) (1.99 g, 5.34 mmol, 17% yield). SFC (Column: Chiralcel OD-H, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.1% ammonium hydroxide in methanol; Temperature: 40 °C; Isocratic elution at 30%B; Flow: 3.0 g / min): retention time 3.46 min; LCMS (Method H) retention time 2.25 min, [M+2H-tBu]+312.1; 'HNMR (400 MHz, DMSO r,) 6: 8.77 (s, 1H), 7.76 (d, J=1.00 Hz, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 4.80 (q, J=6.63 Hz, 1H), 4.39-4.46 (m, 1H), 2.30-2.39 (m, 1H), 2.11-2.25 (m, 3H), 1.47 (d, J=6.75 Hz, 3H), 1.36 (s, 9H).

[0900] EXAMPLES 134-136

[0901] The compounds in Table 14 were prepared according to the general procedures described for Example 132, starting with tert-butyl (4S)-5-amino-4-(6-chloro-3-methyl-l- oxo-1, 3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-5-oxopentanoate (Isomer 2) and the appropriate aryl piperazinone bearing the desired R fragment:

[0902] Isomer 2 CH3O

[0903] TABLE 14

[0904] EXAMPLES 137-139

[0905] The compounds in Table 15 were prepared according to the general procedures described for Example 132, starting with tert-butyl (4S)-5-amino-4-(6-chloro-3-methyl-l- oxo-1, 3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-5-oxopentanoate (Isomer 1) and the appropriate aryl piperazinone bearing the desired R fragment:

[0906] INTERMEDIATES 1-23 AND 1-24 di-tert-butyl (S)-2-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin- di-tert-butyl (S)-2-((S)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6- yl)pentanedioate

[0907] To a stirred solution of methyl 5-bromo-2-(l-bromoethyl)nicotinate (5.8 g, 17.96 mmol) and di-tert-butyl L-glutamate hydrochloride (7.97 g, 26.9 mmol) in acetonitrile (100 mL) was added potassium carbonate (7.45 g, 53.9 mmol) and sodium iodide (4.04 g, 26.9 mmol). The resulting mixture was stirred at 75 °C for 6 h. The reaction mixture was cooled, diluted with cold water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried on sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiCh, 0-50% EtOAc / petroleum ether) to afford di-tert-butyl (2S)-2-(3-bromo-7-methyl-5-oxo- 5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pentanedioate (4.20 g). The two diastereomers were separated by preparative SFC with the following conditions: Column: YMC Cellulose-SC, 50 x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.2% diethylamine in IP A; Isocratic elution at 20%B; Flow Rate: 300 g / min; Temperature : 40°C; UV: 220 nm.

[0908] Fractions containing the first peak were concentrated under reduced pressure to afford di-tert-butyl (S)-2-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)pentanedioate (1.67 g, 3.52 mmol, 20% yield). SFC (Column: YMC Cellulose-SC, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.2% diethylamine in IP A; Temperature: 40 °C; Isocratic elution at 30%B; Flow: 3.0 g / min; UV: 220 nM): retention time 1.80 min; LCMS (Method H) retention time 2.90 min, [M+H-2tBu]+355.1, 357.1; 'HNMR (400 MHz, DMSO-t / r,) 8: 8.93 (d, J=2.13 Hz, 1H), 8.35 (d, J= 2.13 Hz, 1H), 4.63 (q, J= 6.71 Hz, 1H), 4.48-4.56 (m, 1H), 2.25-2.30 (m, 4H), 1.43 (d, J= 6.75 Hz, 3H), 1.37 (s, 9H), 1.34 (s, 9H).

[0909] Fractions containing the second peak were concentrated under reduced pressure to afford di-tert-butyl (S)-2-((S)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)pentanedioate (2.04 g, 4.28 mmol, 24% yield). SFC (Column: YMC Cellulose-SC, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: 0.2% diethylamine in IP A; Temperature: 40 °C; Isocratic elution at 30%B; Flow: 3.0 g / min; UV: 220 nM): retention time 2.12 min; LCMS (Method H) retention time 2.90 min, [M+H-2tBu]+355.1, 357.1;XH NMR (400 MHz, DMSO-t / r,) 6: 8.91 (d, 2.13 Hz,

[0910] 1H), 8.35 (d, J= 2.13 Hz, 1H), 4.66 (q, J= 6.75 Hz, 1H), 4.37-4.43 (m, 1H), 2.19-2.33 (m, 4H), 1.48 (d, J= 6.75 Hz, 3H), 1.35 (s, 9H), 1.34 (s, 9H).

[0911] The absolute configuration at C7 of the pyrrolopyridine ring system of Intermediate 1-23 (peak 1) was assigned as (R) based on single-crystal x-ray diffraction data for this compound. Inferring from this result, the C7 stereochemistry of Intermediate 1-24 (peak 2) was assigned as (S).

[0912] EXAMPLE 140

[0913] (3S)-3-[(7R)-3-{4-[4-(3-chloro-5-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-7-methyl- 5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione

[0914] Intermediate 140A: di-tert-butyl (S)-2-((R)-3-(4-(4-(3-chloro-5-fluorophenoxy)phenyl)-3- oxopiperazin-l-yl)-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6- yl)pentanedioate

[0915] A mixture of di-tert-butyl (S)-2-((R)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)pentanedioate (60 mg, 0.128 mmol), l-(4-(3-chloro-5- fluorophenoxy)phenyl)piperazin-2-one TFA (61.1 mg, 0.141 mmol), bis(dibenzylideneacetone)palladium(0) (3.68 mg, 6.39 pmol), Xantphos (7.40 mg, 0.013 mmol) and potassium carbonate (70.7 mg, 0.511 mmol) in 1,4-dioxane (2 mL) was stirred at 80 °C for 15 h under nitrogen atmosphere. The mixture was cooled to room temperature and purified by flash chromatography (SiCh) to afford di-tert-butyl (S)-2- ((R)-3-(4-(4-(3-chl oro-5 -fluorophenoxy)phenyl)-3 -oxopiperazin- 1 -yl)-7-methyl-5-oxo- 5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pentanedioate (75 mg, 0.106 mmol, 83% yield). LCMS (Method A): retention time 1.16 min, [M+H]+709.2;!H NMR (500 MHz, CHLOROFORM-d) 8 8.48 (d, J=2.6 Hz, 1H), 7.68 (d, J=2.6 Hz, 1H), 7.46-7.34 (m, 2H), 7.15-7.09 (m, 2H), 6.86 (dt, J=8.2, 2.0 Hz, 1H), 6.82 (d, J=0.8 Hz, 1H), 6.66 (dt, J=9.7, 2.2 Hz, 1H), 4.64 (q, J=6.7 Hz, 1H), 4.56 (dd, J=10.0, 5.5 Hz, 1H), 4.21 (s, 2H), 4.10- 3.94 (m, 2H), 3.82-3.68 (m, 2H), 2.65-2.49 (m, 1H), 2.45-2.40 (m, 1H), 2.36-2.24 (m, 2H), 1.56 (d, . / =6,8 Hz, 3H), 1.45 (m, 18H).

[0916] Example 140: TFA (0.760 mL, 9.87 mmol) was added to a mixture of di-tert-butyl (S)-2-((R)-3- (4-(4-(3-chloro-5-fluorophenoxy)phenyl)-3-oxopiperazin-l-yl)-7-methyl-5-oxo-5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pentanedioate (70 mg, 0.099 mmol) in DCM (2 mL) at room temperature. The resulting mixture was stirred for 3 h, then it was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL), then DIEA (0.086 mL, 0.494 mmol) and HATU (83 mg, 0.217 mmol) were added, followed by 2,2,2-trifluoroacetamide (12.3 mg, 0.109 mmol). The reaction was stirred at room temperature for 2 h. The mixture was concentrated and purified via preparative reversed phase chromatography (Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 23-63%B (0.0- 20.0 min), 63-100%B (20.0-20.1 min), 100%B (20.1-24.0 min); Flow: 20 mL / min) to afford (3 S)-3 -[(7R)-3 - {4- [4-(3 -chloro-5-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl }-7- methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (20.8 mg, 36.0 pmol, 36% yield). The enantiomeric excess of this material was not determined. LCMS (Method E) retention time 1.88 min, [M+H]+577.8; 'H NMR (500 MHz, DMSO-d6) 8 10.96 (s, 1H), 8.55 (d, J=2.6 Hz, 1H), 7.67-7.52 (m, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.25- 7.10 (m, 3H), 6.99-6.83 (m, 2H), 4.87-4.68 (m, 1H), 4.60 (br d, J=6.6 Hz, 1H), 4.14 (s, 2H), 3.96-3.84 (m, 2H), 3.77 (br s, 2H), 2.92-2.76 (m, 1H), 2.69-2.56 (m, 2H), 2.11-1.92 (m, 1H), 1.42 (br d, . / =6,8 Hz, 3H).

[0917] EXAMPLE 141

[0918] (3 S)-3 -[(7 S)-3 - { 4- [4-(3 -chi oro-5 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -7 -methyl- 5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione

[0919] Prepared according to the general procedures described for Example 140, starting with l-(4-(3-chloro-5-fluorophenoxy)phenyl)piperazin-2-one TFA and di -tert-butyl (S)-2- ((S)-3-bromo-7-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pentanedioate. LCMS (Method F): retention time 1.82 min, [M+H]+578.2.

[0920] INTERMEDIATES 1-25 AND 1-26 di-tert-butyl (S)-2-((R)-6-chloro-3-methyl-l-oxo-l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- di-tert-butyl (S)-2-((S)-6-chl oro-3 -methyl- 1 -oxo- 1,3 -dihydro-2H-pyrrolo[3,4-c]pyri din-2 -

[0921] To a stirred solution of methyl 5-(l-bromoethyl)-2-chloroisonicotinate (5.3 g, 19.03 mmol) in acetonitrile (60 mL) was added di-tert-butyl L-glutamate (4.93 g, 19.03 mmol), sodium iodide (0.856 g, 5.71 mmol), and K2CO3 (7.89 g, 57.1 mmol). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated. Water (200 mL) was added, then the mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried on Na2SC>4, filtered, and concentrated under reduced pressure. The crude material was purified on SiC>2 (120 g, 0-30% EtOAc / petroleum ether) to obtain di-tert- butyl (2S)-2-(6-chloro-3-methyl-l-oxo-l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- yl)pentanedioate (3 g) as pale white solid. The two diastereomers were separated by preparative SFC with the following conditions: Column: Lux i-Amylose-3, 50 x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: ACN / IPA (50:50); Isocratic elution at 15%B; Flow Rate: 300 g / min; Temperature : 40°C; UV: 220 nm.

[0922] Fractions containing the first peak were concentrated under reduced pressure to afford di-tert-butyl (S)-2-((R)-6-chl oro-3 -methyl- 1 -oxo- 1, 3 -dihydro-2H-pyrrolo[3, 4- c]pyridin-2-yl)pentanedioate (1.42 g, 3.28 mmol, 17% yield). SFC (Column: Lux i- Amylose-3, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: ACN / IPA (50:50); Temperature: 40 °C; Isocratic elution at 20%B; Flow: 3.0 g / min; UV: 220 nM): retention time 2.23 min; LCMS (Method D) retention time 3.30 min, [M+H]+425.2; 'HNMR (400 MHz, DMSO ) 8: 8.80 (s, 1H), 7.77 (d, J= 0.88 Hz, 1H), 4.77 (q, J= 6.63 Hz, 1H), 4.54-4.46 (m, 1H), 2.22-2.31 (m, 4H), 1.46 (d, J = 6.75 Hz, 1H), 1.37 (s, 9H), 1.34 (s, 9H).

[0923] Fractions containing the second peak were concentrated under reduced pressure to afford di-tert-butyl (S)-2-((S)-6-chloro-3-methyl-l-oxo-l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)pentanedioate (832 mg, 1.94 mmol, 10% yield). SFC (Column: Lux i- Amylose-3, 4.6 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: ACN / IPA (50:50); Temperature: 40 °C; Isocratic elution at 20%B; Flow: 3.0 g / min; UV: 220 nM): retention time 2.91 min; LCMS (Method D) retention time 3.29 min, [M+H]+425.2; 'HNMR (400 MHz, DMSO ) 6: 8.81 (s, 1 H), 7.77 (d, J=0.88 Hz, 1 H), 4.81 (q, J=6.63 Hz, 1 H), 4.35-4.43 (m, 1 H), 2.20-2.34 (m, 4 H), 1.50 (d, J=6.63 Hz, 3 H), 1.35 (s, 9 H), 1.34 (s, 9H).

[0924] The absolute configuration at C3 of the pyrrolopyridine ring system of Intermediate 1-26 (peak 2) was assigned as (S) based on single-crystal x-ray diffraction data for this compound. Inferring from this result, the C3 stereochemistry of Intermediate 1-25 (peak 1) was assigned as (R).

