Substituted oxoisoindolinyl piperidine-2,6-dione compounds and AZA analogs thereof as degraders of CDK2

Abstract

Disclosed are compounds of Formula (I): or stereoisomers, tautomers, or salts thereof, wherein Ring A, Ring B, Y, X, R1, R3, R5a, R5b, R5c, and R7 are defined herein. Also disclosed are methods of using such compounds to decrease the level of CDK2 protein; and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of proliferative disorders, such as cancer.

Description

[0001] SUBSTITUTED OXOISOINDOLINYL PIPERIDINE-2,6-DIONE COMPOUNDS AND AZA ANALOGS THEREOF AS DEGRADERS OF CDK2

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the priority benefit of U. S. Provisional Application No.

[0004] 63 / 776,333, filed March 24, 2025; the content of which is herein incorporated by reference in its entirety.

[0005] REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA PATENT CENTER

[0006] Incorporated herein by reference in its entirety is a Sequence Listing entitled, “20260223 SEQ 14500-WO-PCT” comprising SEQ ID NO: 1 through SEQ ID NO: 2, 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 February 23, 2026, and is 3.27 KB.

[0007] DESCRIPTION

[0008] The present invention generally relates to substituted oxoisoindolinyl piperidine-2, 6-dione compounds and aza analogs thereof useful for decreasing the levels of the CDK2 protein. Provided herein are substituted oxoisoindolinyl piperidine-2, 6-dione compounds and aza analogs thereof, 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.

[0009] BACKGROUND OF THE INVENTION

[0010] Cyclin-dependent kinase 2 (CDK2) is a critical enzyme involved in the regulation of the cell cycle, particularly the transition from the G1 phase to the S phase (Ding L, C. J. (2020). The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. Int J Mol Sci., 21:1960); Caruso JA, D. M. (2018). Low-molecular-weight cyclin E in human cancer: cellular consequences andopportunities for targeted therapies. Cancer Res., 78:5481-5491). For example, cyclin E / CDK2 mediates the phosphorylation of Retinoblastoma protein (RB1), resulting in its dissociation from E2F transcription factors that activate the transcription of a suite of genes involved in cell cycle progression, which triggers the transition to S-phase (Ding L, C. J. (2020). Int J Mol Sci., 21:1960). Additionally, activation of cyclin A / CDK2 during S-phase is critical for ensuring DNA replication and S-phase completion, via RB1-independent mechanisms (Ding L, C. J. (2020). Int J Mol Sci., 21:1960). Dysregulation of CDK2 activity has been implicated in the uncontrolled proliferation of cancer cells (Tadesse S, A. A. (2020). Targeting CDK2 in cancer: challenges and opportunities for therapy. Drug Discov Today, 25:406-413; Caruso JA, D. M. (2018). Cancer Res., 78:5481-5491). For example, CDK2 dependency has been shown to be linked to CCNE amplification / overexpression in cancer. CDK2 dependency has also been described in cancer bearing RB1 loss and in breast cancers resistant to CDK4 / 6 inhibitors (Wang, Y. (2023). Phase 1 / 2 study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors. J Clin Oncol, 41(16_suppl):e17546–e17546; Caruso JA, D. M. (2018). Cancer Res., 78:5481-5491); German B, A. S. (2024). MYBL2 Drives Prostate Cancer Plasticity: Inhibiting Its Transcriptional Target CDK2 for RB1-Deficient Neuroendocrine Prostate Cancer. Cancer Res Commun, 4(9):2295-2307).

[0011] Traditional inhibitors of CDK2 have shown limited efficacy due to compensatory mechanisms. Moreover, off-target effects have led to adverse effects in clinical trials. For example, relatively limited selectivity over other kinases and ability to inhibit only active or inactive forms of CDK2 are described limitations of CDK2 inhibitor approach (Arora M, M. J. (2023). Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. Cell, 186(12):2628-2643.e21; Tadesse S, A. A. (2020). Targeting CDK2 in cancer: challenges and opportunities for therapy. Drug Discov Today, 25:406-413;

[0012] Kumarasamy V, W. J. (2025). Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle. Nat Commun., 16(1): 1476).

[0013] There remains a need for therapies that can decrease the levels of CDK2 protein. There also remains a need for therapies that can decrease the levels of CDK2 protein and are selective over GSPT1.

[0014] The present invention fills the foregoing need by providing compounds that are useful to decrease the level of CDK2 protein.The present invention fills the foregoing need by providing compounds that are useful to decrease the level of CDK2 and are selective against degradation of GSPT1.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention provides substituted oxoisoindolinyl piperidine-2, 6-dione compounds and aza analogs of Formula (I), including stereoisomers, tautomers, salts, and prodrugs thereof, which are useful to decrease the levels of the CDK2.

[0017] 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.

[0018] The present invention also provides a method of treating a disease or disorder by decreasing the levels of the CDK2, the method comprising administering to a patient a compound of Formula (I), stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs thereof.

[0019] The present invention also provides processes and intermediates for making the compounds of Formula (I), stereoisomers, tautomers, or salts thereof.

[0020] 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 CDK2 protein levels, for the treatment of certain diseases, including cancer.

[0021] 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.

[0022] These and other features of the invention will be set forth in expanded form as the disclosure continues.

[0023] DETAILED DESCRIPTION

[0024] Applicants have found substituted oxoisoindolinyl piperidine-2, 6-dione compounds and aza analogs thereof that decrease the levels of CDK2 protein. The substituted oxoisoindolinyl piperidine-2, 6-dione compounds and aza analogs are believedto facilitate the interaction of CDK2 protein with the corresponding E3 ubiquitin ligase complex (Cullin4-Cereblon, CUL4-CRBN), with concomitant degradation of the CDK2 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 druggability.

[0025] The first aspect of the present invention provides at least one compound of Formula (I):

[0026] O O

[0027]

[0028] or stereoisomers, tautomers, or salts thereof, wherein:

[0029] (i) X is CR2and Y is CR4;

[0030] (ii) X is CR2and Y is N;

[0031] (iii) X is N and Y is N;

[0032] Ri is hydrogen or -CH3;

[0033] R2is hydrogen or -CH3;

[0034] R3is hydrogen, F, -CH3, -CHF2, or -CH2N(CH3)2;

[0035] R4is hydrogen;

[0036] wherein:

[0037] (i) Rsa, Rsb, and Rsc are each hydrogen;

[0038] (ii) Rsa and Rsb are joined together to form -CH2CH2- or -CH2OCH2-, and Rsc is hydrogen; or

[0039] (iii) Rsa and Rsc are joined together to form -CH2-, and Rsb is hydrogen;

[0040] Ring A is:

[0041] R6c

[0042]

[0043] (ii) indazolyl, indolinyl, dihydrobenzofuranyl, dihydrobenzoxazinyl, tetrahydroquinolinyl,tetrahydrobenzazepinyl, or tetrahydrob enzooxazepinyl;

[0044] Ring B is phenyl, isothiazolyl, Q

[0045]

[0046] , or O;

[0047] R6ais hydrogen, Cl, or Br;

[0048] Reb is hydrogen, -OH, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OH, -OCH2CH2OCH3, -OCF3, -OCH2CH2F, -OCH2CH2NH2, -OCH2CH2NH(CH3), -OCH2CH2N(CH3)2, -OCH2CH2CH2NH2, -OCH2CH2CH2N(CH3)2, -OCH2CHFCH2NH2, -OCH2CF2CH2NH2, -OCH(CH3)CH2NH2, -OCH2CH(CH(CH3)2)NH2, -OCH2CH(CH3)NH2, -OCH2CH(CH2CH3)NH2, -OCH2CH(CHF2)NH2, -OCH2CH(CF3)NH2, -OCH2CH(CH2CHF2)NH2, -OCH2CH2NHC(O)CH3, -B(OH)2, -CH2CH2N(CH3)2, -NH(CH3), -N(CH3)2, -NH(CH2CH2OH), -NH(CH2CH2NH2), -NH(aminocyclobutyl), -NHC(O)CH3, -NHC(0)CH20H, -O(cyclopropyl), -O(cyclobutyl), -O(aminocyclopentyl), -O(methylazetidinyl), -O(methyl pyrrolidinyl), -O(fluoroethyl pyrrolidinyl), -O(trifluoroethyl pyrrolidinyl), -O(methyl azaspiro[3.3]heptanyl), -OCH2(aminocyclopropyl), -OCH2(imidazolyl), -OCH2(methyl imidazolyl), -OCH2(isoxazolyl), -OCH2(oxazolyl), -OCH2(methyl pyrrolidinyl), -OCH2CH2(pyrrolidinyl), morpholinyl, oxazolyl, aminopyrrolidinyl, hydroxypyrrolidinyl, or dihydroimidazo[1,5-a]pyrazinyl;

[0049] Rec is hydrogen or F; and

[0050] R7 is hydrogen or deuterium.

[0051] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0052] One embodiment provides a compound of Formula (I), or stereoisomers or tautomers thereof.

[0053] One embodiment provides a salt of the compound of Formula (I), or stereoisomers or tautomers thereof.

[0054] One embodiment provides a pharmaceutically acceptable salt of the compound of Formula (I), or stereoisomers or tautomers thereof.

[0055] One embodiment provides a compounds of Formula (I) having the structure:o o

[0056]

[0057] or tautomers or salts thereof.

[0058] One embodiment provides a compounds of Formula (I) having the structure:

[0059] O O

[0060]

[0061] or tautomers or salts thereof.

[0062] One embodiment provides a compounds of Formula (I) having the structure:

[0063] O O

[0064]

[0065] or tautomers or salts thereof.

[0066] One embodiment provides a compounds of Formula (I) having the structure:

[0067]

[0068] or tautomers or salts thereof.

[0069] One embodiment provides a compounds of Formula (I) having the structure:o o

[0070]

[0071] or tautomers or salts thereof.

[0072] One embodiment provides a compounds of Formula (I) having the structure:

[0073]

[0074] or tautomers or salts thereof.

[0075] One embodiment provides a compounds of Formula (I) having the structure:

[0076] O O

[0077]

[0078] or tautomers or salts thereof.

[0079] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CR2 and Y is CR4. Compounds of this embodiment have the structure of Formula (II):

[0080]

[0081] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CR2 and Y is N. Compounds of this embodiment have the structure of Formula (III):O O

[0082]

[0083] (III).

[0084] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is N and Y is N. Compounds of this embodiment have the structure of Formula (IV):

[0085] O O

[0086] O

[0087]

[0088] (IV).

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

[0090] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ri is -CH3.

[0091] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CR2; Y is CR4 or N; R2 is hydrogen or -CH3; and R4 is hydrogen. Include in this embodiment are compounds in which R2 is hydrogen. Also included in this embodiment are compounds in which R2 is -CH3.

[0092] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein X is CR2 or N; Y is N; R2 is hydrogen or -CH3; and R4 is hydrogen.

[0093] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R3 is hydrogen.

[0094] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R3 is F, -CH3, -CHF2, or -CH2N(CH3)2.

[0095] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R3 is F, -CH3, or -CHF2.

[0096] One embodiment provides a compound of Formula (I) or stereoisomers,tautomers, or salts thereof, wherein R3 is -CH3 or -CHF2.

[0097] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R3 is -CH3.

[0098] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein R5a, R5b, and R5care each hydrogen. Compounds of this embodiment have the structure of Formula (la):

[0099] O O

[0100]

[0101] (la).

[0102] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Rsaand Rsb are joined together to form -CH2CH2-and Rsc is hydrogen. Compounds of this embodiment have the structure of Formula (lb):

[0103]

[0104] (lb).

[0105] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Rsaand Rsb are joined together to form -CH2OCH2-, and Rsc is hydrogen. Compounds of this embodiment have the structure of Formula (Ic):

[0106]

[0107] (Ic).

[0108] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Rsaand Rsc are joined together to form -CH2-, and Rsb is hydrogen. Compounds of this embodiment have the structure of Formula (ID):

[0109]

[0110] One embodiment provides a compound of Formula (I) or stereoisomers,

[0111] R6c

[0112] jC^^ea

[0113] tautomers, or salts thereof, wherein Ring

[0114]

[0115] A is •~vuv'. Included in this embodiment are compounds in which Reais Cl. Also included in this embodiment are compounds in which Reais Cl, Reb is hydrogen, and Rec is hydrogen.

[0116] One embodiment provides a compound of Formula (I) or stereoisomers,

[0117] R6c

[0118] tautomers, or salts thereof, wherein Ring

[0119]

[0120] A is and Reb is hydrogen or -OCH3. Included in this embodiment are compounds in which Reais Cl and Rec is hydrogen.

[0121] One embodiment provides a compound of Formula (I) or stereoisomers,

[0122] R6c

[0123] X^R6b

[0124] ^[ ^Rsa

[0125] tautomers, or salts thereof, wherein Ring

[0126]

[0127] A is and Reb is -OH, -OCH3, -OCD₃, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OH, -OCH2CH2OCH3, -OCF₃, -OCH2CH2F, -OCH2CH2NH2, -OCH2CH2NH(CH3), -OCH2CH2N(CH3)2, -OCH2CH2CH2NH2, -OCH2CH2CH2N(CH3)2, -OCH2CHFCH2NH2, -OCH2CF2CH2NH2, -OCH(CH3)CH2NH2, -OCH2CH(CH(CH3)2)NH2, -OCH2CH(CH3)NH2, -OCH2CH(CH2CH3)NH2, -OCH2CH(CHF2)NH2, -OCH2CH(CF3)NH2, -OCH2CH(CH2CHF2)NH2, -OCH2CH2NHC(O)CH3, -B(OH)2, -CH2CH2N(CH3)2, -NH(CH3), -N(CH3)2, -NH(CH2CH2OH), -NH(CH2CH2NH2), -NH(aminocyclobutyl), -NHC(O)CH₃, -NHC(O)CH₂OH, -O(cyclopropyl), -O(cyclobutyl), -O(aminocyclopentyl), -O(methylazetidinyl), -O(methyl pyrrolidinyl),-O(fluoroethyl pyrrolidinyl), -O(trifluoroethyl pyrrolidinyl), -O(methyl azaspiro[3.3]heptanyl), -OCH2(aminocyclopropyl), -OCH2(imidazolyl), -OCH2(methyl imidazolyl), -OCH2(isoxazolyl), -OCH2(oxazolyl), -OCH2(methyl pyrrolidinyl), -OCH2CH2(pyrrolidinyl), morpholinyl, oxazolyl, aminopyrrolidinyl, hydroxypyrrolidinyl, or dihydroimidazo[1,5-a]pyrazinyl. Included in this embodiment are compounds in which Rea is Cl and Rsc is hydrogen.

[0128] One embodiment provides a compound of Formula (I) or stereoisomers,

[0129] ^6a

[0130] tautomers, or salts thereof, wherein Ring A is

[0131]

[0132] . Included in this embodiment are compounds in which Reais Cl.

[0133] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ring A is indazolyl, indolinyl, dihydrobenzofuranyl, dihydrobenzoxazinyl, tetrahydroquinolinyl, tetrahydrobenzazepinyl, or tetrahydrobenzooxazepinyl.

[0134] One embodiment provides a compound of Formula (I) or stereoisomers,

[0135] R6cH N

[0136] R

[0137] tautomers, or salts thereof, wherein Ring A

[0138]

[0139] is H H

[0140]

[0141] One embodiment provides a compound of Formula (I) or stereoisomers,

[0142] R6c

[0143] ^6b

[0144] ^6a ^6a tautomers, or salts thereof, wherein Ring

[0145]

[0146] A is or

[0147] One embodiment provides a compound of Formula (I) or stereoisomers,

[0148] H H H N N

[0149] tautomers, or salts thereof, wherein Ring A

[0150]

[0151] is

[0152]

[0153] One embodiment provides a compound of Formula (I) or stereoisomers,

[0154] tautomers, or salts thereof, wherein Ring B is phenyl, isothiazolyl, or

[0155]

[0156] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ring B is phenyl.

[0157] One embodiment provides a compound of Formula (I) or stereoisomers, tautomers, or salts thereof, wherein Ring B is isothiazolyl.

[0158] One embodiment provides a compound of Formula (I) or stereoisomers,

[0159] tautomers, or salts thereof, wherein Ring

[0160]

[0161] B is

[0162] One embodiment provides a compound of Formula (I) or stereoisomers,

[0163] tautomers, or salts thereof, wherein Ring B

[0164]

[0165] is

[0166] One embodiment provides a compound of Formula (I) or stereoisomers,

[0167] tautomers, or salts thereof, wherein Ring

[0168]

[0169] B is

[0170] One embodiment provides a compound of Formula (I) or stereoisomers,

[0171] R6c

[0172] ^6b

[0173] ^6a

[0174] tautomers, or salts thereof, wherein Ring

[0175]

[0176] A is and Ring B is phenyl. Included in this embodiment are compounds in which Reais Cl.

[0177] One embodiment provides a compound of Formula (I) or stereoisomers,R6c

[0178] tautomers, or salts thereof, wherein X is CH; Y is N; Ring A

[0179]

[0180] is; Ring B is phenyl; Ri is hydrogen; R2 is hydrogen; R3 is hydrogen or -CH3; Rsa is hydrogen; Rsb is hydrogen; Rscis hydrogen; Reais Cl; Reb is hydrogen or -OCH3; and Rec is hydrogen.

[0181] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0182]

[0183] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0184]

[0185] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0186]

[0187] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0188]

[0189] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0190]

[0191] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0192]

[0193] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0194]

[0195] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0196]

[0197] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0198]

[0199] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0200]

[0201] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0202]

[0203] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0204]

[0205] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0206]

[0207] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0208]

[0209] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0210]

[0211] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0212]

[0213] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0214] Ncs\

[0215]

[0216] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0217]

[0218] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0219]

[0220] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0221]

[0222] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0223] (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (1);

[0224] (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-methyl-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione (2);

[0225] (35)-3-[5-[(17?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (3);

[0226] (35)-3-[5-(7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (4);

[0227] (35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (5);

[0228] (3S)-3-[5-[(1R,4R)-5-benzhydryl-2-azabicyclo[2.2.1]heptane-2-carbonyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (6);

[0229] (35)-3-[5-[(17?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (7);

[0230] (35)-3-[5-[(17?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-4-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (8);

[0231] (35)-3-[5-[4-[(7?)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (9);

[0232] (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-(difluoromethyl)-l-oxo-isoindolin-2 -yl]piperidine-2, 6-dione (10);

[0233] (3S)-3-[5-[4-[(7?)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (12);

[0234] (37?)-3-[5-[4-[(R)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (17);

[0235] (35)-3-[5-[4-[(7?)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (19);

[0236] (35)-3-[5-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (20);

[0237] (35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-[(dimethylamino)methyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (22);

[0238] [2-chloro-3-[[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l-oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenyl]boronic acid (23);

[0239] (35)-3-[5-[4-[(5)-[2-chloro-3-[2-(dimethylamino)ethoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (24);

[0240] (35)-3-[5-[4-[(5)-[2-chloro-3-(2 -hydroxy ethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (25);

[0241] (35)-3-[5-[4-[(7?)-[2-chloro-3-[2-(dimethylamino)ethoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (26);

[0242] (35)-3-[5-[4-[[2-chloro-3-(methylamino)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (27);

[0243] (35)-3-[5-[4-[[2-chloro-3-(dimethylamino)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (28);

[0244] (35)-3-[5-[4-[(7?)-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (29);

[0245] (35)-3-[5-[4-[(2-chloro-3-oxazol-2-yl-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (30);

[0246] (35)-3-[5-[4-[(R)-[2-chloro-3-(2 -hydroxy ethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (31);

[0247] (35)-3-[5-[4-[(2-chlorophenyl)-isothiazol-5-yl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (32);

[0248] (35)-3-[5-[4-[(5)-[2-chloro-3-[(37?)-l-methylpyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (33);

[0249] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(35)-l-methylpyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dionehydrochloride (34);

[0250] (3S)-3-[5-[4-[(S)-[2-chloro-3-[(3S)-1-methylpyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-1-carbonyl]-6-methyl-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (35);

[0251] 7V-[2-chloro-3-[[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l-oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenyl]acetamide (36);

[0252] (35)-3-[5-[4-[(5)-[2-chloro-3-[[(37?)-l-methylpyrrolidin-3-yl]methoxy]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (37);

[0253] (35)-3-[5-[4-[(5)-[2-chloro-3-[3-(dimethylamino)propoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (38);

[0254] (35)-3-[5-[4-[[2-chloro-3-[2-(dimethylamino)ethyl]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (39);

[0255] (35)-3-[5-[4-[(5)-[2-chloro-3-[(3-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (40);

[0256] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(3-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl]piperidine- 1 -carbonyl]-6-m ethyl- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (41);

[0257] (35)-3-[5-[4-[(7?)-[2-chloro-3-(l-methylazetidin-3-yl)oxy-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (42);

[0258] (35)-3-[5-[4-[(5)-[2-chloro-3-[(l-methylimidazol-2-yl)methoxy]phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (43);

[0259] (3S)-3-[5-[4-[(S)-[2-chloro-3-[(1-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl]piperidine-1-carbonyl]-6-methyl-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (44);

[0260] (35)-3-[5-[4-[(7?)-[2-chloro-3-[2-(methylamino)ethoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (45);

[0261] (35)-3-[5-[4-[(R)-[3-(2-aminoethoxy)-2-chloro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (46);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(l-methylimidazol-2-yl)methoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (47);

[0262] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(l-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (48);

[0263] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (49);

[0264] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(35)-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione (50);

[0265] 35)-3-[5-[4-[(7?)-(2-chloro-3-isopropoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (51);

[0266] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione (52);

[0267] (35)-3-[5-[4-[(5)-[2-chloro-3-(6,8-dihydro-5H-imidazo[l,5-a]pyrazin-7-yl)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (53);

[0268] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-l-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (54);

[0269] (35)-3-[5-[4-[(7?)-[2-chloro-3-(cyclobutoxy)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (55);

[0270] 7V-[2-chloro-3-[[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l-oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenyl]-2-hydroxy-acetamide (56);

[0271] 7V-[2-[2-chloro-3-[(R)-[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l -oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenoxy]ethyl]acetamide (57);

[0272] (35)-3-[5-[4-[(7?)-[3-[(15',35)-3-aminocyclopentoxy]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (58);(3 S)-3 - [5 - [4 - [(7 ) - [3 - [(25)-2-amino-3, 3 -difluoro-propoxy ] -2-chloro-phenyl ]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (59);

[0273] (35)-3-[5-[4-[(7?)-[2-chloro-3-(2 -methoxy ethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (60);

[0274] (35)-3-[5-[4-[(7?)-[3-(3-aminopropoxy)-2-chloro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (61);

[0275] (35)-3-[5-[4-[(7?)-[3-[(25)-2-amino-3-methyl-butoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (62);

[0276] (35)-3-[5-[4-[indolin-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (63);

[0277] (35)-3-[5-[4-[(7?)-[2-chloro-3-[2-[(35)-pyrrolidin-3-yl]ethoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione 4-methylbenzenesulfonic acid (64);

[0278] (35)-3-[5-[4-[(7?)-[2-chloro-3-(methylamino)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (65);

[0279] (35)-3-[5-[4-[(7?)-[3-[(25)-2-aminopropoxy]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (66);

[0280] (3 S)-3 - [5 - [4- [(7?)-[3 - [(25)-3 -amino-2-fluoro-propoxy] -2-chloro-phenyl] -phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (67);

[0281] (35)-3-[5-[4-[(7?)-[3-[(37?)-3-aminopyrrolidin-l-yl]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (68);

[0282] (35)-3-[5-[4-[(7?)-[3-[(l-aminocyclopropyl)methoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (69);

[0283] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-3-hydroxypyrrolidin-l-yl]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (70);

[0284] (35)-3-[5-[4-[(7?)-[3-[(27?)-3-amino-2-fluoro-propoxy]-2-chloro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (71);

[0285] (35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-l-(2-fluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (72);

[0286] (3A')-3-[5-[4-[( / )-[2-chloro-3-(IT / -imidazol-5-ylmethoxy)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (73);

[0287] (35)-3-[5-[4-[(7?)-[2-chloro-3-(oxazol-5-ylmethoxy)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (74);

[0288] (35)-3-[5-[4-[(7?)-[2-chloro-3-(oxazol-4-ylmethoxy)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (75);

[0289] (35)-3-[5-[4-[rel-(5)-indolin-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (76);

[0290] (35)-3-[5-[4-[rel-(7?)-indolin-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (77);

[0291] (35)-3-[5-[4-[(7?)-[3-[(25)-2-amino-3,3,3-trifluoro-propoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (78);

[0292] (35)-3-[5-[4-[(7?)-[3-[((lr,3r)-3-aminocyclobutyl)amino]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (79);

[0293] (35)-3-[5-[4-[(7?)-[3-[(15)-2-amino-l-methyl-ethoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (80);

[0294] (35)-3-[5-[4-[(7?)-[3-[(27?)-2-amino-3,3-difluoro-propoxy]-2-chloro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (81);

[0295] (35)-3-[5-[4-[rel-(5)-[3-(2-aminoethoxy)-2-fluoro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (82);

[0296] (35)-3-[5-[4-[(7?)-[3-(3-amino-2,2-difluoro-propoxy)-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (83);(35)-3-[5-[4-[rel-(7?)-(2-chlorophenyl)-(3-pyridyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (84);

[0297] (35)-3-[5-[4-[(7?)-[3-(2-amino-4,4-difluoro-butoxy)-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (85);

[0298] (35)-3-[5-[4-[(7?)-[3-[(25)-2-aminobutoxy]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (86);

[0299] (35)-3-[5-[4-[(7?)-[3-[(27?)-2-amino-3,3,3-trifluoro-propoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (87);

[0300] (35)-3-[5-[4-[(7?)-[2-chloro-3-(isoxazol-4-ylmethoxy)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (88);

[0301] (35)-3-[5-[4-[(7?)-[2-chloro-3-(isoxazol-5-ylmethoxy)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (89);

[0302] (35)-3-[5-[4-[(R)-(2-chloro-3-morpholino-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (90);

[0303] (35)-3-[5-[4-[(7?)-[2-chloro-3-(isoxazol-3-ylmethoxy)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (91);

[0304] (35)-3-[5-[4-[(7?)-[2-chloro-3-(oxazol-2-ylmethoxy)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (92);

[0305] (35)-3-[6-methyl-l-oxo-5-[4-[phenyl(l,2,3,4-tetrahydroquinolin-5-yl)methyl] piperidine-l-carbonyl]isoindolin-2-yl]piperidine-2, 6-dione (93);

[0306] (35)-3-[5-[4-[(7?)-[2-chloro-3-(2 -hydroxy ethylamino)phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (94);

[0307] (35)-3-[5-[4-[(7?)-[3-[(17?)-2-amino-l-methyl-ethoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (95);

[0308] (3A')-3-[5-[4-[3,4-dihydro-27 / -l,4-benzoxazin-8-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (96);

[0309] (35)-3-[5-[4-[indolin-6-yl(phenyl)methyl]piperi dine-l-carbonyl]-6-methyl- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dione (97);

[0310] (35)-3-[5-[4-[(R)-(2-chloro-3-ethoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (98);

[0311] (35)-3-[5-[4-[(7?)-[3-(2-aminoethylamino)-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (99);

[0312] (3A')-3-[5-[4-[( / ?)-[2-chloro-3-(trideuteriomethoxy)phenyl]-phenyl-methyl]piperidine- 1 -carbonyl]-6-m ethyl- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione ( 100);

[0313] (35)-3-[5-[4-[(7?)-[2-chloro-3-(2 -fluoroethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (101);

[0314] (35)-3-[5-[4-[(R)-[2-chloro-3-(cyclopropoxy)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (102);

[0315] 3-[5-[4-[(R)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dione (103);

[0316] (35)-3-[6-methyl-l-oxo-5-[4-[rel-(5 -phenyl(l,2,3,4-tetrahydroquinolin-5-yl)methyl] piperidine-l-carbonyl]isoindolin-2-yl]piperidine-2, 6-dione (104);

[0317] (35)-3-[5-[4-[(2-chloro-3-pyridyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (105);

[0318] (35)-3-[6-methyl-l-oxo-5-[4-[phenyl(2,3,4,5-tetrahydro-lH-l-benzazepin-6-yl) methyl] piperidine-l-carbonyl]isoindolin-2-yl]piperidine-2, 6-dione (106);

[0319] (35)-3-[6-methyl-l-oxo-5-[4-[phenyl(l,2,3,5-tetrahydro-4,l-benzoxazepin-6-yl) methyl]piperidine- 1 -carbonyl]isoindolin-2-yl]piperidine-2, 6-dione ( 107);

[0320] (35)-3-[5-[4-[2,3-dihydrobenzofuran-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (108);

[0321] (3A')-3-[5-[4-[l7 / -indazol-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (109);

[0322] (35)-3-[5-[4-[(2-chloro-3-methoxy-phenyl)-deuterio-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (110);

[0323] (35 -3-[5-[4-[[2-chloro-3-(trifluoromethoxy)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (111);

[0324] (35)-3-[rel-(15)-6-[4-[(7?)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-l,5-dimethyl-3-oxo-isoindolin-2-yl]piperidine-2, 6-dione (112);

[0325] (35)-3-[5-[4-[rel-(5)-(2-chloro-4-fluoro-3-methoxy-phenyl)-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (113); or(35)-3-[5-[4-[[3-(2-aminoethoxy)-2-bromo-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (114).

[0326] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is:

[0327] (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5JT-pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (11);

[0328] (35)-3-[3-[4-[(7?)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (13);

[0329] (35)-3-[3-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (14);

[0330] (35)-3-[3-[4-[(7?)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5Z7-pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (15);

[0331] (35)-3-[3-[4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5JT-pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (16); or

[0332] (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (18).

[0333] One embodiment provides a compound of Formula (I), or stereoisomers, tautomers, or salts thereof, wherein said compound is (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5Z7-pyrrolo[3,4-Z>]pyrazin-6-yl] piperidine-2, 6-dione (21).

[0334] The compounds of Formula (I) or stereoisomers, tautomers, or salts thereof, are useful to decrease the level of CDK2 protein.

[0335] 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.

[0336] 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 tobe 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.

[0337] 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.

[0338] 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).

[0339] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0340] 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.

[0341] 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.

[0342] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.

