Isoindolinone compounds and their uses

Abstract

The present invention belongs to the field of medicine. The present invention provides an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and a use thereof in the treatment of proliferative diseases. It also provides a pharmaceutical composition comprising said compound or a salt thereof and a pharmaceutically acceptable carrier. (I)

Description

Technology Field

[0001] The present invention falls within the field of medicine. The present invention provides an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and a use thereof in the treatment of proliferative diseases. The present invention also provides a pharmaceutical composition comprising the compound or a salt thereof according to the text and a pharmaceutically acceptable carrier. Background Technology

[0002] Casein kinase 1 alpha (CK1α) is a serine / threonine protein kinase encoded by the gene CSNK1A1 and universally expressed in the CK1 kinase family. CK1α participates in regulating various physiological and pathological processes in cells and coordinates the orderly progression of life through different signaling pathways (Jiang et al. Cell common signal (2018) 16: 23). For example, CK1α acts as a key regulator of the Wnt / β-catenin pathway, directly phosphorylating the Ser45 site of β-catenin and subsequently degrading the proteasome (Liu et al., Cell (2002) 108: 837-847). CK1α also regulates the protein stability of the tumor suppressor p53 by modulating the activity of the MDM2 / MDMX E3 ligase complex (Huart et al., J Biol Chem (2009) 284: 32384-94; Wu et al., Mol Cell Biol (2012) 32: 4821-4832). Although overexpression of CK1α has been reported in many types of human cancer, the precise role of CK1α in the development of each tumor type has not been clearly elucidated (Richter et al. BMC cancer(2018) 18: 140). The Cancer-Dependent Map (DepMap) project showed that CK1α inactivation via clustered regularly spaced short palindromic repeat (CRISPR) / cas9-mediated gene knockout or short hairpin RNA (shRNA)-mediated gene knockout significantly reduced the proliferation and / or survival of many cancer cell lines in various cancer types (Tsherniak et al. Cell (2017) 170: 564-576; Behan et al., Nature (2019) 568: 511-516). In addition, inhibition of CK1α using shRNA interference or D4476 (a CK1α kinase inhibitor) effectively inhibits the development of MLL-AF9 leukemia in mice while having minimal effect on normal hematopoietic stem and progenitor cells (HSPCs) (Jaras et al. J Exp medical , 2014, 211(4): 605-612). Collectively, these data suggest that CK1α is a potential therapeutic target for hematological malignancies and solid tumor indications.

[0003] CK1α is a well-known neoplasm of lenalidomide, an FDA-approved drug for the treatment of human multiple myeloma and low-risk myelodysplastic syndrome with 5q deletion (del(5q)MDS) (Kronke et al., Nature (2015) 523: 183-188). Lenalidomide targets CK1α for polyubiquitination and proteasome degradation using CUL4 / DDB I / CRBN / RBX 1 It acts as a molecular adhesive proteolytic agent that modifies the use of E3 ligase complexes. However, in addition to CK1α, lenalidomide also induces the degradation of numerous other neosubstrates, including Ikaros, Aiolos, ZFP91, and SALL4 (Kronke et al. Science (2014) 343(6168): 301-305; Lu et al., Science (2014) 343(6168): 305-309; Matyskiela et al., Nat Chem Biol (2018) 14(10):981-987; An et al., Nat Commun (2017) 8: 15398). To date, no CK1α selective molecular adhesive degrading agent has been developed for the treatment of cancer and other human diseases.

[0004] GSPT1, also known as eRF3a (eukaryotic release factor 3a), is a key translation termination factor that binds to and activates eRF1 to mediate stop codon recognition and early protein release from translation ribosomes (Zhouravleva et al. EMBO J (1995) 14(16): 4065-4072). Some CRBN-based molecular adhesive degraders, including CC-885 and CC-90009, have been reported to exhibit antitumor efficacy in acute myeloid leukemia (AML) by degrading GSPT1 (Matyskiela et al., Nature (2016) 535: 252-257; Surka et al., Blood (2021) 137(5): 661-677). However, GSPT1 degradation induced by CC-90009 causes severe target toxicities in human AML patients, including hypocalcemia, hypotension, and hyperbilirubinemia (Uy et al., Blood (2019) 134(Supplement_1): 232). Therefore, GSPT1 detargeting degradation must be avoided when developing next-generation CK1α-selective molecular adhesive degraders as therapeutic agents with superior tolerance and lower toxicity. In addition, since the GSPT1 activity of all known classes of Cereblon-based molecular adhesive degraders cannot be clearly predicted by their chemical structure, GSPT1 degradation activity must be carefully analyzed and monitored during development.