[0925] EXAMPLE 142

[0926] (3 S)-3 - [(3R)-6- { 4- [4-(3 -chi oro-5 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -3 -methyl- l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2, 6-dione

[0927] Prepared according to the general procedures described for Example 140, starting with l-(4-(3-chloro-5-fluorophenoxy)phenyl)piperazin-2-one TFA and di-tert-butyl (S)-2- ((R)-6-chl oro-3 -methyl- 1 -oxo-1, 3 -dihydro-2H-pyrrolo[3,4-c]pyri din-2 -yl)pentanedioate. LCMS (Method E): retention time 1.86 min, [M+H]+577.8.

[0928] EXAMPLE 143

[0929] (3S)-3-(6-{4-[4-(3,5-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3-dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione

[0930] Intermediate 143 A: di-tert-butyl (S)-2-(6-(4-(4-(benzyloxy)phenyl)-3 -oxopiperazin- 1-yl)- l-oxoisoindolin-2-yl)pentanedioate

[0931] A mixture of di-tert-butyl (S)-2-(6-bromo-l-oxoisoindolin-2-yl)pentanedioate

[0932] (908 mg, 1.998 mmol), l-(4-(benzyloxy)phenyl)piperazin-2-one (564 mg, 1.998 mmol), Xphos Pd G3 (85 mg, 0.100 mmol) and cesium carbonate (1432 mg, 4.40 mmol) in 1,4- di oxane (15 mL) was stirred at 100 °C for 5 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried QSfeSCh), filtered, and concentrated by rotary evaporation. The crude material was purified by flash chromatography (SiCh) to afford di-tert-butyl (S)-2-(6-(4-(4-(benzyloxy)phenyl)-3-oxopiperazin-l-yl)-l-oxoisoindolin-2- yl)pentanedioate (1.02 g, 1.56 mmol, 78% yield). LCMS (Method A) retention time 1.12 min, [M+H]+656.3; 'H NMR (500 MHz, CHLOROFORM-d) 8 7.55-7.31 (m, 7H), 7.26- 7.19 (m, 2H), 7.12 (dd, J=8.4, 2.4 Hz, 1H), 7.05-6.96 (m, 2H), 5.09 (s, 2H), 4.99 (dd, J=10.9, 4.6 Hz, 1H), 4.69-4.28 (m, 2H), 4.11 (s, 2H), 3.91-3.78 (m, 2H), 3.71-3.58 (m, 2H), 2.45-2.31 (m, 2H), 2.27-2.06 (m, 2H), 1.46 (s, 9H), 1.41 (s, 9H). Intermediate 143B: di -tert-butyl (S)-2-(6-(4-(4-hydroxyphenyl)-3 -oxopiperazin- l-yl)-l- oxoisoindolin-2-yl)pentanedioate

[0933] A mixture of di-tert-butyl (S)-2-(6-(4-(4-(benzyloxy)phenyl)-3 -oxopiperazin- 1- yl)-l-oxoisoindolin-2-yl)pentanedioate (1.02 g, 1.555 mmol) and palladium on carbon (0.083 g, 0.078 mmol) in MeOH (20 mL) was stirred at room temperature under hydrogen balloon for 15 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford di-tert-butyl (S)-2-(6-(4-(4-hydroxyphenyl)-3- oxopiperazin-l-yl)-l-oxoisoindolin-2-yl)pentanedioate (750 mg, 1.33 mmol, 85% yield). LCMS (Method A): retention time 0.97 min, [M+H]+566.3; 'H NMR (500 MHz, CHLOROFORM-d) 8 7.40 (d, J=8.3 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.11 (d, J=8.6 Hz, 3H), 6.82 (d, ,7=8.7 Hz, 2H), 5.00 (dd, J=10.9, 4.6 Hz, 1H), 4.61 (d, J=16.4 Hz, 1H), 4.35 (d, <7=16.4 Hz, 1H), 4.05 (s, 2H), 3.84-3.72 (m, 2H), 3.64-3.52 (m, 2H), 2.43-2.30 (m, 2H), 2.27-2.03 (m, 2H), 1.47 (s, 9H), 1.42 (s, 9H).

[0934] Intermediate 143C: di-tert-butyl (S)-2-(6-(4-(4-(3,5-dichlorophenoxy)phenyl)-3- oxopiperazin- 1 -yl)- 1 -oxoisoindolin-2-yl)pentanedioate

[0935] A mixture of di-tert-butyl (S)-2-(6-(4-(4-hydroxyphenyl)-3 -oxopiperazin- l-yl)-l- oxoisoindolin-2-yl)pentanedioate (50 mg, 0.088 mmol), (3,5-dichlorophenyl)boronic acid (25.3 mg, 0.133 mmol), copper (II) acetate (24.08 mg, 0.133 mmol), DIEA (10.0 pl, 0.124 mmol), and 4A molecule sieves (100 mg) in DCM (2 mL) was stirred under ambient atmosphere at room temperature for 72 h. The mixture was filtered and the filtrate was concentrated. The crude material was purified by silica gel chromatography, eluting with 0 to 100% EtOAc in hexanes, to afford di-tert-butyl (S)-2-(6-(4-(4-(3,5- dichlorophenoxy)phenyl)-3-oxopiperazin-l-yl)-l-oxoisoindolin-2-yl)pentanedioate (20 mg, 32% yield). LCMS (Method A): retention time 1.22 min, [M+H]+710.3; 'H NMR. (500 MHz, CHLOROFORM-d) 8 7.46-7.31 (m, 4H), 7.22-7.05 (m, 4H), 6.93 (d, J=1.8 Hz, 2H), 4.99 (dd, J=10.8, 4.6 Hz, 1H), 4.69-4.29 (m, 2H), 4.16-4.09 (m, 2H), 3.95-3.88 (m, 2H), 3.74-3.64 (m, 2H), 2.41-2.33 (m, 2H), 2.26-2.18 (m, 1H), 2.16-1.99 (m, 1H), 1.46 (s, 9H), 1.41 (s, 9H).

[0936] Example 143:

[0937] TFA (0.163 mL, 2.11 mmol) was added to a mixture of di-tert-butyl (S)-2-(6-(4- (4-(3 , 5 -dichlorophenoxy)phenyl)-3 -oxopiperazin- 1 -yl)- 1 -oxoi soindolin-2- yl)pentanedioate (15 mg, 0.021 mmol) in DCM (1 mL) at room temperature. The resulting mixture was stirred for 4 h, then it was concentrated under reduced pressure. The residue was dissolved in DMF (1 mL), then DIEA (0.018 mL, 0.106 mmol), PyBOP (22.0 mg, 0.042 mmol), and 2,2,2-trifluoroacetamide (2.42 mg, 0.021 mmol) were added. The reaction was stirred at room temperature for 15 h. The mixture was purified via preparative reversed phase chromatography (Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Temperature: 25 °C; Gradient: 30-100%B (0.0-20.0 min), 100%B (20.1-24.0 min); Flow: 20 mL / min) to afford (S)-3-(6-(4-(4-(3,5-dichlorophenoxy)phenyl)-3-oxopiperazin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (1.6 mg, 2.8 pmol, 13% yield over two steps). LCMS (Method A) retention time 1.01 min, [M+H]+579.6; 'H NMR (500 MHz, METHANOL-d4) 6 7.52 (d, J=8.3 Hz, 1H), 7.46-7.43 (m, 2H), 7.38 (d, . / =2,4 Hz, 1H), 7.34 (dd, J=8.4, 2.4 Hz, 1H), 7.20-7.14 (m, 3H), 6.99 (d, J=1.7 Hz, 2H), 5.20-5.11 (m, 1H), 4.46-4.35 (m, 2H), 4.12 (s, 2H), 3.98-3.90 (m, 2H), 3.81-3.73 (m, 2H), 2.94-2.86 (m, 1H), 2.82-2.73 (m, 1H), 2.54-2.44 (m, 1H), 2.20-2.12 (m, 1H).

[0938] INTERMEDIATE 1-27 tert-butyl (S)-5-amino-4-(6-bromo-4-fluoro-l-oxoisoindolin-2-yl)-5-oxopentanoate

[0939] Prepared according to the general procedures described for Intermediate IB, starting with methyl 5-bromo-3-fluoro-2 -methylbenzoate. LCMS (Method C): retention time 2.51 min, [M+2H-tBu]+359.0; 'H NMR (400 MHz, DMSO-d6:D2O (~ 20: 1 v / v)) 8 7.82 (dd, J = 1.60, 8.40 Hz, 1H), 7.73 (d, J = 1.60 Hz, 1H), 7.60 (bs, 1H), 7.24 (bs, 1H), 4.71-4.74 (m, 1H), 4.59-4.70 (m, 2H), 2.16-2.19 (m, 3H), 2.01-2.04 (m, 1H), 1.34 (s, 9H).;19F NMR (376 MHz, DMSO-d6) 6 -116.99 (s, IF).

[0940] EXAMPLE 144

[0941] (3 S)-3 -(4-fluoro- 1 -oxo-6-{ 3 -oxo-4-[4-(2,3 , 5-trifluorophenoxy)phenyl]piperazin- 1 -y 1 } - 2,3 -dihydro- 1 H-i soindol-2-yl)piperidine-2, 6-dione

[0942] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-4-fluoro-l-oxoisoindolin-2-yl)-5- oxopentanoate (40 mg, 0.096 mmol), l-(4-(2,3,5-trifluorophenoxy)phenyl)piperazin-2- one (40.4 mg, 0.125 mmol), cesium carbonate (62.8 mg, 0.193 mmol), and Pd-PEPPSL IHept-Cl (4.69 mg, 4.82 pmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated by rotary evaporation.

[0943] The resulting product was dissolved in acetonitrile (3 mL). Methanesulfonic acid (55.0 pl, 0.847 mmol) was added, and the mixture was stirred at 50 °C for 2 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude material was purified via preparative reversed phase chromatography with the following conditions: Column: XBridge Cl 8, 19 mm x 200 mm, 5 gm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (3S)-3-(4-fluoro-l-oxo-6-{3-oxo-4-[4-(2,3,5- trifluorophenoxy)phenyl]piperazin-l-yl}-2,3-dihydro-lH-isoindol-2-yl)piperidine-2,6- dione (0.5 mg, 0.9% yield). LCMS (Method E) retention time 2.02 min, [M+H]+583.2; 'HNMR (500 MHz, DMSO-d6) 8 7.47-7.35 (m, 3H), 7.20-7.06 (m, 4H), 7.00-6.93 (m, 1H), 5.10 (dd, J= 13.3, 4.9 Hz, 1H), 4.45 (d, J= 16.6 Hz, 1H), 4.29 (d, J= 16.6 Hz, 1H), 4.10 (s, 2H), 3.91-3.81 (m, 2H), 3.79-3.71 (m, 2H), 2.97-2.85 (m, 1H), 2.66-2.56 (m, 1H), 2.47-2.36 (m, 1H), 2.07-1.96 (m, 1H).

[0944] EXAMPLES 145-157

[0945] The compounds in Table 16 were prepared according to the general procedures described for Example 144, starting with tert-butyl (S)-5-amino-4-(6-bromo-4-fhioro-l- oxoisoindolin-2-yl)-5-oxopentanoate and the appropriate aryl piperazinone bearing the desired R fragment:

[0946] TABLE 16

[0947] EXAMPLE 158

[0948] (3 S)-3 -(4-chl oro-6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione

[0949] Intermediate 158A: di-tert-butyl (S)-2-(6-bromo-4-chloro-l-oxoisoindolin-2-yl) pentanedioate

[0950] A solution of methyl 5-bromo-3-chloro-2-methylbenzoate (3.99 g, 15.14 mmol), NBS (3.23 g, 18.17 mmol) and AIBN (0.249 g, 1.514 mmol) in 1,2-di chloroethane (76 ml) was stirred at 85 °C overnight. The reaction mixture was cooled to room temperature and washed with brine. The organic layer was dried over Na?SO4 and concentrated.

[0951] The residue was dissolved in DMF (30 mL), then di-tert-butyl L-glutamate hydrochloride (6.72 g, 22.71 mmol) and DIEA (7.93 ml, 45.4 mmol) were added. The reaction was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc, washed with water, 10% LiCl, brine, dried over Na2SC>4, and concentrated. The crude material was purified by flash chromatography (SiCh, 80 g, 0- 100% EtOAc / hexanes) to afford di-tert-butyl (S)-2-(6-bromo-4-chloro-l-oxoisoindolin-2- yl)pentanedioate (6.99 g, 94 % yield). LCMS (Method A): retention time 1.14 min, [M+Na]+509.9, 511.9.

[0952] Intermediate 158B: di-tert-butyl (S)-2-(4-chloro-6-(4-(4-(3,5-difluorophenoxy)phenyl)-3- oxopiperazin- 1 -yl)- 1 -oxoisoindolin-2-yl)pentanedioate

[0953] A mixture of di-tert-butyl (S)-2-(6-bromo-4-chloro-l-oxoisoindolin-2- yl)pentanedioate (1 g, 2.046 mmol), l-(4-(3,5-difluorophenoxy)phenyl)piperazin-2-one hydrochloride (0.697 g, 2.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.047 g, 0.051 mmol), Xantphos (0.059 g, 0.102 mmol), and CS2CO3 (2.000 g, 6.14 mmol) in 1,4- di oxane (10 mL) was purged with nitrogen. The reaction was stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through Celite, and the filtrate was concentrated. The crude material was purified by flash chromatography (SiO2, 40 g, 0-80% EtOAc / hexanes) to afford di-tert-butyl (S)-2-(4- chloro-6-(4-(4-(3,5-difluorophenoxy)phenyl)-3-oxopiperazin-l-yl)-l-oxoisoindolin-2- yl)pentanedioate (1.33 g, 91% yield). LCMS (Method A): retention time 1.18 min, [M+H]+712.5.