[0343] In accordance with a convention used in the art,

[0344]

[0345] 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.

[0346] The term “amino” refers to the group -NH2.

[0347] The term "oxo" refers to the group =0.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.

[0348] 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:

[0349] N

[0350] [| " N. \ 'NH

[0351] < N' ^N'

[0352]

[0353] H

[0354] 1 H-1,2,3-triazole 2H-1,2,3-triazole

[0355] 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:

[0356] O O

[0357]

[0358]

[0359] 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.

[0360] 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.

[0361] 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, hemi sulfates, 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.

[0362] 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.

[0363] 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.

[0364] 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).

[0365] 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.

[0366] “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 isintended to embody stable compounds.

[0367] The term “CDK2” refers to cyclin-dependent kinase 2.

[0368] The terms “Cyclin-dependent kinase 2 degrader” and “CDK2 degrader” refers to an agent capable of reducing the level of the cyclin-dependent kinase 2 protein by degradation and / or inactivation and / or inhibition and / or reducing the expression levels of the cyclin-dependent kinase 2 protein, or a combination thereof.

[0369] As used herein, “cyclin-dependent kinase 2” protein is encoded by the CDK2 gene, (Gene ID: 1017 also known as CDKN2, p33(CDK2). “Cyclin-dependent kinase 2” protein includes all human isoforms encoded by CDK2 gene as listed below:

[0370] Isoform 1 (P24941-1) MENFQKVEKIGEGTYGVVYKARNKLTGEVVALKKIRLDTETEGVPSTAIR EISLLKELNHPNIVKLLDVIHTENKLYLVFEFLHQDLKKFMDASALTGIPLPLIKSY LFQLLQGLAFCHSHRVLHRDLKPQNLLINTEGAIKLADFGLARAFGVPVRTYTHE VVTLWYRAPEILLGCKYYSTAVDIWSLGCIFAEMVTRRALFPGDSEIDQLFRIFRT LGTPDEVVWPGVTSMPDYKPSFPKWARQDFSKVVPPLDEDGRSLLSQMLHYDP NI< RISAI< AALAHPFFQDVTI< PVPHLRL (SEQ ID NO: 1)

[0371] Isoform 2 (P24941-2, CDK2deltaT) MENFQKVEKIGEGTYGVVYKARNKLTGEVVALKKIRLDTETEGVPSTAIR EISLLKELNHPNIVKLLDVIHTENKLYLVFEFLHQDLKKFMDASALTGIPLPLIKSY LFQLLQGLAFCHSHRVLHRDLKPQNLLINTEGAIKLADFGLARAFGVPVRTYTHE VTRRALFPGDSEIDQLFRIFRTLGTPDEVVWPGVTSMPDYKPSFPKWARQDFSKV VPPLDEDGRSLLSQMLHYDPNKRISAKAALAHPFFQDVTKPVPHLRL (SEQ ID NO: 2)

[0372] 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" CDK2 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 CDK2 protein as, for example, introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing CDK2 protein.

[0373] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type ofintervention 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.

[0374] “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 CDK2 protein in the cells, or effective to treat proliferative disorders, such as cancer.

[0375] 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.

[0376] The term “patient” includes human subjects.

[0377] 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, i.e., 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.

[0378] The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceuticallyacceptable carrier.

[0379] UTILITY

[0380] The compounds of Formula (I) are useful for the treatment of cancer.

[0381] 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.

[0382] One aspect provides a method of treating a disease or disorder by decreasing the level of the CDK2 protein, the method comprising administering to a patient a therapeutically effective amount of an agent to decrease the CDK2 protein level. Suitable agents include small molecules and heterobifunctional molecules such as proteolysis targeting chimeras (PROTAC) molecule. 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. Examples of small molecules include molecular glues (Sasso et al., Biochemistry 2023, 62, 601-623).

[0383] 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 CDK2 protein level, wherein: the CDK2 protein is the amino acid sequence encoded by SEQ ID NOs: 1 or 2. 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.

[0384] 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 CDK2 protein level, wherein the CDK2 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.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 CDK2 protein level, wherein the CDK2 protein level is decreased by at least 75%. 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.

[0385] 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 CDK2 protein level, wherein the CDK2 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.

[0386] 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 CDK2 protein level, wherein the CDK2 protein level is decreased by at least 85%. 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.

[0387] 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 CDK2 protein level, wherein the CDK2 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.

[0388] 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 CDK2 protein level, wherein the CDK2 protein level is decreased by at least 92%. 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.

[0389] 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 anagent to decrease the CDK2 protein level, wherein the CDK2 protein level is decreased by at least 94%. 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.

[0390] 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 CDK2 protein level, wherein the CDK2 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.

[0391] 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 CDK2 protein level, wherein the CDK2 protein level is decreased by at least 96%. 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.

[0392] 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 CDK2 protein level, wherein the CDK2 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.

[0393] In Embodiments 1 to 10, the decrease in the protein levels of the CDK2 protein can be measured using the CDK2 Cellular Degradation assay described hereinbelow.

[0394] 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.

[0395] 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.

[0396] 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.

[0397] 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).

[0398] 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 acompound according to Formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein said cancer is mesothelioma.

[0399] 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.

[0400] 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.

[0401] 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.

[0402] 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.

[0403] 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.

[0404] 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 acompound 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.

[0405] 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.

[0406] 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.

[0407] 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).

[0408] 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).

[0409] 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.

[0410] The compounds for Formula (I) and pharmaceutical compositions comprising atleast one compound of Formula (I) are useful in treating or preventing any diseases or conditions that are associated with the activity of CDK2 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.

[0411] 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 CDK2 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 CDK2 proteins.

[0412] 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.

[0413] In another aspect, compounds of Formula (I) may be co-formulated with an immuno-oncology agent.

[0414] 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.

[0415] 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).

[0416] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligandsthat 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 costimulatory 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 / Fn14, TWEAK, BAFFR, ED AR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, ED AR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a / TNFp, TNFR2, TNFa, LTpR, Lymphotoxin a 1 P2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0417] 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.

[0418] 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.

[0419] 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, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008

[0420] (WO11 / 140249; WO13169264; WO14 / 036357).

[0421] 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 distinctimmune 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.

[0422] 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.

[0423] 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), MEDI-0680 (AMP-514;

[0424] 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.

[0425] 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).

[0426] 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, or IMP-731 or IMP-321 (W008 / 132601, WO09 / 44273).

[0427] 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).

[0428] 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).

[0429] In another aspect, the immuno-oncology agent is an IDO antagonist. SuitableIDO antagonists include, for example, INCB-024360 (W0206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, orNLG-919 (W009 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0430] 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.

[0431] 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).

[0432] 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.

[0433] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0434] In another aspect, the immuno-oncology agent is MGA271 (to B7H3)

[0435] (WO 11 / 109400).

[0436] 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.

[0437] In another aspect, the immuno-oncology agent is a KRAS G12C inhibitor.

[0438] Suitable KRAS G12C inhibitors include LUMAKRAS (sotorasib) or KRAZATI (adagrasib).

[0439] 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.

[0440] 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. Thetherapeutic 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.

[0441] 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 CDK2 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.

[0442] 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.

[0443] 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.

[0444] 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 (Navelbene®), bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-alpha), etoposide, and teniposide.

[0445] 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.

[0446] 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.

[0447] 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).

[0448] Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0449] Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.

[0450] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0451] 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.

[0452] 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.

[0453] Similarly, any STM may also be administered at any point in comparison to the administration of the compound of Formula (I).

[0454] 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.

[0455] PHARMACEUTICAL COMPOSITIONS

[0456] 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.

[0457] 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 includessustained 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.

[0458] 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.

[0459] 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.

[0460] 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.

[0461] 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-methylcellulose and hydroxypropyl-cellulose. Exemplary time delay materials, include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0462] 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.

[0463] 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.

[0464] 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, suchas, 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.

[0465] 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.

[0466] 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.

[0467] 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 emulsifyingagents 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.

[0468] 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.

[0469] 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.

[0470] 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.

[0471] 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, corn 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) ormicellar solubilization (i.e. Tween 80).

[0472] 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.

[0473] 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.

[0474] 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.

[0475] 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.

[0476] 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 intheir 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.

[0477] 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, poly acrylates, 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.

[0478] 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.

[0479] 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.

[0480] 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.

[0481] 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.

[0482] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of CDK2 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.

[0483] 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.

[0484] 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.

[0485] 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.

[0486] 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.

[0487] 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.

[0488] 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.

[0489] 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.

[0490] 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.

[0491] 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.

[0492] 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.

[0493] 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.

[0494] 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.

[0495] If desired, the effective daily dose of the active compound may be administered astwo, 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.

[0496] 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).

[0497] 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.

[0498] METHODS OF PREPARATION

[0499] 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.

[0500] 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 orderof 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.

[0501] EXAMPLES

[0502] 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.

[0503] Materials and Methods

[0504] All reagents and dried solvents were purchased from commercial suppliers and used without further purification unless otherwise stated. Flash column chromatographyon silica gel were performed on a Biotage Isolera Four or a Grace Reverleris X2 automated systems, using prepacked silica RediSep or Interchim puriFlash columns. Reversed-phase chromatography was performed on a Combi Flash Rf automated system, using prepacked C18aqueous RediSep Rf columns.

[0505] NMR spectroscopy:

[0506] Sample preparation: Powders were solubilized in DMSO-d6, vortexed vigorously until the solution was clear and transferred to an NMR tube for data acquisition.

[0507] Liquid-state NMR experiments were recorded on a 600 MHz (14.1 Tesla) Bruker Avance III NMR spectrometer (600 MHz for1H, 151 MHz for13C) using a tripleresonance1H / 19F,15N,13C TR TCI 5 mm cryoprobe (Bruker Biospin, Germany).

[0508] Liquid-state NMR experiments were recorded on a 500 MHz (11.75 Tesla) Bruker Avance NEO NMR spectrometer (500 MHz for1H, 125 MHz for13C) using a Dual Resonance 5 mm BBFO BBF / H iProbe (Bruker Biospin, Germany).

[0509] Liquid-state NMR experiments were recorded on a 400 MHz (9.4 Tesla) Bruker Avance NEO NMR spectrometer (400 MHz for1H, 100 MHz for13C) using a SEI 5 mm probe (Bruker Biospin, Germany).

[0510] All the experiments used for the resonance assignment procedure and the elucidation of the products structure (1D1H, 2D1H-1H-COSY, 2D1H-1H-ROESY, 2D1H-13C-HSQC, 2D1H-13C-HMBC) were recorded at 300 K.1H chemical shifts are reported in (ppm) as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), m (multiplet) or br s (broad singlet).

[0511] LCMS analysis:

[0512] Chemicals for analysis: All reagents used were analytical or ultra gradient grade. Sample preparation: Powders were solubilized in DMSO or MeOH or Acetonitrile or water, or other solvents depending on their solubility, at the concentration around 0.5 mg / mL, vortexed vigorously until the solution was clear and transferred to a LCMS vial for data acquisition.

[0513] Two different LC-UV-MS instruments have been used. 1. Waters Acquity UPLC system equipped with Waters Acquity PDA e-detector coupled with a Waters simple quadruple detector SQD mass spectrometer. 2. Waters HClass equipped with an UPLCeLAMBDA PDA detector coupled with a Waters simple quadruple detector SQD mass spectrometer.

[0514] System 1 was configured in acidic reverse phase conditions. Chromatographic separations were performed with a Waters column Acquity UPLC® CSHTM C18 (2.1x50 mm) 1.7 pm-Eluent A = H2O + 0.02% HCOOH-Eluent B = CH3CN + 0.02% HCOOH-Oven T °C: 55 °C-Gradient: tO 2% B, t4 min 98% B, t4.5 min 98% B, t4.6 min 2% B, t5.0 min 2% B-Flow rate = 1 mL / min or with a Waters column Acquity UPLC® CSHTM C18 (2.1x100 mm) 1.7 pm-Eluent A = H2O + 0.02%HCOOH-Eluent B = CH3CN + 0.02%HCOOH-Oven T °C: 55 °C-Gradient: tO 2% B, tl 5 min 98% B, tl 5.2 min 2% B, tl 8 min 2% B-Flow rate = 0.7 mL / min. The injection volume is set from 0.5 pL to 2 pL; The UV chromatograms were recorded at a wavelength of 220 nm. The mass spectrometer was operated with a source configured in positive or negative electrospray ion mode. The source parameters were source temperature 150 °C; desolvatation temperature 250 °C; cone gas flow 150 (L / h); desolvation gas flow 1000 (L / h); Capillary: 3 kV-Sample cone: 15 / 30 V-Mass range: 120-1500 amu. Data acquisition and data reprocessing were performed using Masslynx software (Waters).

[0515] System 2 was configured as well as in acidic reverse-phase conditions, neutral reverse-phase conditions, or basic reverse phase conditions. Chromatographic separations were performed as follow: Waters Column Acquity UPLC CSH C18 (2.1 x 50 mm) 1.7 pm-Eluent A = H2O + 0.02% HCOOH-Eluent B = CH3CN + 0.02% HCOOH-Oven T °C: 55 °C-Gradient: tO 2% B, t4 min 98% B, t4.5 min 98% B, t4.6 min 2% B, t5.5 min 2% B-Flow rate = 1 mL / min or Waters Column Acquity UPLC CSH C18 (2.1x100 mm) 1.7 pm-Eluent A = H2O + 0.02% HCOOH-Eluent B = CH3CN + 0.02% HCOOH-Oven T°C: 55 °C-Gradient: tO 2% B, tl 5 min 98% B, tl5.2min 2% B, tl8min 2% B-Flow rate = 0,7 mL / min or Waters Column Acquity UPLC CSH C 18 (2.1x50 mm) 1.7 pm-Eluent A = H2O + 0.05%TFA-Eluent B = CH3CN + 0.035%TFA-Oven T°C: 55 °C-Gradient: tO 2% B, t4 min 98% B, t4.5 min 98% B, t4.6 min 2% B, t5.5 min 2% B-Flow rate = 1 mL / min or Waters Column Acquity UPLC CSH C18 (2.1x100 mm) 1.7 pm-Eluent A = H2O + 0.05%TFA-Eluent B = CH3CN + 0.035%TFA-Oven T °C: 55 °C-Gradient: tO 2% B, tl 5 min 98% B, tl5.2min 2% B, tl8min 2% B-Flow rate = 0.7 mL / min or Waters Column Acquity UPLC BEH C18 (2.1x50 mm) 1.7 pm-Eluent A = H2O + AcONH410 mM (Ammoniac in Water adjusted to pH7 with AcOH)-Eluent B = CH3CN-Oven T °C: 45°C-Gradient: tO 2% B, t4 min 90% B, t4.5 min 90% B, t4.6 min 2% B, t5.5 min 2% B-Flow rate = 0.8 mL / min or Waters Column Acquity UPLC BEH C18 (2.1x50 mm) 1.7 pm-Eluent A = H2O + NH4HCO3at 2 mM adjusted to pH10 with NaOH- Eluent B = CH3CN-Oven T °C: 45 °C-Gradient: tO 2% B, t4 min 90% B, t4.5 min 90% B, t4.6 min 2% B, t5.5 min 2% B-Flow rate = 0.8 mL / min. The injection volume is set from 0.5 pL to 2 pL; The UV chromatograms were recorded at a wavelength of 220 nm. The mass spectrometer was operated with a source configured in positive or negative electrospray ion mode. The source parameters were source temperature 150 °C; desolvatation temperature 250 °C; cone gas flow 150 (L / h); desolvatation gas flow 1000 (L / h);

[0516] Capillary: 3 kV-Sample cone: 15 / 30 V-Mass range: 120-1500 amu. Data acquisition and data reprocessing were performed using Masslynx software (Waters).

[0517] LC / HRMS analysis:

[0518] The instrument for LC / HRMS analysis is a Waters Acquity UPLC system equipped with Waters Acquity PDA coupled with a Waters Xevo-G2-XS-QTOF mass spectrometer.

[0519] The System is configured in acidic reverse-phase conditions. Chromatographic separations were performed with aWaters column Cortecs® UPLC®C18 (2.1x100mm) 1.6 pm-Eluent A = H2O + 0.05% TFA-Eluent B = CH3CN + 0.035% TFA-Oven T °C: 55 °C-Gradient: tO 2% B, tl 5 min 98% B, tl 5.2 min 2% B, tl 8 min 2% B-Flow rate = 0.7 mL / min. The injection volume is set from 0.5 pL to 2 pL; The UV chromatograms were recorded at a wavelength of 220 nm. The mass spectrometer was operated with a source configured in positive or negative electrospray ion mode. The source parameters were Analyzer mode: Sensitivity; source temperature 120 °C; desolvatation temperature 550 °C; cone gas flow 50 (L / h); desolvatation gas flow 1200 (L / h); Collision Energy 6V Capillary: 3kV-Sample cone: 40 V-Source offset 80-Mass range: 120-1500 amu, scan time: 0.4 sec. The mass spectrometer is calibrated with sodium formate (Waters service Kit Part. No. 186007091-4). The lock mass used is Leucine enkephaline at 200 pg / pL, infused at 10 pL / min. The lock spray setup parameters are MS mode, single ion (556.2771 Da), sensitivity mode, scan time: 0.2 sec; interval 30 sec; scans to average: 3; mass windows: 0.5 Da (+ / -). Data acquisition and data reprocessing were performed using Masslynx software (Waters).ABBREVIATIONS

[0520] AcOH acetic acid

[0521] AIBN azobisisobutyronitrile

[0522] aq. aqueous

[0523] Boc tert-butoxycarbonyl

[0524] B2pin2 bis(pinacolato)diboron

[0525] Brettphos-Pd-Gl chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4', 6'-triisopropyl- 1, 1 '-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II) Brettphos-Pd-G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l,l'- biphenyl)-2-(2'-amino-l, 1 ' -biphenyl)]palladium(II) methanesulfonate CPME cyclopentyl methyl ether

[0526] DAST (diethylamino)sulfur trifluoride

[0527] DBAD di -tert-butyl azodi carb oxy late

[0528] DCM dichloromethane

[0529] DCE 1,2-di chloroethane

[0530] DIAD diisopropyl azodi carb oxy late

[0531] DIPEA N,N-diisopropylethylamine

[0532] DMAP N,N-dimethylpyridin-4-amine

[0533] DMF N,N-dimethylformamide

[0534] DMSO dimethylsulfoxide

[0535] Et₂O diethyl ether

[0536] EtOAc ethyl acetate

[0537] EtOH ethanol

[0538] FastWorX® trademark of hydrophobic powder

[0539] (g) gas

[0540] g gram(s)

[0541] h hour(s)

[0542] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0543] iPrNH2isopropylamine

[0544] iPrOH isopropanoliPrOAc isopropyl acetate

[0545] KOAc potassium acetate

[0546] MeOH methanol

[0547] MeTHF methyl tetrahydrofuran

[0548] mg milligram(s)

[0549] min minute(s)

[0550] mL milliliter(s)

[0551] mmol millimole(s)

[0552] mol mole(s)

[0553] MTBE methyl tert-butyl ether

[0554] NMR nuclear magnetic resonance

[0555] P- purity

[0556] Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)

[0557] Pd(dppf)Cl₂ [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2palladium(II) acetate

[0558] Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)

[0559] quant. quantitative

[0560] TBAF tetrabutylammonium fluoride

[0561] t-BuONa sodium tert-butoxide

[0562] TFA trifluoroacetic acid

[0563] THF tetrahydrofuran

[0564] T3P propane phosphonic acid anhydride

[0565] XantPhos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) XPhos-Pd-G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0566] y- yield

[0567] pL microliter(s)

[0568] INTERMEDIATE BB-01

[0569] 2-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-l-oxo-isoindoline-5-carboxylic acidO O

[0570]

[0571] (BB-01)

[0572] Intermediate BB-01 A: tert-butyl (45)-5-amino-4-(5-bromo-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate

[0573]

[0574] (BB-01 A)

[0575] To a stirred suspension of tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (4.26 g, 17.9 mmol) in acetonitrile (58 mL) was added DIPEA (8.5 mL, 48.7 mmol). The reaction mixture was stirred for 5 min. Next, methyl 4-bromo-2-(bromomethyl)benzoate (5.00 g, 16.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then at 70 °C overnight. The mixture was cooled to ambient temperature then diluted with EtOAc. The organic layer was washed with a 1 M aqueous solution of HC1 (2x) then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 40% to 100% to afford tert-butyl (45)-5-amino-4-(5 -bromo- l-oxo-isoindolin-2-yl)-5-oxo-pentanoate as an off-white solid (5.33 g, 100% p., 83% y.). m / z [M+H]+= 397.1, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.90-7.85 (m, 1H), 7.71-7.60 (m, 2H), 7.58 (s, 1H), 7.19 (s, 1H), 4.80-4.68 (m, 1H), 4.61 (d, J = 17.9 Hz, 1H), 4.47 (d, J = 17.9 Hz, 1H), 2.24-2.07 (m, 3H), 2.07-1.87 (m, 1H), 1.32 (s, 9H).

[0576] Intermediate BB-01

[0577] In sealed vial, to a stirred solution of tert-butyl (45)-5-amino-4-(5-bromo-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (5.33 g, 13.4 mmol) in DMF (45 mL) under argon were added successively ethanedioic acid dihydrate (2.54 g, 20.1 mmol), XantPhos (388 mg, 0.671 mmol), and Pd(OAc)2 (152 mg, 0.671 mmol). The reaction mixture was degassed with argon for 5 min. Acetic anhydride (1.9 mL, 20.1 mmol) and DIPEA (3.5 mL, 20.1 mmol) were added. The reaction mixture was stirred at 100 °C for 4 h. The reactionmixture was cooled to ambient temperature then concentrated under reduced pressure. The reaction mixture was poured into a saturated aqueous solution of NaHCO3. The aqueous layer was washed with EtOAc (2x). The aqueous layer was acidified to pH 3-4 with a 1 M aqueous solution of HC1 then extracted with EtOAc (3x). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindoline-5-carboxylic acid as a pale yellow foam (4.35 g, 81% p., 73% y.). m / z [M+H]⁺ = 363.3, ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 12.99 (s, 1H), 8.17 (t, J = 1.1 Hz, 1H), 8.05 (dd, J = 7.9, 1.4 Hz, 1H), 7.80 (dd, J = 7.9, 0.7 Hz, 1H), 7.60 (d, J = 12.5 Hz, 1H), 7.21 (s, 1H), 4.82-4.71 (m, 1H), 4.66 (d, J = 17.9 Hz, 1H), 4.53 (d, J = 17.9 Hz, 1H), 2.17 (t, J = 4.1 Hz, 3H), 2.07-1.94 (m, 1H), 1.32 (s, 9H).

[0578] INTERMEDIATE BB-02

[0579] 2-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-4-methyl-l-oxo-isoindoline-5-carboxylic acid

[0580]

[0581] (BB-02) Intermediate BB-02A: tert-butyl (45)-5-amino-4-(5-bromo-4-methyl-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate

[0582]

[0583] (BB-02A)

[0584] In a sealed vial, to a stirred suspension of tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (313 mg, 1.31 mmol) in dry acetonitrile (2.0 mL) at ambient temperature was added DIPEA (458 pL, 2.62 mmol). The reaction mixture was stirred for 30 min. A solution of methyl 4-bromo-2-(bromomethyl)-3-methyl-benzoate (621 mg, 0.656 mmol) in dry acetonitrile (1.5 mL) was added. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed withbrine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 1% to 50%. Fractions were combined and concentrated under reduced pressure. The residue was solubilized in a minimum amount of DCM and the solution was added dropwise to stirred solution of n-pentane. The resulting mixture was stirred for 30 min. The suspension was filtered, washed with n-pentane, and dried under reduced pressure to afford tert-butyl (4S)-5-amino-4-(5-bromo-4-methyl-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate as a pale yellow solid (204 mg, 99% p., 75% y.). m / z [M+Na]⁺ = 435.3, ¹H NMR (DMSO-d₆): δ (ppm) 7.72 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.45 (d, 8.0 Hz, 1H), 7.19 (s, 1H), 4.73 (dd, J = 9.4, 3.5 Hz, 1H), 4.59 (d, J = 17.7 Hz, 1H), 4.49 (d, J = 17.8 Hz, 1H), 2.36 (s, 3H), 2.23-2.10 (m, 3H), 2.06-1.94 (m, 1H), 1.34 (s, 9H).

[0585] Intermediate BB-02

[0586] In an autoclave, to a stirred solution of tert-butyl (45)-5-amino-4-(5-bromo-4-methyl-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (204 mg, 0.491 mmol) in dry DMF (1.7 mL) under argon were added successively ethanedioic acid dihydrate (93.0 mg, 0.740 mmol), Xantphos (14.0 mg, 0.025 mmol) and Pd(OAc)2 (5.7 mg, 0.025 mmol). The reaction mixture was degassed with argon for 5 min then acetic anhydride (68.0 pL, 0.740 mmol) and DIPEA (129 pL, 0.737 mmol) were added. The reaction mixture was stirred at 100 °C overnight. The reaction was quenched with the addition of saturated aqueous solution of NaHCO3. EtOAc was added to the mixture. The phases were separated, and the aqueous layer washed with EtOAc. The aqueous layer was acidified to pH 3-4 with a 1 M aqueous solution of HC1 and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was triturated with n-pentane and stirred for 30 min. The suspension was filtered, washed with n-pentane, and dried under reduced pressure to afford 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-4-methyl-1-oxo-isoindoline-5-carboxylic acid as a white solid (126 mg, 95% p., 65% y.). m / z [M+Na]⁺ = 399.4, ¹H NMR (DMSO-d₆): δ (ppm) 13.17 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.20 (s, 1H), 4.79-4.71 (m, 1H), 4.59 (d, J = 17.6 Hz, 1H), 4.50 (d, J = 17.6 Hz, 1H), 2.49 (s, 3H), 2.26-2.11 (m, 3H), 2.08-1.97 (m, 1H), 1.34 (s, 9H).INTERMEDIATE BB-03

[0587] 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-fluoro-l-oxo-isoindoline-5-carboxylic acid

[0588] O O

[0589]

[0590] ° (BB-03)

[0591] Intermediate BB-03 A: methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate

[0592] O

[0593] O"

[0594] Br

[0595]

[0596] (BB-03A)

[0597] To a stirred solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (4.05 g, 16.4 mmol) in acetonitrile (55 mL) were added 1 -bromopyrrolidine-2, 5-dione (3.21 g, 18.0 mmol) and AIBN (269 mg, 1.64 mmol). The reaction mixture was irradiated with a white lamp (6200 K) for 2 h. The mixture was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 2% to 20% to afford methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate as a yellow oil (5.13 g, 84% p., 81% y.). m / z [M+H]+= no ionization,1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.05 (d, J= 6.8 Hz, 1H), 7.79 (d, J= 9.3 Hz, 1H), 4.97 (s, 2H), 3.88 (s, 3H).

[0598] Intermediate BB-03B: tert-butyl (45)-5-amino-4-(5-bromo-6-fluoro-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate

[0599] O O

[0600]

[0601] (BB-03B)

[0602] To a stirred suspension of tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (3.98 g, 16.7 mmol) in acetonitrile (26 mL) at 0 °C was added DIPEA (5.5 mL, 31.5 mmol) dropwise. The reaction mixture was stirred for 30 min at 0 °C. A solution of methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (5.13 g, 15.7 mmol) inacetonitrile (45 mL) was added dropwise over 30 min at 0 °C. The reaction mixture was then stirred at 70 °C overnight. The mixture was cooled to ambient temperature then concentrated under reduced pressure. The residue was triturated in water for 1 h, filtered, washed with water, and dried under reduced pressure. The residue was triturated in a mixture of n-pentane / EtOAc (5 / 1) for 1 h, filtered, washed with n-pentane and dried under reduced pressure at 50 °C overnight to afford tert-butyl (4S)-5-amino-4-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate as an off-white solid (5.19 g, 99% p., 79% y.). m / z [M+H]⁺ = 415.1, ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.03 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.21 (s, 1H), 4.72 (dd, J = 9.6, 3.8 Hz, 1H), 4.60 (d, J = 17.7 Hz, 1H), 4.45 (d, J = 17.7 Hz, 1H), 2.22-2.07 (m, 3H), 2.05-1.90 (m, 1H), 1.33 (s, 9H).

[0603] Intermediate BB-03

[0604] In an autoclave, to a stirred solution of tert-butyl (45)-5-amino-4-(5-bromo-6-fluoro-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (5.18 g, 12.5 mmol) in DMF (25 mL) under argon were added successively ethanedioic acid dihydrate (2.36 g, 18.7 mmol), XantPhos (361 mg, 0.624 mmol), and Pd(OAc)₂ (141 mg, 0.624 mmol). The reaction mixture was degassed with argon for 5 min. Next, acetic anhydride (1.7 mL, 18.7 mmol) and DIPEA (3.3 mL, 18.7 mmol) were added. The reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into a 1 M aqueous solution of NaHCO₃. The aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 3-4 with a concentrated aqueous solution of HCl, and then extracted with EtOAc (3x). The combined organic layers were dried using a phase separator and concentrated under reduced pressure. The residue was triturated in DCM. MTBE was added and the residue was triturated for 2 h. The suspension was filtered, washed with MTBE, and dried under reduced pressure to afford 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-fluoro-1-oxo-isoindoline-5-carboxylic acid as an off-white solid (2.96 g, 96% p., 60% y.). m / z [M+H]⁺ = 381.4, ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 13.56 (s, 1H), 8.09 (d, J = 6.1 Hz, 1H), 7.67-7.52 (m, 2H), 7.24 (s, 1H), 4.80-4.69 (m, 1H), 4.69-4.41 (m, 2H), 2.24-2.08 (m, 3H), 2.08-1.87 (m, 1H), 1.33 (s, 9H).INTERMEDIATE BB-04

[0605] 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-methyl-1-oxo-isoindoline-5-carboxylic acid

[0606] O O

[0607] T ||.. < H3C CH3

[0608]

[0609] ° (BB-04) Intermediate BB-04A: methyl 4-bromo-2,5-dimethyl-benzoate

[0610] O

[0611] H3CX^^Y^OX'CH3

[0612]

[0613] Br CH3 (BB-04A)

[0614] To a stirred solution of 4-bromo-2,5-dimethylbenzoic acid (10.0 g, 41.5 mmol) in MeOH (130 mL) at 25 °C was added sulfuric acid (442 pL, 8.29 mmol). The reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled down to ambient temperature. Additional oxalyl dichloride (3.6 mL, 41.5 mmol) was added dropwise. The reaction mixture was stirred at reflux for 4 h then at 25 °C for 48 h. The reaction mixture was concentrated under reduced pressure. The residue was solubilized in EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-2,5-dimethyl-benzoate as an off-white solid (8.03 g, 98% p., 78% y.). m / z [M+H]+= no ionization, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.76 (s, 1H), 7.58 (s, 1H), 3.81 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H).