[0005] A first embodiment of the present invention is a compound represented by structural formula (I):

[0006] (I),

[0007] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0008] Another embodiment of the present invention is a compound represented by structural formula (II):

[0009] (II),

[0010] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0011] Another embodiment of the present invention is a compound represented by structural formula (III):

[0012] (III),

[0013] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0014] Another embodiment of the present invention is a compound represented by structural formula (IV):

[0015] (IV),

[0016] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0017] Another embodiment of the present invention is a compound represented by structural formula (V):

[0018] (V),

[0019] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0020] Another embodiment of the present invention is a compound represented by structural formula (VI):

[0021] (VI),

[0022] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0023] Another embodiment of the present invention is a compound represented by structural formula (VII):

[0024] (VII),

[0025] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0026] Another embodiment of the present invention is a compound represented by structural formula (VIII):

[0027] (VIII),

[0028] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0029] Another embodiment of the present invention is a compound represented by structural formula (IX):

[0030] (IX),

[0031] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0032] Another embodiment of the present invention is a compound represented by structural formula (X):

[0033] (X),

[0034] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0035] Another embodiment of the present invention is a compound represented by the structural formula (XI):

[0036] (XI),

[0037] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0038] Another embodiment of the present invention is a compound represented by structural formula (XII):

[0039] (XII),

[0040] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0041] Another embodiment of the present invention is a compound represented by structural formula (XIII):

[0042] (XIII),

[0043] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0044] Another embodiment of the present invention is a compound represented by structural formula (XIV):

[0045] (XIV),

[0046] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0047] Another embodiment of the present invention is a compound represented by the structural formula (XV):

[0048] (XV),

[0049] or relating to a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described in the present invention.

[0050] Another embodiment of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to the present invention or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is used, for example, in the treatment of a proliferative disease in a patient. Specific details for implementing the invention

[0051] The present invention relates to a compound represented by the following structural formula or a pharmaceutically acceptable salt thereof. Variants of the following structural formula will be described in the paragraph below. The present invention relates to substituent variables (e.g., R) defined in the text. a , R b , R 1 , R 2 , R 3 It should be understood that it includes all combinations of (etc.). The compound according to the present invention or its salt is used in the treatment of proliferative diseases.

[0052] A first embodiment of the present invention is a compound represented by structural formula (I):

[0053] (I),

[0054] or relating to a pharmaceutically acceptable salt thereof,

[0055] In the above structural formula (I):

[0056] Moiety is 1-6 R a C selectively substituted by 3-8 Cycloalkyl, 1-6 Rs a It is a 4-10-membered monocyclic or noncyclic heterocyclic having 1-3 heteroatoms selected from N, O, and S, selectively substituted by;

[0057] Each R ais independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, but R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0058] Moiety has 2 or more R a If including, 2 R a It selectively bonds to atoms connected to them to form carbon rings or heterocycles;

[0059] Moiety is 1-6 R b 6-18 aryls selectively substituted by, 1-6 R b It is a 5-18-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, selectively substituted by, and

[0060] Each R b is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, but R 11 and R 12is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0061] Moiety has 2 or more R b If including, 2 R b It selectively bonds to atoms connected to them to form carbon rings or heterocycles.

[0062] In the first aspect of the first embodiment, Moiety , , , and Selected from a group consisting of, in each case, n is independently 0, 1, 2, 3, 4, 5, or 6; in each case, X 1 is independently C, N, O, or S; in each case, X 2 is independently C, N, O, or S; in each case, X 3 is independently C, N, O, or S; in each case, X 4 is independently C, N, O, or S; in each case, X 5 is independently C, N, O, or S; in each case, X 6 is independently C, N, O, or S. The wavy line indicates a connection point. The remaining variables (e.g., R a ) is as described and defined in the first embodiment.