[0954] Example 158:

[0955] To a solution of di-tert-butyl (S)-2-(4-chloro-6-(4-(4-(3,5- difluorophenoxy)phenyl)-3 -oxopiperazin- 1 -yl)- 1 -oxoi soindolin-2-yl)pentanedioate (1.33 g, 1.867 mmol) in DCM (5 mL) was added anisole (0.408 mL, 3.73 mmol) and TFA (5 mL). The reaction was stirred at room temperature for 2 h and then concentrated. The residue was co-evaporated with DCM / toluene three times, then the resulting product was dissolved in DCM (20 mL). To this mixture was added 2,2,2-trifluoroacetamide (0.232 g, 2.054 mmol) and HATU (1.562 g, 4.11 mmol), followed by dropwise addition of DIEA (2.61 mL, 14.94 mmol). The reaction was then stirred at room temperature for 30 min and concentrated. The residue was dry loaded onto Celite and purified by flash chromatography (SiCh, 40 g, 0-100% EtOAc / DCM, then hold at 100% EtOAc) to afford partially purified product (1.16 g). This material was further purified via preparative SFC chromatography with the following conditions: Column: Chiralcel OJ-H, 30 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Isocratic elution at 25 %B over 20.0 min; Flow Rate: 109.5 mL / min; Column Temperature: 35 °C. Fraction collection was triggered by UV (220 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford di-tert-butyl (S)-2- (4-chloro-6-(4-(4-(3, 5-difluorophenoxy)phenyl)-3 -oxopiperazin- 1 -yl)-l -ox oisoindolin-2- yl)pentanedioate (680 mg, 63% yield). SFC (Conditions: Column: Chiralcel OJ-H, 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Temperature: 25 °C; Isocratic elution at 25 %B over 10 min; Flow: 2.0 mL / min; Detection: UV (220 nm) and UV (254 nm)): retention time 4.13 min (99% ee); LCMS (Method E): retention time 1.79 min, [M+H]+581.3; 'H NMR (400 MHz, DMSO-d6) 8 11.00 (s, 1H), 7.51-7.42 (m, 2H), 7.35 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.21- 7.15 (m, 2H), 7.03 (tt, J=9.4, 2.3 Hz, 1H), 6.77 (dd, J=8.6, 2.3 Hz, 2H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.44-4.35 (m, 1H), 4.30-4.20 (m, 1H), 4.13 (s, 2H), 3.93-3.84 (m, 2H), 3.82- 3.72 (m, 2H), 2.99-2.85 (m, 1H), 2.71-2.57 (m, 1H), 2.46 (br d, J=8.6 Hz, 1H), 2.06-1.93 (m, 1H).

[0956] EXAMPLES 159-160

[0957] The compounds in Table 17 were prepared according to the general procedures described for Example 158, starting with di-tert-butyl (S)-2-(6-bromo-4-chloro-l- oxoisoindolin-2-yl)pentanedioate and the appropriate aryl piperazinone bearing the desired R fragment: TABLE 17

[0958] EXAMPLE 161

[0959] (3 S)-3 -(6- { 4 - [4-(3 , 5-difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -4-methyl- 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione

[0960] Intermediate 161A: di-tert-butyl 2-(6-(4-(4-(3,5-difluorophenoxy)phenyl)-3- oxopiperazin- 1 -yl)-4-m ethyl- 1 -oxoisoindolin-2-yl)pentanedioate A mixture of di-tert-butyl (S)-2-(4-chloro-6-(4-(4-(3,5-difluorophenoxy)phenyl)-

[0961] 3-oxopiperazin-l-yl)-l-oxoisoindolin-2-yl)pentanedioate (130 mg, 0.183 mmol), trimethylboroxine (0.128 mL, 0.913 mmol), Pd-PEPPSI-IHept-Cl (8.88 mg, 9.13 pmol), and potassium carbonate (101 mg, 0.730 mmol) in 1,4-dioxane (1.5 mL) was purged with nitrogen and stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The filtrate was concentrated and the residue was purified by flash chromatography (SiCh, 4 g, 0-100% EtOAc / hexanes) to afford di-tert-butyl (S)-2-(6-(4-(4-(3,5-difluorophenoxy)phenyl)-3- oxopiperazin-l-yl)-4-methyl-l-oxoisoindolin-2-yl)pentanedioate (124 mg, 98% yield). LCMS (Method A): retention time 1.11 min, [M+H]+692.4.

[0962] Example 161 :

[0963] To a solution of di-tert-butyl (S)-2-(6-(4-(4-(3,5-difluorophenoxy)phenyl)-3- oxopiperazin-l-yl)-4-methyl-l-oxoisoindolin-2-yl)pentanedioate (1.47 g, 2.125 mmol) in DCM (5 mL) was added anisole (0.464 mL, 4.25 mmol) and TFA (5 mL). The reaction was stirred at room temperature for 2 h and then concentrated. The residue was coevaporated with DCM / toluene three times, then the resulting product was dissolved in DCM (20 mL). To this mixture was added 2,2,2-trifluoroacetamide (0.264 g, 2.337 mmol) and HATU (1.778 g, 4.67 mmol), followed by dropwise addition of TEA (2.37 mL, 17.0 mmol). The reaction was then stirred at room temperature for 30 min and concentrated. The residue was dry loaded onto Celite and purified by flash chromatography (SiCh, 40 g, 0-100% EtOAc / DCM, then hold at 100% EtOAc) to afford partially purified product (1.73 g). This material was further purified via preparative SFC chromatography with the following conditions: Column: Chiralpak IH, 30 mm x 250 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Isocratic elution at 45 %B over 20.0 min; Flow Rate: 94.75 mL / min; Column Temperature: 35 °C. Fraction collection was triggered by UV (220 nm). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (3S)-3-(6-{4-[4- (3 , 5 -difluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } -4-m ethyl- 1 -oxo-2, 3 -dihydro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (374 mg, 30% yield). SFC (Column: Chiralpak IH, 4.6 mm x 150 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA / ACN (50:50); Temperature: 45.0 °C; Isocratic elution at 45 %B over 20.0 min; Flow: 2.0 mL / min; Detection: PDA (210 nm-400 nm)): retention time 5.54 min (99% ee); LCMS (Method E): retention time 1.64 min, [M+H]+561.3; 'H NMR (400 MHz, DMSO-d6) 8 10.98 (s, IH), 7.52-7.39 (m, 2H), 7.25-7.13 (m, 3H), 7.09-6.94 (m, 2H), 6.84-6.68 (m, 2H), 5.13 (dd, J=13.2, 5.1 Hz, IH), 4.41-4.26 (m, IH), 4.25-4.12 (m, IH), 4.05 (s, 2H), 3.93-3.80 (m, 2H), 3.77-3.62 (m, 2H), 3.03-2.84 (m, IH), 2.72-2.58 (m, IH), 2.47-2.37 (m, IH), 2.32 (s, 3H), 2.09-1.95 (m, IH). EXAMPLES 162-169

[0964] The compounds in Table 18 were prepared according to the general procedures described for Example 161, using the appropriate organoboron reagent to install the desired R2substituent (i.e., ethyl boronic acid, cyclopropylboronic acid, 4, 4,5,5- tetramethyl-2-(oxetan-3-ylmethyl)-l,3,2-dioxaborolane, potassium(methoxymethyl) trifluoroborate, or 2-(2-methoxyethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane) with RuPhos Pd G3 in the first step and the appropriate aryl piperazinone bearing the desired R fragment in the last step:

[0965] TABLE 18

[0966] EXAMPLE 170

[0967] (3 S)-3 -(6- { 4 - [4 - (3 , 5 -difluorophenoxy )phenyl ]-3 -oxopiperazin- 1 -yl } -4-hy droxy- 1 -oxo-

[0968] 2,3 -dihydro- 1 H-i soindol-2-yl)piperidine-2, 6-dione

[0969] Intermediate 170A: methyl 3-acetoxy-5-bromo-2-methylbenzoate

[0970] To a stirred solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (50 g, 204 mmol) in DCM (500 mL), was added TEA (42.7 mL, 306 mmol). The resulting mixture was cooled to 0 °C, then acetyl chloride (17.4 mL, 245 mmol) was added slowly, and the reaction was stirred for 1.5 h. Water was then added, and the layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to afford crude methyl 3-acetoxy-5-bromo-2-methylbenzoate (54 g, 92% yield) as a brownish oil, which was carried into the next step without further purification.XH NMR (300 MHz, CHLOROFORM-d) 8 7.91 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 3.90 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H).

[0971] Intermediate 170B: methyl 3-acetoxy-5-bromo-2-(bromomethyl)benzoate

[0972] To a stirred solution of methyl 3-acetoxy-5-bromo-2-methylbenzoate (54 g, 188 mmol) in acetonitrile (750 mL), was added AIBN (6.18 g, 37.6 mmol), followed by NBS (50.2 g, 282 mmol). The reaction mixture was stirred for 20 h at 90 °C. Volatiles were removed under reduced pressure. The residue was washed with water, then the aqueous layer was decanted. The residue was dissolved in ethyl acetate, washed with water followed by brine solution, dried over sodium sulfate, filtered, and concentrated. The crude solid was triturated with 300 mL petroleum ether and stirred for 1 h. The solid was filtered and washed with petroleum ether (100 mL) to afford crude methyl 3-acetoxy-5- bromo-2-(bromomethyl)benzoate (43 g), which was carried into the next step without further purification.

[0973] Intermediate 170C: tert-butyl (S)-5-amino-4-(6-bromo-4-hydroxy-l-oxoisoindolin-2-yl)- 5-oxopentanoate

[0974] To a stirred solution of methyl 3-acetoxy-5-bromo-2-(bromomethyl)benzoate (43 g) and tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (33.7 g, 141 mmol) in 2-propanol (600 mL), was added DIEA (123 mL, 705 mmol). The reaction was stirred at 85 °C for 15 h. Volatiles were removed under reduced pressure. The crude residue was dissolved in ethyl acetate, washed with water, followed by brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by reversed phase chromatography to afford tert-butyl (S)-5-amino-4-(6-bromo-4-hydroxy-l-oxoisoindolin- 2-yl)-5-oxopentanoate (8.8 g, 21.02 mmol, 11% yield over two steps) as pale brown solid. LCMS (Method D): retention time 2.20 min, [M+H]+413.0, 415.0.

[0975] Example 170:

[0976] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-4-hydroxy-l-oxoisoindolin-2-yl)- 5-oxopentanoate (35 mg, 0.085 mmol), l-(4-(3,5-difluorophenoxy)phenyl)piperazin-2- one (28.3 mg, 0.093 mmol), cesium carbonate (55.2 mg, 0.169 mmol), and Pd-PEPPSI- IHept-Cl (4.12 mg, 4.23 pmol) in 1,4-dioxane (1.5 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SC>4), filtered, and concentrated by rotary evaporation. The resulting crude product was dissolved in acetonitrile (3 mL), followed by methanesulfonic acid (55.0 pl, 0.847 mmol) and stirred at 40 °C for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude material was purified via preparative reversed phase chromatography with the following conditions: Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Gradient: 21-61%B (0.0-20.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative reversed phase chromatography with the following conditions: Column: Xbridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Gradient: 19-59%B (0.0-20.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (S)-3-(6-(4-(4-(3,5- difluorophenoxy)phenyl)-3 -oxopiperazin- 1 -yl)-4-hydroxy- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione (0.4 mg, 0.9% yield). LCMS (Method E) retention time 1.66 min, [M+H]+563.3.

[0977] EXAMPLE 171

[0978] (3S)-3-(4-hydroxy-6-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione

[0979] Prepared according to the general procedures described for Example 170, starting with l-(4-(o-tolyloxy)phenyl)piperazin-2-one. LCMS (Method F): retention time 1.69 min, [M+H]+541.1.

[0980] EXAMPLE 172 (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-ethoxy-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione

[0981] To a solution of tert-butyl (S)-5-amino-4-(6-bromo-4-hydroxy-l-oxoisoindolin-2- yl)-5-oxopentanoate (100 mg, 0.242 mmol) in DMF (2 mL) was added iodoethane (377 mg, 2.420 mmol) and cesium carbonate (158 mg, 0.484 mmol). The reaction was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SC>4 and concentrated to give crude tert-butyl (S)-5-amino-4-(6-bromo-4-ethoxy-l-oxoisoindolin-2-yl)-5- oxopentanoate, which was used in the next step without further purification.