[0615] Intermediate BB-04B: methyl 4-bromo-2-(bromomethyl)-5-methyl-benzoate

[0616] O

[0617] H3C JL CH3

[0618] JI U-- Br

[0619]

[0620] Br (BB-04B)

[0621] To a stirred solution of 1 -bromopyrrolidine-2, 5-dione (6.34 g, 35.6 mmol) in acetonitrile (104 mL) were added methyl 4-bromo-2,5-dimethylbenzoate (8.03 g, 32.4 mmol) and AIBN (532 mg, 3.24 mmol). The reaction mixture was irradiated with a white lamp (6200 K) for 3 h. The mixture was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc incyclohexane from 0% to 20% to afford methyl 4-bromo-2-(bromomethyl)-5-methyl-benzoate as a white solid (9.06 g., 50% p., 44% y.). m / z [M+H]+= no ionization.

[0622] Intermediate BB-04C: tert-butyl (45)-5-amino-4-(5-bromo-6-methyl-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate

[0623] O O

[0624]

[0625] (BB-04C)

[0626] To a stirred solution of methyl 4-bromo-2-(bromomethyl)-5-methyl-benzoate (9.06 g, 28.1 mmol) in acetonitrile (90 mL) at ambient temperature were added tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (7.39 g, 31.0 mmol) and DIPEA (15 mL, 84.4 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO₃ and EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 5% to 50% to afford tert-butyl (4S)-5-amino-4-(5-bromo-6-methyl-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate as a white solid (1.70 g, 86% p., 13% y.). m / z [M+Na]⁺ = 433.1, ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) 7.89 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 4.72 (dd, J = 10.2, 4.5 Hz, 1H), 4.57 (d, J = 17.6 Hz, 1H), 4.42 (d, J = 17.7 Hz, 1H), 2.44 (s, 3H), 2.19-2.09 (m, 3H), 2.00-1.92 (m, 1H), 1.34 (s, 9H).

[0627] Intermediate BB-04

[0628] In an autoclave, to a stirred solution of tert-butyl (45)-5-amino-4-(5-bromo-6-methyl-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (1.70 g, 4.13 mmol) in DMF (14 mL) were added ethanedioic acid dihydrate (782 mg, 6.20 mmol), XantPhos (120 mg, 0.207 mmol), and Pd(OAc)2 (47.8 mg, 0.207 mmol). The mixture was degassed with argon for 5 min. Next, acetic anhydride (573 pL, 6.20 mmol) and DIPEA (1.1 mL, 6.20 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured in a saturated aqueous solutionof NaHCO₃. The aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 1 with a 12 M aqueous solution of HCl. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and dried under reduced pressure. The crude material was purified by reverse-phase preparative chromatography using a gradient of acetonitrile in water (0.1% AcOH) from 0% to 100% then, by chiral supercritical chromatography (Waters Prep SFC200, Chiralpak IC (5 μm, 250 x 30 mm), CO₂ / (MeOH + 0.5% IprNH₂) (70 / 30) as mobile phase, flow rate 100 mL / min, 100 bars) to afford (first isomer eluted) 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-methyl-1-oxo-isoindoline-5-carboxylic acid as a white powder (230 mg, 98% p., 15% y.). m / z [M+Na]⁺ = 399.3, ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 13.13 (s, 1H), 8.00 (s, 1H), 7.62 (t, J = 0.7 Hz, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 4.74 (dd, J = 10.3, 4.2 Hz, 1H), 4.60 (d, J = 17.6 Hz, 1H), 4.46 (d, J = 17.6 Hz, 1H), 2.59 (s, 3H), 2.15 (h, J = 2.8 Hz, 3H), 2.06-1.89 (m, 1H), 1.33 (s, 9H).

[0629] INTERMEDIATE BB-05

[0630] 2-[(1R)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-methyl-1-oxo-isoindoline-5-carboxylic acid

[0631]

[0632] In an autoclave, to a stirred solution of tert-butyl (45)-5-amino-4-(5-bromo-6-methyl-l-oxo-isoindolin-2-yl)-5-oxo-pentanoate (1.70 g, 4.13 mmol) in DMF (14 mL) were added ethanedioic acid dihydrate (782 mg, 6.20 mmol), XantPhos (120 mg, 0.207 mmol), and Pd(OAc)₂ (47.8 mg, 207 μmol). The mixture was degassed with argon for 5 min. Next, acetic anhydride (573 μL, 6.20 mmol) and DIPEA (1.1 mL, 6.20 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured in a saturated aqueous solution of NaHCO₃. The aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 1 with a 12 M aqueous solution of HCl. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and dried under reduced pressure. The crude material was purified by reverse-phasepreparative chromatography using a gradient of acetonitrile in water (0.1% AcOH) from 0% to 100% then, by chiral supercritical chromatography (Waters Prep SFC200, Chiralpak IC (5 pm, 250 x 30 mm), CO2 / (MeOH + 0.5% iPrNH2) (70 / 30) as mobile phase, flow rate 100 mL / min, 100 bars) to afford (second isomer eluted) 2-[(1R)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-methyl-1-oxo-isoindoline-5-carboxylic acid as a white powder (230 mg, 98% p., 15% y.). m / z [M+Na]+= 399.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 13.13 (s, 1H), 7.99 (s, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 4.74 (dd, J= 10.3, 4.2 Hz, 1H), 4.59 (d, J= 17.6 Hz, 1H), 4.46 (d, J= 17.6 Hz, 1H), 2.58 (s, 3H), 2.20-2.10 (m, 3H), 2.02-1.92 (m, 1H), 1.33 (s, 9H).

[0633] INTERMEDIATE BB-06

[0634] 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-6-vinyl-isoindoline-5-carboxylic acid

[0635] II0 0

[0636] y- NH2

[0637] I If N. < H3C CH3

[0638]

[0639] o (BB-06) Intermediate BB-06A: methyl 4-bromo-5-iodo-2-methyl-benzoate

[0640] O

[0641] B

[0642]

[0643] r'CH3(BB-06A)

[0644] In a three-neck round-bottom flask equipped with a thermometer, under argon, a solution of 4-bromo-5-iodo-2-methylbenzoic acid (5.00 g, 13.9 mmol) in dry MeOH (100 mL) was stirred at 0 °C. Thionyl chloride (4.1 mL, 55.7 mmol) was added dropwise over 2 min. The mixture was stirred at ambient temperature for 16 h and then at 60 °C for 4 h. The mixture was concentrated, and the residue was partitioned between a saturated aqueous solution of NaHCO3and EtOAc. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, filtered through hydrophobic paper, and concentrated to afford methyl 4-bromo-5-iodo-2-methyl-benzoate as a beige solid (4.77 g, 96% p., 93% y.). m / z [M+H]+= no ionization, 'H NMR (400 MHz, DMSO-d6): 6 (ppm) 8.23 (s, 1H), 7.74 (s, 1H), 3.82 (s, 3H), 2.44 (s, 3H).Intermediate BB-06B: methyl 4-bromo-2-(bromomethyl)-5-iodo-benzoate

[0645] O CH

[0646] O'3

[0647] J

[0648] Br

[0649]

[0650] (BB-06B)

[0651] In a sealed tube under argon, AIBN (212 mg, 1.29 mmol) was added to a stirred solution of methyl 4-bromo-5-iodo-2-methyl-benzoate (4.77 g, 12.9 mmol) and 1-bromopyrrolidine-2, 5-dione (2.53 g, 14.2 mmol) in dry acetonitrile (50 mL). The mixture was irradiated with a white lamp (6200 K) for 2 h and was concentrated. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 10% to afford methyl 4-bromo-2-(bromomethyl)-5-iodo-benzoate as an off-white solid (5.35 g, 75% p., 72% y.). m / z [M+H]+= no ionization.

[0652] Intermediate BB-06C: (tert-butyl (4S)-5-amino-4-(5-bromo-6-iodo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate

[0653] O O

[0654]

[0655] (BB-06C)

[0656] To a stirred suspension of tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (3.12 g, 13.1 mmol) in acetonitrile (20 mL) at 0 °C was added DIPEA (4.3 mL, 24.7 mmol) dropwise. The reaction mixture was stirred for 30 min at 0 °C. A solution of methyl 4-bromo-2-(bromomethyl)-5-iodo-benzoate (5.35 g, 12.3 mmol) in acetonitrile (35 mL) was added dropwise over 30 min at 0 °C. The reaction mixture was then stirred at 70 °C overnight. The mixture was cooled to ambient temperature then concentrated under reduced pressure. The residue was triturated in water (60 mL) for 1 h, filtered, washed with water, and dried under reduced pressure. The residue was triturated in / / -pentane / EtOAc (5 / 1) for 1 h, filtered, washed with / / -pentane and dried under reduced pressure at 50 °C overnight to afford tert-butyl (4S)-5-amino-4-(5-bromo-6-iodo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate as an off-white solid (5.07 g, 92% p., 72% y.). m / z [M+H]+= 523.2, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.15 (s, 1H), 8.05 (s, 1H), 7.58 (s, 1H), 7.27-7.15 (m, 1H), 4.77-4.64 (m, 1H), 4.53 (d, J= 18.0 Hz, 1H), 4.40 (d, J = 18.1 Hz, 1H), 2.23-2.05 (m, 3H), 2.05-1.86 (m, 1H), 1.33 (s, 9H).Intermediate BB-06D: tert-butyl (4S)-5-amino-4-(5-bromo-1-oxo-6-vinyl-isoindolin-2-yl)-5-oxo-pentanoate

[0657] NH2

[0658] H3C CH3

[0659] -\ V-CH:

[0660]

[0661] (BB-06D)

[0662] To a stirred solution of tert-butyl (4S)-5-amino-4-(5-bromo-6-iodo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (2.00 g, 3.82 mmol) in a mixture of 1,4-dioxane (15 mL) and water (3.8 mL) were added successively K2CO3(1,32 g, 9.56 mmol) then 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (778 pL, 4.59 mmol). The reaction mixture was degassed with argon. Pd(PPh₃)₄ (442 mg, 0.382 mmol) was added and the reaction mixture was stirred at 90 °C overnight. Additional 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (707 mg, 4.59 mmol) and Pd(PPh₃)₄ (442 mg, 0.382 mmol) were added and the reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was cooled to ambient temperature and diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 1% to 100% to afford tert-butyl (4S)-5-amino-4-(5-bromo-1-oxo-6-vinyl-isoindolin-2-yl)-5-oxo-pentanoate as a yellow solid (2.13 g, 65% p., 85% y.). m / z [M+H]+= 423.2.

[0663] Intermediate BB-06

[0664] In an autoclave, to a stirred solution of tert-butyl (4S)-5-amino-4-(5-bromo-1-oxo-6-vinyl-isoindolin-2-yl)-5-oxo-pentanoate (2.13 g, 5.03 mmol) in DMF (10 mL) were added successively ethanedioic acid dihydrate (950 mg, 7.54 mmol), XantPhos (145 mg, 0.251 mmol), and Pd(OAc)2 (56.9 mg, 0.251 mmol). The reaction mixture was degassed with argon for 5 min. Next, acetic anhydride (697 pL, 7.54 mmol) and DIPEA (1.3 mL, 7.54 mmol) were added. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into a 1 M aqueous solution of NaHCO3. The aqueous layer was washed with EtOAc (3x). The aqueous layer was acidified to pH 3-4 with a 12 M aqueous solution of HC1then extracted with EtOAc (3x). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to afford 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-6-vinyl-isoindoline-5-carboxylic acid as an orange oil (1.06 g, 89% p., 48% y.). m / z [M+H]+= 389.3.

[0665] INTERMEDIATE BB-07

[0666] benzyl 4-benzoylpiperidine-l -carboxylate

[0667] O

[0668]

[0669] (BB-07)

[0670] To a stirred suspension of phenyl(4-piperidyl)methanone hydrochloride (25.0 g, 0.109 mol) in DCM (155 mL) at 0 °C were added successively triethylamine (35 mL, 0.250 mol) and benzyl carbonochloridate (17 mL, 0.119 mol) dropwise. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of saturated aqueous solution of NH4Cl. The aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried using a phase separator, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 5% to 60%. The fractions were combined and concentrated under reduced pressure to afford benzyl 4-benzoylpiperidine-l -carboxylate as a pale yellow oil (32.5 g, 81% p., 75% y.). m / z [M+H]+= 324.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.03-7.92 (m, 2H), 7.64 (qt, J= 8.6, 1.3 Hz, 1H), 7.58-7.48 (m, 2H), 7.42-7.20 (m, 5H), 5.09 (s, 2H), 4.05 (dt, J = 13.1, 3.0 Hz, 2H), 3.67 (tt, J= 11.3, 3.6 Hz, 1H), 3.02 (s, 2H), 1.80 (d, J= 11.4 Hz, 2H), 1.44 (qd, J= 12.2, 4.2 Hz, 2H).

[0671] INTERMEDIATE BB-08

[0672] benzyl 4-[(A)-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate

[0673]

[0674] (BB-08)

[0675] Intermediate BB-08 A: (3-bromo-2-chloro-phenoxy)-tert-butyl-dimethyl-silane

[0676] H3C CH3

[0677] 3\ LCH3

[0678] HsC-Si^cHs

[0679]

[0680] (BB-08A)

[0681] To a stirred solution of 3-bromo-2-chlorophenol (16.2 g, 78.1 mmol) in DCM (200 mL) were added successively tri ethylamine (24 mL, 172 mmol), DMAP (954 mg, 7.81 mmol), and tert-butyl-chloro-dimethyl-silane (12.9 g, 85.9 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified through a pad of silica gel using a mixture of cyclohexane / EtOAc (9 / 1) as eluent to afford (3 -bromo-2-chloro-phenoxy -lerl-butyl-dimethyl-silane as a light-yellow liquid (24.5 g, 92% p., 90% y.). m / z [M+H]+= no ionization, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.36 (dd, J = 8.1, 1.4 Hz, 1H), 7.18 (t, J = 8.2 Hz, 1H), 7.03 (dd, J = 8.2, 1.4 Hz, 1H), 0.99 (s, 9H), 0.23 (s, 6H).

[0682] Intermediate BB-08B: benzyl 4-[[3-[ter / -butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-phenyl-methyl]piperidine-l -carboxylate

[0683]

[0684] (BB-08B)

[0685] To a stirred solution of (3-bromo-2-chloro-phenoxy)-tert-butyl-dimethyl-silane (16.7 g, 47.8 mmol) and benzyl 4-benzoylpiperidine-l -carboxylate (14.0 g, 43.4 mmol) in dry THF (215 mL) at -78 °C under nitrogen was added 1.6 M w-butyllithium in hexanes (41 mL, 65.1 mmol). The reaction mixture was stirred at -78 °C for 10 min and at ambient temperature for 16 h. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl, water. EtOAc were added. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried using a phase separator and concentrated under vacuum. The crude material was purified on a pad of silica gel using cyclohexane / EtOAc (80 / 20) as eluent to afford benzyl 4-[[3-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-hydroxy-phenyl-methyl]piperidine-l -carboxylate as a yellow oil (18.5 g, 83% p., 63% y.). m / z [M+H]+= no ionization.

[0686] Intermediate BB-08C: benzyl 4-[[3-[tert-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-phenyl-methyl]piperidine-l -carboxylate

[0687]

[0688] (BB-08C)

[0689] To a stirred solution of triethylsilane (13 mL, 81.4 mmol) and TFA (62 mL, 814 mmol) in DCM (250 mL) at -20 °C was added a solution of benzyl 4-[[3-[ / c / 7-butyl (dimethyl)silyl]oxy-2-chloro-phenyl]-hydroxy-phenyl-methyl]piperidine-l-carboxylate(18.5 g, 27.1 mmol) in DCM (80 mL) dropwise over 1 h. The mixture was warmed up to ambient temperature and stirred overnight. The reaction mixture was slowly poured into a 2 M aqueous solution of NaOH (407 mL, 814 mmol) precooled at 0 °C. The layers were separated, and the aqueous layer extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified through a pad of silica gel using cyclohexane / EtOAc (85 / 15) as eluent to afford benzyl 4-[[3-[ter / -butyl(dimethyl) silyl]oxy-2-chloro-phenyl]-phenyl-methyl] piperidine- 1 -carboxylate as a colorless oil (10.8 g, 98% p., 71% y.). m / z [M+H]+= 550.5, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.39-7.32 (m, 6H), 7.31-7.24 (m, 4H), 7.23-7.11 (m, 2H), 6.81 (dd, J=7.9, 1.5 Hz, 1H), 5.05 (s, 2H), 4.14 (d, J=11.2 Hz, 1H), 3.96 (dd, J=13.4, 3.2 Hz, 2H), 2.77 (s, 2H), 2.48-2.36 (m, 1H), 1.51-1.41 (m, 1H), 1.36 (m, 1H), 1.07-0.94 (m, 11H), 0.19 (s, 3H), 0.16 (s, 3H).

[0690] Intermediate BB-08

[0691] To a stirred solution of benzyl 4-[[3-[terLbutyl(dimethyl)silyl]oxy-2-chloro-phenyl]-phenyl-methyl]piperidine-l -carboxylate (10.8 g, 19.3 mmol) in THF (60 mL) under nitrogen was added 1 M TBAF in THF (29 mL, 28.9 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 1 h. The reaction was quenched with the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 1% to 50% then, by chiral supercritical chromatography (Supersep, Chiralpak AD-H (20 pm, 250 x 50 mm), CO2 / MeOH 65 / 35 as mobile phase, flow rate 900 g / min, 100 bars) and by chiral reverse-phase (Novasep, Chiralpack OD-H (20 pm, 300 x 76.6mm), MeOH as mobile phase, flow rate 275 mL / min) to afford benzyl 4-[( / ?)-(2-chl oro-3 -hydroxy-phenyl )-phenyl -methyl ]pi peri di ne-1-carboxylate (first isomer eluted) as a white solid (1.88 g, 99% p, 22% y., e. e. >99.9%). m / z [M+H]+= 436.3, 'H NMR (400 MHz, DMSO-d6): 6 (ppm) 10.01 (s, 1H), 7.39-7.29 (m, 7H), 7.26 (t, J = 7.6 Hz, 2H), 7.20-7.07 (m, 3H), 6.80-6.74 (m, 1H), 5.05 (s, 2H), 4.12 (d, J = 11.2 Hz, 1H), 3.96 (dt, J= 13.2, 3.4 Hz, 2H), 2.78 (s, 2H), 2.42 (m, 1H), 1.50 (d, J= 13.0 Hz, 1H), 1.36 (d, J = 13.2 Hz, 1H), 1.09-0.89 (m, 2H), [a]D= +45 “mL.diTr'.g-1[20 °C, Na lamp, 589 nm, C = 2.8 mg / mL, EtOH],INTERMEDIATE BB-09

[0692] benzyl 4-[(A)-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate

[0693]

[0694] (BB-09)

[0695] To a stirred solution of benzyl 4-[[3-[ / c / 7-butyl(dimethyl)silyl]oxy-2-chloro-phenyl]-phenyl-methyl]piperidine-l -carboxylate (10.8 g, 19.3 mmol) in THF (60 mL) under nitrogen was added 1 M TBAF in THF (29 mL, 28.9 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 1 h. The reaction was quenched with the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 1% to 50% then, by chiral supercritical chromatography (Supersep, Chiralpak AD-H (20 pm, 250 x 50 mm), CO2 / MeOH 65 / 35 as mobile phase, flow rate 900 g / min, 100 bars) and by chiral reverse-phase (Novasep, Chiralpack OD-H (20 pm, 300 x 76.6 mm), MeOH as mobile phase, flow rate 275 mL / min) to afford benzyl 4-[(A)-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-1-carboxylate (second isomer eluted) as a white solid (2.05 g, 95% p, 24% y., e.e.

[0696] >99.9%). m / z [M+H]+= 436.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 10.00 (s, 1H), 7.40-7.22 (m, 9H), 7.19-7.05 (m, 3H), 6.82-6.74 (m, 1H), 5.05 (s, 2H), 4.12 (d, J= 11.3 Hz, 1H), 3.96 (d, J= 13.2 Hz, 2H), 2.77 (s, 2H), 2.42 (q,. / = 11.7 Hz, 1H), 1.50 (d, J = 13.0 Hz, 1H), 1.36 (d, J = 13.1 Hz, 1H), 1.11-0.89 (m, 2H), [a]D= -46 “mL.dm3.g-1[20 °C, Na lamp, 589 nm, C = 2.8 mg / mL, EtOH],

[0697] INTERMEDIATE BB-10

[0698] 4-[(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide

[0699]

[0700] Intermediate BB-10A: benzyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl]piperidine-l-carb oxy late

[0701]

[0702] (BB-10A)

[0703] To a stirred solution of l-bromo-2-chloro-benzene (548 pL, 4.64 mmol) in dry THF (15 mL) at -78 °C under argon was added a 2.5 M solution of w-butyllithium in hexanes (1.9 mL, 4.64 mmol) over 10 min. After the end of addition, a solution of benzyl 4-benzoylpiperidine-l -carboxylate (1.00 g, 3.09 mmol) in dry THF (7.5 mL) was added over 15 minutes keeping the temperature below -60 °C. The reaction mixture was allowed to warm up to ambient temperature overnight. The reaction was quenched with the addition of saturated aqueous solution of NH4Cl. Water and EtOAc were added. The phases were separated, and the aqueous phase extracted with EtOAc. The combined organic layers were washed with brine, dried over hydrophobic paper, and concentrated under reduced pressure. The resulting white foam was triturated in Et2O / / 7-pentane (9 / 1) (5.0 mL). The resulting precipitate was filtered, washed with w-pentane, and dried under reduced pressure at 50 °C overnight to afford benzyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl]piperidine-l -carboxylate as a white powder (958 mg, 95% p., 68% y). m / z [M+H]+= 436.2,1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.05-7.98 (m, 1H), 7.45-7.10 (m, 13H), 5.50 (s, 1H), 5.05 (s, 2H), 4.04 (d, J= 13.2 Hz, 2H), 3.16 (s, 1H), 2.88 (s, 2H), 1.54 (s, 1H), 1.33 (dddd, J= 43.8, 19.5, 14.1, 5.8 Hz, 3H).

[0704] Intermediate BB-10B: benzyl 4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carb oxy late

[0705]

[0706] (BB-10B)

[0707] To a stirred solution of benzyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl] piperidine- 1 -carboxylate (958 mg, 2.09 mmol) in DCM (7.5 mL) at 0 °C under nitrogen were added successively triethylsilane (1.0 mL, 6.26 mmol) and TFA (4.8 mL, 62.6 mmol) while maintaining the temperature below 5 °C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched at 0 °C with the addition of a saturated aqueous solution of K2CO3. The phases were separated, and the aqueous phase extracted with DCM. The combined organic layers were washed with brine, dried over hydrophobic paper, filtered, and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 15%. The fractions were concentrated under vacuum to afford benzyl 4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l -carboxylate as a colorless oil (206 mg, 98% p., 23% y.). m / z [M+H]+= 420.0, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.70 (dd, J= 7.9, 1.6 Hz, 1H), 7.40-7.24 (m, 11H), 7.21-7.13 (m, 2H), 5.05 (s, 2H), 4.11 (d, J = 11.2 Hz, 1H), 4.00-3.83 (m, 2H), 2.78 (s, 2H), 2.50-2.42 (m, 1H), 1.46 (d, J= 13.3 Hz, 1H), 1.38 (d, J= 13.7 Hz, 1H), 1.11-0.95 (m, 2H).

[0708] Intermediate BB-10

[0709] A sealed vial was charged with a suspension of benzyl 4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l -carboxylate (130 mg, 0.310 mmol) in dry acetonitrile (3.9 mL) at ambient temperature under nitrogen. Iodo(trimethyl)silane (132 pL, 0.929 mmol) was added dropwise, the mixture was stirred at ambient temperature for 1 h. The mixture was stirred at 0 °C and MeOH (150 pL, 3.71 mmol) was added dropwise. The mixture was stirred at ambient temperature for 20 min and was then concentrated under reduced pressure. Et2O was added to the residue. The resulting mixture was stirred at ambient temperature for 1 h. The solid was filtered, washed with Et2O, and dried under reduced pressure at 50 °C for 16 h to afford 4-[(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide as a white powder (114 mg, 99% p., 88% y.). m / z [M+H]+= 286.3,1H NMR(400 MHz, DMSO-d6): 6 (ppm) 8.41 (s, 1H), 8.09 (s, 1H), 7.66 (dd, J= 7.9, 1.7 Hz, 1H), 7.45-7.15 (m, 8H), 4.11 (d, J= 11.2 Hz, 1H), 3.24 (d, J= 12.6 Hz, 2H), 2.84 (s, 2H), 2.67-2.54 (m, 1H), 1.55 (t, J= 16.6 Hz, 2H), 1.34-1.20 (m, 2H).

[0710] INTERMEDIATE BB-11

[0711] 4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide

[0712]

[0713] (BB-11)

[0714] Intermediate BB-11 A: benzyl 4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carb oxy late

[0715]

[0716] (BB-11 A)

[0717] To a stirred solution of benzyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl] piperidine- 1 -carboxylate (2.03 g, 4.42 mmol) in DCM (16 mL) at -50 °C under nitrogen were added triethylsilane (2.14 mL, 13.3 mmol) dropwise. TFA (10 mL, 0.133 mol) was added dropwise very slowly (keeping the temperature below -40 °C). DCM (16 mL) was added. The reaction mixture was allowed to warm up to ambient temperature overnight. The reaction mixture was slowly added to a stirred aqueous solution of 10 M NaOH (13 mL, 0.133 mol) at 0 °C (maintaining the temperature below 10 °C). The phases were separated, and the aqueous phase extracted with EtOAc. The combined organic layers were washed with brine, dried using hydrophobic paper and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 12%. The desired fractions were concentrated under reduced pressure to afford (benzyl 4-[(2-chlorophenyl)-phenyl-methyl]piperidine-1 -carboxylate as a colorless oil (873 mg, 97% p., 46% y.) then, by chiral supercritical chromatography (Waters Prep SFC200, Chiralpak AD (5 pm, 250 x 30 mm), CO2 / zPrOH (70 / 30) as mobile phase, flow rate 100 mL / min) to afford benzyl 4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l -carboxylate (first isomer) as a colorless gum (370 mg, 93% p., 19% y., e. e. > 99.9%). m / z [M+H]+= 420.3, 'H NMR (400 MHz, DMSO-d6): 6 (ppm) 7.70 (dd, J= 1.7, 7.8 Hz, 1H), 7.33 (m, 11H), 7.18 (m, 2H), 5.05 (s, 2H), 4.11 (d, J= 11.2 Hz, 1H), 3.97 (d, J= 13.2 Hz, 2H), 2.78 (s, 2H), 1.42 (dd, J= 13.2, 32.7 Hz, 2H), 1.02 (m, 3H), [a]o= +17 “mL.dm'hg'1[20 °C, Na lamp, 589 nm, C = 6.2 mg / mL, EtOH],

[0718] Intermediate BB-11

[0719] A vial was charged with a suspension of (benzyl 4-(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l -carboxylate, 370 mg, 0.881 mmol) in dry acetonitrile (8.8 mL) at ambient temperature under nitrogen. Iodo(trimethyl)silane (376 pL, 2.64 mmol) was added dropwise and the mixture was stirred at ambient temperature for 1 h. The mixture was stirred at 0 °C. MeOH (428 pL, 10.6 mmol) was added dropwise and the mixture was stirred at ambient temperature for 20 min and was concentrated. Et2O was added to the residue. The resulting mixture was stirred at ambient temperature for 1 h. The solid was filtered, washed with Et2O, and dried under reduced pressure at ambient temperature for 16 h to afford 4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide as a yellow solid (309 mg, 95% p., 81% y.). m / z [M+H]+= 286.2, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.41 (s, 1H), 8.09 (s, 1H), 7.66 (dd, J= 1.6, 7.9 Hz, 1H), 7.36 (m, 6H), 7.21 (m, 2H), 4.11 (d, J= 11.2 Hz, 1H), 3.24 (d, J= 12.5 Hz, 2H), 2.84 (p, J= 11.4, 11.4, 11.4, 11.4 Hz, 2H), 2.60 (m, 1H), 1.55 (m, 2H), 1.26 (m,2H), [a]D= +25 “mL.dm3.g-1[20 °C, Na lamp, 589 nm, C = 2.75 mg / mL, MeOH],

[0720] INTERMEDIATE BB-12

[0721] 4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide

[0722]

[0723] Intermediate BB-12A: benzyl 4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carb oxy late

[0724]

[0725] (BB-12A)

[0726] To a stirred solution of benzyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl] piperidine- 1 -carboxylate (2.03 g, 4.42 mmol) in DCM (16 mL) at -50 °C under nitrogen were added triethylsilane (2.1 mL, 13.3 mmol) dropwise. TFA (10 mL, 0.133 mol) was added dropwise (keeping the temperature below -40 °C). DCM (16 mL) was added. The reaction mixture was allowed to warm up to ambient temperature overnight. The reaction mixture was slowly added into a stirred 10 M aqueous solution of NaOH (13 mL, 133 mmol) at 0 °C (keeping the temperature below 10 °C). The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried using hydrophobic paper and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 12%. The fractions were concentrated under reduced pressure to afford benzyl 4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l -carboxylate as a colorless oil (873 mg, 97% p., 46% y.) then, by chiral supercritical chromatography (Waters Prep SFC200, Chiralpak AD (5 pm, 250 x 30 mm), CO2 / zPrOH (70 / 30) as mobile phase, flow rate 100 mL / min) to afford benzyl 4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine-l -carboxylate (second isomer) as a colorless gum (380 mg, 97% p., 20% y., e. e. = 98.8%). m / z [M+H]+= 420.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.70 (dd, J= 1.7, 7.8 Hz, 1H), 7.33 (m, 11H), 7.18 (m, 2H), 5.05 (s, 2H), 4.11 (d, J= 11.2 Hz, 1H), 3.97 (d, J= 13.2 Hz, 2H), 2.78 (s, 2H), 1.42 (dd, J= 13.2, 32.7 Hz, 2H), 1.02 (m, 3H), [a]o= -24 “mL.dm'hg'1[20 °C, Na lamp, 589 nm, C = 4.65 mg / mL, EtOH],

[0727] Intermediate BB-12

[0728] A vial was charged with a suspension of benzyl 4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine-l -carboxylate (380 mg, 0.905 mmol) in dry acetonitrile (9.0 mL) at ambient temperature under nitrogen. Iodo(trimethyl)silane (386 pL, 2.71 mmol) was added dropwise, the mixture was stirred at ambient temperature for 1 h. The mixture was stirred at 0 °C and MeOH (440 pL, 10.9 mmol) was added dropwise. The mixture wasstirred at ambient temperature for 20 min and was concentrated. Et2O was added to the residue. The resulting mixture was stirred at ambient temperature for 1 h. The solid was filtered, washed with Et2O, and dried under reduced pressure at ambient temperature for 16 h to afford 4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide as a yellow solid (324 mg, 96% p., 83% y.). m / z [M+H]+= 286.2,1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.41 (s, 1H), 8.09 (s, 1H), 7.66 (dd, J= 1.6, 7.9 Hz, 1H), 7.36 (m, 6H), 7.21 (m, 2H), 4.11 (d, J= 11.2 Hz, 1H), 3.24 (d, J= 12.5 Hz, 2H), 2.84 (p, J= 11.4, 11.4, 11.4, 11.4 Hz, 2H), 2.60 (m, 1H), 1.55 (m, 2H), 1.26 (m,2H), [a]D=-24omL.dm-1.g-1[20 °C, Na lamp, 589 nm, C = 2.45 mg / mL, MeOH],

[0729] INTERMEDIATE BB-13

[0730] 4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine hydroiodide

[0731]

[0732] Intermediate BB-13A: benzyl 4-[(2-chloro-3-methoxy-phenyl)-hydroxy-phenyl-methyl] piperidine- 1 -carboxylate

[0733]

[0734] (BB-13A)

[0735] In a three neck round-bottom flask equipped with a thermometer, a 2.5 M solution of w-butyllithium in hexanes (11 mL, 27.6 mmol) was added to a solution of l-bromo-2-chl oro-3 -methoxybenzene (6.23 g, 27.6 mmol) in THF (9.0 mL) and hexanes (81 mL) at -78 °C under argon, over 10 min (keeping the temperature below -70 °C). Directly after the end of the first addition, a solution of benzyl 4-benzoylpiperidine-l -carboxylate (6.00 g, 18.4 mmol) in THF (45 mL) was added over 30 min keeping the temperature below -60 °C. The reaction mixture was allowed to warm up to ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl. Water and EtOAc were added. The phases were separated and the aqueous phase was extractedwith EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 0% to 100%. The desired fractions were combined and concentrated under reduced pressure. The solid was triturated in cyclohexane and stirred at ambient temperature for 20 min. The precipitate was filtered and dried under reduced pressure at 50 °C for 16 h to afford benzyl 4-[(2-chloro-3-methoxy-phenyl)-hydroxy-phenyl-methyl]piperidine-l -carboxylate as a white powder (710 mg, 89% p., 7% y.). m / z [M+H]+= 466.3,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.62 (dd, J= 1.4, 8.1 Hz, 1H), 7.33 (m, 8H), 7.24 (dd, J= 6.9, 8.3 Hz, 2H), 7.14 (m, 1H),7. OO (dd, J= 1.4, 8.3 Hz, 1H), 5.45 (s, 1H), 5.05 (s, 2H), 4.03 (m, 2H), 3.75 (s, 3H), 3.19 (s, 1H), 2.86 (s, 2H), 1.57 (s, 1H),1.26 (qt, J= 10.5, 10.5, 20.0, 20.0, 20.0 Hz, 3H).