[0063] Preferably, Moiety However,

[0064] In each case, n is independently 0, 1, 2, 3, 4, 5, or 6;

[0065] In each case, X 1 is independently C, N, O, or S;

[0066] In each case, X2 is independently C, N, O, or S;

[0067] In each case, X 3 is independently C, N, O, or S;

[0068] In each case, R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0069] In the second aspect of the first embodiment, Moiety or ..., wherein in each case, m is independently 0, 1, 2, 3, 4, 5 or 6; and in each case, Y 1 is independently C, N, O, or S; in each case, Y 2 is independently C, N, O, or S; in each case, Y 3 is independently C, N, O, or S; in each case, Y 4 is independently C, N, O, or S; in each case, Y 5 is independently C, N, O, or S. The wavy line indicates a connection point. The remaining variables (e.g., R b ) is as described and defined in the first embodiment.

[0070] Preferably, Moiety However,

[0071] In each case, m is independently 0, 1, 2, 3, 4, or 5;

[0072] In each case, Y 1 is independently C, N, O, or S;

[0073] In each case, Y 2 is independently C, N, O, or S;

[0074] In each case, Y 3 is independently C, N, O, or S;

[0075] In each case, Y 4 is independently C, N, O, or S;

[0076] In each case, Y 5 is independently C, N, O, or S;

[0077] In each case, R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0078] In the third aspect of the first embodiment, The number of substituents connected to the moiety is 0, 1, 2, 3, 4, 5, or 6.

[0079] In the fourth aspect of the first embodiment, The number of heteroatoms included in the moiety is 0, 1, 2, or 3.

[0080] In the fifth aspect of the first embodiment, The number of substituents connected to the moiety is 0, 1, 2, 3, 4, 5, or 6.

[0081] In the sixth aspect of the first embodiment, The number of heteroatoms included in the moiety is 0, 1, 2, or 3.

[0082] In the seventh aspect of the first embodiment, Moiety

[0083] , , , , , , , , , , , , , , , , , Selected from.

[0084] Preferably, Moiety , , , , , , , , , , , , , , , Selected from.

[0085] In the eighth aspect of the first embodiment, Moiety , , , , , It is selected from. Preferably, Moiety , , , , , , , , , Selected from.

[0086] In the ninth aspect of the first embodiment, R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , , is selected from trifluoromethyl and ethoxy. Preferably, R a is hydrogen, fluorine, chlorine, methyl, cyano, methoxy, , , is selected from trifluoromethyl.

[0087] In the tenth aspect of the first embodiment, R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , , is selected from trifluoromethyl and ethoxy. Preferably, R b is hydrogen, fluorine, chlorine, methyl, cyano, methoxy, , , is selected from trifluoromethyl.

[0088] In the 11th aspect of the first embodiment, the structural formula (I) is as follows.

[0089] (I-1)

[0090] In the 12th aspect of the first embodiment, the structural formula (I) is as follows.

[0091] (I-2)

[0092] In the 13th aspect of the first embodiment, the compound represented by structural formula (I) is

[0093] Compounds represented as (I-3),

[0094] or a pharmaceutically acceptable salt thereof,

[0095] n is 0, 1, 2, or 3;

[0096] m is 0, 1, 2, or 3;

[0097] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0098] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0099] In the 14th aspect of the first embodiment, the compound represented by structural formula (I) is

[0100] Compounds represented as (I-4),

[0101] or a pharmaceutically acceptable salt thereof,

[0102] n is 0, 1, 2, or 3;

[0103] m is 0, 1, 2, or 3;

[0104] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0105] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0106] In the 15th aspect of the first embodiment, the compound represented by structural formula (I) is

[0107] Compounds represented as (I-5),

[0108] or a pharmaceutically acceptable salt thereof,

[0109] n is 0, 1, 2, or 3;

[0110] m is 0, 1, 2, or 3;