[0982] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-4-ethoxy-l-oxoisoindolin-2-yl)- 5 -oxopentanoate (30 mg), l-(4-(3,5-difluorophenoxy)phenyl)piperazin-2-one (22.75 mg, 0.075 mmol), cesium carbonate (44.3 mg, 0.136 mmol), and Pd-PEPPSI-IHept-Cl (3.31 mg, 3.40 pmol) in 1,4-di oxane (2 mL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried QSfeSCh), filtered, and concentrated by rotary evaporation. The resulting crude product was dissolved in acetonitrile (3 mL), followed by methanesulfonic acid (55.0 pl, 0.847 mmol) and stirred at 50 °C for 2 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude material was purified via preparative reversed phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Gradient: 29-69%B (0.0-20.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l- yl}-4-ethoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (3.1 mg, 2% yield over two steps). LCMS (Method E) retention time 1.97 min, [M+H]+591.0; 'H NMR (500 MHz, DMSO-d6) 8 10.90 (s, 1H), 7.41 (d, J= 8.9 Hz, 2H), 7.12 (d, J= 8.8 Hz, 2H), 6.99-6.89 (m, 1H), 6.82-6.73 (m, J= 10.8 Hz, 2H), 6.72-6.66 (m, 2H), 5.01 (dd, J= 13.1, 5.2 Hz, 1H), 4.24 (br d, J= 16.8 Hz, 1H), 4.15 (q, J= 6.9 Hz, 2H), 4.10 (d, J= 17.0 Hz, 1H), 4.01 (s, 2H), 3.86-3.77 (m, 2H), 3.71-3.61 (m, 2H), 2.91-2.77 (m, 1H), 2.60-2.51 (m, 1H), 2.43-2.30 (m, 1H), 1.98-1.89 (m, 1H), 1.30 (t, J= 6.9 Hz, 3H).

[0983] EXAMPLES 173-187

[0984] The compounds in Table 19 were prepared according to the general procedures described for Example 172, using the appropriate alkyl halide to install Ri and the appropriate aryl piperazinone bearing the desired R fragment:

[0985] TABLE 19

[0986] EXAMPLE 188

[0987] (3 S)-3 - [4-(difluoromethoxy)-6- { 4- [4 - (3 , 5 -di fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 - yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione

[0988] Intermediate 188 A: methyl 5-bromo-3-(difluoromethoxy)-2-methylbenzoate

[0989] To a solution of methyl 5-bromo-3-hydroxy-2-methylbenzoate (500 mg, 2.04 mmol) in acetonitrile (20 mL) at -20 °C was added a cold solution of potassium hydroxide (1145 mg, 20.40 mmol) in water (10 mL). Diethyl (bromodifluoromethyl)phosphonate (1.090 mL, 6.12 mmol) was added dropwise while keeping the temperature below -20 °C. At the end of the addition, the reaction medium was warmed to room temperature and stirred for 16 h. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated. The crude material was purified by flash chromatography (SiC>2, 5-10% EtOAc / petroleum ether) to obtain methyl 5-bromo-3-(difluoromethoxy)-2- methylbenzoate (350 mg, 58% yield) as a white solid. Intermediate 188B: methyl 5-bromo-2-(bromomethyl)-3-(difluoromethoxy)benzoate

[0990] To a solution of methyl 5-bromo-3-(difluoromethoxy)-2-methylbenzoate (3.75 g, 12.71 mmol) in DCE (30 mL) was added NBS (2.488 g, 13.98 mmol), followed by AIBN

[0991] (0.417 g, 2.54 mmol). The reaction was stirred at 90 °C for 3 h. Solvent was removed to obtain a crude paste, to which 50 mL of 10% EtOAc in petroleum ether was added and shaken for 1 min, then solids were filtered off. The filter cake was washed with 50 mL of 10% EtOAc in petroleum ether again. The filtrate was collected and solvent was removed under vacuum to obtain crude methyl 5-bromo-2-(bromomethyl)-3- (difluoromethoxy)benzoate (4.88 g) as a pale brown liquid, which was carried into the next step without further purification.

[0992] Intermediate 188C: tert-butyl (S)-5-amino-4-(6-bromo-4-(difluoromethoxy)-l- oxoisoindolin-2-yl)-5-oxopentanoate

[0993] To a solution of methyl 5-bromo-2-(bromomethyl)-3-(difluoromethoxy)benzoate (4.86 g, 13.0 mmol) in DMF (35 mL) was added tert-butyl (S)-4,5-diamino-5- oxopentanoate (2.89 g, 14.3 mmol) and DIEA (11.35 mL, 65.0 mmol). The reaction was stirred for 16 h at 75 °C. The mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (2x). The combined organic layers were dried on Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography (SiO2, 20-40% EtOAc in petroleum ether) to obtain tert-butyl (S)-5- amino-4-(6-bromo-4-(difluorom ethoxy)- 1 -oxoi soindolin-2-yl)-5 -oxopentanoate (3.6 g, 7.34 mmol, 57% yield) as pale white solid. LCMS (Method C): retention time 2.56 min, [M+2H-tBu]+407.0.

[0994] Example 188:

[0995] A mixture of tert-butyl 5-amino-4-(6-bromo-4-(difluoromethoxy)-l- oxoisoindolin-2-yl)-5 -oxopentanoate (80 mg, 0.173 mmol), l-(4-(3,5- difhiorophenoxy)phenyl)piperazin-2-one (55.2 mg, 0.181 mmol), cesium carbonate (113 mg, 0.345 mmol), and Pd-PEPPSI-IHept-Cl (16.80 mg, 0.017 mmol) in 1,4-dioxane ( 3 mL) was degassed by nitrogen sparging, blanketed under nitrogen, and stirred at 100 °C for 3 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a Celite pad. The filtrate was washed with dilute HC1, followed by brine. The organic phase was dried overNa2SC>4, filtered, and concentrated by rotary evaporation. The residue was taken up in ACN (2 mL), treated with methanesulfonic acid (33.6 pl, 0.518 mmol), and stirred at 60 °C overnight. The mixture was purified via preparative reversed phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Gradient: 29-69%B (0.0-20.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. LCMS (Method F): retention time 1.92 min, [M+H]+613.2; 'H NMR (500 MHz, DMSO-d6) 8 10.98 (s, 1H), 7.53 (s, 1H), 7.49-7.44 (m, J=8.9 Hz, 2H), 7.38 (s, 1H), 7.24 (s, 1H), 7.20- 7.16 (m, . / =8,9 Hz, 2H), 7.13 (s, 1H), 7.06 (s, 1H), 7.00 (t, J=8.9 Hz, 1H), 6.78-6.72 (m, 2H), 5.09 (dd, J=13.2, 5.3 Hz, 1H), 4.40 (d, J=16.9 Hz, 1H), 4.25 (d, J=16.7 Hz, 1H), 4.11 (s, 2H), 3.89 (br t, J=5.1 Hz, 2H), 3.77-3.73 (m, 2H), 3.51-3.46 (m, 1H), 2.90 (ddd, J=17.5, 13.1, 4.9 Hz, 1H), 2.62-2.54 (m, 11H), 2.49-2.40 (m, 1H), 2.04-1.98 (m, 1H).

[0996] EXAMPLES 189-190

[0997] The compounds in Table 20 were prepared according to the general procedures described for Example 188, using the appropriate aryl piperazinone bearing the desired R fragment:

[0998] TABLE 20

[0999] EXAMPLE 191

[1000] (3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4-(oxan-4- yloxy)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione Intermediate 191A: methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4- yl)oxy)benzoate

[1001] To a solution of tetrahydro-2H-pyran-4-ol (1.667 g, 16.32 mmol), methyl 5- bromo-3 -hydroxy -2 -methylbenzoate (2 g, 8.16 mmol), and triphenylphosphine (4.28 g, 16.32 mmol) in THF ( 30 mL) was added diisopropyl azodi carb oxy late (3.17 ml, 16.32 mmol) dropwise at 0 °C. The reaction was stirred at room temperature overnight. The mixture was concentrated by rotary evaporation and the residue was purified via flash chromatography on silica gel to afford methyl 5-bromo-2-methyl-3-((tetrahydro-2H- pyran-4-yl)oxy)benzoate (2.1g, 71% yield) as a clear oil. LCMS (Method A): retention time 1.04 min, [M+H]+328.7, 330.6.

[1002] Intermediate 191B: tert-butyl (S)-5-amino-4-(6-bromo-l-oxo-4-((tetrahydro-2H-pyran-4- yl)oxy)isoindolin-2-yl)-5-oxopentanoate

[1003] To a solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4- yl)oxy)benzoate (2.1 g, 5.81 mmol) in DCE (36.3 mL) was added NBS (1.343 g, 7.55 mmol) and AIBN (0.191 g, 1.161 mmol). The resulting mixture was degassed by nitrogen sparging and stirred overnight at 85 °C in a sealed tube. The mixture was cooled to room temperature, diluted with DCM, and washed with 10% aqueous sodium thiosulfate solution. The organic phase was separated and washed with water. The organic layer was then dried by stirring with Na2SO4. The mixture was filtered, and the filtrate was concentrated in vacuo to afford a crude oil that was used directly for the next step. The oil was taken up in DMF (10 mL), then tert-butyl (S)-4,5-diamino-5- oxopentanoate (1.665 g, 6.97 mmol) and DIEA (3.04 ml, 17.42 mmol) were added. The resulting mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The aqueous phase was back- extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and filtered, and concentrated in vacuo. The crude material was purified via flash chromatography on silica gel to afford tert-butyl (S)-5-amino-4-(6-bromo-l-oxo-4- ((tetrahydro-2H-pyran-4-yl)oxy)isoindolin-2-yl)-5-oxopentanoate (2.6 g, 90% yield). LCMS (Method A): retention time 0.90 min, [M+Na]+519.0, 520.9;XH NMR (500 MHz, CHLOROFORM-d) 8 7.52 (d, J=1.4 Hz, 1H), 7.12 (d, J=1.2 Hz, 1H), 6.50 (br s, 1H), 5.54 (br s, 1H), 4.94-4.87 (m, 1H), 4.60 (tt, J=7.9, 3.9 Hz, 1H), 4.47 (d, J=17.8 Hz, 1H), 4.35 (d, J=17.9 Hz, 1H), 4.03-3.96 (m, 2H), 3.68-3.59 (m, 2H), 2.46-2.20 (m, 3H), 2.19- 2.02 (m, 3H), 1.91-1.74 (m, 3H), 1.48-1.43 (m, 9H). Example 191 :

[1004] A mixture of tert-butyl (S)-5-amino-4-(6-bromo-l-oxo-4-((tetrahydro-2H-pyran- 4-yl)oxy)isoindolin-2-yl)-5-oxopentanoate (100 mg, 0.201 mmol), l-(4-(3,5- difluorophenoxy)-2-fluorophenyl)piperazin-2-one (79 mg, 0.221 mmol), cesium carbonate (197 mg, 0.603 mmol), and Pd-PEPPSI-IHept-Cl (19.56 mg, 0.020 mmol) in 1,4-di oxane (2 mL) was degassed by nitrogen sparging, blanketed under nitrogen, and stirred at 100 °C for 3 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a Celite pad. The filtrate was washed with dilute HC1, followed by brine. The organic phase was dried over Na2SC>4, filtered, and concentrated by rotary evaporation. The residue was taken up in ACN (1 mL), treated with methanesulfonic acid (39.2 pl, 0.603 mmol), and stirred at 50 °C overnight. The crude material was purified via preparative reversed phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM ammonium acetate, Mobile Phase B: ACN / H2O (95:5) with 10 mM ammonium acetate; Gradient: 27-67%B (0.0-20.0 min); Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. LCMS (Method F) retention time 1.91 min, [M+H]+664.9;!H NMR (500 MHz, DMSO-d6) 8 10.96 (s, 1H), 7.52 (t, J=8.7 Hz, 1H), 7.20 (dd, J=11.0, 2.4 Hz, 1H), 7.11-6.99 (m, 2H), 6.96 (s, 1H), 6.91-6.83 (m, 3H), 5.09 (dd, J=13.1, 5.0 Hz, 1H), 4.86 (dt, J=8.0, 4.0 Hz, 1H), 4.31 (d, J=16.8 Hz, 1H), 4.17 (br d, J=16.7 Hz, 1H), 4.10 (s, 2H), 3.86 (br dd, J=10.5, 4.2 Hz, 2H), 3.80-3.70 (m, 4H), 3.53 (br t, J=8.8 Hz, 1H), 3.41 (br s, 1H), 2.95-2.85 (m, 1H), 2.61-2.53 (m, 13H), 2.49-2.38 (m, 1H), 2.07-1.95 (m, 3H), 1.67- 1.58 (m, 2H).