[0736] Intermediate BB-13B: benzyl 4-[(A)-(2-chl oro-3 -methoxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate

[0737] %H3

[0738]

[0739] (BB-13B)

[0740] To a stirred solution of benzyl 4-[(2-chloro-3-methoxy-phenyl)-hydroxy-phenyl-methyl]piperidine-l -carboxylate (5.39 g, 11.6 mmol) in DCM (88 mL) at -50 °C under nitrogen were added tri ethylsilane (4.80 mL, 29.8 mmol) dropwise. A solution of TFA (23.0 mL, 0.300 mol) in DCM (44 mL) was added dropwise very slowly (keeping the temperature below -40 °C). The reaction mixture was allowed to warm up to ambient temperature and was stirred overnight. The reaction mixture was slowly poured to a stirred aqueous solution of 2 M NaOH (150 mL, 0.300 mol) at 0 °C (keeping the temperature below 10 °C). The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried using a hydrophobic paper and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 20%. The desired fractions were concentrated under reduced pressure toafford a colorless gum (benzyl 4-[(2-chloro-3-methoxy-phenyl)-phenyl-methyl] piperidine- 1 -carboxylate (4.04 g, 95% p., 73% y)). The product was purified by chiral reverse-phase (Hypersep, Chiralpak IC (20 pm, 300 x 50 mm), MeOH as mobile phase, flow rate 120 mL / min) to afford benzyl 4-[( / ?)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate (first isomer eluted) as a colorless gum (1.68 g, 90% p, 29% y., e.e. > 99.9%). m / z [M+H]+= 450.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.32 (m, 11H), 7.16 (m, 1H), 6.95 (dd, J = 2.2, 7.4 Hz, 1H), 5.05 (s, 2H), 4.16 (d, J = 11.2 Hz, 1H),3.96 (d, J = 13.2 Hz, 2H), 3.80 (s, 3H), 2.78 (s, 2H), 2.45 (t, J = 11.3, 11.3 Hz, 1H), 1.42 (dd, J = 13.2, 36.8 Hz, 2H), 1.00 (dd, J = 12.9, 25.7 Hz, 2H).

[0741] Intermediate BB-13

[0742] A vial was charged with a suspension of benzyl 4-[( / ?)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate (1.88 g, 3.73 mmol) in dry acetonitrile (37 mL) at ambient temperature under nitrogen. Iodo(trimethyl)silane (1.6 mL, 11.2 mmol) was added dropwise, the mixture was stirred at ambient temperature for 1 h. The mixture was cooled to 0 °C and MeOH (1.8 mL, 44.8 mmol) was added dropwise. The mixture was stirred at ambient temperature for 20 min and was concentrated under reduced pressure. Et2O was added to the residue. The resulting mixture was stirred at ambient temperature for 1 h. The solid was filtered, washed with Et2O, and dried under reduced pressure at ambient temperature for the weekend to afford 4-[(R)-(2-chl oro-3 -methoxy -phenyl)-phenyl-methyl]piperidine hydroiodide as a yellow solid (1.70 g, 95% p., 97% y.). m / z [M+H]+= 316.3, 'H NMR (400 MHz, DMSO-d6): 68.40 (s, 1H), 8.09 (s, 1H), 7.25 (m, 7H), 6.98 (dd, J = 1.3, 8.2 Hz, 1H), 4.16 (d, J = 11.3Hz, 1H), 3.81 (s, 3H), 3.22 (s, 2H), 2.84 (m, 2H), 2.58 (d, J = 11.3 Hz, 1H), 1.55 (m, 2H), 1.26 (m, 2H), [a]D= +54 “mL.dm'hg'1[20 °C, Na lamp, 589 nm, C = 2.4 mg / mL, MeOH],

[0743] INTERMEDIATE BB-14

[0744] 4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine hydroiodide

[0745]

[0746] Intermediate BB-14A: benzyl 4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl] piperidine- 1 -carboxylate

[0747] n

[0748] : H3

[0749]

[0750] (BB-14A)

[0751] To a stirred solution of benzyl 4-[(2-chloro-3-methoxy-phenyl)-hydroxy-phenyl-methyl]piperidine-l -carboxylate (5.39 g, 11.6 mmol) in DCM (88 mL) at -50 °C under nitrogen were added tri ethylsilane (4.8 mL, 29.8 mmol) dropwise. A solution of TFA (23 mL, 300 mmol) in DCM (44 mL) was added dropwise (keeping the temperature below -40 °C). The reaction mixture was allowed to warm up to ambient temperature and was stirred overnight. The reaction mixture was slowly poured to a stirred 2 M aqueous solution of NaOH (150 mL, 300 mmol) at 0 °C (keeping the temperature below 10 °C). The phases were separated, and the aqueous phase extracted with EtOAc. The combined organic layers were washed with brine, dried using hydrophobic paper and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 20%. Fractions were concentrated under reduced pressure to afford benzyl 4-[(2-chl oro-3 -methoxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate as a colorless gum (4.04 g, 95% p., 73% y). The product was purified by chiral reverse-phase (Hypersep, Chiralpak IC (20 pm, 300 x 50 mm), MeOH as mobile phase, flow rate 120 mL / min) to afford benzyl 4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate (second isomer eluted) as a colorless gum (1.78 g, 99% p, 34% y., e. e. = 99.5%). m / z [M+H]+= 450.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.31 (m, 11H), 7.16 (m, 1H), 6.95 (dd, J= 2.2, 7.4 Hz, 1H), 5.05 (s, 2H), 4.16 (d, J= 11.2 Hz, 1H), 3.96 (m, 2H), 3.80 (s, 3H), 2.78 (s, 2H), 2.45 (m, 1H), 1.42 (dd, J= 13.1, 36.6 Hz, 2H), 1.01 (m, 2H).

[0752] Intermediate BB-14

[0753] A vial was charged with a suspension of benzyl 4-[fS')-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate (1.93 g, 4.24 mmol) in dry acetonitrile (39 mL) at ambient temperature under nitrogen. Iodo(trimethyl)silane (1.8 mL, 12.7mmol) was added dropwise. The mixture was stirred at ambient temperature for 1 h. The mixture was cooled to 0 °C and MeOH (2.1 mL, 50.9 mmol) was added dropwise. The mixture was stirred at ambient temperature for 20 min and was concentrated. Et2O was added to the residue. The resulting mixture was stirred at ambient temperature for 1 h. The solid was filtered, washed with Et2O, and dried under reduced pressure at ambient temperature for 72 h to afford 4-[(N)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl] piperidine hydroiodide as a yellow solid (1.74 g, 97% p., 90% y). m / z [M+H]+= 316.3, 'H NMR (400 MHz, DMSO-d6): 68.40 (s, 1H), 8.09 (s, 1H), 7.26 (m, 7H), 6.98 (dd, J = 1.2, 8.2 Hz, 1H), 4.16 (d, J= 11.3 Hz, 1H),3.81 (s, 3H), 3.22 (s, 2H), 2.84 (m, 2H), 2.58 (q, J= 11.5, 11.5, 11.6 Hz, 1H), 1.55 (m, 2H), 1.27 (m, 2H), [a]D=-53 °mL.dnr1.g-1[20 °C, Na lamp, 589 nm, C = 3.9 mg / mL, MeOH],

[0754] INTERMEDIATE BB- 15

[0755] 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5H-pyrrolo[3,4-b] pyrazine-3 -carboxylic acid

[0756]

[0757] (BB-15) Intermediate BB-15A: diethyl 3-(bromomethyl)-6-methyl-pyrazine-2,5-dicarboxylate O

[0758] H3C N

[0759] 3Y0 CH3

[0760]

[0761] (BB-15A) To a stirred solution of 2,5-diethyl 3,6-dimethylpyrazine-2,5-dicarboxylate (500 mg, 1.90 mmol) in acetonitrile (6.0 mL) were added 1 -bromopyrrolidine-2, 5-dione (373 mg, 2.09 mmol) and AIBN (31.9 mg, 0.190 mmol). The reaction mixture was irradiated with a white lamp (6200 K) for 48 h. The mixture was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 0% to 20% to afford diethyl 3-(bromomethyl)-6-methyl-pyrazine-2,5-dicarboxylate as a white solid (402 mg, 69% p., 44% y.). m / z [M+H]+= 331.1, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 4.94 (s, 2H), 4.42 (m,4H), 1.67 (s, 3H), 1.36 (tq, J = 4.6, 7.1 Hz, 6H).Intermediate BB-15B: ethyl 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5H-pyrrolo[3,4-b]pyrazine-3 -carboxylate

[0762] O O NH2

[0763] Ni H3C CH3

[0764] N' -A KCH

[0765]

[0766] (BB-15B) To a stirred solution of diethyl 3-(bromomethyl)-6-methyl-pyrazine-2,5-dicarboxylate (402 mg, 0.838 mmol) in acetonitrile (3.0 mL) at 25 °C were added tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (224 mg, 0.921 mmol) and DIPEA (439 pL, 2.51 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 5% to 50% to afford ethyl 6-[(LS')-4- / c / 7-butoxy-1 -carbamoyl -4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyrazine-3-carboxylate as a yellow solid (204 mg, 92% p., 55% y.). m / z [M+Na]+= 429.3,1H NMR (400 MHz, DMSO-de): 8 (ppm) 7.58 (s, 1H), 7.27 (s, 1H), 4.82 (dd, J= 3.7, 10.6 Hz, 1H), 4.59 (s, 2H), 4.43 (q, J= 7.1 Hz, 2H), 2.78 (s, 3H), 2.24 (m, 3H), 2.01 (m, 1H), 1.38 (m, 3H), 1.34 (s, 9H).

[0767] Intermediate BB-15

[0768] To a stirred solution of ethyl 6-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyrazine-3-carboxylate (204 mg, 0.462 mmol) in THF (2.5 mL) at 0 °C was added a 0.5 M aqueous solution of Li OH (970 pL, 0.485 mmol). The reaction mixture was stirred at 0 °C for 20 min. Water and EtOAc were added. The aqueous layer was washed with EtOAc then acidified with a 12 M aqueous solution of HC1 until pH 1. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyrazine-3 -carboxylic acid as a white solid (64 mg, 80% p. 29%y.). m / z [M+Na]+= 401.0.

[0769] INTERMEDIATE BB-16

[0770] 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5H-pyrrolo[3,4-b] pyridine-3 -carboxylic acid

[0771] O O

[0772] H3C N / / A_NH2

[0773]

[0774] 0(BB-16)

[0775] Intermediate BB-16A: dimethyl 3-methyl-l-oxido-pyridin-l-ium-2,5-dicarboxylate O O

[0776] fV JL CH3

[0777]

[0778] ° (BB-16A)

[0779] To a stirred solution of dimethyl 3-methylpyridine-2,5-dicarboxylate (3.00 g, 14.3 mmol) in DCM (57 mL) at 0 °C was added 3-chlorobenzenecarboperoxoic acid (8.59 g, 35.9 mmol) portion wise. The reaction mixture was stirred at ambient temperature overnight. Additional 3-chlorobenzenecarboperoxoic acid (3.54 g, 14.3 mmol) was added and the reaction mixture was stirred for 8 h. The reaction mixture was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100% to afford dimethyl 3-methyl-l-oxido-pyridin-l-ium-2,5-dicarboxylate as brown oil (2.26 g, 99% p., 69% y.). m / zO. [M+H]+= 226.2, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.49 (dd, J= 1.4, 0.7 Hz, 1H), 7.83 (dd, J= 1.4, 0.8 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 2.28 (s, 3H).

[0780] Intermediate BB-16B: dimethyl 6-chloro-3-methyl-pyridine-2,5-dicarboxylate

[0781] O CLNJL CH3

[0782]

[0783] O (BB-16B)

[0784] To a stirred solution of dimethyl 3-methyl-l-oxido-pyridin-l-ium-2,5-dicarboxylate (2.26 g, 10.0 mmol) in toluene (56 mL) was added phosphoryl trichloride (1.0 mL, 11.0 mmol). The reaction mixture was stirred at 100 °C overnight. The reactionmixture was cooled to ambient temperature and the mixture was diluted with EtOAc. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford dimethyl 6-chloro-3-methyl-pyridine-2,5-dicarboxylate as an orange solid (2.02 g, 87% p., 72% y.). m / z [M+H]+= 244.2, ' H NMR (400 MHz, DMSO-d6): 6 (ppm) 8.29 (d, J= 0.7 Hz, 1H), 3.90 (d, J= 3.2 Hz, 6H), 2.49 (d, J= 0.7 Hz, 3H).

[0785] Intermediate BB-16C: dimethyl 3,6-dimethylpyridine-2,5-dicarboxylate

[0786] O

[0787] H3C N JLO^CH3

[0788] H3C'°Y^^CH3

[0789]

[0790] ° (BB-16C)

[0791] To a stirred solution of dimethyl 6-chloro-3-methyl-pyridine-2,5-dicarboxylate (2.02 g, 8.29 mmol) in 1,4-dioxane (21 mL) under nitrogen were added successively K2CO3(4.58 g, 33.2 mmol), a solution of 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane in THF (50% p., 2.6 mL, 9.12 mmol) and then Pd(PPh₃)₄ (958 mg, 0.829 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered through a glass fiber filter and washed with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 2% to 50% to afford 3,6-dimethylpyridine-2,5-dicarboxylate as a yellow solid (730 mg, 96% p., 38% y.). m / z =[M+H]+= 224.2, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.15 (s, 1H), 3.88 (d, J= 1.8 Hz, 6H), 2.67 (s, 3H), 2.42 (t, J= 0.7 Hz, 3H).

[0792] Intermediate BB-16D: dimethyl 3-(bromomethyl)-6-methyl-pyridine-2,5-dicarboxylate O

[0793] H3C N JL CH3

[0794] H3C'OyJ^1^Br

[0795]

[0796] O (BB-16D)

[0797] To a stirred solution of dimethyl 3,6-dimethylpyridine-2,5-dicarboxylate (730 mg,3.27 mmol) in acetonitrile (16 mL) were added 1 -bromopyrrolidine-2, 5-dione (640 mg, 3.60 mmol) and AIBN (53.7 mg, 0.327 mmol). The reaction mixture was irradiated with a white lamp (6200 K) overnight. The mixture was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 2% to 50% to afford dimethyl 6-(bromomethyl)-3-methyl-pyridine-2,5-dicarboxylate as a pale yellow oil (843 mg, 49% p., 42% y.). m / z [M+H]+= no ionization.

[0798] Intermediate BB-16E: methyl 6-[(LS')-4-tert-butoxy-l -carbamoyl-4-oxo-butyl]-2-methyl- 7 -oxo- 5H-py rrol o [3, 4-b ] py ri dine-3 -carb oxy 1 ate

[0799]

[0800] (BB-16E) To a stirred suspension of tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (706 mg, 2.96 mmol) in acetonitrile (4.6 mL) at 0 °C was added DIPEA (975 pL, 5.58 mmol) dropwise. The reaction mixture was stirred for 30 min at 0 °C. A solution of dimethyl 3-(bromomethyl)-6-methyl-pyridine-2,5-dicarboxylate (843 mg, 2.79 mmol) in acetonitrile (8.0 mL) was added dropwise over 30 min at 0 °C. The reaction mixture was stirred to ambient temperature for 1 h then at 70 °C overnight. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 2% to 100% to afford methyl 6-[(LS')-4- / c / 7-butoxy- l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>] pyridine-3 -carboxylate as a yellow solid (690 mg, 70% p., 44% y.). m / z [M+H]+= 392.3.

[0801] Intermediate BB-16

[0802] To a stirred solution of methyl 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyridine-3-carboxylate (690 mg, 1.76 mmol) in THF (5.9mL) was added a 2 M aqueous solution of LiOH (925 pL, 1.85 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The crude was purified by reversephase preparative chromatography using a gradient of acetonitrile in water from 0% to 100% (0.1% AcOH) to afford [(15)-4- / er / -butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyridine-3 -carboxylic acid as a white solid (52.9 mg, 65% p., 5% y.). m / z [M+H]+= 378.3.

[0803] INTERMEDIATE BB-17

[0804] 2-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-6-[(dimethylamino)methyl]-l-oxo- isoindoline-5-carboxylic acid acetic acid

[0805] HO CH3

[0806]

[0807] (BB-17) Intermediate BB-17A: methyl 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-[(dimethylamino)methyl]-l-oxo-isoindoline-5-carboxylate

[0808]

[0809] (BB-17A) To a stirred suspension of dimethyl 2,5-bis(bromomethyl)benzene-l,4-dicarboxylate (565 mg, 1.49 mmol) in acetonitrile (15 mL) at 0 °C was added DIPEA (1.3 mL, 7.43 mmol) and then a 2 M solution of A-methylmethanamine in THF (743 pL, 1.49 mmol) dropwise. The reaction mixture was stirred for 1.5 h at 0 °C and for 1 h at ambient temperature. The reaction mixture was cooled to 0 °C and / c / 7-butyl (45)-4-amino-4-carbamoylbutanoate hydrochloride (373 mg, 1.56 mmol) was added portion wise. The reaction mixture was stirred for 1 h at 0 °C and for 1 h at ambient temperature then at 70 °C overnight. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crudewas purified by reverse-phase preparative chromatography using a gradient of acetonitrile in water from 0% to 100% (0.1% AcOH). Select fractions were poured in a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 2-[(LS')-4- / c77-butoxy-l -carbamoyl-4-oxo-butyl]-6-[(dimethylamino)methyl]-l-oxo-isoindoline-5-carboxylate as a white solid (93.8 mg, 92% p., 13% y.). m / z [M+H]+= 434.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.82 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.20 (s, 1H), 4.82-4.70 (m, 1H), 4.61 (d, J = 17.8 Hz, 1H), 4.49 (d, J= 17.9 Hz, 1H), 3.84 (s, 3H), 3.74-3.52 (m, 2H), 2.24-2.05 (m, 9H), 2.04-1.89 (m, 1H), 1.32 (s, 9H).

[0810] Intermediate BB-17

[0811] To a stirred solution of methyl 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-[(dimethylamino)methyl]-l-oxo-isoindoline-5-carboxylate (93.0 mg, 0.215 mmol) in THF (1.4 mL) and water (340 pL) at 0 °C was added a 2 M aqueous solution of LiOH (113 pL, 0.225 mmol). The reaction mixture was stirred at 0 °C for 4 h. Additional 2 M aqueous solution of LiOH (113 pL, 0.225 mmol) was added. The reaction mixture was stirred at 0 °C for 4 h. The reaction was quenched with the addition of AcOH and purified by reverse-phase preparative chromatography using a gradient of acetonitrile in water from 0% to 100% (0.1% AcOH in water) to afford acetic acid 2-[(LS')-4-tert-butoxy- l-carbamoyl-4-oxo-butyl]-6-[(dimethylamino)methyl]-l-oxo-isoindoline-5-carboxylic acid as a colorless gum (23.6 mg, 70% p., 16% y.). m / z [M+H]+= 420.3.

[0812] INTERMEDIATE BB- 18

[0813] benzyl 4-[(3-bromo-2-chloro-phenyl)-phenyl-methyl]piperidine-l -carboxylate

[0814]

[0815] (BB-18)

[0816] Intermediate BB-18A: benzyl 4-[(3-bromo-2-chloro-phenyl)-hydroxy-phenyl-methyl] piperidine- 1 -carboxylate

[0817]

[0818] (BB-18 A)

[0819] To a stirred solution of l,3-dibromo-2-chlorobenzene (10.2 g, 37.2 mmol) and benzyl 4-benzoylpiperidine-l -carboxylate (10.0 g, 30.9 mmol) in dry THF (150 mL) at -78 °C under nitrogen was added a 1.6 M solution of / / -butyllithium in hexanes (29 mL, 46.4 mmol). The reaction mixture was stirred at -70 °C for 10 min and at ambient temperature for 12 h. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl, water. EtOAc were added. The phases were separated, and the aqueous phase extracted with EtOAc. The combined organic layers were washed with brine, dried using a phase separator and concentrated under reduced pressure. The crude was solubilized in a minimum of DCM and added to a stirring solution of cyclohexane. The resulting precipitate was filtered, washed with cyclohexane, and dried under reduced pressure to afford benzyl 4-[(3-bromo-2-chloro-phenyl)-hydroxy-phenyl-methyl] piperidine- 1 -carboxylate as a white solid (7.26 g, 89% p., 41% y.). m / z [M+H]+= 514.0, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.05 (dd, J= 8.0, 1.6 Hz, 1H), 7.66 (dd, J= 8.0, 1.5 Hz, 1H), 7.43-7.20 (m, 10H), 7.20-7.13 (m, 1H), 5.66 (s, 1H), 5.05 (s, 2H), 4.03 (d, J = 12.9 Hz, 2H), 3.15 (s, 1H), 2.88 (s, 3H), 1.55 (s, 1H), 1.40-1.07 (m, 2H).

[0820] Intermediate BB-18

[0821] To a stirred solution of triethylsilane (6.1 mL, 37.7 mmol) in DCM (40 mL) at -15 °C under nitrogen was added TFA (29 mL, 0.379 mol) dropwise. A solution of benzyl 4-[(3-bromo-2-chloro-phenyl)-hydroxy-phenyl-methyl]piperidine-l-carboxylate (7.26 g, 12.6 mmol) in DCM (75 mL) was added dropwise (keeping the temperature below -10 °C). The reaction mixture was allowed to warm up to ambient temperature for 3 h. The reaction mixture was basified with a 2 M aqueous solution of NaOH (189 mL, 0.379 mol) at 0 °C. The aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried using hydrophobic paper and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 15%. Select fractions were concentratedunder reduced pressure to afford benzyl 4-[(3-bromo-2-chloro-phenyl)-phenyl-methyl] piperidine- 1 -carboxylate as colorless gum (4.84 g, 93% p., 72% y). m / z [M+H]+= 498.1,1H NMR (400 MHz, DMSO-d6): 6 (ppm) 7.76 (dd, J= 7.9, 1.5 Hz, 1H), 7.61 (dd, J= 7.9, 1.4 Hz, 1H), 7.39-7.24 (m, 10H), 7.23-7.14 (m, 1H), 5.05 (s, 2H), 4.19 (d, J= 11.2 Hz, 1H), 3.97 (d, J= 13.4 Hz, 2H), 2.78 (s, 2H), 2.46 (d, J= 11.1 Hz, 1H), 1.47 (d, J= 13.1 Hz, 1H), 1.35 (d, J= 13.1 Hz, 1H), 1.12-0.93 (m, 2H).

[0822] INTERMEDIATE BB-19

[0823] benzyl 4-[(A)-(3-bromo-2-chloro-phenyl)-phenyl-methyl]piperidine-l -carboxylate

[0824]

[0825] (BB-19)

[0826] To a stirred solution of triethylsilane (4.0 mL, 24.8 mmol) and TFA (19 mL, 0.248 mol) in DCM (90 mL) at -15 °C was added a solution of benzyl 4-[(3-bromo-2-chloro-phenyl)-hydroxy-phenyl-methyl]piperidine-l -carboxylate (4.26 g, 8.27 mmol) in DCM (23 mL) dropwise. The mixture was stirred at -15 °C for 2 h and then warmed up to ambient temperature overnight. The reaction mixture was slowly poured into a cooled 1 M aqueous solution of NaOH (248 mL, 0.248 mol) at 0 °C. The layers were separated, and the aqueous layer extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 1% to 60% to afford benzyl 4-[(3-bromo-2-chloro-phenyl)-phenyl-methyl]piperidine-l-carboxylate as an off-white foam (1.89 g, 97% p., 44% y.) and then, by chiral reversephase (Novasep, ChiralCel OD (20 pm, 300 x 76.6 mm), MeOH as mobile phase, flow rate 275 mL / min) to afford benzyl 4-[( / ?)-(3-bromo-2-chloro-phenyl)-phenyl-methyl]piperidine-l -carboxylate (second isomer eluted) as a yellow gum (849 mg, 93% p., 19% y.). m / z [M+H]+= 498.1, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.75 (dd, J= 7.9, 1.5 Hz, 1H), 7.60 (dd, J= 7.9, 1.4 Hz, 1H), 7.39-7.22 (m, 9H), 7.21-7.15 (m, 1H), 5.05 (s, 2H), 4.18 (d, J= 11.1 Hz,lH), 3.97 (d, J= 13.3 Hz, 2H), 2.77 (brs, 2H), 2.54-2.44 (m, 2H), 1.46 (d, J= 13.1 Hz, 1H), 1.34 (d, 13.1 Hz, 1H), 1.13-0.90 (m, 2H), [a]D= +57“mL.dm'hg'1[20 °C, Na lamp, 589 nm, C = 3.9 mg / mL, EtOH],

[0827] INTERMEDIATE BB-20

[0828] Benzyl 4-[(5)-(3-bromo-2-chloro-phenyl)-phenyl-methyl]piperidine-l-carboxylate

[0829]

[0830] (BB-20)

[0831] To a stirred solution of triethylsilane (4.0 mL, 24.8 mmol) and TFA (19 mL, 0.248 mol) in DCM (90 mL) at -15 °C was added a solution of benzyl 4-[(3-bromo-2-chloro-phenyl)-hydroxy-phenyl-methyl]piperidine-l -carboxylate (4.26 g, 8.27 mmol) in DCM (23 mL) dropwise. The mixture was stirred at -15 °C for 2 h and then warmed up to ambient temperature overnight. The reaction mixture was slowly poured into a cooled 1 M aqueous solution of NaOH (248 mL, 0.248 mol) at 0 °C. The layers were separated, and the aqueous layer extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 1% to 60% to afford benzyl 4-[(3-bromo-2-chloro-phenyl)-phenyl-methyl]piperidine-l-carboxylate as an off-white foam (1.89 g, 97% p., 44% y.)) then, by chiral reverse-phase (Novasep, ChiralCel OD (20 pm, 300 x 76.6 mm), MeOH as mobile phase, flow rate 275 mL / min) to afford benzyl 4-[(A')-(3-bromo-2-chloro-phenyl)-phenyl -methyl] piperidine- 1-carboxylate (first isomer eluted) as an off-white foam (873 mg, 95% p., 20% y.). m / z [M+H]+= 498.1, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.76 (dd, J= 8.0, 1.5 Hz, 1H), 7.61 (dd, J= 8.0, 1.4 Hz, 1H), 7.41-7.24 (m, 9H), 7.24-7.11 (m, 1H), 5.05 (s, 2H), 4.19 (d, J= 11.2 Hz, 1H), 3.97 (d, J= 13.1 Hz, 2H), 2.77 (brs, 2H), 2.51-2.47 (m, 2H), 1.47 (d, J= 13.1 Hz, 1H), 1.35 (d, J= 13.1 Hz, 1H), 1.03 (dqd, J= 24.4, 12.4, 4.2 Hz, 2H), [a]D=-50 “mL.dm'hg'1[20 °C, Na lamp, 589 nm, C = 7.0 mg / mL, EtOH],

[0832] INTERMEDIATE BB-21

[0833] benzyl 4-[bromo(phenyl)methylene]piperidine- 1 -carboxylate

[0834]

[0835] (BB-21)

[0836] Intermediate BB-21 A: benzyl 4-benzylidenepiperidine-l -carboxylate

[0837]

[0838] (BB-21A)

[0839] To a stirred solution of benzyltriphenylphosphonium chloride (15.0 g, 38.5 mmol) in dry THF (125 mL) at -78 °C was added a 1.6 M solution of w-butyllithium in hexanes (27 mL, 42.2 mmol) dropwise. The reaction mixture was allowed to warm up to ambient temperature and stirred until the solution became red / orange. The reaction mixture was cooled to -78 °C and a solution of benzyl 4-oxopiperidine-l -carboxylate (16.3 g, 69.7 mmol) in dry THF (63 mL) was added dropwise. The reaction mixture was allowed to warm up to ambient temperature and stirred overnight. The reaction was quenched with the addition of water and EtOAc was added. The reaction mixture was washed with a saturated aqueous solution of NH4Cl then brine, dried over Na2SO4, filtered, and the solvent was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 0% to 20% to afford benzyl 4-benzylidenepiperidine-l -carboxylate as a colorless oil (7.86 g, 100% p., 66% y.). m / z [M+H]+= 308.3,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.44-7.28 (m, 7H), 7.26-7.17 (m, 3H), 6.39 (s, 1H), 5.10 (s, 2H), 3.51 (s, 2H), 3.43 (s, 2H), 2.46-2.39 (m, 2H), 2.32 (td, J = 5.6, 1.3 Hz, 2H).