[0111] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0112] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0113] In the 16th aspect of the first embodiment, the compound represented by structural formula (I) is

[0114] Compounds represented as (I-6),

[0115] or a pharmaceutically acceptable salt thereof,

[0116] n is 0, 1, 2, or 3;

[0117] m is 0, 1, 2, or 3;

[0118] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0119] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0120] In the 17th aspect of the first embodiment, the compound represented by structural formula (I) is

[0121] Compounds represented as (I-7),

[0122] or a pharmaceutically acceptable salt thereof,

[0123] n is 0, 1, 2, or 3;

[0124] m is 0, 1, 2, or 3;

[0125] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0126] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0127] In the 18th aspect of the first embodiment, the compound represented by structural formula (I) is

[0128] Compounds represented as (I-8),

[0129] or a pharmaceutically acceptable salt thereof,

[0130] n is 0, 1, 2, or 3;

[0131] m is 0, 1, 2, or 3;

[0132] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0133] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0134] In the 19th aspect of the first embodiment, the compound represented by structural formula (I) is

[0135] Compounds represented by (I-9),

[0136] or a pharmaceutically acceptable salt thereof,

[0137] n is 0, 1, 2, or 3;

[0138] m is 0, 1, 2, or 3;

[0139] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0140] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0141] In the 12th aspect of the first embodiment, the compound represented by structural formula (I) is

[0142] Compounds represented as (I-10),

[0143] or a pharmaceutically acceptable salt thereof,

[0144] n is 0, 1, 2, or 3;

[0145] m is 0, 1, 2, or 3;

[0146] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0147] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0148] In the 21st aspect of the first embodiment, the compound represented by structural formula (I) is

[0149] Compounds designated as (I-11),

[0150] or a pharmaceutically acceptable salt,

[0151] n is 0, 1, 2, or 3;

[0152] m is 0, 1, 2, or 3;

[0153] Each R ais independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0154] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0155] In the 22nd aspect of the first embodiment, the compound represented by structural formula (I) is

[0156] Compounds represented as (I-12),

[0157] or a pharmaceutically acceptable salt thereof,

[0158] n is 0, 1, 2, or 3;

[0159] m is 0, 1, 2, or 3;

[0160] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0161] Each R bis independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0162] In the 23rd aspect of the first embodiment, the compound represented by structural formula (I) is

[0163] Compounds represented as (I-13),

[0164] or a pharmaceutically acceptable salt thereof,

[0165] n is 0, 1, 2, or 3;

[0166] m is 0, 1, 2, or 3;

[0167] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0168] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0169] In the 24th aspect of the first embodiment, the compound represented by structural formula (I) is

[0170] Compounds designated as (I-14),

[0171] or a pharmaceutically acceptable salt thereof,

[0172] n is 0, 1, 2, or 3;

[0173] m is 0, 1, 2, or 3;

[0174] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0175] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0176] In the 25th aspect of the first embodiment, the compound represented by structural formula (I) is

[0177] Compounds designated as (I-15),

[0178] or a pharmaceutically acceptable salt thereof,

[0179] n is 0, 1, 2, or 3;

[0180] m is 0, 1, 2, or 3;

[0181] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0182] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0183] In the 26th aspect of the first embodiment, the compound represented by structural formula (I) is

[0184] Compounds represented as (I-16),

[0185] or a pharmaceutically acceptable salt thereof,

[0186] n is 0, 1, 2, or 3;

[0187] m is 0, 1, 2, or 3;

[0188] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0189] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0190] In the 27th aspect of the first embodiment, the compound represented by structural formula (I) is

[0191] Compound designated as (I-17),

[0192] or a pharmaceutically acceptable salt thereof,

[0193] n is 0, 1, 2, or 3;

[0194] m is 0, 1, 2, or 3;

[0195] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0196] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0197] In the 28th aspect of the first embodiment, the compound represented by structural formula (I) is

[0198] Compounds designated as (I-18),

[0199] or a pharmaceutically acceptable salt thereof,

[0200] n is 0, 1, 2, or 3;

[0201] m is 0, 1, 2, or 3;