[1005] EXAMPLES 192-193

[1006] The compounds in Table 21 were prepared according to the general procedures described for Example 191, using the appropriate alcohol to install Ri and incorporating the appropriate aryl piperazinone containing the desired R fragment:

[1007] TABLE 21

[1008] INTERMEDIATE 1-28 tert-butyl (S)-5-amino-4-(6-bromo-l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)-5- oxopentanoate

[1009] Intermediate I-28A: 5-bromo-2-methyl-3-(trifluoromethoxy)benzoic acid

[1010] To a solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (3 g, 10.53 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (50 mL) was added potassium carbonate (2.91 g, 21.05 mmol), silver carbonate (2.90 g, 10.53 mmol), potassium trifluoro(methyl)borate (2.95 g, 24.21 mmol) and pentamethylcyclopentadienyliridium(III)chloride dimer (0.562 g, 1.053 mmol). The mixture was stirred at 100 °C for 48 h in a sealed tube. Solvent was removed, then EtOAc (100 mL) and water (100 mL) were added. The aqueous layer was acidified to pH 2-3, then the organic layer was separated, washed with brine (100 mL), dried on Na2SO4, filtered, and concentrated. The crude material was purified by reversed phase chromatography to obtain 5-bromo-2-methyl-3-(trifluoromethoxy)benzoic acid (720 mg, 23% yield; ~4: 1 mixture of isomers) as an off-yellow solid. Data reported for peaks associated with major product. LCMS (Method D): retention time 2.68 min, [M- H]’ 296.8; 'HNMR (400 MHz, DMSC ,) 6 13.52-13.75 (m, 1H), 7.94 (d, J=2.00 Hz, 1H), 7.81 (s, 1H), 2.39 (s, 3H);19F NMR (377 MHz, DMSC ,) 6 -56.74 (s, IF).

[1011] Intermediate I-28B: methyl 5-bromo-2-methyl-3-(trifluoromethoxy)benzoate

[1012] To a solution of 5-bromo-2-methyl-3-(trifluoromethoxy)benzoic acid (720 mg, 2.408 mmol) in acetone (5 mL) was added K2CO3 (666 mg, 4.82 mmol) followed by methyl iodide (0.753 mL, 12.04 mmol). The reaction was stirred overnight, then solvent was removed. The residue was taken up in EtOAc (100 mL), dried on Na2SC>4, filtered and concentrated. The crude material was purified on SiC>2 (40 g, 0-5% EtOAc in petroleum ether) to obtain methyl 5-bromo-2-methyl-3-(trifluoromethoxy)benzoate (716 mg, 95 % yield; ~4: 1 mixture of isomers) as an off-white solid. Data reported for peaks associated with major product.XH NMR (400 MHz, DMSO- e) 6: 7.96 (d, J= 2.13 Hz, 1H), 7.86 (s, 1H), 3.86 (s, 3H), 2.37 (s, 3H).19F NMR (377 MHz, DMSC ,) 6: -56.80 (s, IF).

[1013] Intermediate I-28C: methyl 5-bromo-2-(bromomethyl)-3-(trifluoromethoxy)benzoate To a stirred solution of methyl 5-bromo-2-methyl-3-(trifluoromethoxy)benzoate (946 mg, 3.02 mmol) in DCE (10 mL) was added NBS (511 mg, 2.87 mmol) and AIBN (149 mg, 0.907 mmol). The reaction was stirred at 80 °C for 2 h. Solvent was removed and the crude material was purified on SiCh (24 g, 0-2% EtOAc / petroleum ether) to obtain methyl 5-bromo-2-(bromomethyl)-3-(trifluoromethoxy)benzoate (1.047 g, 88 % yield; ~4: 1 mixture of isomers) as a colorless liquid. Data reported for peaks associated with major product. 'H NMR (400 MHz, DMSO ) 6: 8.04 (d, J= 2.00 Hz, 1H), 7.92-

[1014] 7.95 (m, 1H), 4.88 (s, 2H), 3.91 (s, 3H);19F NMR (376 MHz, DMSO ) 6: -55.93 (s, IF).

[1015] Intermediate 1-28:

[1016] To a solution of methyl 5-bromo-2-(bromomethyl)-3-(trifluoromethoxy)benzoate (1045 mg, 2.67 mmol) in ACN (2 mL) was added tert-butyl (S)-4,5-diamino-5- oxopentanoate (1078 mg, 5.33 mmol), followed by DIEA (1.397 mL, 8.00 mmol). The reaction mixture was stirred at 80 °C for 2 h, then solvent was removed under reduced pressure. The crude material was purified by reversed phase chromatography to afford tert-butyl (S)-5-amino-4-(6-bromo-l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)-5- oxopentanoate (815 mg, 63% yield) as a white solid. LCMS: (Method D): retention time

[1017] 2.96 min, [M+2H-tBu]+424.8, 426.8; 'H NMR (400 MHz, DMSO ) 6 7.93 (d, J= 1.50 Hz, 1H), 7.90-7.92 (m, 1H), 7.61 (br s, 1H), 7.24 (br s, 1H), 4.68-4.78 (m, 1H), 4.53-4.67 (m, 2H), 2.14-2.20 (m, 3H), 1.97-2.09 (m, 1H), 1.32 (s, 9H),19F NMR (376 MHz, DMSO-ifc) 8 -56.73 (s, IF).

[1018] EXAMPLES 194-195

[1019] The compounds in Table 22 were prepared according to the general procedures described for Example 132, starting with tert-butyl (S)-5-amino-4-(6-bromo-l-oxo-4- (trifluoromethoxy)isoindolin-2-yl)-5-oxopentanoate and the appropriate aryl piperazinone bearing the desired R fragment:

[1020] TABLE 22

[1021] INTERMEDIATE 1-29 tert-butyl (S)-5-amino-4-(6-bromo-5-fluoro-l-oxoisoindolin-2-yl)-5-oxopentanoate

[1022] Prepared according to the general procedures described for Intermediate IB, starting with methyl 5-bromo-4-fluoro-2 -methylbenzoate. LCMS (Method D): retention time 2.52 min, [M+H]+415.2, 417.2; 'H NMR (400 MHz, DMSO-d6) 8 7.98 (d, J= 6.4 Hz, 1H), 7.68 (d, J= 8.5 Hz, 1H), 7.59 (brs, 1H), 7.20 (brs, 1H), 4.76-4.68 (m, 1H), 4.64- 4.42 (m, 2H), 2.22-2.14 (m, 3H), 2.02-1.92 (m, 1H), 1.33 (s, 9H).

[1023] EXAMPLES 196-204

[1024] The compounds in Table 23 were prepared according to the general procedures described for Example 144, starting with tert-butyl (S)-5-amino-4-(6-bromo-5-fluoro-l- oxoisoindolin-2-yl)-5-oxopentanoate and the appropriate aryl piperazinone bearing the desired R fragment:

[1025] TABLE 23

[1026]

[1027] INTERMEDIATE 1-30 tert-butyl (S)-5 -amino-4-(6-bromo-7-fluoro- 1 -oxoi soindolin-2-yl)-5 -oxopentanoate Prepared according to the general procedures described for Intermediate 1-28, starting with 3-bromo-2-fluorobenzoic acid. LCMS (Method D): retention time 2.48 min, [M+2H-tBu]+359.0, 361.0; 'H NMR (400 MHz, DMSO-d6) 8 7.91 (dd, J= 6.2, 8.1 Hz, 1H), 7.58 (brs, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.21 (brs, 1H), 4.69 (dd, J= 4.5, 10.4 Hz, 1H), 4.62-4.41 (m, 2H), 2.22-2.11 (m, 3H), 2.01-1.92 (m, 1H), 1.33 (s, 9H).

[1028] EXAMPLES 205-211

[1029] The compounds in Table 24 were prepared according to the general procedures described for Example 144, starting with tert-butyl (S)-5-amino-4-(6-bromo-7-fhioro-l- oxoisoindolin-2-yl)-5 -oxopentanoate and the appropriate aryl piperazinone bearing the desired R fragment:

[1030] TABLE 24

[1031] INTERMEDIATE 1-31 di -tert-butyl (S)-2-(6-bromo-4-chloro-5-methoxy-l-oxoisoindolin-2-yl)pentanedioate

[1032] Intermediate 1-31 A: methyl 3-chloro-4-hydroxy-2-methylbenzoate

[1033] To a solution of methyl 4-hydroxy-2-methylbenzoate (1.00 g, 6.02 mmol) in DMF

[1034] (10 mL) was added NCS (804 mg, 6.02 mmol) and the mixture was heated at 60 °C for

[1035] 16 h. The reaction mixture was diluted with saturated aqueous ammonium chloride, and extracted with EtOAc (3x). The combined organic layers were dried and concentrated. The residue was purified on 24 g SiC>2 (0-100% EtOAc / hexanes) to give a mixture of two regioisomers, which were separated by SFC to afford methyl 3-chloro-4-hydroxy-2- methylbenzoate (530 mg, 2.64 mmol, 44% yield). LCMS(ESI): [M+H]+201.0; 'HNMR (500 MHz, CHLOROFORM-d) 8 7.82 (d, J=8.7 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 5.99 (s, 1H), 3.90 (s, 3H), 2.70 (s, 3H).

[1036] Intermediate 1-3 IB: methyl 5-bromo-3-chloro-4-hydroxy-2-methylbenzoate

[1037] To a solution of methyl 3-chloro-4-hydroxy-2-methylbenzoate (530 mg, 2.64 mmol) in DCE (12 mL) was added acetic acid (0.302 mL, 5.28 mmol) and bromine (0.150 mL, 2.91 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated in vacuo to give crude methyl 5-bromo-3-chloro-4-hydroxy-2- methylbenzoate in a quantitative yield. LCMS(ESI): [M+H]+278.9, 280.8; 'HNMR (500 MHz, CHLOROFORM-d) 6 8.06 (s, 1H), 6.27 (s, 1H), 3.91 (s, 3H), 2.67 (s, 3H). Intermediate 1-31C: methyl 5-bromo-3-chloro-4-methoxy-2-methylbenzoate

[1038] To a solution of crude methyl 5-bromo-3-chloro-4-hydroxy-2-methylbenzoate in 5 mL of DMF was added potassium carbonate (730 mg, 5.28 mmol) and iodomethane (0.198 mL, 3.17 mmol). The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with 10 mL of water, extracted with EtOAc (3 x 20 mL). The combined organic layers were dried and concentrated. The residue was purified on 24 g SiC>2 with 0-30% EtOAc / hexanes to give methyl 5-bromo-3-chloro-4-methoxy-2- methylbenzoate (711 mg, 2.42 mmol, 92% yield). LCMS(ESI): [M+H]+292.9, 294.6.

[1039] Intermediate 1-3 ID: methyl 5-bromo-2-(bromomethyl)-3,4-dimethoxybenzoate

[1040] A mixture of methyl 5-bromo-3-chloro-4-methoxy-2-methylbenzoate (711 mg, 2.42 mmol), NBS (647 mg, 3.63 mmol), and AIBN (39.8 mg, 0.242 mmol) in 12 mL of DCE was stirred at 85 °C for 4 h. The reaction mixture was concentrated with 5 g of Celite. The residue was purified on 24 g SiCh with 0-30% EtOAc / hexanes to give methyl 5-bromo-2-(bromomethyl)-3,4-dimethoxybenzoate (863 mg, 2.35 mmol, 97% yield). NMR (500 MHz, CHLOROFORM-d) 8 8.15 (s, 1H), 5.13 (s, 2H), 3.97 (s, 6H).

[1041] Intermediate 1-31 :

[1042] To a solution of methyl 5-bromo-2-(bromomethyl)-3,4-dimethoxybenzoate in DMF (11 mL) was added di-tert-butyl L-glutamate hydrochloride (823 mg, 2.78 mmol) and DIEA (1.214 mL, 6.95 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3x25 mL). The combined organic layers were dried and concentrated. The residue was purified on 12 g SiO? with 0-60% EtOAc / hexanes to give di-tert-butyl (S)-2-(6-bromo-4-chl oro-5 - methoxy-l-oxoisoindolin-2-yl)pentanedioate (946 mg, 1.82 mmol, 79% yield). LCMS(ESI): [M+3H-2tBu]+405.8, 407.8.

[1043] INTERMEDIATE 1-32 di -tert-butyl (S)-2-(6-bromo-4-fluoro-5-methoxy-l-oxoisoindolin-2-yl)pentanedioate

[1044] Intermediate I-32A: methyl 3-fluoro-4-hydroxy-2-methylbenzoate

[1045] O

[1046] A_CH3JCX HO' / ^Y^CH3

[1047] F (I-32A)

[1048] To a suspension of methyl 4-hydroxy-2-methylbenzoate (1.00 g, 6.02 mmol) in

[1049] ACN (25 mL) was added Selectfluor (2.99 g, 8.42 mmol). The mixture was heated at 60 °C for 4 h, then it was concentrated. The residue was taken into 100 mL EtOAc, washed with 1 N HC1, brine, dried over Na2SC>4, filtered, and concentrated to give a light brown solid. The crude material was purified on 40 g SiCh (0-100% EtOAc / hexanes) to give a mixture of two regioisomers, which was further purified on a 40 g SiCh RediSep Gold column (0-40% EtOAc / hexanes) to give methyl 3 -fluoro-4-hydroxy-2-m ethylbenzoate (512 mg, 2.78 mmol, 46% yield). LCMS(ESI): [M+H]+ 184.9; 'HNMR (500 MHz, CHLOROFORM-d) 8 7.78-7.66 (m, 1H), 6.93-6.81 (m, 1H), 5.51-5.40 (m, 1H), 3.92- 3.86 (m, 3H), 2.62-2.52 (m, 3H).