[0840] Intermediate BB-21

[0841] To a stirred solution of benzyl 4-benzylidenepiperidine-l -carboxylate (7.86 g, 25.6 mmol) in chloroform (74 mL) at 0 °C was added K2CO3(5.30 g, 38.4 mmol) then a solution of molecular bromine (1.6 mL, 30.7 mmol) in CHCI3 (12 mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight. DCM was added and the reaction mixture was washed with a saturated aqueous solution of NH4Cl then brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was solubilized in MeOH (118 mL) and a solution of NaOH (10.2 g, 256 mmol) in water (44 mL) was added. The reaction mixture was stirred at 40 °C for2 h. DCM was added and the reaction mixture was washed with a 12 M aqueous solution of HC1, brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 2% to 40% to afford benzyl 4-[bromo(phenyl)methylene] piperidine- 1 -carboxylate as a pink oil (8.16 g, 97% p., 80% y.). m / z [M+H]+= 388.2, 'H NMR (400 MHz, DMSO-d6): 6 (ppm) 7.45-7.27 (m, 10H), 5.09 (s, 2H), 3.55 (s, 2H), 3.38 (s, 2H), 2.62-2.55 (m, 2H), 2.26-2.14 (m, 2H).

[0842] INTERMEDIATE BB-22

[0843] 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-7-oxo-5JH-pyrrolo[3,4-Z>]pyridine-3- carboxylic acid

[0844] O O

[0845] Ax A KNH2

[0846] IT.. < H3C CH3

[0847]

[0848] O (BB-22)

[0849] Intermediate 22A: methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate

[0850] O N JL CH3

[0851] r Tr

[0852] o Ax A. Br

[0853] B

[0854]

[0855] r (BB-22A)

[0856] To a stirred solution of methyl 5-bromo-3-methylpyridine-2-carboxylate (3.00 g, 13.0 mmol) in acetonitrile (65 mL) were added 1 -bromopyrrolidine-2, 5-dione (2.55 g, 14.3 mmol) and AIBN (214 mg, 1.30 mmol). The reaction mixture was irradiated with a white lamp (6200 K) overnight. The mixture was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 2% to 100% to afford methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate as a white solid (3.36 g, 88% p., 73% y.). m / z [M+H]+= 308.0,!H NMR (400 MHz, DMSO-d6): δ (ppm) 8.77 (d, J= 2.2 Hz, 1H), 8.41 (d, J= 2.2 Hz, 1H), 4.91 (s, 2H), 3.91 (s, 3H).

[0857] Intermediate 22B: tert-butyl (45)-5-amino-4-(3-bromo-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxo-pentanoate

[0858]

[0859] (BB-22B)

[0860] To a stirred suspension of tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (2.75 g, 11.5 mmol) in acetonitrile (18 mL) at 0 °C was added DIPEA (3.8 mL, 21.8 mmol) dropwise. The reaction mixture was stirred for 30 min at 0 °C. A solution of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (3.36 g, 10.9 mmol) in acetonitrile (31 mL) was added dropwise over 30 min at 0 °C. The reaction mixture was then stirred at 70 °C overnight. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 2% to 100% to afford tert-butyl (45)-5-amino-4-(3-bromo-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl)-5-oxo-pentanoate as a pale yellow foam (2.62 g, 97% p., 59% y.). m / z [M+H]+= 398.2, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.84 (d, 1H), 8.39 (d, 1H), 7.69-7.54 (m, 1H), 7.23 (s, 1H), 4.82-4.71 (m, 1H), 4.60 (d, 1H), 4.49 (d, 1H), 2.24-2.11 (m, 3H), 2.04-1.94 (m, 1H), 1.33 (s, 9H).

[0861] Intermediate BB-22

[0862] In a sealed pressure vessel, to a stirred solution of tert-butyl (45)-5-amino-4-(3-bromo-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl)-5-oxo-pentanoate (2.61 g, 6.55 mmol) in DMF (13 mL) were added successively ethanedioic acid dihydrate (1.24 g, 9.83 mmol), XantPhos (190 mg, 0.328 mmol), and Pd(OAc)2 (74 mg, 0.328 mmol). The reaction mixture was degassed with argon for 5 min, and then acetic anhydride (909 pL, 9.83 mmol) and DIPEA (1.7 mL, 9.83 mmol) were added. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into a 1 M aqueous solution of NaHCO3. The aqueous layer was washed with EtOAc (3x). The aqueous layer was acidified to pH 3-4 with a 12 M aqueous solution of HC1. The acidic aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentratedunder reduced pressure to afford 6-[(LS')-4- / c 7-butoxy-l -carbamoyl-4-oxo-butyl]-7-oxo-5 J / -pyrrolo[3,4-Z>]pyridine-3 -carboxylic acid as a yellow gum (1.96 g, 98% p., 81% y.). m / z [M+H]+= 364.3,1H NMR (400 MHz, DMSO-d6): 6 (ppm) 13.70 (s, 1H), 9.18 (d, 1H), 8.55 (d, 1H), 7.63 (s, 1H), 7.25 (s, 1H), 4.80 (dd, 1H), 4.66 (d, 1H), 4.55 (d, 1H), 2.28-2.11 (m, 3H), 2.10-1.92 (m, 1H), 1.32 (s, 9H).

[0863] INTERMEDIATE BB-23

[0864] tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chl oro-3 -hydroxy-phenyl)-phenyl- methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0865]

[0866] Intermediate 23 A: 2-chloro-3-[(A)-phenyl(4-piperidyl)methyl]phenol hydroiodide

[0867]

[0868] To a stirred solution of benzyl 4-[(A)-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-l -carboxylate (2.18 g, 4.95 mmol) in acetonitrile (24 mL) at ambient temperature was added iodo(trimethyl)silane (2.11 mL, 14.9 mmol) dropwise. The reaction mixture was stirred 10 min at ambient temperature then cooled to 0 °C with an ice bath and MeOH (2.4 mL, 59.4 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 15 min then concentrated under reduced pressure. Et2O was added to the crude and the mixture was stirred at ambient temperature for 30 min. The resulting precipitate was filtered, washed with Et2O, and dried under reduced pressure at 50 °C for 12 h to afford 2-chloro-3-[(A)-phenyl(4-piperidyl)methyl]phenol hydroiodide as a yellow powder (2.08 g, 96% p, 94% y.). m / z [M+H]+= 302.2, 'H NMR (400 MHz, DMSO-d6): 6 (ppm) 10.07 (s, 1H), 8.41 (d, J= 11.3 Hz, 1H) 8.08(d, J= 11.4 Hz, 1H), 7.37-7.33 (m, 2H), 7.29 (dd, J= 8.4, 6.8 Hz, 2H), 7.22-7.16 (m,lH) 7.14 (t, J= 7.8 Hz, 1H), 7.07 (dd, J= 7.9, 1.6 Hz, 1H), 6.80 (dd, = 7.9, 1.5 Hz, lH) 4.12 (d, J= 11.2 Hz, 1H), 3.24 (d, J = 12.7 Hz, 2H), 2.84 (p, J= 11.5 Hz, 2H), 2.61-2.50 (m, 1H), 1.61 (d, J= 14.0 Hz, 1H), 1.51 (d, J= 14.0 Hz, 1H), 1.33-1.17 (m, 2H), [a]D= +39omL.dm-1.g-1[20 °C, Na lamp, 589 nm, C = 3.5 mg / mL, MeOH],

[0869] Intermediate BB-23

[0870] To a solution of 2-chloro-3-[(A)-phenyl(4-piperidyl)methyl]phenol hydroiodide (2.17 g, 4.84 mmol) in DMF (24 mL), were added 2-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-6-methyl-l-oxo-isoindoline-5-carboxylic acid (1.91 g, 5.08 mmol), DIPEA (2.6 mL, 14.5 mmol) and HATU (2.82 g, 7.26 mmol). The mixture was stirred at ambient temperature for 1 h. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. EtOAc was added. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NH4Cl then brine, filtered over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) (+1% of a 7 N solution of NH3 in MeOH) in cyclohexane from 20% to 100 to afford tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an off-white solid (3.02 g, 100% p., 95% y.). m / z [M+H]+= 660.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 9.99 (d, J= 22.0 Hz, 1H), 7.95 (s, 1H), 7.55 (d, J= 9.7 Hz, 2H), 7.48-7.35 (m, 1H), 7.35-7.05 (m, 6H), 6.77 (dt, J= 23.8, 4.7 Hz, 1H), 4.71 (dd, J= 10.3, 3.9 Hz, 1H), 4.62-4.35 (m, 3H), 3.27-3.13 (m, 1H), 3.04-2.93 (m, 1H), 2.89 (s, 3H), 2.83-2.73 (m, 3H), 2.33 (d, J= 4.5 Hz, 1H), 2.23 (s, 2H), 2.16-2.11 (m, 3H), 2.03-1.91 (m, 1H), 1.51-1.44 (m, 1H), 1.37-1.23 (m, 9H), 1.18-0.89 (m, 1H).

[0871] INTERMEDIATE BB-24

[0872] tert-butyl (45)-5-amino-4-[5-[4-[(5)-(2-chloro-3-hydroxy-phenyl)-phenyl- methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0873]

[0874] ° (BB-24) Intermediate 24A: 2-chloro-3-[(5)-phenyl(4-piperidyl)methyl]phenol hydroiodide

[0875]

[0876] To a stirred solution of benzyl 4-[fS')-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl] piperidine- 1 -carboxylate (2.34 g, 5.31 mmol) in acetonitrile (25 mL) at ambient temperature under nitrogen was added iodo(trimethyl)silane (2.3 mL, 15.9 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 1 h. MeOH (2.6 mL, 63.8 mmol) was added at 0 °C. The mixture was stirred at ambient temperature for 15 min and was concentrated under reduced pressure. Et2O was added and the resulting mixture was stirred at ambient temperature for 1 h. The solid was filtered, washed with Et2O, and dried under reduced pressure to afford 2-chloro-3-[(5)-phenyl(4-piperidyl) methyl]phenol hydroiodide as a yellow powder (2.20 g, 98% p., 94% y.). m / z [M+H]+= 302.2,1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.07 (s, 1H), 8.13 (s, 2H), 7.38-7.25 (m, 4H), 7.23-7.10 (m, 2H), 7.06 (dd, J= 7.9, 1.5 Hz, 1H), 6.80 (dd, J= 7.9, 1.5 Hz, 1H),4.12 (d, J= 11.2 Hz, 1H), 3.23 (d, J= 12.6 Hz, 2H), 2.83 (q, J= 10.2 Hz, 2H), 2.55 (s, 1H), 1.61 (d, J= 14.3 Hz, 1H), 1.51 (d, J= 13.6 Hz, 1H), 1.25 (p, J= 12.6 Hz, 2H), [a]D=-41 “mL.dm'hg'1[20 °C, Na lamp, 589 nm, C = 2.9 mg / mL, MeOH],

[0877] Intermediate BB-24

[0878] To a solution of 2-chloro-3-[(5)-phenyl(4-piperidyl)methyl]phenol hydroiodide (2.16 g, 5.02 mmol) in DMF (25 mL), were added 2-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-6-methyl-l-oxo-isoindoline-5-carboxylic acid (1.98 g, 5.27 mmol), DIPEA (2.6 mL, 15.1 mmol), and HATU (2.92 g, 7.53 mmol). The mixture was stirred at ambient temperature for 1 h. Water, EtOAc, and FastWorX® were added. The organic solvent wasevaporated, and the resin was filtered in a solid deposit cartridge. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) (+1% of a 7 M solution of NH3 in MeOH) in cyclohexane from 10% to 100%. The desired fractions were combined and concentrated under reduced pressure to afford tert-butyl (46')- 5-amino-4-[5-[4-[fS')-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an off-white solid (3.40 g, 84% p., 86% y.). m / z [M+Na]+= 682.3.

[0879] EXAMPLE 1

[0880] (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-isoindolin-2-yl]piperidine-2,6- dione

[0881]

[0882] Intermediate 1A: 4-benzhydrylpiperidine

[0883]

[0884] A mixture of sodium borohydride (347 mg, 9.16 mmol) and diphenyl(4-piperidyl) methanol (250 mg, 0.916 mmol) was added portion wise to a stirred solution of TFA (11 mL, 137 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was solubilized in DCM. The organic layer was washed with a 1 M aqueous solution of NaOH, brine and then dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-benzhydrylpiperidine as a white powder (167 mg, 99% p., 72% y.). m / z [M+H]+= 252.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.55 (brs, 1H), 7.41-7.23 (m, 9H), 7.21-7.11 (m, 2H), 3.60 (d, J = 11.2 Hz, 1H), 3.21 (dt, J= 13.0, 3.4 Hz, 2H), 2.82 (td, J= 12.8, 3.0 Hz, 2H), 1.58-1.49 (m, 2H), 1.32-1.13 (m, 2H).

[0885] Intermediate IB: tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0886]

[0887] In a sealed vial under nitrogen, to a stirred solution of 4-benzhydrylpiperidine (69.0 mg, 0.276 mmol), 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-l-oxo-isoindoline-5-carboxylic acid (100 mg, 0.276 mmol), and DIPEA (193 pL, 1.10 mmol) in dry EtOAc (2.0 mL) was added a solution of T3P in MeTHF (50% w / w, 263 mg, 0.414 mmol). The mixture was stirred at ambient temperature for 5 h. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of MeOH in DCM from 0% to 10% to afford tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a white solid (36.0 mg, 97% p., 21% y.). m / z [M+Na]+= 618.5, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.71 (d, J= 7.9 Hz, 1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.43 (dd, J= 7.8, 1.4 Hz, 1H), 7.42-7.34 (m, 4H), 7.31-7.22 (m, 4H), 7.18 (s, 1H), 7.17-7.08 (m, 2H), 4.77-4.70 (m, 1H), 4.61 (d, J= 17.8 Hz, 1H), 4.47 (d, J= 18.0 Hz, 2H), 3.63 (d, J= 11.2 Hz, 1H), 3.50 (s, 1H), 3.01 (s, 1H), 2.78 (s, 1H), 2.51 (s, 1H), 2.21-2.10 (m, 3H), 2.04-1.91 (m, 1H), 1.54 (s, 1H), 1.31 (s, 10H), 1.12 (t, = 11.8 Hz, 2H).

[0888] Example 1

[0889] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (35.0 mg, 0.0588 mmol) and 4-methylbenzenesulfonic acid hydrate (34.0 mg, 0.177 mmol) in acetonitrile (500 pL) was stirred at 80 °C for 4 h. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried using hydrophobic paper and concentrated under reduced pressure. The crude was purified byflash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. Select fractions were concentrated under reduced pressure. The residue was solubilized in a minimum amount of DCM and the solution was added dropwise to stirred solution of w-pentane. The resulting residue was triturated for 3 h, filtered, washed with w-pentane, and dried under reduced pressure at 50 °C for 64 h to afford (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid (10.0 mg, 96.7% p., 31% y.). m / z [M+H]+= 522.2, 'H NMR (500 MHz, DMSO-d6): δ (ppm) 10.97 (s, 1H), 7.75 (d, J= 7.8 Hz, 1H), 7.58 (s, 1H), 7.46 (dd, J= 7.7, 1.2 Hz, 1H), 7.43-7.33 (m, 4H), 7.33-7.21 (m, 4H), 7.20-7.07 (m, 2H), 5.12 (dd, J= 13.3, 5.2 Hz, 1H), 4.58-4.26 (m, 3H), 3.62 (d, J= 11.1 Hz, 1H), 3.57-3.43 (m, 1H), 3.11-2.96 (m, 1H), 2.91 (ddd, J= 17.5, 13.6, 5.5 Hz, 1H), 2.84-2.69 (m, 1H), 2.65-2.52 (m, 2H), 2.39 (qd, J = 13.2, 4.6 Hz, 1H), 2.08-1.93 (m, 1H) 1.61-1.47 (m, 1H) 1.36 (br s, 1H) 1.11 (br d, J= 11.1 Hz, 2H).

[0890] EXAMPLE 2

[0891] (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-methyl-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione

[0892]

[0893] Intermediate 2A: tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0894]

[0895] In a round-bottom flask, to a stirred suspension of 2-[(15)-4-terLbutoxy-l-carbamoyl-4-oxo-butyl]-6-methyl-l-oxo-isoindoline-5-carboxylic acid (70 mg, 0.177 mmol) in EtOAc (1.7 mL) were added successively 4-benzhydrylpiperidine (53 mg, 0.212mmol), DIPEA (93 pL, 0.530 mmol), and a solution of T3P in MeTHF (50% w / w, 169 mg, 0.265 mmol). The reaction mixture was stirred at ambient temperature for 3 h.

[0896] Additional solution of T3P in MeTHF (50% w / w, 169 mg, 0.265 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of water. The layers were separated. The organic layer was washed with water (3x), with brine, dried using a phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 5% to 80%. The desired fractions were combined and concentrated under reduced pressure. The resulting residue was solubilized in DCM and the organic layer was washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried using a phase separator cartridge and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a pale yellow foam (36.0 mg, 94% p.,31% y.). m / z [M+H]+= 610.6, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.56 (s, 2H), 7.41-7.09 (m, 12H), 4.71 (d, J= 10.3 Hz, 1H), 4.50 (dq, J= 33.4, 16.8 Hz, 3H), 3.61 (d, J= 10.6 Hz, 1H), 3.24 (d, J= 13.8 Hz, 1H), 2.97 (t, J= 12.9 Hz, 1H), 2.77 (s, 1H), 2.51 (s, 2H), 2.32 (s, 1H), 2.24 (s, 3H), 2.14 (s, 3H), 1.98 (d, J= 9.0 Hz, 1H), 1.55 (s, 1H), 1.31 (d, J = 18.6 Hz, 9H), 1.06 (d, J= 12.6 Hz, 2H).

[0897] Example 2

[0898] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (34.0 mg, 0.0558 mmol) and 4-methylbenzenesulfonic acid hydrate (31.8 mg, 0.167 mmol) in acetonitrile (340 pL) was stirred at 80 °C for 16 h. The mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine. Layers were separated using hydrophobic paper and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. Fractions were concentrated under reduced pressure. The resulting solid was solubilized in the minimum amount of DCM and the homogenous solution was addeddropwise to a stirred solution of / / -pentane. The mixture was stirred for 4 h. The resulting precipitate was filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C for 16 h to afford (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid (6.0 mg, 97.4% p., 19% y.). m / z [M+H]+= 536.4, 'H NMR (600 MHz, DMSO-d6): δ (ppm) 10.97 (br s, 1H), 7.60 (d, 1H, J= 4.7 Hz), 7.4-7.3 (m, 5H), 7.3-7.2 (m, 4H), 7.2-7.1 (m, 2H), 5.1-5.0 (m, 1H), 4.6-4.5 (m, 1H), 4.5-4.2 (m, 2H), 3.7-3.6 (m, 1H), 3.3-2.7 (m, 4H), 2.6-2.5 (m, 2H), 2.4-2.2 (m, 4H), 2.1-1.9 (m, 1H), 1.6 -0.9 (m, 4H).

[0899] EXAMPLE 3

[0900] (35)-3-[5-[(U?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-l-oxo-isoindolin- 2-yl]piperidine-2, 6-dione

[0901]

[0902] Intermediate 3A: tert-butyl (U?,55)-3-benzhydryl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carb oxy late

[0903]

[0904] A round-bottom flask was charged with benzhydryl bromide (1,30 g, 4.74 mmol) and N-Boc-nortropinone (1,00 g, 4.31 mmol) in dry THF (21 mL) under nitrogen. The mixture was cooled to -78 °C and a 2.5 M solution of w-butyllithium in hexanes (3.8 mL, 9.47 mmol) was added dropwise over 20 min. The resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl. The mixture was extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified on silica gel using a gradient of a mixture of EtOAc / EtOH (3 / 1) in cyclohexane from 0% to 70% to afford tert-butyl (LR,5S)-3-benzhydryl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate as a white powder (470 mg, 93% p., 26% y.). m / z [M-Boc+2H]+= 338.4, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.52-7.45 (m, 4H), 7.25 (dd, J= 8.3, 6.9 Hz, 4H), 7.18-7.12 (m, 2H), 4.43 (s, 1H), 3.99 (d, J= 6.1 Hz, 2H), 3.51 (s, 1H), 2.12 (d, J= 6.6 Hz, 2H), 1.70 (d, J= 41.3 Hz, 3H), 1.44 (s, 3H), 1.39 (s, 9H).

[0905] Intermediate 3B: (lA,55)-3-benzhydryl-8-azabicyclo[3.2. l]octan-3-ol

[0906]

[0907] To a stirred solution of tert-butyl (lA,55)-3-benzhydryl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (235 mg, 0.554 mmol) in EtOH (3.0 mL) at ambient temperature were added successively triethylamine (270 pL, 1.67 mmol), palladium on carbon (10% w / w, 59 mg, 0.0555 mmol) and AcOH (32 pL, 0.556 mmol). The reaction mixture was stirred at 80 °C overnight. Additional palladium on carbon (10% w / w, 59 mg, 0.0555 mmol), AcOH (32 pL, 0.556 mmol), and triethylamine (270 pL, 1.67 mmol) were added. The reaction mixture was stirred at 80 °C for 5 h and then at ambient temperature for 72 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude was diluted in dry DCE (3.0 mL). Triethylsilane (272 pL, 1.67 mmol) and TFA (128 pL, 16.7 mmol) were added. The reaction mixture was stirred at ambient temperature overnight. EtOAc was added and the reaction mixture was washed with a saturated aqueous solution of NaHCO3then brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to afford (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octan-3-ol as a colorless oil (170 mg, 96% p., quant, yield), m / z [M+H]+= 294.3.

[0908] Intermediate 3C: (lA,55)-3-benzhydryl-8-azabicyclo[3.2. l]oct-2-ene

[0909]

[0910] To a stirred solution of (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octan-3-ol (170 mg, 0.579 mmol) in dry THF (2.9 mL) at ambient temperature was added sulfuric acid (618 pL, 11.6 mmol). The reaction mixture was stirred at 70 °C overnight. EtOAc was added and the reaction mixture was washed with a saturated aqueous solution of NaHCO3then brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 0% to 100% to afford (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]oct-2-ene as a yellow oil (103 mg, 98% p.,63% y.). m / z [M+H]+= 276.4,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.35-7.27 (m, 4H), 7.20 (dtd, J= 7.5, 5.2, 2.5 Hz, 2H), 7.15-7.07 (m, 4H), 4.34 (q, J= 5.3 Hz, 1H), 4.08 (q, J= 5.2 Hz, 3H), 3.46-3.42 (m, 1H), 3.39 (q, J= 3.3 Hz, 2H), 1.65-1.48 (m,4H).

[0911] Intermediate 3D: (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane

[0912]

[0913] To a stirred solution of (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]oct-2-ene (103 mg, 0.374 mmol) in EtOH (2.0 mL) at ambient temperature were added palladium on carbon (10% w / w, 40.0 mg, 0.0374 mmol), AcOH (21.4 pL, 0.374 mmol), and triethylsilane (181 pL, 1.12 mmol). The reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was filtered through a glass fiber filter and washed with EtOAc. The filtrate was concentrated under reduced pressure. The reaction mixture was washed with a saturated aqueous solution of NaHCO3, then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane as a white solid (87.0 mg, 97% p., 81% y.). m / z [M+H]+= 278.4,1H NMR (400 MHz, DMSO-d6): 6 (ppm) 7.35 (ddd, J= 8.0, 5.0, 1.4 Hz, 4H), 7.29-7.19 (m, 4H), 7.16-7.07 (m, 2H), 3.30 (td, J= 13.9, 5.3 Hz, 5H), 2.71-2.52 (m, 1H), 1.63 (dd, J = 23.0, 2.2 Hz, 4H), 1.27-1.17 (m, 1H), 1.13-0.95 (m, 2H).

[0914] Intermediate 3E: tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0915]

[0916] In a sealed vial under argon, to a stirred solution of (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane (87.0 mg, 0.314 mmol), 2-[(15)-4-te / 7-butoxy-l -carbamoyl-4-oxo-butyl]-l-oxo-isoindoline-5-carboxylic acid (116 mg, 0.314 mmol), and DIPEA (219 pL, 1.25 mmol) in EtOAc (1.0 mL) was added a solution of T3P in EtOAc (50% w / w, 299 mg, 0.470 mmol). The reaction mixture was stirred at ambient temperature for 70 h. The reaction was quenched with the addition of water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with a 0.5 N aqueous solution of HC1, a saturated aqueous solution of NaHCO3, brine, filtered through hydrophobic paper, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 70% to afford tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a white foam (100 mg, 99% p., 51% y.). m / z [M+H]+= 622.6.

[0917] Example 3

[0918] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (100 mg, 0.161 mmol) and 4-methylbenzenesulfonic acid hydrate (91.8 mg, 0.482 mmol) in acetonitrile (1.0 mL) was stirred at 70 °C for 16 h. The mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, filtered through hydrophobic paper, and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. The desired fractions were concentrated under reduced pressure. The resulting solid was solubilized in the minimum amount of DCM and the homogenous solution was added dropwise to a stirred solution of / / -pentane. The mixture was stirred for 1 h. The resulting

[0919] Illprecipitate was filtered, washed with w-pentane, and dried under reduced pressure at 50 °C overnight to afford (35)-3-[5-[(U?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid (48.0 mg, 99.0% p., 53% y.). m / z [M+H]+= 548.4, 'H NMR (500 MHz, DMSO-d6): δ (ppm) 10.99 (s, 1H), 7.77 (dd, J= 7.75, 4.00 Hz, 1H), 7.69 (d, J= 10.63 Hz, 1H), 7.63-7.50 (m, 1H), 7.49-7.35 (m, 4H), 7.26 (dt, J= 13.70, 7.47 Hz, 4H), 7.18-6.96 (m, 2H), 5.13 (dd, J= 13.26, 5.00 Hz, 1H), 4.71-4.54 (m, 1H), 4.53-4.31 (m, 2H), 3.59 (d, J= 11.01 Hz, 2H), 3.00-2.90 (m, 1H) 2.89 (br d, J= 5.50 Hz, 1H), 2.66-2.57 (m, 1H), 2.40 (brt, J= 13.32 Hz, 1H), 2.14-2.02 (m, 1H), 2.01-1.66 (m, 5H), 1.46-1.16 (m, 3H).

[0920] EXAMPLE 4

[0921] (35)-3-[5-(7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-l-oxo-isoindolin- 2-yl]piperidine-2, 6-dione

[0922] O O

[0923] y V- NH

[0924] hl. ( \=O

[0925]

[0926] Intermediate 4A: tert-butyl 7-[hydroxy(diphenyl)methyl]-3-oxa-9-azabicyclo[3.3.1 ]nonane-9-carboxylate

[0927]

[0928] In a three-necked round-bottom flask under nitrogen, to a stirred solution of 9- / e / V-butyl 7-methyl 3-oxa-9-azabicyclo[3.3.1]nonane-7,9-dicarboxylate (242 mg, 0.823 mmol) in dry THF (3.1 mL) at 0 °C under nitrogen was added a 3 M solution of bromo(phenyl)magnesium (603 pL, 1.81 mmol) in dry THF. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NH4Cl at 0 °C. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried using a phase separator cartridge and concentrated under reduced pressure to afford tert-butyl 7-[hydroxy(diphenyl)methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate as a pale yellow oil (349 mg, 45% p., 47% y.). m / z [M+H]+= 336.3.

[0929] Intermediate 4B: 7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane

[0930]

[0931] In a round-bottom flask, to a solution of tert-butyl 7-[hydroxy(diphenyl)methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (348 mg, 0.382 mmol) in dry DCM (3.0 mL), was added triethylsilane (410 pL, 2.57 mmol). The reaction mixture was cooled to 0 °C and TFA (195 pL, 25.5 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was basified with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried using a phase separator cartridge, and concentrated under reduced pressure to afford 7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane as a pale yellow solid (118 mg, 46% p., 48% y.). m / z [M+H]+= 294.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 9.31 (s, 1H), 7.34 (dd, J= 8.1, 1.4 Hz, 3H), 7.27 (s, 2H), 7.15 (tdd, J= 8.7, 7.0, 1.9 Hz, 3H), 6.77-6.72 (m, 2H), 3.74-3.67 (m, 4H), 3.43-3.37 (m, 2H), 2.89-2.79 (m, 2H), 1.64-1.52 (m, 2H), 1.35 (dddd, J= 14.0, 11.5, 7.0, 3.6 Hz, 2H).