[0202] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0203] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0204] In the 29th aspect of the first embodiment, the compound represented by structural formula (I) is

[0205] Compound designated as (I-19),

[0206] or a pharmaceutically acceptable salt thereof,

[0207] n is 0, 1, 2, or 3;

[0208] m is 0, 1, 2, or 3;

[0209] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0210] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0211] In the 30th aspect of the first embodiment, the compound represented by structural formula (I) is

[0212] Compounds represented as (I-20),

[0213] or a pharmaceutically acceptable salt thereof,

[0214] n is 0, 1, 2, or 3;

[0215] m is 0, 1, 2, or 3;

[0216] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0217] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0218] In the 31st aspect of the first embodiment, the compound represented by structural formula (I) is

[0219] Compounds designated as (I-21),

[0220] or a pharmaceutically acceptable salt thereof,

[0221] n is 0, 1, 2, or 3;

[0222] m is 0, 1, 2, or 3;

[0223] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0224] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0225] In the 32nd aspect of the first embodiment, the compound represented by structural formula (I) is

[0226] Compounds designated as (I-22),

[0227] or a pharmaceutically acceptable salt thereof,

[0228] n is 0, 1, 2, or 3;

[0229] m is 0, 1, 2, or 3;

[0230] Each Ra is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0231] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0232] In the 33rd aspect of the first embodiment, the compound represented by structural formula (I) is

[0233] Compounds represented as (I-23),

[0234] or a pharmaceutically acceptable salt thereof,

[0235] n is 0, 1, 2, or 3;

[0236] m is 0, 1, 2, or 3;

[0237] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0238] Each R bis independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0239] In the 34th aspect of the first embodiment, the compound represented by structural formula (I) is

[0240] Compounds designated as (I-24),

[0241] or a pharmaceutically acceptable salt thereof,

[0242] n is 0, 1, 2, or 3;

[0243] m is 0, 1, 2, or 3;

[0244] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0245] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0246] In the 35th aspect of the first embodiment, the compound represented by structural formula (I) is

[0247] Compounds designated as (I-25),

[0248] or a pharmaceutically acceptable salt thereof,

[0249] n is 0, 1, 2, or 3;

[0250] m is 0, 1, 2, or 3;

[0251] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0252] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0253] In the 36th aspect of the first embodiment, the compound represented by structural formula (I) is

[0254] Compound represented as (I-26),

[0255] or a pharmaceutically acceptable salt thereof,

[0256] n is 0, 1, 2, or 3;

[0257] m is 0, 1, 2, or 3;

[0258] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0259] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0260] In the 37th aspect of the first embodiment, the compound represented by structural formula (I) is

[0261] Compound designated as (I-27),

[0262] or a pharmaceutically acceptable salt thereof,

[0263] n is 0, 1, 2, or 3;

[0264] m is 0, 1, 2, or 3;

[0265] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0266] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0267] In the 38th aspect of the first embodiment, the compound represented by structural formula (I) is

[0268] Compounds designated as (I-28),

[0269] or a pharmaceutically acceptable salt thereof,

[0270] n is 0, 1, 2, or 3;

[0271] m is 0, 1, 2, or 3;

[0272] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0273] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0274] In the 39th aspect of the first embodiment, the compound represented by structural formula (I) is

[0275] Compound designated as (I-29),

[0276] or a pharmaceutically acceptable salt thereof,

[0277] n is 0, 1, 2, or 3;

[0278] m is 0, 1, 2, or 3;

[0279] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0280] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0281] In the 40th aspect of the first embodiment, the compound represented by structural formula (I) is

[0282] Compounds represented as (I-30),

[0283] or a pharmaceutically acceptable salt thereof,

[0284] n is 0, 1, 2, or 3;

[0285] m is 0, 1, 2, or 3;

[0286] Each R a is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , Selected from trifluoromethyl and ethoxy;

[0287] Each R b is independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0288] A second embodiment of the present invention is a compound represented by structural formula (II).

[0289] (II),

[0290] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0291] A third embodiment of the present invention is a compound represented by structural formula (III).