[1050] Intermediate L32B: methyl 5-bromo-3-fluoro-4-hydroxy-2-methylbenzoate

[1051] To a solution of methyl 3-fluoro-4-hydroxy-2-methylbenzoate (800 mg, 4.34 mmol) in DCE (12 mL) was added acetic acid (0.497 mL, 8.69 mmol) and bromine (0.246 mL, 4.78 mmol). The reaction was stirred at 50 °C for 16 h. The mixture was diluted with water and extracted with DCM (3 x 40 mL). The combined organic layers were concentrated and purified on a 40 g SiO? column (0-60% EtOAC / hexanes) to give methyl 5-bromo-3-fluoro-4-hydroxy-2-methylbenzoate (550 mg, 2.09 mmol, 48% yield). LCMS(ESI): 262.9, 265.0; 'HNMR (500 MHz, CHLOROFORM-d) 6 8.08 (d, J=1.9 Hz, 1H), 4.07 (d, . / =2,4 Hz, 3H), 2.54 (d, J=2.9 Hz, 3H).

[1052] Intermediate I-32C: methyl 5-bromo-3-fluoro-4-methoxy-2-methylbenzoate

[1053] O

[1054] Br. J-L CH3

[1055] H3C"O' / ^^CH3

[1056] F (I-32C)

[1057] To a solution of methyl 5-bromo-3-fluoro-4-hydroxy-2-methylbenzoate (580 mg, 2.205 mmol) in DMF (4 mL) was added potassium carbonate (609 mg, 4.41 mmol) and iodomethane (0.165 mL, 2.65 mmol) at room temperature. The reaction was stirred for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried and concentrated. The residue was purified on a 24 g SiC>2 column (0-30% EtOAc / hexanes) to give methyl 5-bromo-3-fluoro-4-methoxy- 2 -methylbenzoate (584 mg, 2.11 mmol, 96% yield). LCMS(ESI): [M+H]+277.0, 278.7; 'HNMR (500 MHz, CHLOROFORM-d) 8 7.95 (d, J=2.1 Hz, 1H), 4.04 (d, . / =2,2 Hz, 3H), 3.91 (s, 3H), 2.50 (d, J=2.9 Hz, 3H).

[1058] Intermediate I-32D: methyl 5-bromo-2-(bromomethyl)-3-fluoro-4-methoxybenzoate

[1059] A mixture of methyl 5-bromo-3-fluoro-4-methoxy-2-methylbenzoate (584 mg, 2.11 mmol), NBS (563 mg, 3.16 mmol), and AIBN (34.6 mg, 0.211 mmol) in 10 mL DCE was stirred at 60 °C for 16 h. The reaction mixture was concentrated with 4 g of Celite. The residue was purified on a 24 g SiC>2 column (0-30% EtOAc / hexanes) to give methyl 5-bromo-2-(bromomethyl)-3-fluoro-4-methoxybenzoate (735 mg, 2.07 mmol, 98% yield). LCMS(ESI): [M+H]+354.8, 356.8; 'HNMR (500 MHz, CHLOROFORM- d) 6 8.05 (d, J=1.9 Hz, 1H), 5.00 (d, . / =2,5 Hz, 2H), 4.09 (d, . / =2,5 Hz, 3H), 3.96 (s, 3H).

[1060] Intermediate 1-32:

[1061] To a solution of methyl 5-bromo-2-(bromomethyl)-3-fluoro-4-methoxybenzoate (735 mg, 2.07 mmol) in DMF (10 mL) was added di-tert-butyl L-glutamate hydrochloride (733 mg, 2.48 mmol) and DIEA (1.08 mL, 6.19 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with 10 mL of water then extracted with EtOAc (3 x 25 mL). The combined organic layers were dried and concentrated. The residue was purified on a 12 g SiCh column (0-60% EtOAc / hexanes) to afford di-tert- butyl (S)-2-(6-bromo-4-fluoro-5-methoxy-l-oxoisoindolin-2-yl)pentanedioate (880 mg, 1.75 mmol, 85% yield). LCMS(ESI): [M+H]+502.0, 503.9.

[1062] INTERMEDIATE 1-33 di-tert-butyl (S)-2-(6-bromo-4,5-dimethoxy-l-oxoisoindolin-2-yl)pentanedioate

[1063] Intermediate I-33A: methyl 5-bromo-3,4-dihydroxy-2-methylbenzoate

[1064] To a suspension of methyl 3,4-dihydroxy-2-methylbenzoate (1.00 g, 5.49 mmol) in DCE (20 mL) was added acetic acid (0.943 mL, 16.47 mmol) and bromine (0.283 mL, 5.49 mmol) at room temperature. The reaction was stirred 45 min. The mixture was concentrated to dryness to give methyl 5-bromo-3,4-dihydroxy-2-methylbenzoate (1.33 g, 5.09 mmol, 93% yield). LCMS(ESI): [M+H]+260.9, 262.9; 'HNMR (500 MHz, CHLOROFORM-d) 8 7.70 (s, 1H), 3.89 (s, 3H), 2.50 (s, 3H).

[1065] Intermediate I-33B: methyl 5-bromo-3,4-dimethoxy-2-methylbenzoate

[1066] To a solution of methyl 5-bromo-3,4-dihydroxy-2-methylbenzoate (500 mg, 1.915 mmol) in DMF (5 mL) at was added potassium carbonate (1059 mg, 7.66 mmol) and iodomethane (0.263 mL, 4.21 mmol). The reaction was stirred at room temperature for 1.5 h. The mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried and concentrated to give crude methyl 5-bromo-3,4- dimethoxy-2-methylbenzoate (440 mg, 1.52 mmol, 79% yield). LCMS(ESI): [M+H]+ 288.9, 290.8.

[1067] Intermediate L33C: methyl 5-bromo-2-(bromomethyl)-3,4-dimethoxybenzoate

[1068] To a solution of methyl 5-bromo-3,4-dimethoxy-2-methylbenzoate (440 mg, 1.522 mmol) in 7.6 mL of DCE was added NBS (406 mg, 2.283 mmol) and AIBN (24.99 mg, 0.152 mmol). The reaction was stirred at 60 °C for 16 h. Celite (4 g) was added and the mixture was concentrated. The residue was purified on a 40 g SiCh column (0-35% EtOAc / hexanes) to give methyl 5-bromo-2-(bromomethyl)-3,4-dimethoxybenzoate (550 mg, 1.49 mmol, 98% yield). LCMS(ESI): [M+H]+ 366.7, 368.7; 'HNMR (500 MHz, CHLOROFORM-d) 8 7.99 (s, 1H), 5.05 (s, 2H), 4.04 (s, 3H), 3.95 (d, J=1.9 Hz, 6H).

[1069] Intermediate 1-33:

[1070] To a solution of methyl 5-bromo-2-(bromomethyl)-3,4-dimethoxybenzoate (550 mg, 1.49 mmol) in DMF (7.5 mL) was added...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or stereoisomers, tautomers, or salts thereof, wherein:(i) X is CRi and Y is CR2 or N; or(ii) X is N and Y is CR2; one of W and Z is CH, CRe, or N and the other of W and Z is CRe or CH;Ri is hydrogen, F, Cl, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -0CHF2, -OCH2CHF2, -0CH2CN, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -N(CH3)(CH2CH3), -CH2(oxetanyl), -OCH2(cyclopropyl), -O(cyclopropyl), -O(cyclobutyl), -O(cyclopentyl), -O(tetrahydropyranyl), -N(CH3)2, cyclopropyl, cyclopentyl, azetidinyl, fluoroazetidinyl, or pyrrolidinyl;R2 is hydrogen, F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, or cyclopropyl;R3is hydrogen or F;R4 is hydrogen or -CH3;Rs is F or -CH3;Re is F or Cl; each R7 is independently F, Cl, -CH3, -CHF2, or -OCH3; m is zero or 1; n is zero or 1; and p is zero, 1, 2, or 3.

2. The compound according to claim 1 having the structure:or stereoisomers, tautomers, or salts thereof, wherein:Ri is hydrogen, F, Cl, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -OCHF2, -OCH2CHF2, -OCH2(cyclopropyl), -O(cyclopropyl), -O(cyclobutyl), -O(cyclopentyl), -O(tetrahydropyranyl), -N(CH3)2, cyclopropyl, or azetidinyl;R2is hydrogen, F, or -OCH3; andR5is -CH3.

3. The compound according to claim 1, or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is CR2or N.

4. The compound according to claim 1, or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is CR2.

5. The compound according to claim 1, or stereoisomers, tautomers, or salts thereof, wherein X is CRi and Y is N.

6. The compound according to claim 1, or stereoisomers, tautomers, or salts thereof, wherein X is N and Y is CR2.

7. The compound according to claim 1, or stereoisomers, tautomers, or salts thereof, whereinW is CH or C s; andZ is CRs or CH.

8. The compound according to claim 1, or stereoisomers, tautomers, or salts thereof, wherein L is -O-.

9. The compound according to claim 1, or stereoisomers, tautomers, or salts thereof, wherein Ri is hydrogen, F, -CH3, -OCH3, or -OCD3.

10. The compound according to claim 1, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein said compound is:

11. The compound according to claim 8, or tautomers or pharmaceutically acceptable salts thereof, wherein said compound is:

12. The pharmaceutically acceptable salt of the compound according to claim 8 or tautomers thereof, wherein said compound is:

13. The compound according to claim 1, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein said compound is:

14. The pharmaceutically acceptable salt of the compound according to claim 8 or tautomers thereof, wherein said compound is:

15. The compound according to claim 1, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein said compound is:

16. The pharmaceutically acceptable salt of the compound according to claim 8 or tautomers thereof, wherein said compound is:

17. The pharmaceutically acceptable salt of the compound according to claim 8 or tautomers thereof, wherein said compound is:(3 S)-3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (1);3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (2);(3 S)-3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-m ethoxy- 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (3 );(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (4);(3 S)-3 -(6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (5);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (6);(3 S)-3 -(3 - { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (7);3 -(3 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -5 -oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (8);(3 S)-3 -(6- { 4- [4-(3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (9);(3S)-3-(6-{4-[4-(5-chloro-2-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (10);(3S)-3-(6-{4-[4-(2-methoxyphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (11);(3 S)-3 - [6 - (4 - { 4- [2-(difluoromethyl)phenoxy ]phenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (12);3 - [6-(4 - { 4- [(3 ,4-difluorophenyl)methyl]phenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (13);3-[6-(4-{4-[difluoro(phenyl)methyl]phenyl}-3-oxopiperazin-l-yl)-l-oxo-2,3-dihydro- lH-isoindol-2-yl]piperidine-2, 6-dione (14);(3 S)-3 -(6- { 4- [4-(2, 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (15);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (16);(3 S)-3 -(6- { 4- [4 - (3 ,4-difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (17);(3S)-3-(l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l-yl}-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (18);(3S)-3-(6-{4-[2-fluoro-4-(2,4,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l- oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (19);(3 S)-3 -(6- { 4- [4 - (3 -fluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (20);(3S)-3-(6-{4-[2-fluoro-4-(2,3,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (21);3 -(6- { 4- [4-(2,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (22);3 -(6-{4-[4-(2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihydro- 1H- isoindol-2-yl)piperidine-2, 6-dione (23);3 -(6- { 4- [4-(2-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihy dro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (24);3 -(6- { 4- [4-(2-chlorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (25);3 -(6- { 4- [4-(2,6-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (26);3 - { 6- [4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2, 3 -dihydro- 1 H- isoindol-2-yl}piperidine-2, 6-dione (27);3 - { 6- [4-(4-benzylphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2,3 -dihy dro- 1 H-i soindol-2- yl}piperidine-2, 6-dione (28);3 -(6- { 4- [4-(2, 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (29);3 -(6- { 4- [4-(3 ,4-difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (30);3 -(6- { 4- [4-(4-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihy dro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (31);3 -(6- { 4- [4-(4-fluoro-2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (32);3 -(6- { 4- [4 -( 5 -fluoro-2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (33);3 -( 1 -oxo-6- { 3 -oxo-4- [4-(2, 4, 5 -trifluorophenoxy )phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (34);3 -( 1 -oxo-6- { 3 -oxo-4- [4 - (2 , 3 , 5 -trifluorophenoxy )phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- IH-isoindol -2 -yl)piperidine-2, 6-dione (35);3 -( 1 -oxo-6- { 3 -oxo-4- [4 - (2 , 3 ,4-trifluorophenoxy)phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (36);3 -( 1 -oxo-6- { 3 -oxo-4- [4-(3 ,4,5 -trifluorophenoxy )phenyl]piperazin- 1 -yl } -2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (37);3 -(6- { 4- [4 - (2 , 3 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihy dro- lH-isoindol-2-yl)piperidine-2, 6-dione (38);3 -(6- { 4- [2-fluoro-4-(2-fluorophenoxy)phenyl ] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (39);3 -(6- { 4- [4-(3 -fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 -dihy dro- 1 H- isoindol-2-yl)piperidine-2, 6-dione (40);3 -(6- { 4- [4-(2,4-difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (41);3 - [ 6 -(4 - { 4 - [ (3 , 5 -difluorophenyl)methyl]phenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo-2,3 - dihy dro- IH-isoindol -2 -yl]piperidine-2, 6-dione (42);3 - [6-(4- { 4- [(3 , 5-difluorophenyl)methyl]-2-fluorophenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (43);3 -(6- { 4- [4 -(2 , 3 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (44);3-(l-oxo-6-{3-oxo-4-[4-(l-phenylcyclopropyl)phenyl]piperazin-l-yl}-2,3-dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (45);3 - { 1 -oxo-6- [3 -oxo-4-(6-phenoxypyri din-3 -yl)piperazin- 1 -yl] -2, 3 -dihydro- 1 H- isoindol -2 -yl}piperidine-2, 6-dione (46);3 -(6- { 4- [2-fluoro-4-(3 -fluorophenoxy )phenyl ] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (47);3-[6-(4-{4-[l-(3,4-difluorophenyl)cyclopropyl]phenyl}-3-oxopiperazin-l-yl)-l-oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (48);3 -(6- { 4- [3 -fluoro-4-(2-fluorophenoxy)phenyl ]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (49);3 -(6- { 4- [2-fluoro-4-(4-fluorophenoxy)phenyl ]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (50);3 -[6-(4- {4-[ 1 -(3 , 5-difluorophenyl)cy cl opropyl] phenyl } -3 -oxopiperazin- 1 -yl)- 1 -oxo-2.3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (51);3-(6-{4-[4-(2,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (52);3 -(6- { 4- [4 - (3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (53);3 -(6- { 4- [4-(2-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (54);3 -(4-m ethoxy-6- { 4-[4-(2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (55);3-(6-{4-[4-(2-chlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (56);3 - { 6- [4-(4-benzylphenyl)-3 -oxopiperazin- 1 -yl] -4-methoxy- 1 -oxo-2,3 -dihydro- 1 H- isoindol-2-yl}piperidine-2, 6-dione (57);3 -(6- { 4- [4-(4-fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (58);3 -(4-methoxy- 1 -oxo-6- { 3 -oxo-4- [4-(2,4, 5 -trifluorophenoxy)phenyl]piperazin- 1 -yl } -2.3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (59);3-(6-{4-[2-fluoro-4-(2-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (60);3-(6-{4-[4-(2,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (61);3 - [ 6 -(4 - { 4 - [ (3 , 5 -difluorophenyl)methyl]phenyl } -3 -oxopiperazin- 1 -yl)-4-methoxy- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (62);3-(4-methoxy-l-oxo-6-{3-oxo-4-[4-(l-phenylcyclopropyl)phenyl]piperazin-l-yl}-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (63);3 -(6- { 4- [6-(3 -fluorophenoxy)pyri din-3 -yl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (64);3-(6-{4-[3-fluoro-4-(2-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (65);(3S)-3-(6-{4-[4-(2,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (66);(3 S)-3-(6-{4-[4-(5-chloro-2-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl} -4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (67);(3 S)-3 -(6- { 4- [4 - (2 , 3 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (68);(3S)-3-(4-methoxy-l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l- yl}-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (69);(3S)-3-(6-{4-[4-(3-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l-oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (70);(3 S)-3 -(6- { 4- [4-(2,6-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (71);(3 S)-3 - { 6-[4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl]-4-methoxy- 1 -oxo-2,3- dihydro- IH-isoindol -2 -yl}piperidine-2, 6-dione (72);(3 S)-3 - [6 - (4 - { 4- [2-(difluoromethyl)phenoxy ]phenyl } -3 -oxopiperazin- 1 -yl)-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (73);(3S)-3-(6-{4-[4-(2,3-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (74);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (75);(3 S)-3 -(6- { 4- [4 - (3 ,4-difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (76);(3S)-3-(6-{4-[2-fluoro-4-(2,4,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (77);(3S)-3-(6-{4-[2-fluoro-4-(3-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (78);(3S)-3-(6-{4-[4-(3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (79);(3S)-3-(6-{4-[2-fluoro-4-(2,3,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (80);(3 S)-3 -(6- { 4-[4-(2, 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (81);(3 S)-3 -(6- { 4 - [4-(3 ,4-difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (82);(3S)-3-(6-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-lH,2H,3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (83);(3 S)-3 -(6- { 4 - [4-(3 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- 1H,2H,3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (84);(3S)-3-(l-oxo-6-{3-oxo-4-[4-(2,4,5-trifluorophenoxy)phenyl]piperazin-l-yl}- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (85);(3 S)-3 -(6- { 4 - [4 - (3 , 5 -difluoro-2-methylphenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (86);(3S)-3-(6-{4-[4-(3,4-difluoro-2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (87);(3 S)-3 -(1 -oxo-6- { 3 -oxo-4-[4-(2,3 , 5-trifluorophenoxy)phenyl]piperazin- 1 -y 1 } - lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (88);(3S)-3-(6-{4-[2-fluoro-4-(2,4,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l- oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (89);(3 S)-3 -(6- { 4-[4-(2, 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -y 1 } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (90);(3S)-3-(3-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-5-oxo-5H,6H,7H- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (91);(3 S)-3 -(5 -oxo-3 - { 3 -oxo-4-[4-(2, 3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 -y 1 } - 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (92);(3S)-3-(3-{4-[4-(3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (93);(3S)-3-(3-{4-[2-fluoro-4-(2,3,5-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5- oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (94);(3S)-3-(6-{4-[4-(3-chloro-5-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (95);3 -(6- {4- [4-(3 -chi oro-5 -fluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (96);(3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (97);(3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (98);(3S)-3-(6-{4-[2-chloro-4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (99);(3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (100);(3S)-3-(6-{4-[4-(3-chloro-5-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (101);(3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (102);(3S)-3-(6-{4-[4-(3-chloro-5-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-l- oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (103);(3S)-3-(6-{4-[4-(3,4-dichlorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (104);(3 S)-3 -(6- { 4- [4-(3 -chi oro-5 -fluorophenoxy )-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (105);3-(6-{4-[4-(3,4-dichlorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-lH,2H,3H- pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (106);3 -(6- { 4- [4-(3 -chi oro-5 -fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (107);(3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2,3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (108);(3S)-3-(6-{4-[5-(3,5-difluorophenoxy)-3-fluoropyridin-2-yl]-3-oxopiperazin-l-yl}-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (109);3 -[6-(4- {4-[ 1 -(3 , 5-difluorophenyl)cy cl opropyl] phenyl } -3 -oxopiperazin- 1 -yl)-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (110);(3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -yl } -4-m ethoxy - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (111);(3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)-3 -fluoropy ridin-2-yl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (112);(3 S)-3 -[( lR)-5- {4- [4-(3 , 5-difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (113);(3S)-3-[(lR)-5-{4-[4-(3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (114);(3 S)-3 - [( 1 R)-5 - { 4- [4-(4-fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -methyl-3 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (115);(3 S)-3 -[( lR)-5- {4- [4-(3 , 5-difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -methyl-3 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (116);(3S)-3-[(lR)-5-{4-[4-(2,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (117);(3S)-3-[(lR)-5-{4-[4-(3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-l- methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (118);(3S)-3-[(lR)-l-methyl-3-oxo-5-{3-oxo-4-[4-(2,4,5- trifluorophenoxy)phenyl]piperazin-l-yl}-2,3-dihydro-lH-isoindol-2-yl]piperidine-2,6- di one (119);(3 S)-3-[(lR)-5-{4-[4-(2-methoxyphenoxy)phenyl]-3-oxopiperazin-l-yl}-l -methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (120);(3 S)-3 - [( 1 R)-5 - { 4- [4-(2, 3 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (121);(3 S)-3 - [( 1 R)-5 - { 4- [4-(2, 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (122);(3 S)-3 -[( lR)-5- {4- [2-fluoro-4-(3 -fluorophenoxy )phenyl]-3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (123);(3 S)-3 - [( 1 R)-5 - { 4- [4-(3 ,4-difluoro-2-m ethylphen oxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 -methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (124);(3S)-3-[(lR)-l-methyl-3-oxo-5-{3-oxo-4-[4-(2,3,5- trifluorophenoxy)phenyl]piperazin-l-yl}-2,3-dihydro-lH-isoindol-2-yl]piperidine-2,6- dione (125);(3 S)-3 - [( 1 S)-5 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -y 1 } - 1 - methyl-3-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (126);(3S)-3-[(lS)-5-{4-[4-(4-fluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-methyl-3- oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (127);(3 S)-3 - [( 1 S)-5 - { 4- [4-(3 , 5 -difluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } - 1 -methyl-3 - oxo-2, 3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (128);(3 S)-3 - [(7R)-3 - { 4- [4-(3 , 5 -difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -7 -methyl-5 - oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (129);(3 S)-3 - [(7R)-3 - { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 7 - methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (130);(3 S)-3 - [(7 S)-3 - { 4- [4 - (3 , 5 -difluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } -7 -methyl-5 - oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (131);(3S)-3-[(7S)-7-methyl-5-oxo-3-{3-oxo-4-[4-(2,3,5- trifluorophenoxy)phenyl]piperazin-l-yl}-5H,6H,7H-pyrrolo[3,4-b]pyridin-6- yl]piperidine-2, 6-dione (132);(3S)-3-[(7R)-7-methyl-5-oxo-3-{3-oxo-4-[4-(2,3,5- trifluorophenoxy)phenyl]piperazin-l-yl}-5H,6H,7H-pyrrolo[3,4-b]pyridin-6- yl]piperidine-2, 6-dione (133);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-3-methyl-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (134);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-3- methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (135);(3S)-3-(3-methyl-l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l- yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (136);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-3-methyl-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (137);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 3 - methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (138);(3 S)-3 -(3 -methyl- 1 -oxo-6- { 3 -oxo-4- [4-(2, 3 , 5 -trifluorophenoxy )phenyl ]piperazin- 1 - yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (139);(3 S)-3 - [(7R)-3 - { 4- [4-(3 -chi oro-5 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -y 1 } - 7 - methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (140);(3 S)-3 - [(7 S)-3 - { 4- [4 - (3 -chi oro-5 -fluorophenoxy )phenyl]-3 -oxopiperazin- 1 -y 1 } - 7 - methyl-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (141);(3 S)-3 - [(3R)-6- { 4- [4-(3 -chi oro-5 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -y 1 } - 3 - methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2, 6-dione (142);(3 S)-3 -(6- { 4- [4 - (3 , 5 -di chlorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (143);(3 S)-3 -(4-fluoro- 1 -oxo-6- { 3 -oxo-4- [4-(2,3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl } -2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione ( 144);(3 S)-3 -(4-fluoro-6- { 4-[4-(2-fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (145);(3S)-3-(4-fluoro-6-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (146);(3S)-3-(6-{4-[4-(3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-l-oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (147);(3 S)-3 - { 4-fluoro-6- [4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl}piperidine-2, 6-dione (148);(3 S)-3 -(6- { 4- [4-(2, 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-fluoro- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (149);(3 S)-3 -(6- { 4- [4 - ( 5 -chloro-2-fluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } -4-fluoro- 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (150);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-fluoro- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (151);(3S)-3-(6-{4-[4-(2,3-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (152);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (153);(3 S)-3 -(6- { 4- [4-(2, 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (154);(3 S)-3 -(4-fluoro-6- { 4 - [4-(3 -fluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl }- 1 -oxo-2,3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (155);(3 S)-3 -(4-fluoro-6- { 4- [2-fluoro-4-(3 -fluorophenoxy )phenyl] -3 -oxopiperazin- 1 -y 1 } - 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (156);(3S)-3-(6-{4-[4-(3,5-difluoro-2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-4- fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (157);(3 S)-3 -(4-chl oro-6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (158);(3S)-3-(4-chloro-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } - 1 -oxo-2,3 -dihydro- 1 H-isoindol-2-yl)piperidine-2, 6-dione (159);(3S)-3-(4-chloro-6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (160);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methyl-l-oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (161);3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -4-methyl- 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (162);(3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -yl } -4-methyl- 1 - oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (163);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-ethyl- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (164);3-(4-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } - 1 -oxo-2,3 -dihydro- 1 H-isoindol-2-yl)piperidine-2, 6-dione (165);(3 S)-3 -(4-cy cl opropyl-6- { 4- [4-(3 ,5 -difluorophenoxy )phenyl]-3 -oxopiperazin- 1 -yl } - 1 - oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (166);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-[(oxetan-3- yl)methyl]-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (167);3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-(methoxymethyl)-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (168);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethyl)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (169);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-hydroxy-l- oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (170);(3 S)-3 -(4-hydroxy-6-{4-[4-(2-methylphenoxy)phenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (171);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-ethoxy-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (172);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-propoxy -2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (173);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethoxy)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (174);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- ethoxy- 1 -oxo-2, 3 -dihydro- 1 H-i soindol-2-yl)piperi dine-2, 6-dione (175);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-4- propoxy-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (176);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(propan-2 -yloxy)-2, 3 -dihydro- IH-isoindol -2 -yl)piperi dine-2, 6-dione (177);(3S)-3-(4-cyclopropoxy-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperi dine-2, 6-dione (178);(3S)-3-[4-(cyclopentyloxy)-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- 1 H-i soindol -2 -y 1 ] pi p eri dine-2, 6-dione (179);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4-(propan- 2 -yloxy)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (180);(3 S)-3 -(4-cy clopropoxy-6- { 4 - [4 - (3 , 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 -y 1 } - 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (181);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- (2H3)methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (182);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2H3)methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (183);(3 S)-3 - [4-(2,2-difluoroethoxy)-6- { 4- [4 - (3 , 5 -di fluor ophenoxy)phenyl ]-3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- IH-isoindol -2 -y 1 ]piperi dine-2, 6-dione ( 184);(3 S)-3 - [4-(cy clopropylmethoxy)-6- { 4- [4-(3 , 5 -difluorophenoxy )phenyl ]-3 - oxopiperazin-l-yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (185);2-[(6- { 4 - [4 -(3 , 5 -difluorophenoxy)phenyl]-3 -oxopiperazin- 1 -yl } -2-[(3 S)-2,6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindol-4-yl)oxy]acetonitrile (186);2-[(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-2-[(3S)-2,6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindol-4-yl)oxy]acetonitrile (187);(3 S)-3 - [4-(difluoromethoxy)-6- { 4- [4 - (3 , 5 -di fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 - yl } - 1 -oxo-2, 3 -dihydro- 1 H-isoindol -2 -yl]piperidine-2, 6-dione (188);(3 S)-3 - [4-(difluoromethoxy)-6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl ]-3 - oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl]piperidine-2, 6-dione (189);(3S)-3-[4-(difluoromethoxy)-6-{4-[6-(2-methylphenoxy)pyridin-3-yl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- IH-isoindol -2 -yl]piperidine-2, 6-dione (190);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- (oxan-4-yloxy)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (191);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(oxan-4- yloxy)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (192);(3S)-3-(4-cyclobutoxy-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (193);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4- (trifluoromethoxy)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (194);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(trifluoromethoxy)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (195);(3 S)-3 -(5 -fluoro- 1 -oxo-6- { 3 -oxo-4- [4 -(2 , 3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl } -2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (196);(3 S)-3 -(6- { 4- [4 - (3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -5 -fluoro- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (197);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -5 -fluoro- 1 -oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (198);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } - 5 - fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (199);(3 S)-3 -(5 -fluoro-6- { 4 - [4 - (3 -fluor ophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (200);(3 S)-3 -(5 -fluoro-6- { 4-[2-fluoro-4-(2, 3 , 5 -trifluorophenoxy)phenyl] -3 -oxopiperazin- 1 - yl } - 1 -oxo-2, 3 -dihydro- 1 H-isoindol-2-yl)piperidine-2, 6-dione (201 );(3 S)-3 -(5 -fluoro-6- {4-[2-fluoro-4-(2, 4,5 -trifluorophenoxy)phenyl]-3 -oxopiperazin- 1 - yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (202);(3S)-3-(6-{4-[4-(2,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-fluoro-l-oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (203);(3 S)-3 -(5 -fluoro- 1 -oxo-6- { 3 -oxo-4- [4-(2,4, 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl}-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (204);(3S)-3-(6-{4-[4-(2,6-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-7-fluoro-l-oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (205);(3 S)-3 -(6- { 4- [4-(2-chlorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -7-fluoro- 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (206);(3 S)-3 -(7 -fluoro-6- { 4-[4-(2-fluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (207);(3 S)-3 -(6- { 4- [4 - (3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -7-fluoro- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (208);(3S)-3-(7-fluoro-6-{4-[4-(2-methylphenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-2,3- dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (209);(3 S)-3 - { 7 -fluoro-6- [4-(2-fluoro-4-phenoxyphenyl)-3 -oxopiperazin- 1 -yl] - 1 -oxo-2, 3 - dihydro- IH-isoindol -2 -yl}piperidine-2, 6-dione (210);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-7-fluoro-l-oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (211);(3 S)-3 -(4-chl oro-6- { 4- [4-(3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -y 1 } - 5 - methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (212);(3 S)-3 -(4-methoxy- 1 -oxo-6- { 3 -oxo-4- [4-(2, 3 ,4-trifluorophenoxy)phenyl]piperazin- 1 - yl } -2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (213);(3 S)-3 -(6- { 4- [4-(2-chl oro-3 ,4-difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (214);(3S)-3-(6-{4-[2-fluoro-4-(2,3,4-trifluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (215);(3S)-3-(6-{4-[4-(2-chloro-3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } -4-methoxy- 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (216);(3S)-3-(6-{4-[4-(2-chloro-4,6-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (217);(3S)-3-(6-{4-[4-(2-chloro-4,6-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl } -4-methoxy- 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (218);(3S)-3-(4-fluoro-l-oxo-6-{3-oxo-4-[4-(2,3,4-trifluorophenoxy)phenyl]piperazin-l- yl } -2,3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (219);(3S)-3-(6-{4-[4-(2-chloro-3,4-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4- fluoro- 1 -oxo-2, 3 -dihydro- IH-isoindol -2 -yl)piperidine-2, 6-dione (220);(3S)-3-(4-fluoro-6-{4-[2-fluoro-4-(2,3,4-trifluorophenoxy)phenyl]-3-oxopiperazin-l- yl } - 1 -oxo-2, 3 -dihydro- lH-isoindol-2-yl)piperidine-2, 6-dione (221 );(3S)-3-(6-{4-[4-(2-chloro-3,4-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl}-4-fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (222);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-methoxy-l- oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (223);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (224);(3S)-3-(6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-5-methoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (225);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4,5-dimethoxy- 1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (226);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -y 1 } -4, 5 - dimethoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (227);(3 S)-3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy)pyridin-2-yl] -3 -oxopiperazin- 1 -y 1 } -4, 5 - dimethoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (228);(3S)-3-(4-chloro-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l- yl}-5-methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (229);(3S)-3-(4-chloro-6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (230);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-fluoro-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (231);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- fluoro-5 -methoxy- 1 -oxo-2, 3 -dihydro- 1 H-i soindol -2 -yl)piperidine-2, 6-dione (232);(3S)-3-(6-{4-[5-(3,5-difluorophenoxy)pyridin-2-yl]-3-oxopiperazin-l-yl}-4-fluoro-5- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (233);3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -5 -methoxy - 4-methyl-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (234);3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-methoxy-4-methyl-1 -oxo-2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (235);3 -(6- { 4- [5 -(3 , 5 -difluorophenoxy )pyri din-2 -yl] -3 -oxopiperazin- 1 -yl } -5 -methoxy -4- methyl-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (236);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4-(propan-2 -yl)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (237);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(propan-2-yl)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (238);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- (hydroxymethyl)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (239);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4- (hydroxymethyl)-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (240);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methyl-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (241);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3-oxopiperazin-l-yl}-4- methyl-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (242);(3S)-3-(4-methyl-l-oxo-6-{3-oxo-4-[4-(2,3,5-trifluorophenoxy)phenyl]piperazin-l- yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (243);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-ethyl- 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (244);3-(4-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (245);(3S)-3-(4-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-3- oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3 ,4-c]pyri din-2 -yl)piperidine-2, 6-dione(246);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- (methoxymethyl)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione(247);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethyl)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (248);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl }-4- methoxy-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (249);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-methoxy-l- oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (250);(3 S)-3 -(4-methoxy- 1 -oxo-6- { 3 -oxo-4- [4-(2, 3 , 5 -trifluorophenoxy)phenyl]piperazin- 1 - yl}-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (251);(3 S)-3 -(6- { 4- [4 - (2 -fluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } -4-methoxy- 1 -oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (252);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-4-ethoxy-l-oxo- lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (253);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } - 1 -oxo- 4-(propan-2-yloxy)-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (254);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo-4-(propan- 2 -yloxy)-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (255);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(2- methoxyethoxy)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (256);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -4-(2- methoxyethoxy)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (257);3 -(3 - { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -2-methoxy-5 -oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (258);(3 S)-3 -(3 - { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -2- methoxy-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (259);(3 S)-3 -(3 - { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl]-3 -oxopiperazin- 1 -yl } -2- ethoxy-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (260);(3S)-3-(3-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-2-ethoxy-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (261);(3S)-3-(3-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-2-methyl-5-oxo- 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (262);(3 S)-3 - [4-(azetidin- 1 -y 1 ) - 6 - { 4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 - oxopiperazin- 1 -yl } - 1 -oxo- lH,2H,3H-pyrrolo[3 ,4-c]pyri din-2 -yl]piperidine-2, 6-dione (263);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl }-4- (dimethylamino)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (264);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-4-(pyrrolidin-l-yl)-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (265);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(3 - fluoroazetidin-l-yl)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione(266);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4- [ethyl(methyl)amino]-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione(267);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } -4-(ethylamino)- l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (268);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl }-4- (methylamino)-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl)piperidine-2, 6-dione (269);(3S)-3-[4-(cyclopropylamino)-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin- l-yl}-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2, 6-dione (270);(3 S)-3 - [4-(difluoromethyl)-6- { 4 - [4 - (3 , 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 - yl}-l-oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2, 6-dione (271);(3 S)-3 -(6- { 4- [4 - (3 , 5 -difluorophenoxy)phenyl] -3 -oxopiperazin- 1 -yl } - 1 -oxo-4- (trifluoromethyl)-2,3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (272);(3S)-3-[4-(difluoromethyl)-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l- yl}-l-oxo-2,3-dihydro-lH-isoindol-2-yl]piperidine-2, 6-dione (273);6- { 4- [4-(3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -oxopiperazin- 1 -yl } -2 - [ (3 S)-2, 6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindole-4-carbonitrile (274);6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-2-[(3S)-2,6- dioxopiperidin-3-yl]-l-oxo-2,3-dihydro-lH-isoindole-4-carbonitrile (275);(3S)-3-(6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-5-methyl-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (276);3-(5-cyclopropyl-6-{4-[4-(3,5-difluorophenoxy)phenyl]-3-oxopiperazin-l-yl}-l-oxo- 2, 3-dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (277);3 -(6- { 4- [4-(3 , 5 -difluorophenoxy )phenyl] -3 -oxopiperazin- 1 -yl } -5 -ethyl- 1 -oxo-2, 3 - dihydro-lH-isoindol-2-yl)piperidine-2, 6-dione (278);(3S)-3-{6-[(2R)-4-[4-(2,4-difluorophenoxy)phenyl]-2-methyl-5-oxopiperazin-l-yl]-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (279);(3S)-3-{6-[(2S)-4-[4-(2,4-difluorophenoxy)phenyl]-2-methyl-5-oxopiperazin-l-yl]-4-methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (280);3-{6-[(2S)-4-[4-(3,5-difluorophenoxy)-2-fluorophenyl]-2-methyl-5-oxopiperazin-l- yl]-4-methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (281);(3S)-3-{6-[(2S)-4-[4-(3,5-difluorophenoxy)phenyl]-2-methyl-5-oxopiperazin-l-yl]-4- methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (282);(3 S)-3 - { 6 - [ (3 S)-4- [4 - (3 , 5 -difluorophenoxy)-2-fluorophenyl] -3 -methyl-5- oxopiperazin-l-yl]-4-fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione(283);(3 S)-3 - { 6-[(3R)-4-[4-(3 , 5-difluorophenoxy)-2-fluorophenyl]-3 -methyl-5- oxopiperazin-l-yl]-4-fluoro-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione(284);3 - { 6- [(2 S)-4- [4 - (3 , 5 -difluorophenoxy)phenyl] -2-methyl-3 -oxopiperazin- 1 -y 1 ] -4 - methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (285); or3 - { 6- [(2R)-4-[4-(3 , 5 -difluorophenoxy )phenyl ]-2-methyl-3 -oxopiperazin- 1 -y 1 ] -4 - methoxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl}piperidine-2, 6-dione (286).

18. A pharmaceutical composition comprising a compound according to claim 1 or tautomers thereof; and a pharmaceutically acceptable carrier.

19. A compound or a tautomer or a pharmaceutically acceptable salt thereof according to claim 1, for use in the treatment of cancer.

20. The compound or a tautomer or a pharmaceutically acceptable salt thereof, for use according to claim 19, wherein said cancer is selected from cancer of the colon, gastric, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, and melanoma.

21. The compound or a tautomer or a pharmaceutically acceptable salt thereof, for use according to claim 19, in combination with a second agent, wherein said second agent is selected from an antagonist of PD1 / PD-L1 axis, an antagonist of CTLA4, a chemotherapeutic agent, radiation, or an anti-tumor vaccine.

22. The compound or a tautomer or a pharmaceutically acceptable salt thereof, for use according to claim 19, wherein Cyclin El protein level is decreased and wherein said Cyclin El is the amino acid sequence encoded by SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, or 9.

23. The compound or a tautomer or a pharmaceutically acceptable salt thereof, for use according to claim 22, wherein said Cyclin El protein level is decreased by at least 50%.

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