[0932] Intermediate 4C: tert-butyl (45)-5-amino-4-[5-(7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0933]

[0934] To a stirred solution of 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-l-oxo-isoindoline-5-carboxylic acid (156 mg, 0.430 mmol) in EtOAc (2.0 mL) were added successively 7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane (115 mg, 0.180 mmol),DIPEA (210 pL, 1.20 mmol) and a solution of T3P in MeTHF (50% w / w, 374 mg, 0.588 mmol). The reaction mixture was stirred at ambient temperature for 2 h. Additional solution of T3P in MeTHF (50% w / w, 374 mg, 0.588 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. Additional solution of T3P in MeTHF (50% w / w, 374 mg, 0.588 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried using a phase separator cartridge and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 5% to 60% to afford tert-butyl (45)-5-amino-4-[5-(7-benzhydryl -3-oxa-9-azabicyclo[3.3.1 ]nonane-9-carbonyl)- 1-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a pale yellow solid (20.2 mg, 94% p., 35% y). m / z [M+H]+= 638.5,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.74 (d, J= 7.8 Hz, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.51 (d, J= 7.8 Hz, 1H), 7.41-7.21 (m, 8H), 7.14 (dt, J= 19.4, 8.0 Hz, 3H), 4.77-4.70 (m, 1H), 4.63 (d, J= 17.8 Hz, 1H), 4.49 (dd, J= 17.9, 3.6 Hz, 1H), 4.42 (s, 1H), 3.88 (d, J= 11.4 Hz, 1H), 3.73-3.61 (m, 3H), 3.53 (s, 2H), 3.43 (d, J= 11.2 Hz, 1H), 2.16 (d, J= 3.0 Hz, 3H), 1.99 (s, 2H), 1.69 (d, J= 13.5 Hz, 1H), 1.50 (dd, J = 27.0, 11.6 Hz, 2H), 1.31 (d, = 3.3 Hz, 9H).

[0935] Example 4

[0936] To a stirred solution of tert-butyl (45)-5-amino-4-[5-(7-benzhydryl-3-oxa-9-azabicyclo[3.3. l]nonane-9-carbonyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (20.2 mg, 0.021 mmol) in acetonitrile (170 pL) was added 4-methylbenzenesulfonic acid hydrate (8.6 mg, 0.045 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to ambient temperature and diluted with water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of a EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in a minimum amount of acetone and the homogenous solution was added to / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane and dried under reduced pressure at 50 °C overnight to afford (35)-3-[5-(7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione as a white powder (3.3 mg, 98.3% p., 27% y.). m / z [M+H]+= 564.3, 'H NMR (500 MHz, DMSO-d6): δ (ppm) 10.99 (s, 1H), 7.78 (d, J= 7.8 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J= 7.8 Hz, 1H), 7.4-7.3 (m, 4H), 7.3-7.2 (m, 4H), 7.2-7.1 (m, 2H), 5.12 (td, J= 13.2, 4.7 Hz, 1H), 4.6-4.3 (m, 3H), 3.9-3.4 (m, 7H), 3.0-2.8 (m, 1H), 2.7-2.6 (m, 1H), 2.5-2.3 (m, 1H), 2.1-1.9 (m, 1H), 1.8-1.6 (m, 1H), 1.6-1.3 (m, 3H).

[0937] EXAMPLE 5

[0938] (35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione

[0939]

[0940] Intermediate 5A: tert-butyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl]piperidine-l-carb oxy late

[0941]

[0942] To a stirred solution of l-bromo-2-chloro-benzene (157 pL, 1.33 mmol) in dry THF (1.0 mL) at -78 °C under argon was added a 1.6 M solution of / / -butyllithium in hexanes (829 pL, 1.33 mmol). The mixture was stirred at -78 °C for 30 min. A solution of tert-butyl 4-benzoylpiperidine-l -carboxylate (200 mg, 0.663 mmol) in dry THF (1.0 mL) was added and the reaction mixture was stirred for 1 h at -78 °C. The reaction was quenched with the addition of a saturated aqueous solution of NH₄Cl. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in / / -heptane from 1% to 50%. Fractions were combined and concentrated under reduced pressure to afford tert-butyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl]piperidine-l-carboxylate asa white foam (221 mg, 94% p., 78% y.). m / z [M-Boc+2H]+= 302.3,1H NMR (400 MHz, DMSO-de): 6 (ppm) 8.03-7.99 (m, 1H), 7.41-7.34 (m, 3H), 7.28-7.20 (m, 4H), 7.18-7.13 (m, 1H), 5.48 (s, 1H), 3.95 (s, 2H), 3.11 (s, 1H), 2.71 (d, J= 35.6 Hz, 2H), 1.52 (s, 1H), 1.37 (s, 9H), 1.25 (ddd, J= 37.0, 14.4, 8.0 Hz, 3H).

[0943] Intermediate 5B: 4-[(2-chlorophenyl)-phenyl-methyl]piperidine

[0944]

[0945] In a sealed vial, to a stirred solution of tert-butyl 4-[(2-chlorophenyl)-hydroxy-phenyl-methyl]piperidine-l -carboxylate (220 mg, 0.515 mmol) and triethylsilane (410 pL, 2.57 mmol) in dry DCM (1.7 mL) was added dropwise TFA (118 pL, 15.4 mmol) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature overnight. The reaction mixture was poured into a mixture of ice and an aqueous solution of NaOH (33% w / w). The aqueous layer was extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-[(2-chlorophenyl)-phenyl-methyl] piperidine as a colorless oil (200 mg, 70% p. 95% y.). m / z [M+H]+= 286.1,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.67 (dd, J= 7.8, 1.7 Hz, 1H), 7.52-7.09 (m, 10H), 4.09 (d, J= 11.1Hz, 1H), 2.88-2.65 (m, 3H), 2.46-2.15 (m, 4H), 1.34 (dd, J= 21.7, 13.1 Hz, 1H).

[0946] Intermediate 5C: tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0947]

[0948] In a sealed vial under argon, a solution of 4-[(2-chlorophenyl)-phenyl-methyl] piperidine (75.0 mg, 0.184 mmol), 2-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-6-methyl- l-oxo-isoindoline-5-carboxylic acid (87.3 mg, 0.220 mmol) and DIPEA (128 pL, 0.735 mmol) in EtOAc (1.8 mL) was stirred at ambient temperature. A solution of T3P in EtOAc (50% w / w, 164 pL, 0.276 mmol) was added and the mixture was stirred at ambient temperature for 16 h. A saturated aqueous solution of NaHCO3was added and the aqueous layer was extracted with EtOAc (2X). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 1% to 70%. Fractions were combined and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a white foam (41.0 mg, 98% p., 34% y.). m / z [M+H]+= 644.3,1H NMR (400 MHz, DMSO-d6).

[0949] Example 5

[0950] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (39.0 mg, 0.060 mmol) and 4-methylbenzenesulfonic acid hydrate (34.5 mg, 0.182 mmol) in acetonitrile (390 pL) was stirred at 70 °C for 16 h. The mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine. Layers were separated using hydrophobic paper and the filtrate was concentrated under reduced. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. The desired fractions were concentrated. The resulting gum was solubilized in a minimum amount of DCM and the solution was added dropwise to stirred solution of / / -pentane. The mixture was stirred for 1 h. The resulting precipitate was filtered, washed with n-pentane and dried under reduced pressure at 50 °C for 16 h to afford (35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione as a white solid (13.5 mg, 97.6% p, 38% y.). m / z [M+H]+= 570.4,1H NMR (600 MHz, DMSO-d6): δ (ppm) 10.97 (s, 1H), 7.78-7.66 (m, 1H), 7.62-7.59 (m, 1H), 7.50-7.27 (m, 6H), 7.26-7.11 (m, 3H), 5.16-5.04 (m, 1H), 4.52 (br s, 1H), 4.46-4.37 (m, 1H), 4.33-4.27 (m, 1H), 4.17-4.12 (m, 1H), 3.28-3.17 (m, 1H), 3.03-2.85 (m, 2H),2.81-2.71 (m, 1H), 2.65-2.53 (m, 2H), 2.42-2.35 (m, 1H), 2.35-2.20 (m, 3H), 1.98 (br s, 1H), 1.70-0.89 (m, 4H).

[0951] EXAMPLE 6

[0952] (35)-3-[5-[(U?,47?)-5-benzhydryl-2-azabicyclo[2.2.1]heptane-2-carbonyl]-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione

[0953]

[0954] Intermediate 6A: tert-butyl (15,45)-5-benzhydryl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0955]

[0956] (6A)

[0957] To a stirred solution of benzhydryl bromide (715 mg, 2.60 mmol) and (15,45)-2-Boc-5-oxo-2-azabicyclo[2.2.1]heptane (500 mg, 2.37 mmol) in dry THF (12 mL) at -78 °C under nitrogen was added a 2.5 M solution of w-butyllithium in hexanes (2.1 mL, 5.21 mmol) dropwise. The reaction mixture was stirred for 1 h at -78 °C. The reaction was quenched with the addition of a saturated aqueous solution of NH₄Cl. The reaction mixture was allowed to warm up to ambient temperature and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane from 1% to 50% to afford tert-butyl (15,45)-5-benzhydryl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate as a white foam (182 mg, 99% p., 20% y.). m / z [M+H]+= 380.3, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.60-7.55 (m, 2H), 7.46 (d, J= 7.5 Hz, 2H), 7.24 (t, J = 7.4 Hz, 4H), 7.19-7.10 (m, 2H), 4.90 (d, J= 6.2 Hz, 1H), 3.97 (d, J= 24.2 Hz, 2H), 3.55 (dd, J= 14.3, 9.5 Hz, 1H), 2.89 (t, J= 10.3 Hz, 1H), 2.24 (s, 1H), 1.97 (d, J= 16.2 Hz, 1H), 1.71-1.48 (m, 2H), 1.36 (m, 10H).Intermediate 6B: (lA,4A)-5-benzhydryl-2-azabicyclo[2.2.1]heptane

[0958]

[0959] To a stirred solution of tert-butyl (15,45)-5-benzhydryl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (180 mg, 0.474 mmol) in THF (1.6 mL) was added sulfuric acid (758 pL, 14.2 mmol). The reaction mixture was stirred at 65 °C for 24 h. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. In a sealed vial, to a stirred solution of the crude in EtOH (1.6 mL) was added palladium on carbon (10% w / w, 50.5 mg, 0.0474 mmol). The reaction mixture was degassed with argon for 5 min and triethylsilane (383 pL, 2.37 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. Additional palladium on carbon (10% w / w, 50.5 mg, 0.047 mmol) and triethylsilane (383 pL, 2.37 mmol) were added and the reaction mixture was stirred for 24 h. The reaction mixture was filtered through a glass fiber filter and the filtrate was concentrated under reduced pressure to afford (lA,4A)-5-benzhydryl-2-azabicyclo[2.2.1]heptane as a yellow oil (868 mg, 65% p., quant, yield), m / z [M+H]+= 264.4.

[0960] Intermediate 6C: tert-butyl (45)-5-amino-4-[5-[(lA,4A)-5-benzhydryl-2-azabicyclo[2.2.1]heptane-2-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0961] NH2

[0962] H3C CH3

[0963] -x 'ACH

[0964]

[0965] To a stirred suspension of 2-[(15')-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-l-oxo-isoindoline-5-carboxylic acid (125 mg, 0.345 mmol) in EtOAc (3.4 mL) were addedsuccessively (lA,4A)-5-benzhydryl-2-azabicyclo[2.2.1]heptane (99.9 mg, 0.379 mmol), DIPEA (181 pL, 1.03 mmol), and then a solution of T3P in MeTHF (50% w / w, 329 mg, 0.517 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 2% to 100% to afford tert-butyl (45)-5-amino-4-[5-[(lA,4A)-5-benzhydryl-2-azabicyclo[2.2.1]heptane-2-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an off-white solid (143 mg, 99% p., 68% y.). m / z [M+H]+= 608.7.

[0966] Example 6

[0967] To a stirred solution of tert-butyl (45)-5-amino-4-[5-[(lA,4A)-5-benzhydryl-2-azabicyclo[2.2. l]heptane-2-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (140 mg, 0.230 mmol) in acetonitrile (2.3 mL) was added 4-methylbenzenesulfonic acid hydrate (131 mg, 0.691 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in the minimum amount of DCM and the homogenous solution was added to a solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with pentane, and dried under reduced pressure at 50 °C overnight to afford (3S)-3-[5-[(1R,4R)-5-benzhydryl-2-azabicyclo[2.2.1]heptane-2-carbonyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione as a white solid (52.5 mg, 99.2% p., 42% y.). m / z [M+H]+= 534.3,1H NMR (500 MHz, DMSO-d6): δ (ppm) 10.99 (br s, 1H), 7.79-7.74 (m, 1H), 7.65 (s, 1H), 7.54 (ddd, J= 7.8, 2.9, 1.3 Hz, 1H), 7.51-7.05 (m, 10H), 5.22-5.05 (m, 1H), 4.57-4.43 (m, 1H), 4.43-4.32 (m, 1H), 3.99-3.94 (m, 1H), 3.76-3.53 (m, 1H), 3.47-3.34 (m, 2H), 3.30-3.04 (m, 2H), 2.97-2.85 (m, 1H), 2.67-2.56 (m, 1H), 2.44-2.33 (m, 1H), 2.28-2.05 (m, 1H), 2.04-1.97(m, 1H), 1.91-1.45 (m, 2H), 1.24-1.11 (m, 1H).

[0968] EXAMPLE 7

[0969] (35)-3-[5-[(U?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-fluoro-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione

[0970] O

[0971]

[0972] (7) Intermediate 7A: (U?,55)-3-benzhydrylidene-8-azabicyclo[3.2.1]octane

[0973]

[0974] (7A)

[0975] In a sealed vial under argon, sulfuric acid (3.7 mL, 70.1 mmol) was added to a stirred solution of tert-butyl (U?,55)-3-benzhydryl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (968.4 mg, 2.34 mmol) in THF (4.5 mL). The mixture was stirred at 65 °C for 16 h. The reaction was quenched with the addition of a saturated aqueous solution of Na2CC>3. The aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (U?,55)-3-benzhydrylidene-8-azabicyclo[3.2.1]octane as an orange oil (705 mg, 89% p., 97% y.). m / z [M+H]+= 276.2,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.36-7.28 (m, 4H), 7.25-7.20 (m, 2H), 7.19-7.12 (m, 4H), 3.75-3.65 (m, 2H), 3.36-3.30 (m, 2H), 2.37 (dd, J= 15.2, 3.1 Hz, 1H), 2.24 (dt, J= 14.6, 1.9 Hz, 1H), 1.86-1.76 (m, 2H), 1.68 (q, J= 6.5 Hz, 1H), 1.54-1.39 (m, 2H).

[0976] Intermediate 7B: (15,57?)-3-benzhydryl-8-azabicyclo[3.2.1]octane

[0977]

[0978] In a sealed vial, to a stirred solution of (15,5A)-3-benzhydrylidene-8-azabicyclo[3.2.1]octane (705 mg, 2.28 mmol) in EtOH (4.5 mL) at ambient temperature were added palladium on carbon (10% w / w, 242 mg, 0.228 mmol) and AcOH (130 pL, 2.28 mmol). The suspension was degassed with argon for 5 min. Triethylsilane (1.1 mL, 6.84 mmol) was added and the reaction mixture was stirred at 80 °C for 16 h. Additional palladium on carbon (10% w / w, 242 mg, 0.228 mmol), AcOH (130 pL, 2.28 mmol) and triethylsilane (1.1 mL, 6.84 mmol) were added and the reaction mixture was stirred at ambient temperature for 10 min and at 80 °C for 23 h. Additional AcOH (130 pL, 2.28 mmol), palladium on carbon (10% w / w, 242 mg, 0.228 mmol), and triethylsilane (1.1 mL, 6.84 mmol) were added and the reaction mixture was stirred at ambient temperature for 10 min, at 80 °C for 5.5 h and at ambient temperature for 4 days. Additional palladium on carbon (10% w / w, 242 mg, 0.228 mmol), AcOH (130 pL, 2.28 mmol) and triethylsilane (1.1 mL, 6.84 mmol) were added and the reaction mixture was stirred at ambient temperature for 10 min and at 80 °C for 23 h. The reaction mixture was filtered through a pad of talc, washed with EtOH and the filtrate was concentrated under reduced pressure. The resulting residue was triturated in / / -pentane, filtered, and dried under reduced pressure to afford (15,5A)-3-benzhydryl-8-azabicyclo[3.2.1]octane as a white solid (201 mg, 93% p., 30% y.). m / z [M+H]+= 278.3, ' H NMR (400 MHz, DMSO-d6): 88.64 (s, 1H), 7.43 (td, J= 8.3, 1.3 Hz, 4H), 7.28 (td, J= 7.6, 3.3 Hz, 4H), 7.21-7.11 (m, 2H), 3.84 (d, J= 12.0 Hz, 2H), 2.95-2.76 (m, 1H), 2.11-1.99 (m, 3H), 1.91 (d, J= 2.2 Hz, 2H), 1.51 (p, J= 2.8 Hz, 1H), 1.43-1.32 (m, 3H).

[0979] Intermediate 7C: tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-fluoro-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0980]

[0981] In a sealed vial under argon, a solution of (lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane (70.0 mg, 0.25 mmol), 2-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-6-fluoro-l-oxo-isoindoline-5-carboxylic acid (120 mg, 0.303 mmol) and DIPEA(176 pL, 1.01 mmol) in EtOAc (2.5 mL) was stirred at ambient temperature. A solution of T3P in EtOAc (50% w / w, 225 pL, 0.379 mmol) was added and the mixture was stirred at ambient temperature for 15 h. Additional DIPEA (176 pL, 1.01 mmol) and a solution of T3P in EtOAc (50% w / w, 225 pL, 0.379 mmol) were added and the reaction mixture was stirred at 60 °C for 3 h. A saturated aqueous solution of NaHCO3was added and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 1% to 100%. Fractions were combined and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-fluoro-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an off-white foam (75.6 mg, 99% p., 46% y.). m / z [M+H]+= 640.5, ' H NMR (400 MHz, DMSO-d6): δ (ppm) 7.75-7.65 (m, 1H), 7.57 (dd, J= 8.4, 6.6 Hz, 2H), 7.47-7.35 (m, 4H), 7.32-7.20 (m, 5H), 7.19-7.13 (m, 1H), 7.13-7.06 (m, 1H), 4.73 (dd, J= 10.3, 4.7 Hz, 1H), 4.59 (td, J= 17.6, 17.5, 7.4 Hz, 2H), 4.47 (dd, J= 17.7, 7.3 Hz, 1H), 3.91 (dd, J= 12.3, 6.6 Hz, 1H), 3.71-3.59 (m, 1H), 2.96-2.58 (m, 1H), 2.17 (q, J= 8.4, 6.8, 6.8 Hz, 3H), 2.00 (d, J= 11.0 Hz, 3H), 1.89-1.74 (m, 3H), 1.37-1.21 (m, 11H), 1.09 (d, J= 13.7 Hz, 1H).

[0982] Example 7

[0983] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-fluoro-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (72.0 mg, 0.113 mmol) and 4-methylbenzenesulfonic acid hydrate (64.0 mg, 0.338 mmol) in acetonitrile (720 pL) was stirred at 70 °C for 16 h. The mixture was cooled to ambient temperature, a saturated aqueous solution of NaHCO3was added, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, filtered through hydrophobic paper, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. The desired fractions were concentrated under reduced pressure. The residue was solubilized in a minimum amount of DCM and the solution was added dropwise to a stirred solution of / -pentane. The precipitate was stirred at ambient temperature for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C for 16 h to afford (35)-3-[5-[(lA,55)-3-benzhydryl-8-azabicy clo[3.2. l]octane-8-carbonyl]-6-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid (31.9 mg, 99.7% p., 49% y.). m / z [M+H]+= 566.4,1H NMR (500 MHz, DMSO-de): 8 (ppm) 11.01 (s, 1H), 7.76-7.67 (m, 1H), 7.62 (t, J= 7.4 Hz, 1H), 7.45-7.37 (m, 4H), 7.31-7.21 (m, 4H), 7.18-7.09 (m, 2H), 5.17-5.08 (m, 1H), 4.65-4.52 (m, 1H), 4.52-4.44 (m, 1H), 4.40-4.33 (m, 1H), 3.92 (dd, J= 12.3, 5.8 Hz, 0.55H), 3.72-3.65 (m, 0.45H), 3.54 (d, J= 11.3 Hz, 1H), 2.95-2.87 (m, 1H), 2.70-2.57 (m, 2H), 2.46-2.35 (m, 1H), 2.09-1.71 (m, 6H), 1.47-1.22 (m, 2H), 1.16-1.08 (m, 1H).

[0984] EXAMPLE 8

[0985] (35)-3-[5-[(17?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-4-methyl-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione

[0986]

[0987] Intermediate 8A: tert-butyl (45)-5-amino-4-[5-[(17?,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-4-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0988]

[0989] To a stirred solution of 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-4-methyl-l-oxo-isoindoline-5-carboxylic acid (70.0 mg, 0.177 mmol) in dry DMF (1.7 mL) under argon were added successively HATU (80.6 mg, 0.212 mmol) and DIPEA (154 pL, 0.883 mmol). The mixture was stirred for 45 min at ambient temperature. (LR,5S)-3-benzhydryl-8-azabicyclo[3.2.1]octane (63.2 mg, 0.212 mmol) was added and the solution was stirred at ambient temperature for 1 h. The reaction was quenched with the addition of water. EtOAc was added, followed by the addition of FastWorX® powder. EtOAc was removed under reduced pressure. The resin was filtered and washed with water. The resin was triturated in EtOAc, filtered, and the filtrate was concentrated under reduced pressureto afford tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-4-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a white solid (95.0 mg, 96% p., 81% y.). m / z [M+H]+= 636.6,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.58-7.53 (m, 2H), 7.45-7.41 (m, 2H), 7.38 (d, J= 7.5 Hz, 3H), 7.32-7.27 (m, 2H), 7.27-7.21 (m, 2H), 7.21-7.05 (m, 3H), 4.77-4.71 (m, 1H), 4.63-4.51 (m, 2H), 4.46 (dd, J= 17.6, 6.9 Hz, 1H), 3.93 (d, J= 12.6 Hz, 1H), 3.59-3.45 (m, 1H), 2.69 (s, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 2.04 (dd, J= 14.5, 7.3 Hz, 1H), 1.93-1.65 (m, 4H), 1.40 (d, J= 15.2 Hz, 1H), 1.35 (d, J= 3.1 Hz, 1H), 1.31 (d, J= 2.6 Hz, 9H), 1.24 (d, J= 5.3 Hz, 1H), 1.07 (d, J= 14.3 Hz, 1H).

[0990] Example 8

[0991] A sealed vial was successively charged with tert-butyl (45)-5-amino-4-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-4-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (93.7 mg, 0.147 mmol) and 4-methylbenzenesulfonic acid hydrate (84.1 mg, 0.442 mmol) in acetonitrile (737 pL). The reaction mixture was stirred at reflux overnight. The reaction was quenched with the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 2% to 80%. The crude was solubilized in minimum amount of DCM and the homogeneous solution was added dropwise to a stirred solution of w-pentane. The resulting precipitate was filtered and dried under reduced pressure at 50 °C overnight to afford (35)-3-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-4-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white powder (32.0 mg, 96.8% p., 37% y.). m / z [M+H]+= 562.4,1H NMR (500 MHz, DMSO-d6): 6 (ppm) 11.00 (s, 1H), 7.7-7.5 (m, 1H), 7.5-7.3 (m, 5H), 7.3-7.2 (m, 4H), 7.2-7.0 (m, 2H), 5.2-5.1 (m, 1H), 4.7-4.5 (m, 1H), 4.5-4.1 (m, 2H), 4.0-3.4 (m, 2H), 3.1-2.6 (m, 3H), 2.5-2.1 (m, 4H), 2.1-1.6 (m, 6H), 1.5-1.0 (m, 3H).

[0992] EXAMPLE 9

[0993] (35)-3-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione

[0994]

[0995] Intermediate 9A: tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine- 1 -carbonyl]- l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0996]

[0997] (9A) In a sealed vial under argon, a solution of 4-[(2-chlorophenyl)-phenyl-methyl] piperidine (515 mg, 0.883 mmol), 2-[(LS')-4-te / 7-butoxy-l-carbamoyl-4-oxo-butyl]-l-oxo-isoindoline-5-carboxylic acid (388 mg, 1.06 mmol) and DIPEA (617 pL, 3.53 mmol) in dry EtOAc (8.5 mL) was stirred at ambient temperature. A solution of T3P in EtOAc (50% w / w, 788 pL, 1.32 mmol) was added and the mixture was stirred at ambient temperature for 16 h. A saturated aqueous solution of NaHCO3was added and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 1% to 100%. Fractions were combined and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l -carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a white foam (229 mg, 93% p., 38% y)). m / z [M+H]+= 630.5, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.71 (d, J= 7.8 Hz, 2H), 7.58 (d, J= 17.0 Hz, 2H), 7.45 (d, J= 7.8 Hz, 1H), 7.42-7.12 (m, 9H), 4.76-4.71 (m, 1H), 4.61 (d, J= 17.9 Hz, 1H), 4.47 (d, J= 17.6 Hz, 2H), 4.17 (d, J= 11.1 Hz, 1H), 3.51 (s, 1H), 3.01 (s, 1H), 2.77 (s, 1H), 2.68-2.56 (m, 1H), 2.21-2.10 (m, 3H), 2.05-1.93 (m, 1H), 1.64-1.36 (m, 2H), 1.31 (s, 10H), 1.07 (d, J= 7.0 Hz, 1H).

[0998] Intermediate 9B: tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl] piperidine- 1 -carbonyl]- l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[0999]

[1000] 7c / 7-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (223 mg) was purified by chiral supercritical chromatography (Waters Prep SFC200, Chiralpak AD (5 pm, 250 x 4.6 mm), CCh / iPrOH 70 / 30 as mobile phase, flow rate 2.4 mL / min, 104 bars) to afford (first isomer eluted) tert-butyl (45)-5-amino-4-[5-[4-[(7?)-(2-chlorophenyl)-phenyl-methyl] piperidine- 1 -carbonyl]- l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a white solid (110 mg, 85% p., 44% y., d.e. > 99.9%). m / z [M+H]+= 630.4,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.76-7.69 (m, 2H), 7.45 (d, J= 7.7 Hz, 1H), 7.42-7.13 (m, 9H), 4.73 (dd, J= 10.4, 4.0 Hz, 1H), 4.61 (d, J= 17.9 Hz, 1H), 4.47 (d, J= 17.6 Hz, 2H), 4.17 (d, J= 11.2 Hz, 1H), 3.51 (s, 1H), 3.01 (s, 1H), 2.61 (d, J= 11.2 Hz, 1H), 2.15 (d, J= 8.7 Hz, 3H), 1.99 (s, 3H), 1.46 (s, 2H), 1.31 (s, 9H), 1.27-1.20 (m, 2H), 1.09 (s, 1H).

[1001] Example 9

[1002] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[5-[4-[(7?)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (104 mg, 0.144 mmol) and 4-methylbenzenesulfonic acid hydrate (81.9 mg, 0.431 mmol) in acetonitrile (1.0 mL) was stirred at 85 °C for 16 h. A saturated aqueous solution of NaHCO3was added and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried through hydrophobic paper, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The desired fractions were concentrated under reduced pressure. The resulting solid was solubilized in the minimum amount of acetone and the homogenous solution was added dropwise to a stirred solution of / / -pentane. The mixture was stirred for 2 h. The resulting precipitate was filtered, washed with / / -pentane and dried under reduced pressure at 50 °C for 16 h to afford (35)-3-[5-[4-[(R)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid(34.0 mg, 97.6% p., 42% y.). m / z [M+H]+= 556.3, H NMR (500 MHz, DMSO-d6): δ (ppm) 10.99 (s, 1H), 7.75 (d, J= 7.8 Hz, 2H,), 7.61 (s, 1H), 7.49 (br d, J= 7.5 Hz, 1H), 7.4-6.9 (m, 8H), 5.12 (dd, J= 5.2, 13.3 Hz, 1H), 4.6-4.3 (m, 3H), 4.17 (br d, J= 11.4 Hz, 1H,), 3.6-3.4 (m, 1H), 3.1-3.0 (m, 1H), 3.0-2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.7-2.6 (m, 2H), 2.5-2.3 (m, 1H), 2.1-1.9 (m, 1H), 1.7-0.8 (m, 4H), [a]D= -28 “mL.dm’hg’1[20 °C, Na lamp, 589 nm, C = 1.0 mg / mL, DMSO],

[1003] EXAMPLE 10

[1004] (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-(difluoromethyl)-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione

[1005]

[1006] Intermediate 10A: tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-6-vinyl-isoindolin-2-yl]-5-oxo-pentanoate

[1007]

[1008] To a solution of 4-benzhydrylpiperidine (605.0 mg, 2.41 mmol), 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-6-vinyl-isoindoline-5-carboxylic acid (1.00 g, 2.29 mmol), and DIPEA (1.6 mL, 9.17 mmol) in dry EtOAc (22 mL) was stirred at ambient temperature. A solution of T3P in EtOAc (50% w / w, 2.1 mL, 3.44 mmol) was added and the mixture was stirred at ambient temperature for 23 h. A saturated aqueous solution of NaHCO3was added and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 1% to 100%. The fractions were combined and concentrated under reduced pressure to afford tert-butyl(45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-6-vinyl-isoindolin-2-yl]-5-oxo-pentanoate as a yellow foam (417 mg, 91% p., 27% y.). m / z [M+H]+= 622.5, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.94 (d, J= 8.6 Hz, 1H), 7.56 (s, 1H), 7.47-7.32 (m, 5H), 7.29 (t, J= 7.6 Hz, 2H), 7.23 (t, J= 7.6 Hz, 2H), 7.20-7.14 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 6.67 (ddd, J= 42.5, 17.4, 11.1 Hz, 1H), 5.98 (dd, J=21.8, 17.5 Hz, 1H), 5.41 (dd, J = 29.1, 11.2 Hz, 1H), 4.74 (d, J= 10.5 Hz, 1H), 4.65-4.40 (m, 3H), 3.61 (d, J = 11.1 Hz, 1H), 3.19 (d, J= 13.2 Hz, 1H), 2.94 (q, J= 12.6 Hz, 1H), 2.79 (t, J= 12.5 Hz, 1H), 2.51 (s, 2H), 2.20-2.09 (m, 3H), 2.05-1.92 (m, 1H), 1.55 (s, 1H), 1.35-1.27 (m, 9H), 1.14-0.92 (m, 2H).