[0292] (III),

[0293] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0294] The fourth embodiment of the present invention is a compound represented by structural formula (IV).

[0295] (IV),

[0296] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less; The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0297] The fifth embodiment of the present invention is a compound represented by structural formula (V).

[0298] (V),

[0299] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less; The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0300] The sixth embodiment of the present invention is a compound represented by structural formula (VI).

[0301] (VI),

[0302] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less; The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0303] The seventh embodiment of the present invention is a compound represented by structural formula (VII).

[0304] (VII),

[0305] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0306] The eighth embodiment of the present invention is a compound represented by structural formula (VIII).

[0307] (VIII),

[0308] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0309] The ninth embodiment of the present invention is a compound represented by structural formula (IX).

[0310] (IX),

[0311] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less; The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0312] The 10th embodiment of the present invention is a compound represented by structural formula (X).

[0313] (X),

[0314] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less; The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0315] The eleventh embodiment of the present invention is a compound represented by the structural formula (XI).

[0316] (XI),

[0317] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 3 or less; The total number of heteroatoms included in the moiety is 3 or less. The remaining variables are as described and defined in the first embodiment or any aspect thereof.

[0318] The 12th embodiment of the present invention is a compound represented by structural formula (XII).

[0319] (XII),

[0320] or a pharmaceutically acceptable salt thereof,

[0321] In the above structural formula (XII):

[0322] In each case, R 1 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0323] In each case, R 2 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0324] In each case, R 3 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0325] In each case, R 4 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0326] In each case, R 5is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0327] In each case, p is independently 0, 1, or 2;

[0328] In each case, q is independently 0, 1, or 2;

[0329] In each case, r is independently 0, 1, or 2;

[0330] In each case, s is independently 0, 1, or 2;

[0331] In each case, t is independently 0, 1, or 2;

[0332] In each case, X 7 C(R 15 )2, N(R 16 ), O or S and;

[0333] In each case, R 15 or R 16 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0334] In each case, R 6 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0335] In each case, R 7 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0336] In each case, R 8 is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0337] In each case, R 9is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl);

[0338] In each case, R 10is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl), and the additional condition is The total number of heteroatoms included in the moiety is 6 or less.

[0339] In the first aspect of the 12th embodiment, R 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 15 or R 16 Each independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0340] The 13th embodiment of the present invention is a compound represented by structural formula (XIII).

[0341] (XIII),

[0342] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 6 or less. The remaining variables are as described and defined in the 12th embodiment or any aspect thereof.

[0343] In the first aspect of the 13th embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 Each independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0344] The 14th embodiment of the present invention is a compound represented by structural formula (XIV).

[0345] (XIV),

[0346] or a pharmaceutically acceptable salt thereof, and additional conditions are The total number of heteroatoms included in the moiety is 5 or less. The remaining variables are as described and defined in the 12th embodiment or any aspect thereof.

[0347] In the first aspect of the 14th embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 Each independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , It is selected from trifluoromethyl and ethoxy.

[0348] The 15th embodiment of the present invention is a compound represented by the structural formula (XV).

[0349] (XV),

[0350] or a pharmaceutically acceptable salt thereof,

[0351] In the above structural formula (XV):

[0352] In each case, X8 independently C(R 17 )2, N(R 18 ), O or S and;

[0353] In each case, R 17 or R 18is independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C6 alkanoyl, C2-C6 alkyl ester, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, (mono- and di-C1-C6 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), -C0-C4 alkyl-(phenyl), -C0-C4 alkylOC(O)OC1-C6 alkyl, -C0-C4alkylOC(O)C1-C6alkyl, -C0-C4alkylC(O)OC1-C6alkyl, C0-C4alkyl-(4-7-membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, C0-C4alkyl-(5-6-membered unsaturated or aromatic heterocyclic ring) having 1, 2, or 3 heteroatoms independently selected from N, O, and S, -C(O)OR 11 , -C0-C4alkylNR 11 R 12 , -C(O)NR 11 R 12 , -SO2R 11 , -SO2NR 11 R 12 , -OC(O)R 11 and -C(NR 11 )NR 11 R 12 Selected from, R 11 and R 12 is independently selected from hydrogen, C1-C6 alkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl), and

[0354] The auxiliary conditions are The total number of heteroatoms included in the moiety is 6 or less. The remaining variables are as described and defined in the 12th embodiment or any aspect thereof.