[1009] Intermediate 10B: tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-formyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[1010]

[1011] In a sealed vial, to a stirred solution of tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-6-vinyl-isoindolin-2-yl]-5-oxo-pentanoate (417.0 mg, 0.610 mmol) in a mixture of THF (16 mL) and water (3.6 mL) were added successively 2,6-lutidine (141 pL, 1.22 mmol), NalCh (522 mg, 2.44 mmol), and a 15 M aqueous solution of OsC>4 (203 pL, 0.0305 mmol) at 0 °C. The mixture was allowed to warm up to ambient temperature and stirred for 16 h. The reaction was quenched with the addition of a saturated aqueous solution of Na2S2O5. EtOAc was added to the mixture. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting gum was solubilized in the minimum amount of DCM and the homogenous solution was added dropwise to a stirred solution of n-pentane. The mixture was stirred overnight. The resulting precipitate was filtered, washed with w-pentane, and dried under vacuum to afford tertebutyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-formyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a beige solid (393 mg, 90% p., 93% y.). m / z [M+H]+= 624.5, 'H NMR (400 MHz, DMSO-d6): 6 (ppm) 10.04 (s, 1H), 8.23 (s, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.43-7.39 (m, 2H), 7.37-7.33 (m, 2H), 7.29 (t, J= 7.6, 7.6 Hz, 2H), 7.22 (t, J= 7.6, 7.6 Hz, 3H), 7.19-7.14 (m, 1H), 7.10 (t, J= 7.4, 7.4 Hz, 1H), 4.78-4.66 (m, 2H), 4.58 (dd, J= 18.8, 4.0 Hz, 1H), 4.50 (d, J= 13.0 Hz, 1H), 3.60 (d, J= 11.2 Hz, 1H), 3.21 (d, J= 13.6 Hz, 1H), 2.94 (t, J = 12.7, 12.7 Hz, 1H), 2.81 (t, J= 12.3, 12.3 Hz, 1H), 2.54 (d, J= 11.0 Hz, 1H), 2.17 (dq, J = 10.7, 6.0, 6.0, 5.9 Hz, 3H), 1.99 (t, J= 9.3, 9.3 Hz, 1H), 1.56 (d, J= 13.0 Hz, 1H), 1.31 (d, J= 5.3 Hz, 9H), 1.24 (s, 1H), 1.17 (d, J= 12.7 Hz, 1H), 1.08-0.92 (m, 1H).

[1012] Intermediate 10C: tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-(difluoromethyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[1013]

[1014] In a sealed vial, to a stirred solution of tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-formyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (42.0 mg, 0.0606 mmol) in dry DCM (610 pL) at ambient temperature under argon was added DAST (101 pL, 0.727 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction was quenched with the addition of a saturated solution of NaHCO3. The mixture was extracted with DCM (2x). The combined organic layers were washed brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 1% to 100%. Fractions were combined and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-(difluoromethyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an off-white solid (27.0 mg, 86% p., 59% y.). m / z [M+H]+= 646.3.

[1015] Example 10

[1016] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-(difluoromethyl)-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (27.0 mg, 0.0417 mmol) and 4-methylbenzenesulfonic acid hydrate (23.9 mg,0.125 mmol) in acetonitrile (270 pL) was stirred at 70 °C for 16 h. The mixture was cooled to ambient temperature and poured into a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, filtered through hydrophobic paper, and concentrated. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. The desired fractions were concentrated under reduced pressure. The resulting gum was solubilized in the minimum amount of DCM and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The mixture was stirred for 2 h. The resulting precipitate was filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C for 16 h to afford (35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-(difluoromethyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid (5.5 mg, 90.9% p., 20% y.). m / z [M+H]+= 572.5,1H NMR (600 MHz, DMSO-d6): δ (ppm) 11.00 (s, 1H), 7.91 (s, 1H), 7.69-7.62 (m, 1H), 7.42-7.32 (m, 4H), 7.31-7.20 (m, 4H), 7.18-6.88 (m, 3H), 5.13 (dt, J = 13.20, 4.11 Hz, 1H), 4.79-4.14 (m, 3H), 3.60 (br d, J= 9.10 Hz, 1H), 3.28-2.71(m, 4H), 2.64-2.52 (m, 2H), 2.44-2.34 (m, 1H), 2.07-1.95 (m, 1H), 1.62-0.86 (m, 4H).

[1017] EXAMPLE 11

[1018] (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5JT- pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione

[1019]

[1020] Intermediate 11 A: tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl]-5-oxo-pentanoate

[1021]

[1022] To a solution of 4-[(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide (132 mg, 0.316 mmol) in DMF (3.2 mL), were added 6-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridine-3-carboxylic acid (115 mg, 0.316 mmol), a 0.5 M solution of HATU in DMF (948 pL, 0.474 mmol), and DIPEA (276 pL, 1.58 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Water was added and the aqueous layer was extracted with EtOAc (2x). The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 5% to 50%. The desired fractions were combined and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5JH-pyrrolo[3,4-Z>]pyri din-6-yl]-5-oxo-pentanoate as an off-white powder (131 mg, 97% p., 64% y.). m / z [M+H]+= 631.6,1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.70 (d, J= 1.9 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.47-7.08 (m, 9H), 4.77 (dd, J= 10.5, 4.0 Hz, 1H), 4.61 (d, J = 18.5 Hz, 1H), 4.49 (d, J= 18.5 Hz, 2H), 4.18 (d, J= 11.2 Hz, 1H), 3.50 (s, 1H), 3.07 (d, J = 14.3 Hz, 1H), 2.79 (d, J= 12.7 Hz, 1H), 2.71-2.56 (m, 1H), 2.24-2.12 (m, 3H), 2.04-1.92 (m, 1H), 1.53 (d, J = 44.6 Hz, 1H), 1.31 (s, 9H).

[1023] Example 11

[1024] In a sealed vial under argon, a solution of tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5H-pyrrolo[3,4-Z>]pyri din-6-yl]-5-oxo-pentanoate (131 mg, 0.201 mmol) in dry acetonitrile (1.2 mL) was stirred at ambient temperature. 4-Methylbenzenesulfonic acid hydrate (191 mg, 1.01 mmol) was added and the solution was stirred at 75 °C for 3 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and a saturated aqueous solution NaHCO3was added dropwise. Water was added and the mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse-phase preparative chromatography using a gradient of acetonitrile in water from 0% to 100% (0.1% AcOH). Desired fractions were combined, and acetonitrile was removed under reduced pressure. The suspension was filtered, washed with water and dried under reduced pressure at 50 °C for 16 h to afford (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-7-oxo-5JT-pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione as a white solid (22.7 mg, 98.7% p., 20% y.). m / z [M+H]+= 557.3,1H NMR (600 MHz, DMSO-d6): δ (ppm) 11.01 (s, 1H), 8.73 (s, 1H), 8.10 (br s, 1H), 7.84-7.66 (m, 1H), 7.46-7.07 (m, 8H), 5.16 (dd, J= 13.4, 5.1 Hz, 1H), 4.60-4.30 (m, 3H), 4.25-4.09 (m, 1H), 3.51 (ddd, J= 4.4, 2.4, 1.2 Hz, 1H), 3.18-2.98 (m, 1H), 2.90 (ddd, J= 17.5, 13.6, 5.4 Hz, 1H), 2.71-2.85 (m, 1H), 2.68-2.57 (m, 2H), 2.47-2.34 (m, 1H), 2.06-1.96 (m, 1H), 1.66-1.08 (m, 4H).

[1025] EXAMPLE 12

[1026] (35)-3-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l- oxo-isoindolin-2-yl]piperidine-2, 6-dione

[1027] O

[1028]

[1029] (12) Intermediate 12A: tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[1030]

[1031] (12A) To a stirred suspension of 2-[(15 -4-tertebutoxy-l-carbamoyl-4-oxo-butyl]-6-methyl-l-oxo-isoindoline-5-carboxylic acid (240 mg, 0.638 mmol) in EtOAc (6.0 mL) were added successively 4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide (290 mg, 0.701 mmol), DIPEA (557 pL, 3.19 mmol), and a solution of T3P in EtOAc (50% w / w, 759 pL, 1.28 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as alight orange solid (406 mg, 92% p. 91% y.). m / z [M+H]+= 644.3,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.71 (dd, J= 21.4, 7.9 Hz, 1H), 7.56 (d, J= 8.9 Hz, 2H), 7.51-7.09 (m, 10H), 4.72 (dd, J= 10.3, 3.9 Hz, 1H), 4.63-4.48 (m, 2H), 4.42 (d, J= 17.5 Hz, 1H), 4.15 (dd, J = 11.0, 7.4 Hz, 1H), 3.22 (t, J= 15.4 Hz, 1H), 2.97 (q, J= 13.5 Hz, 1H), 2.77 (t, J= 11.4 Hz, 1H), 2.59 (d, J= 11.5 Hz, 1H), 2.38-2.20 (m, 3H), 2.15 (t, J= 3.8 Hz, 3H), 1.97 (s, 1H), 1.68-1.45 (m, 1H), 1.45-1.26 (m, 10H), 1.12 (d, J= 7.5 Hz, 2H), [a]D=-11 “.mL.dm’hg’1[20 °C, Na lamp, 589 nm, C = 1.3 mg / mL, DMSO],

[1032] Example 12

[1033] To a stirred solution of tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (406 mg, 0.580 mmol) in acetonitrile (3.0 mL) at ambient temperature was added 4-methylbenzenesulfonic acid hydrate (551 mg, 2.90 mmol). The reaction mixture was stirred at 80 °C for 1 h. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. EtOAc was added to the mixture. The mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The resulting gum was solubilized in a minimum of acetone and added dropwise to a stirred solution of / / -pentane. The resulting precipitate was filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C for 12 h to afford (35)-3-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white powder (140 mg, 99.7% p.,42% y.). m / z [M+H]+= 570.3,1H NMR (500 MHz, DMSO-d6): δ (ppm) 10.97 (s, 1H), 7.80-7.66 (m, 1H), 7.61 (br d, J= 5.8 Hz, 1H), 7.52-7.11 (m, 9H), 5.15-5.05 (m, 1H), 4.60-4.48 (m, 1H), 4.48-4.24 (m, 2H), 4.19-4.12 (m, 1H), 3.31-3.17 (m, 1H), 3.04-2.86 (m, 2H), 2.83-2.72 (m, 1H), 2.66-2.55 (m, 2H), 2.43-2.30 (m, 2H), 2.25 (s, 2H), 2.07-1.91 (m, 1H), 1.71-0.90 (m, 4H), [a]D= -25 “.mL.dm3.g-1[20 °C, Na lamp, 589 nm, C = 1.2 mg / mL, DMSO],

[1034] EXAMPLE 13

[1035] (35)-3-[3-[4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-57 / -pyrrolo[3,4-A]pyridin-6-yl]piperidine-2, 6-dione

[1036]

[1037] Intermediate 13A: tert-butyl (45)-5-amino-4-[3-[4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl]-5-oxo-pentanoate

[1038]

[1039] To a stirred suspension of 6-[(LS')-4- / c77-butoxy-l-carbamoyl-4-oxo-butyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridine-3 -carboxylic acid (75.0 mg, 0.206 mmol) in EtOAc (2.1 mL) were added successively 4-[(R)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine hydroiodide (101 mg, 0.227 mmol), DIPEA (180 pL, 1.03 mmol), and then a solution of T3P in MeTHF (50% th, 197 mg, 0.310 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 2% to 100% to afford tert-butyl (45)-5-amino-4-[3-[4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate as an off-white solid (89.0 mg, 100% p., 65% y.). m / z [M+H]+= 661.3,1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.70 (s, 1H), 8.07 (s, 1H), 7.60 (s, 1H), 7.27 (qd, J = 26.3, 10.6 Hz, 8H), 6.95 (s, 1H), 4.77 (dd, J= 10.4, 3.9 Hz, 1H), 4.61 (d, J= 19.4 Hz, 1H), 4.49 (d, J= 18.2 Hz, 2H), 4.23 (d, J= 11.2 Hz,lH), 3.80 (d, J= 11.0 Hz, 3H), 3.49 (s, 1H), 3.07 (d, J= 13.1 Hz, 1H), 2.79 (d, J= 12.0 Hz, 1H), 2.59 (d, J= 11.3 Hz, 1H), 2.17 (d, J= 7.8 Hz, 3H), 1.99-1.95 (m, 1H), 1.70-0.97 (m, 13H).

[1040]

[1041] Example 13

[1042] To a stirred solution of tert-butyl (45)-5-amino-4-[3-[4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate (89.0 mg, 0.135 mmol) in acetonitrile (1.3 mL) was added 4-methylbenzenesulfonic acid hydrate (128 mg, 0.673 mmol). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of a EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in the minimum amount of DCM and the homogenous solution was added to / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (35 -3-[3-[4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>] pyridin-6-yl]piperidine-2, 6-dione as a white solid (39.6 mg, 100% p., 50% y.). m / z [M+H]+= 587.4,1H NMR (500 MHz, DMSO-d6): δ (ppm) 11.02 (s, 1H), 8.74 (s, 1H), 8.10 (br s, 1H), 7.37 (br d, J= 8.63 Hz, 2H), 7.34-7.23 (m, 4H), 7.23-7.09 (m, 1H), 6.97 (br d, J= 1.38 Hz, 1H), 5.17 (dd, J= 13.26, 5.13 Hz, 1H), 4.59-4.33 (m, 3H), 4.23 (br d, J = 10.76 Hz, 1H), 3.80 (br d, J= 14.13 Hz, 3H), 3.63-3.48 (m, 1H), 3.17-2.99 (m, 1H), 2.91 (ddd, J= 17.54, 13.60, 5.50 Hz, 1H), 2.86-2.72 (m, 1H), 2.69-2.56 (m, 2H), 2.43 (dd, J= 13.07, 4.69 Hz, 1H), 2.08-1.97 (m, 1H), 1.68-1.47 (m, 1H), 1.47-1.30 (m, 1H), 1.30- 1.20 (m, 1H), 1.19-1.06 (m, 1H).

[1043] EXAMPLE 14

[1044] (35)-3-[3-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7- oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione

[1045]

[1046] Intermediate 14A: tert-butyl (45)-5-amino-4-[3-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl]-5-oxo-pentanoate

[1047]

[1048] To a stirred suspension of 6-[(15 -4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridine-3 -carboxylic acid (75.0 mg, 0.206 mmol) in EtOAc (2.1 mL) were added successively 4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine hydroiodide (101 mg, 0.227 mmol), DIPEA (180 pL, 1.03 mmol), and then a solution of T3P in MeTHF (50% th, 197 mg, 0.310 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 2% to 100% to afford tert-butyl (45)-5-amino-4-[3-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate as an off-white solid (89.3 mg, 100% p., 65% y.). m / z [M+H]+= 661.4,1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.70 (s, 1H), 8.07 (s, 1H), 7.60 (s, 1H), 7.27 (dt, J = 38.6, 26.2 Hz, 8H), 6.96 (s, 1H), 4.83-4.70 (m, 1H), 4.61 (d, J= 18.1 Hz, 1H), 4.50 (d, J= 20.2 Hz, 2H), 4.23 (d, J= 11.1 Hz, 1H), 3.80 (d, J= 10.0 Hz, 3H), 3.50 (s, 1H), 3.07 (d, J= 15.3 Hz, 1H), 2.80 (s, 1H), 2.59 (d, J= 10.7 Hz, 1H), 2.19 (d, J= 2.5 Hz, 3H), 2.07-1.87 (m, 1H), 1.72-1.00 (m, 13H).Example 14

[1049] To a stirred solution of tert-butyl (45)-5-amino-4-[3-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate (89.0 mg, 0.135 mmol) in acetonitrile (1.3 mL) was added 4-methylbenzenesulfonic acid hydrate (128 mg, 0.673 mmol). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of a EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in the minimum amount of DCM and the homogenous solution was added to / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (35 -3-[3-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>] pyridin-6-yl]piperidine-2, 6-dione as a white solid (33.4 mg, 100% p., 42% y.). m / z [M+H]+= 587.4,1H NMR (500 MHz, DMSO-d6): δ (ppm) 11.02 (s, 1H), 8.74 (s, 1H), 8.11 (br s, 1H), 7.42-7.35 (m, 2H), 7.35-7.23 (m, 4H), 7.22-7.09 (m, 1H), 7.04-6.88 (m, 1H), 5.17 (dd, J= 13.3, 5.1 Hz, 1H), 4.59-4.34 (m, 3H), 4.31-4.12 (m, 1H), 3.89-3.73 (m, 3H), 3.62-3.45 (m, 1H), 3.19-2.99 (m, 1H), 2.91 (ddd, J= 17.5, 13.6, 5.3 Hz, 1H), 2.86-2.72 (m, 1H), 2.68-2.55 (m, 2H), 2.49-2.36 (m, 1H), 2.08-1.97 (m, 1H), 1.68-1.05 (m, 4H).

[1050] EXAMPLE 15

[1051] (35)-3-[3-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5JT- pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione

[1052]

[1053] Intermediate 15 A: tert-butyl (45)-5-amino-4-[3-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl]-5-oxo-pentanoate

[1054]

[1055] To a stirred solution of 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridine-3 -carboxylic acid (120 mg, 0.330 mmol) in EtOAc (1.6 mL) at ambient temperature were added a solution of T3P in EtOAc (50% w / w, 252 mg, 0.396 mmol), DIPEA (138 pL, 0.789 mmol), and 4-[(A)-(2-chlorophenyl)-phenyl-methyl] piperidine hydroiodide (167 mg, 0.363 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. EtOAc was added to the mixture. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100% to afford tert-butyl (45)-5-amino-4-[3-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate as a white solid (105 mg, 100% p.,50% y.). m / z [M+H]+= 631.4, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 8.70 (s, 1H), 8.08 (d, J= 1.8 Hz, 1H), 7.74 (m, 1H), 7.60 (s, 1H), 7.27 (m, 9H), 4.77 (dd, J= 10.5, 3.9 Hz, 1H), 4.61 (d, J= 18.5 Hz, 1H), 4.49 (d, J= 18.8 Hz, 2H), 4.17 (d, J = 11.1 Hz, 1H), 3.49 (s, 1H), 3.07 (d, J= 13.1 Hz, 1H), 2.77 (m, 1H), 2.64 (m, 1H), 2.17 (m, 3H), 1.98 (m, 1H), 1.53 (m, 1H), 1.31 (s, 9H), 1.17 (m, 3H).

[1056] Example 15

[1057] To a stirred solution of tert-butyl (45)-5-amino-4-[3-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate (105 mg, 0.166 mmol) in acetonitrile (1.1 mL) at ambient temperature was added 4-methylbenzenesulfonic acid hydrate (63.3 mg, 0.333 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to ambient temperature and diluted with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine,dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of a EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in a minimum amount of acetone and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (3A)-3-[3-[4-[(R)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyri din-6-yl]piperidine-2, 6-dione as a white powder (6.0 mg, 99.3% p., 6% y.). m / z [M+H]+= 557.4, 'H NMR (500 MHz, DMSO-d6): δ (ppm) 11.02 (s, 1H), 8.74 (s, 1H), 8.11 (br s, 1H), 7.8-7.7 (m, 1H), 7.6-6.9 (m, 8H), 5.17 (dd, J= 13.3, 5.1 Hz, 1H), 4.8-4.3 (m, 3H), 4.18 (br dd, J= 9.6-1.5 Hz, 1H), 3.7-3.4 (m, 1H), 3.2-3.0 (m, 1H), 3.0-2.7 (m, 2H), 2.7-2.6 (m, 2H), 2.43 (br dd, J= 13.1, 4.6 Hz, 1H), 2.1-1.9 (m, 1H), 1.8-0.9 (m, 4H).

[1058] EXAMPLE 16

[1059] (35)-3-[3-[4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5JT- pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione

[1060]

[1061] Intermediate 16 A: tert-butyl (45)-5-amino-4-[3-[4-[(5)-(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl]-5-oxo-pentanoate

[1062]

[1063] To a stirred solution of 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-7-oxo- 5 J / -pyrrolo[3,4-Z>]pyridine-3 -carboxylic acid (120 mg, 0.330 mmol) in EtOAc (1.6 mL) at ambient temperature were added a solution of T3P in EtOAc (50% w / w, 252 mg, 0.396 mmol), DIPEA (138 pL, 0.789 mmol), and 4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide (167 mg, 0.363 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was cooled to ambient temperature and diluted with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of a EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in a minimum amount of acetone and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / -pentane, and dried under reduced pressure at 50 °C overnight to afford tert-butyl (45)-5-amino-4-[3-[4-[(5)-(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-7-oxo-5JT-pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate as a white solid (87.5 mg, 98%p., 41% y.). m / z [M+H]+= 631.4,1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.70 (d, J= 1.8 Hz, 1H), 8.08 (s, 1H), 7.75 (m, 1H), 7.60 (s, 1H), 7.29 (m, 9H), 4.78 (m, 1H), 4.61 (m, 1H), 4.49 (m, 2H), 4.17 (d, J= 11.1 Hz, 1H), 3.50 (m, 1H), 3.07 (m, 1H), 2.79 (m, 1H), 2.64 (m, 1H), 2.18 (m, 3H), 1.99 (m, 1H), 1.59 (m, 1H), 1.39 (m, 1H), 1.31 (s, 9H), 1.18 (m, 2H).

[1064] Example 16

[1065] To a stirred solution of tert-butyl (45)-5-amino-4-[3-[4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate (89.3 mg, 0.139 mmol) in acetonitrile (1.0 mL) at ambient temperature was added 4-methylbenzenesulfonic acid hydrate (52.7 mg, 0.277 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to ambient temperature and diluted with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of a EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in a minimum amount of acetone and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (35 -3-[3-[4-[(5)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione as a white powder (6.9 mg, 98.8% p., 9% y.). m / z [M+H]+= 557.3,1H NMR (600 MHz, DMSO-d6): δ (ppm) 11.01 (s, 1H), 8.73 (s, 1H), 8.10 (br s, 1H), 7.77-7.70 (m, 1H), 7.40-7.34 (m, 3H), 7.34-7.24 (m, 3H), 7.24-7.13 (m, 2H), 5.16 (dd, J= 13.4, 5.1 Hz, 1H), 4.54-4.45 (m, 2H), 4.43-4.36 (m, 1H), 4.18 (br d, J= 10.3 Hz, 1H), 3.51 (br s, 1H), 3.13-3.00 (m, 1H), 2.90 (ddd, J= 17.4, 13.6, 5.5 Hz, 1H), 2.85-2.75 (m, 1H), 2.66-2.57 (m, 2H), 2.46-2.38 (m, 1H), 2.04-1.98 (m, 1H), 1.65-1.28 (m, 2H), 1.26-1.11 (m, 2H).

[1066] EXAMPLE 17

[1067] (3A)-3-[5-[4-[(R)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l- oxo-isoindolin-2-yl]piperidine-2, 6-dione

[1068] O

[1069]

[1070] (17) Intermediate 17 A: tert-butyl (4A)-5-amino-4-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[1071]

[1072] (17A) In a vial under nitrogen were successively charged 2-[(lA)-4-te / 7-butoxy-l-carbamoyl-4-oxo-butyl]-6-methyl-l-oxo-isoindoline-5-carboxylic acid (393 mg, 1.04 mmol) and 4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide (450 mg, 1.07 mmol) in dry DCM (4.3 mL). The mixture was cooled down to 0 °C. DIPEA (931 pL, 5.33 mmol) and a solution of T3P in DCM (53% w / w, 960 mg, 1.60 mmol) were added dropwise. The mixture was allowed to warm up to ambient temperature and was stirred for 45 min. After completion, the reaction was quenched with the addition of a saturated aqueous solution of NH4Cl at 0 °C. Next, DCM was added. The aqueous layer was extracted with DCM. The combined organic layers were washed with a saturated aqueoussolution of NH4Cl, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 50%. Fractions were concentrated under reduced pressure to afford te / 7-butyl (4A)-5-amino-4-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl] piperidine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a white solid (565 mg, 99% p., 81% y.). m / z = [M+H]+644.5, 'H NMR (400 MHz, DMSO-d6): δ (ppm) 7.77-7.66 (m, 1H), 7.56 (t, J= 6.3 Hz, 2H), 7.48-7.07 (m, 10H), 4.75-4.68 (m, 1H), 4.54 (d, J= 15.4 Hz, 2H), 4.42 (dd, J= 17.2, 7.4 Hz, 1H), 4.19-4.11 (m, 1H), 3.20 (d, J= 17.5 Hz, 1H), 2.98 (q, J= 13.5 Hz, 1H), 2.82-2.71 (m, 1H), 2.59 (d, J= 12.1 Hz, 1H), 2.33 (d, J= 4.1 Hz, 1H), 2.24 (s, 3H), 2.17-2.09 (m, 3H), 1.97 (t, J = 7.5 Hz, 1H), 1.66-1.43 (m, 1H), 1.36-1.24 (m, 10H), 1.11 (t, J= 11.8 Hz, 2H).

[1073] Example 17

[1074] To a stirred solution of tert-butyl (4A)-5-amino-4-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (513 mg, 0.788 mmol) in acetonitrile (5.4 mL) was added 4-methylbenzenesulfonic acid hydrate (375 mg, 1.97 mmol). The reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was cooled to ambient temperature. A saturated aqueous solution of NaHCO3and iPrOAc, were added to the reaction mixture. The layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCO3(3x), with a saturated aqueous solution ofNH Cl, brine, dried overNa2SO4, filtered, and concentrated under reduced pressure. The crude was co-evaporated with acetonitrile (2x) and was concentrated under reduced pressure to afford (3A)-3-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid (369 mg, 95% p., 78% y.). m / z [M+H]+= 570.4,1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.97 (s, 1H), 7.71 (d, J= 18.2 Hz, 1H), 7.60 (s, 1H), 7.50-7.11 (m, 9H), 5.08 (s, 1H), 4.64-4.36 (m, 2H), 4.30 (d, J= 16.9 Hz, 1H), 4.14 (d, J= 11.1Hz, 1H), 3.22 (s, 1H), 3.06-2.83 (m, 2H), 2.76 (s, 1H), 2.59 (d, J= 15.5 Hz, 2H), 2.34 (s, 2H), 2.25 (s, 2H), 1.99 (s, 1H), 1.60 (s, 2H), 1.14 (s, 2H).

[1075] EXAMPLE 18

[1076] (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione

[1077]

[1078] Intermediate 18 A: tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-2-methyl-7-oxo-5H-pyrrolo[3,4-b]pyridin-6-yl]-5-oxo-pentanoate

[1079]

[1080] To a stirred suspension of 6-[(15)-4-tert-butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyridine-3-carboxylic acid (52.0 mg, 0.138 mmol) in EtOAc (689 pL) were added successively 4-[(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide (59.9 mg, 0.145 mmol), DIPEA (120 pL, 0.689 mmol), and then a solution of T3P in MeTHF (50% th, 132 mg, 0.207 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 2% to 100% to afford tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate as a white solid (22.8 mg, 94% p., 24% y.). m / z [M+H]+= 645.3.

[1081] Example 18

[1082] To a stirred solution of tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyridin-6-yl]-5-oxo-pentanoate (22.5 mg, 0.0349 mmol) in acetonitrile (349 pL) was added 4-methylbenzenesulfonic acid hydrate (33.2 mg, 0.174 mmol). The reaction mixture wasstirred at 80 °C for 4 h. The reaction mixture was cooled to ambient temperature. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by reverse-phase preparative chromatography using a gradient of acetonitrile in water from 0% to 100% (0.1% AcOH). The desired fractions were concentrated under reduced pressure. The residue was basified with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was solubilized in the minimum amount of DCM and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>] pyridin-6-yl] piperidine-2, 6-dione as a white solid (8.0 mg, 98.6% p., 40% y.). m / z [M+H]+= 571.3, 'H NMR (600 MHz, DMSO-d6): δ (ppm) 11.00 (br s, 1H), 8.01-7.82 (m, 1H), 7.78-7.64 (m, 1H), 7.42-7.10 (m, 8H), 5.19-5.10 (m, 1H), 4.60-4.25 (m, 3H), 4.15 (s, 1H), 3.29-2.72 (m, 4H), 2.65-2.52 (m, 3H), 2.45 (br s, 3H), 2.08-1.91 (m, 1H), 1.73-0.90 (m, 4H).

[1083] EXAMPLE 19

[1084] (35)-3-[5-[4-[(7?)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6- methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione

[1085]

[1086] Intermediate 19A: tert-butyl (45)-5-amino-4-[5-[4-[(7?)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[1087]

[1088] To a stirred suspension of 4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl] piperidine hydroiodide (158 mg, 0.338 mmol) in EtOAc (2.1 mL) were added successively 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-methyl-1-oxo-isoindoline-5-carboxylic acid (125.0 mg, 0.327 mmol, DIPEA (295 pL, 1.69 mmol), and then a solution of T3P in EtOAc (50% w / w, 151 pL, 0.507 mmol). The reaction mixture was stirred at ambient temperature overnight. Additional solution of T3P in EtOAc (50% w / w, 151 pL, 0.507 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with the addition of water. FastWorX® powder was added. The organic solvent was evaporated under reduced pressure. Then, the reaction mixture was filtered through a loading cartridge and washed with an aqueous solution of NaHCO3and brine. The loading cartridge was flushed with nitrogen for 5 min and then loaded on a flash column chromatography. The crude was purified using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. Fractions were concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chl oro-3 -methoxy-phenyl)-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl- 1-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an off-white solid (146 mg, 97% p., 62% y.). m / z [M+H]+= 674.3. [a]o = +10 °.mL.dm'1.g'1[20 °C, Na lamp, 589 nm, C = 1.9 mg / mL, MeOH],

[1089] Example 19

[1090] To a stirred solution of tert-butyl (45)-5-amino-4-[5-[4-[(A)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (150 mg, 0.216 mmol) in acetonitrile (1.5 mL) at ambient temperature was added 4-methylbenzenesulfonic acid hydrate (123 mg, 0.649 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to ambient temperature and diluted with water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentratedunder reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in a minimum amount of DCM and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (35)-3-[5-[4-[(R)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione as a white powder (48.6 mg, 99.8% p., 37% y.). m / z [M+H]+= 600.3, 'H NMR (500 MHz, DMSO-d6): δ (ppm) 10.97 (s, 1H), 7.65-7.56 (m, 1H), 7.52-7.21 (m, 7H), 7.21-7.09 (m, 1H), 7.02-6.87 (m, 1H), 5.16-5.04 (m, 1H), 4.57-4.16 (m, 4H), 3.84-3.75 (m, 3H), 3.26 (br d, J= 10.3 Hz, 1H), 3.07-2.68 (m, 3H), 2.65-2.54 (m, 2H), 2.44-2.20 (m, 4H), 2.06-1.93 (m, 1H), 1.74-0.82 (m, 4H).

[1091] EXAMPLE 20

[1092] (35)-3-[5-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6- methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione

[1093] O

[1094]

[1095] (20) Intermediate 20A: tert-butyl (45)-5-amino-4-[5-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[1096]

[1097] (20A) To a stirred suspension of 4-[(A)-(2-chl oro-3 -methoxy -phenyl)-phenyl-methyl] piperidine hydroiodide (150 mg, 0.338 mmol) in EtOAc (2.1 mL) were added successively 2-[(15)-4-te / 7-butoxy-l-carbamoyl-4-oxo-butyl]-6-methyl-l-oxo-isoindoline-5-carboxylic acid (127 mg, 0.338 mmol), DIPEA (295 pL, 1.69 mmol), andthen a solution of T3P in EtOAc (50% w / w, 151 pL, 0.507 mmol). The reaction mixture was stirred at ambient temperature overnight. Additional solution of T3P in EtOAc (50% w / w, 151 pL, 0.507 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with the addition of water. FastWorX® powder was added. The organic solvent was evaporated under reduced pressure. Then, the reaction mixture was filtered through a loading cartridge and washed with an aqueous solution of NaHCO3and brine. The loading cartridge was flushed with nitrogen for 5 min and then loaded on a flash column chromatography. The crude was purified using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 0% to 100%. Select fractions were concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-[4-[(5)-(2-chl oro-3 -methoxy-phenyl)-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl- 1-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an off-white solid (108 mg, 92% p., 44% y.). m / z [M+H]+= 674.4. [a]o = -38o.mL.dm-1.g'1[20 °C, Na lamp, 589 nm, C = 1.8 mg / mL, MeOH],

[1098] Example 20

[1099] To a stirred solution of tert-butyl (45)-5-amino-4-[5-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (108 mg, 0.160 mmol) in acetonitrile (1.1 mL) at ambient temperature was added 4-methylbenzenesulfonic acid hydrate (91.3 mg, 0.480 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to ambient temperature and diluted with water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of a EtOAc / EtOH (3 / 1) in cyclohexane from 10% to 100%. The residue was solubilized in a minimum amount of DCM and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (35)-3-[5-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white powder (28.3 mg, 99.8% p., 29% y.). m / z [M+H]+= 600.3, 'H NMR (500 MHz, DMSO-d6): δ (ppm) 10.97 (s, 1H), 7.65-7.57 (m, 1H), 7.50-7.10 (m, 8H), 7.01-6.86 (m, 1H),5.17-5.03 (m, 1H), 4.58-4.48 (m, 1H), 4.48-4.36 (m, 1H), 4.36-4.16 (m, 2H), 3.86-3.74 (m, 3H), 3.29-3.13 (m, 1H), 3.06-2.84 (m, 2H), 2.83-2.70 (m, 1H), 2.65-2.54 (m, 2H), 2.47-2.22 (m, 4H), 2.05-1.92 (m, 1H), 1.69-0.85 (m, 4H).

[1100] EXAMPLE 21

[1101] (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo- 5J / -pyrrolo[3,4-Z>]pyrazin-6-yl]piperidine-2, 6-dione

[1102]

[1103] Intermediate 21 A: tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine-l-carbonyl]-2-methyl-7-oxo-5H-pyrrolo[3,4-b]pyrazin-6-yl]-5-oxo-pentanoate

[1104]

[1105] To a solution of 4-[(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide (70.0 mg, 0.169 mmol) in DMF (1.7 mL) were added 6-[(15)-4-ter / -butoxy-l-carbamoyl-4-oxo-butyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyrazine-3-carboxylic acid (64 mg, 0.169 mmol), HATU (99.5 mg, 0.254 mmol), and DIPEA (148 pL, 0.846 mmol). The mixture was stirred at ambient temperature for 16 h. Water was added and the aqueous layer was extracted with EtOAc (2x). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc / EtOH (3 / 1) in n-heptane from 5% to 50%. The desired fractions were combined, concentrated under reduced pressure, and dried under reduced pressure to afford tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyrazin-6-yl]-5-oxo-pentanoate as an off-white powder (91.0 mg, 97% p., 81% y.). m / z [M+Na]+= 668.4,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.78-7.67 (m, 1H), 7.56 (s, 1H), 7.44-7.27 (m, 5H),7.26-7.13 (m, 3H), 4.89-4.74 (m, 1H), 4.57-4.46 (m, 3H), 4.17 (d, J= 11.2 Hz, 1H), 3.26 (d, J= 2.9 Hz, 1H), 3.03 (q, J= 13.2 Hz, 1H), 2.86 (q, J= 12.0 Hz, 1H), 2.63 (d, J= 11.4 Hz, 1H), 2.58-2.54 (m, 3H), 2.38-2.11 (m, 3H), 2.11-1.88 (m, 1H), 1.59 (dd, J= 38.6, 13.0 Hz, 1H), 1.38 (d, J = 13.1 Hz, 1H), 1.35-1.31 (m, 9H), 1.31-1.22 (m, 1H), 1.15 (dd, J = 28.0, 14.4 Hz, 2H).

[1106] Example 21

[1107] In a sealed vial, a solution of tert-butyl (45)-5-amino-4-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5Z7-pyrrolo[3,4-Z>]pyrazin-6-yl]-5-oxo-pentanoate (90.0 mg, 0.135 mmol) and 4-methylbenzenesulfonic acid hydrate (128 mg, 0.676 mmol) in acetonitrile (2.0 mL) was stirred at 70 °C for 7 h. The mixture was cooled to ambient temperature and poured into a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude was purified by flash column chromatography on silica gel using a gradient of EtOH in DCM from 0% to 5%. The desired fractions were concentrated under reduced pressure. The resulting residue was solubilized in a minimum amount of DCM and a large excess of / / -pentane was added. The resulting suspension was filtered, washed with / / -pentane, and dried under reduced pressure at 40 °C for 16 h to afford (35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5J / -pyrrolo[3,4-Z>]pyrazin-6-yl]piperidine-2, 6-dione as a white powder (41.8 mg, 97.5% p., 53% y.). m / z [M+H]+= 572.3, 'H NMR (600 MHz, DMSO-d6): δ (ppm) 11.03 (s, 1H), 7.81-7.62 (m, 1H), 7.43-7.37 (m, 2H), 7.37-7.32 (m, 2H), 7.32-7.24 (m, 2H), 7.24-7.18 (m, 1H), 7.18-7.11 (m, 1H), 5.30-5.14 (m, 1H), 4.58-4.53 (m, 1H), 4.53-4.46 (m, 1H), 4.45-4.38 (m, 1H), 4.17 (dd, J= 11.30, 2.64 Hz, 1H), 3.36-3.31 (m, 1H), 3.08-2.96 (m, 1H), 2.96-2.89 (m, 1H), 2.88-2.78 (m, 1H), 2.69-2.63 (m, 1H), 2.62-2.58 (m, 1H), 2.57 (dd, J= 2.93, 1.91 Hz, 3H), 2.44 (br dd, J= 13.13, 4.33 Hz, 1H), 2.07-1.97 (m, 1H), 1.70-1.50 (m, 1H), 1.44-1.26 (m, 1H), 1.22- 1.10 (m, 1H), 1.10-0.99 (m, 1H).

[1108] EXAMPLE 22

[1109] (35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6- [(dimethylamino)methyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione

[1110]

[1111] Intermediate 22A: tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl] piperidine- l-carbonyl]-6-[(dimethylamino)methyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate

[1112]

[1113] To a stirred suspension of acetic acid 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-[(dimethylamino)methyl]-1-oxo-isoindoline-5-carboxylic acid (23.0 mg, 0.0480 mmol) in EtOAc (238 pL) and DCM (48 pL) were added successively DIPEA (83.8 pL, 0.480 mmol), 4-[(2-chlorophenyl)-phenyl-methyl]piperidine hydroiodide (59.5 mg, 0.144 mmol), and then a solution of T3P in MeTHF (50% w / w, 76.3 mg, 0.120 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the addition of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by reverse-phase preparative chromatography using a gradient of acetonitrile in water from 0% to 100% (0.1% AcOH). Acetonitrile was removed under reduced pressure. The aqueous layer was basified with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-[(dimethylamino)methyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate as an orange gum (42.3 mg, 29% p., 37% y.). m / z [M+H]+= 687.3.Example 22

[1114] To a stirred solution of tert-butyl (45)-5-amino-4-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-[(dimethylamino)methyl]-l-oxo-isoindolin-2-yl]-5-oxo-pentanoate (42.3 mg, 0.0615 mmol) in acetonitrile (620 pL) was added 4-methylbenzenesulfonic acid hydrate (58.5 mg, 0.308 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using a gradient of EtOH in DCM from 0% to 20%. The residue was solubilized in the minimum amount of DCM and the homogenous solution was added to a stirred solution of / / -pentane dropwise. The resulting precipitate was triturated for 1 h, filtered, washed with / / -pentane, and dried under reduced pressure at 50 °C overnight to afford (35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-[(dimethylamino)methyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione as a white solid (1.1 mg, 99.4% p., 3% y.). m / z [M+H]+= 613.3, 'H NMR (600 MHz, DMSO-d6): δ (ppm) 10.97 (d, J= 3.8 Hz, 1H), 7.8-7.6 (m, 2H), 7.5-7.0 (m, 9H), 5.2-5.0 (m, 1H), 4.6-4.4 (m, 2H), 4.4-4.3 (m, 1H), 4.2-4.0 (m, 1H), 3.9-3.5 (m, 1H), 3.3-3.0 (m, 2H), 3.0-2.5 (m, 5H), 2.4-2.3 (m, 1H), 2.2-2.1 (m, 6H), 2.0-1.9 (m, 1H), 1.7-1.0 (m, 4H).

[1115] EXAMPLE 23

[1116] [2-chloro-3-[[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l-oxo-isoindoline-5-carbonyl]- 4-piperidyl]-phenyl-methyl]phenyl]boronic acid

[1117] OH

[1118]

[1119] Intermediate 23 A: benzyl 4-[[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl]-phenyl-methyl]piperidine-l -carboxylate

[1120]

[1121] To a stirred solution of benzyl 4-[(3-bromo-2-chloro-phenyl)-phenyl-methyl] piperidine- 1 -carboxylate (1.00 g, 1.86 mmol) in 1,4-dioxane (10 mL) at ambient temperature was added B2pin2 (531 mg, 2.05 mmol) and KO Ac (549 mg, 5.59 mmol). The reaction mixture was degassed with argon for 15 min and Pd(dppf)C12 (140 mg, 0.186 mmol) was added. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through a pad of talc and washed with EtOAc. A saturated aqueous solution of NH4Cl was added to the filtrate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried using hydrophobic paper, and concentrated under reduced pressure to afford benzyl 4-[[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-phenyl-methyl] piperidine- 1 -carboxylate as a brown gum (1.36 g, 80% p., quant, yield)), m / z [M+Na]+= 568.3,1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.78 (dd, J= 7.7, 1.9 Hz, 1H), 7.41-7.23 (m, 11H), 7.21-7.11 (m, 1H), 5.05 (s, 2H), 4.24-4.15 (m, 1H), 3.97 (d, J= 13.3 Hz, 2H), 2.77 (m, 2H) 2.49 (s, 1H), 1.53-1.32 (m, 2H), 1.28 (s, 6H), 1.07 (s, 6H), 1.04-0.90 (m, 2H).

[1122] Intermediate 23B: 4-[[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-phenyl-methyl]piperidine hydroiodide

[1123] CH3

[1124] 1 Al 6J^CH3

[1125] Q H^CH3

[1126]

[1127] H Hl(23B)

[1128] A round-bottom flask was charged with a suspension of benzyl 4-[[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-phenyl-methyl]piperidine-l-carboxylate (200 mg, 0.293 mmol) in dry acetonitrile (3.7 mL) at ambient temperature under nitrogen. Iodo(trimethyl)silane (125 pL, 0.879 mmol) was added dropwise. Themixture was stirred at ambient temperature for 1 h. The mixture was cooled to 0 °C and MeOH (142 pL, 3.52 mmol) was added dropwise. The mixture was stirred at ambient...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):O Oor stereoisomers, tautomers, or salts thereof, wherein:(i) X is CR2and Y is CR4;(ii) X is CR2and Y is N;(iii) X is N and Y is N;Ri is hydrogen or -CH3;R2is hydrogen or -CH3;R3is hydrogen, F, -CH3, -CHF2, or -CH2N(CH3)2;R4is hydrogen;wherein:(i) Rsa, R5b, and Rsc are each hydrogen;(ii) Rsa and Rsb are joined together to form -CH2CH2- or -CH2OCH2-, and Rsc is hydrogen; or(iii) Rsa and Rsc are joined together to form -CH2-, and Rsb is hydrogen;Ring A is:R6c(ii) indazolyl, indolinyl, dihydrobenzofuranyl, dihydrobenzoxazinyl, tetrahydroquinolinyl, tetrahydrobenzazepinyl, or tetrahydrobenzooxazepinyl;Ring B is phenyl,isothiazolyl,R6ais hydrogen, Cl, or Br;Reb is hydrogen, -OH, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OH, -OCH2CH2OCH3, -OCF3, -OCH2CH2F, -OCH2CH2NH2, -OCH2CH2NH(CH3), -OCH2CH2N(CH3)2, -OCH2CH2CH2NH2, -OCH2CH2CH2N(CH3)2, -OCH2CHFCH2NH2, -OCH2CF2CH2NH2, -OCH(CH3)CH2NH2, -OCH2CH(CH(CH3)2)NH2, -OCH2CH(CH3)NH2, -OCH2CH(CH2CH3)NH2, -OCH2CH(CHF2)NH2, -OCH2CH(CF3)NH2, -OCH2CH(CH2CHF2)NH2, -OCH2CH2NHC(O)CH3, -B(OH)2, -CH2CH2N(CH3)2, -NH(CH3), -N(CH3)2, -NH(CH2CH2OH), -NH(CH2CH2NH2), -NH(aminocyclobutyl), -NHC(O)CH3, -NHC(O)CH2OH, -O(cyclopropyl), -O(cyclobutyl), -O(aminocyclopentyl), -O(methylazetidinyl), -O(methyl pyrrolidinyl), -O(fluoroethyl pyrrolidinyl), -O(trifluoroethyl pyrrolidinyl), -O(methyl azaspiro[3.3]heptanyl), -OCH2(aminocyclopropyl), -OCH2(imidazolyl), -OCH2(methyl imidazolyl), -OCH2(isoxazolyl), -OCH2(oxazolyl), -OCH2(methyl pyrrolidinyl), -OCH2CH2(pyrrolidinyl), morpholinyl, oxazolyl, aminopyrrolidinyl, hydroxypyrrolidinyl, or dihydroimidazo[1,5-a]pyrazinyl;Rec is hydrogen or F; andR7 is hydrogen or deuterium.

2. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, having the structure:

3. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, having the structure:O O4. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, having the structure:O O5. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, wherein R3 is -CH3.

6. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof,R6cX^Rebwherein Ring Ais » / wwx7. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, wherein Ring B is phenyl.

8. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, wherein R5a, R5b, and R5care each hydrogen.

9. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, wherein:R6cRing Ais » / wwxRing B is phenyl;R3is -CH3;R5a, R5b, and R5care each hydrogen; andR6ais Cl.

10. The compound according to claim 1 or stereoisomers, tautomers, or salts thereof, wherein said compound is:(35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (1);(35)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-methyl-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione (2);(35)-3-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (3);(35)-3-[5-(7-benzhydryl-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (4);(35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (5);(35)-3-[5-[(lA,4A)-5-benzhydryl-2-azabicyclo[2.2.1]heptane-2-carbonyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (6);(35)-3-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (7);(35)-3-[5-[(lA,55)-3-benzhydryl-8-azabicyclo[3.2.1]octane-8-carbonyl]-4-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (8);(35)-3-[5-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (9);(3S)-3-[5-(4-benzhydrylpiperidine-l-carbonyl)-6-(difluoromethyl)-l-oxo-isoindolin-2-yl] piperidine-2, 6-dione (10);(35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5Z7-pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (11);(35)-3-[5-[4-[(7?)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (12);(35)-3-[3-[4-[(7?)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5 / / -pyrrolo[3,4-A]pyridin-6-yl]piperidine-2, 6-dione (13);(35)-3-[3-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5 / / -pyrrolo[3,4-A]pyridin-6-yl]piperidine-2, 6-dione (14);(3A')-3-[3-[4-[( / )-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5 / / -pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (15);(3A')-3-[3-[4-[CS')-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-7-oxo-5 / / -pyrrolo[3,4-Z>]pyridin-6-yl]piperidine-2, 6-dione (16);(37?)-3-[5-[4-[(R)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (17);(35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5 / / -pyrrolo[3,4-A]pyridin-6-yl]piperidine-2, 6-dione (18);(35)-3-[5-[4-[(R)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (19);(35)-3-[5-[4-[(5)-(2-chloro-3-methoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (20);(35)-3-[3-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-2-methyl-7-oxo-5 / / -pyrrolo[3,4-A]pyrazin-6-yl]piperidine-2, 6-dione (21);(35)-3-[5-[4-[(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-[(dimethylamino)methyl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (22);[2-chloro-3-[[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l-oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenyl]boronic acid (23);(35)-3-[5-[4-[(5)-[2-chloro-3-[2-(dimethylamino)ethoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (24);(35)-3-[5-[4-[(5)-[2-chloro-3-(2 -hydroxy ethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (25);(35)-3-[5-[4-[(7?)-[2-chloro-3-[2-(dimethylamino)ethoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (26);(35)-3-[5-[4-[[2-chloro-3-(methylamino)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (27);(35)-3-[5-[4-[[2-chloro-3-(dimethylamino)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (28);(35)-3-[5-[4-[(7?)-(2-chloro-3-hydroxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (29);(35)-3-[5-[4-[(2-chloro-3-oxazol-2-yl-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (30);(35)-3-[5-[4-[(R)-[2-chloro-3-(2 -hydroxy ethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (31);(35)-3-[5-[4-[(2-chlorophenyl)-isothiazol-5-yl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (32);(35 -3-[5-[4-[(5 -[2-chloro-3-[(37?)-l-methylpyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (33);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(35)-l-methylpyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (34);((3S)-3-[5-[4-[(S)-[2-chloro-3-[(3S)-1-methylpyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl] piperidine-1-carbonyl]-6-methyl-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (35);7V-[2-chloro-3-[[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l-oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenyl]acetamide (36);(35)-3-[5-[4-[(5)-[2-chloro-3-[[(37?)-l-methylpyrrolidin-3-yl]methoxy]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (37);(35)-3-[5-[4-[(5)-[2-chloro-3-[3-(dimethylamino)propoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (38);(35)-3-[5-[4-[[2-chloro-3-[2-(dimethylamino)ethyl]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (39);(35)-3-[5-[4-[(5)-[2-chloro-3-[(3-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (40);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(3-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (41);(35)-3-[5-[4-[(7?)-[2-chloro-3-(l-methylazetidin-3-yl)oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (42);(35)-3-[5-[4-[(5)-[2-chloro-3-[(l-methylimidazol-2-yl)methoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (43);(3S)-3-[5-[4-[(S)-[2-chloro-3-[(1-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl] piperidine-1-carbonyl]-6-methyl-1-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (44);(35)-3-[5-[4-[(7?)-[2-chloro-3-[2-(methylamino)ethoxy]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (45);(35)-3-[5-[4-[(7?)-[3-(2-aminoethoxy)-2-chloro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (46);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(l-methylimidazol-2-yl)methoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (47);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(l-methylimidazol-4-yl)methoxy]phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (48);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy]phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (49);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(35)-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (50);(3S)-3-[5-[4-[(R)-(2-chloro-3-isopropoxy-phenyl)-phenyl-methyl]piperidine-1-carbonyl]-6-methyl-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (51);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (52);(35)-3-[5-[4-[(5)-[2-chloro-3-(6,8-dihydro-5H-imidazo[l,5-a]pyrazin-7-yl)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (53);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-l-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione (54);(35)-3-[5-[4-[(7?)-[2-chloro-3-(cyclobutoxy)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (55);7V-[2-chloro-3-[[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l-oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenyl]-2-hydroxy-acetamide (56);7V-[2-[2-chloro-3-[(R)-[l-[2-[(35)-2,6-dioxo-3-piperidyl]-6-methyl-l -oxo-isoindoline-5-carbonyl]-4-piperidyl]-phenyl-methyl]phenoxy]ethyl]acetamide (57);(35)-3-[5-[4-[(7?)-[3-[(15',3< S)-3-aminocyclopentoxy]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (58);(35)-3 - [5 - [4-[( / )-[3 - [(25)-2-amino-3, 3 -difluoro-propoxy ] -2-chloro-phenyl ]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (59);(35)-3-[5-[4-[(7?)-[2-chloro-3-(2-methoxy ethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (60);(35)-3-[5-[4-[(7?)-[3-(3-aminopropoxy)-2-chloro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (61);(35)-3-[5-[4-[(7?)-[3-[(25)-2-amino-3-methyl-butoxy]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (62);(35)-3-[5-[4-[indolin-4-yl(phenyl)methyl]piperi dine-l-carbonyl]-6-methyl- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (63);(35)-3-[5-[4-[(7?)-[2-chloro-3-[2-[(35)-pyrrolidin-3-yl]ethoxy]phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione 4-methylbenzenesulfonic acid (64);(35)-3-[5-[4-[(7?)-[2-chloro-3-(methylamino)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (65);(35)-3-[5-[4-[(7?)-[3-[(25)-2-aminopropoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (66);(3 S)-3 - [5 - [4- [(7 ) - [ 3 - [(25)-3 -amino-2-fluoro-propoxy ] -2-chloro-phenyl] -phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (67);(35)-3-[5-[4-[(7?)-[3-[(37?)-3-aminopyrrolidin-l-yl]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (68);(35)-3-[5-[4-[(7?)-[3-[(l-aminocyclopropyl)methoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (69);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-3-hydroxypyrrolidin-l-yl]phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (70);(35)-3 - [5 - [4-[( / ?)-[3 - [(27?)- 3 -amino-2-fluoro-propoxy ] -2-chloro-phenyl] -phenyl -methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (71);(35)-3-[5-[4-[(7?)-[2-chloro-3-[(37?)-l-(2-fluoroethyl)pyrrolidin-3-yl]oxy-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2,6-dione hydrochloride (72);(3A')-3-[5-[4-[( / )-[2-chloro-3-(IT / -imidazol-5-ylmethoxy)phenyl]-phenyl -methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (73);(35)-3-[5-[4-[(7?)-[2-chloro-3-(oxazol-5-ylmethoxy)phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (74);(35)-3-[5-[4-[(7?)-[2-chloro-3-(oxazol-4-ylmethoxy)phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (75);(35)-3-[5-[4-[rel-(5)-indolin-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (76);(35)-3-[5-[4-[rel-(7?)-indolin-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (77);(35)-3-[5-[4-[(7?)-[3-[(25)-2-amino-3,3,3-trifluoro-propoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (78);(35)-3-[5-[4-[(7?)-[3-[((lr,3r)-3-aminocyclobutyl)amino]-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (79);(35)-3-[5-[4-[(7?)-[3-[(15)-2-amino-l-methyl-ethoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (80);(35)-3-[5-[4-[(7?)-[3-[(27?)-2-amino-3,3-difluoro-propoxy]-2-chloro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (81);(35)-3-[5-[4-[rel-(5)-[3-(2-aminoethoxy)-2-fluoro-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (82);(35)-3-[5-[4-[(7?)-[3-(3-amino-2,2-difluoro-propoxy)-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (83);(35)-3-[5-[4-[rel-(7?)-(2-chlorophenyl)-(3-pyridyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (84);(35)-3-[5-[4-[(7?)-[3-(2-amino-4,4-difluoro-butoxy)-2-chloro-phenyl]-phenyl-methyl] piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (85);(35)-3-[5-[4-[(7?)-[3-[(25)-2-aminobutoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (86);(35)-3-[5-[4-[(7?)-[3-[(27?)-2-amino-3,3,3-trifluoro-propoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (87);(35)-3-[5-[4-[(7?)-[2-chloro-3-(isoxazol-4-ylmethoxy)phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (88);(35)-3-[5-[4-[(R)-[2-chloro-3-(isoxazol-5-ylmethoxy)phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (89);(35)-3-[5-[4-[(R)-(2-chloro-3-morpholino-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (90);(35)-3-[5-[4-[(7?)-[2-chloro-3-(isoxazol-3-ylmethoxy)phenyl]-phenyl-methyl]piperidine- 1 -carbonyl]-6-m ethyl- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione (91);(3 S)-3 - [5 - [4- [( / )-[2-chl oro-3 -(oxazol-2-ylmethoxy)phenyl] -phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (92);(35)-3-[6-methyl-l-oxo-5-[4-[phenyl(l,2,3,4-tetrahydroquinolin-5-yl)methyl]piperidine-l-carbonyl]isoindolin-2-yl]piperidine-2, 6-dione (93);(35)-3-[5-[4-[(7?)-[2-chloro-3-(2 -hydroxy ethylamino)phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (94);(35)-3-[5-[4-[(7?)-[3-[(17?)-2-amino-l-methyl-ethoxy]-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (95);(3ri)-3-[5-[4-[3,4-dihydro-27 / -l,4-benzoxazin-8-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (96);(35)-3-[5-[4-[indolin-6-yl(phenyl)methyl]piperi dine-l-carbonyl]-6-methyl- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dione (97);(35)-3-[5-[4-[(7?)-(2-chloro-3-ethoxy-phenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (98);(35)-3-[5-[4-[(7?)-[3-(2-aminoethylamino)-2-chloro-phenyl]-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (99);(3ri)-3-[5-[4-[( / ?)-[2-chloro-3-(trideuteriomethoxy)phenyl]-phenyl-methyl]piperidine-1 -carbonyl]-6-m ethyl- 1 -oxo-isoindolin-2-yl]piperidine-2, 6-dione ( 100);(35)-3-[5-[4-[(7?)-[2-chloro-3-(2 -fluoroethoxy )phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (101);(35)-3-[5-[4-[(R)-[2-chloro-3-(cyclopropoxy)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (102);3-[5-[4-[(R)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl- 1-oxo-isoindolin-2-yl]piperidine-2, 6-dione (103);(35)-3-[6-methyl-l-oxo-5-[4-[rel-(5 -phenyl(l,2,3,4-tetrahydroquinolin-5-yl)methyl] piperidine-l-carbonyl]isoindolin-2-yl]piperidine-2, 6-dione (104);(35)-3-[5-[4-[(2-chloro-3-pyridyl)-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (105);(35)-3-[6-methyl-l-oxo-5-[4-[phenyl(2,3,4,5-tetrahydro-lH-l-benzazepin-6-yl)methyl] piperidine- l-carbonyl]isoindolin-2-yl]piperidine-2, 6-dione (106);(35)-3-[6-methyl-l-oxo-5-[4-[phenyl(l,2,3,5-tetrahydro-4,l-benzoxazepin-6-yl)methyl] piperidine- l-carbonyl]isoindolin-2-yl]piperidine-2, 6-dione (107);(35)-3-[5-[4-[2,3-dihydrobenzofuran-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (108);(3k)-3-[5-[4-[IT / -indazol-4-yl(phenyl)methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (109);(35)-3-[5-[4-[(2-chloro-3-methoxy-phenyl)-deuterio-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (110);(35)-3-[5-[4-[[2-chloro-3-(trifluoromethoxy)phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (111);(35)-3-[rel-(15)-6-[4-[(A)-(2-chlorophenyl)-phenyl-methyl]piperidine-l-carbonyl]- I,5-dimethyl-3-oxo-isoindolin-2-yl]piperidine-2, 6-dione (112);(3 S)-3 - [5 - [4- [rel -(5)-(2-chloro-4-fluoro-3 -methoxy-phenyl)-phenyl-methyl]piperi dine- l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (113); or(35)-3-[5-[4-[[3-(2-aminoethoxy)-2-bromo-phenyl]-phenyl-methyl]piperidine-l-carbonyl]-6-methyl-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (114).

11. A pharmaceutical composition comprising a compound according to claim 1 or tautomers or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

12. A method for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound, a tautomer or a pharmaceutically acceptable salt thereof according to claim 1.

13. The method according to claim 12 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.

14. The method according to claim 12 further comprising administering to said patient a therapeutically effective amount of a second agent, wherein said second agent is selected from an antagonist of PD1 / PD-L1 axis, an antagonist of CTLA4, an antagonist of LAG-3, a chemotherapeutic agent, radiation, or an anti-tumor vaccine, prior to, simultaneously with or after administration of said compound.

15. The method according to claim 26, wherein said compound decreases the level of CDK2 protein and wherein said CDK21 is the amino acid sequence encoded by SEQ ID NOs: 1 or 2.

16. The method according to claim 15, wherein said CDK2 protein level is decreased by at least 70%.

Images