[0355] In the first aspect of the 15th embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 17 or R 18 Each independently hydrogen, fluorine, chlorine, bromine, methyl, cyano, methoxy, ethyl, trifluoromethoxy, , , , , , , , , selected from trifluoromethyl and ethoxy. In any embodiment or any aspect thereof, the number of substituents connected thereto may be 0, 1, 2, 3, 4, 5 or 6.

[0356] In any of the above embodiments or any aspect thereof, m may be 0, 1, 2, 3, 4, 5, or 6.

[0357] In any of the above embodiments or any aspect thereof, n may be 0, 1, 2, 3, 4, 5, or 6.

[0358] The present invention also relates to the following compounds:

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] Pharmaceutically acceptable salts of the compounds of the present invention are further included. For example, salts of the compounds of the present invention containing amines or other basic groups may be obtained by reacting the compounds with a suitable organic or inorganic acid to produce pharmaceutically acceptable anionic salt forms. Examples of anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, bichloride, edetate, edicilate, estolate, esylate, fumarate, glycoptate, gluconate, glutamate, glycolyllyl larsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, lead silate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, acetate, It includes succinate, sulfate, tanninate, tartarate, teoclate, tosylate, and trithiodide salts.

[0370] Salts of the compounds of the present invention containing carboxylic acids or other acidic functional groups can be prepared through a reaction with a suitable base. These pharmaceutically acceptable salts can be prepared through pharmaceutically acceptable cation bases, which include alkali metal salts (particularly sodium and potassium), alkaline earth metal salts (particularly calcium and magnesium), aluminum salts and ammonium salts, and salts that can be prepared from physiologically acceptable organic bases, e.g. trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis(2-hydroxyethyl)amine, tri(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroaviethylamine, N,N'-bisdehydroaviethylamine, glucamine, N-methylglucamine, colidin, quinine, quinoline, and basic amino acids (e.g., lysine and arginine).

[0371] The present invention further comprises various isomers and mixtures thereof. Some compounds of the present invention may exist in various stereoisomer forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images do not overlap, most commonly because they contain asymmetrically substituted carbon atoms that act as chiral centers. “Enantiomers” refers to one of a pair of molecules that are mirror images of each other and do not overlap. Diastereoisomers are stereoisomers that are not related to mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. “R” and “S” indicate the arrangement of substituents around one or more chiral carbon atoms. Where the chiral center is not defined as R or S, a pure enantiomer or a mixture of the two arrangements exists.

[0372] The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or separated from a mixture of isomers.

[0373] The disclosed compounds may possess one or more stereocenters, and each stereocenter may exist independently in an R or S configuration. Even if the compound itself is isolated into monostereoisomers and is enantiomerically / diastereomericly pure, if the absolute stereochemistry is not determined at the stereocenter, the stereochemical configuration is indicated by (*) at the indicated center.

[0374] In one embodiment, the compound according to the present invention has an optically active or racemic form. It should be understood that the compound according to the present invention comprises racemic, optically active, positional isomer and stereoisomer forms, or a combination thereof, having therapeutically useful properties according to the present invention.

[0375] The preparation of the optically active form may be implemented in any suitable manner and, non-limiting examples, include the decomposition of the racemic form using recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In another embodiment, a mixture of one or more isomers is used as the compound according to the present invention. In another embodiment, the compound according to the present invention comprises one or more chiral centers. Such compounds may be prepared by any method including stereoselective synthesis, enantiomer-selective synthesis, or separation of a mixture of enantiomers or diastereomers. The separation of the compound and its isomers may be implemented in any manner and, non-limiting examples, include chemical methods, enzymatic methods, fractional crystallization, distillation, and chromatography.

[0376] If the absolute R or S stereochemistry of a compound cannot be determined, it may be identified by the retention time after chromatography under specific chromatographic conditions determined by the chromatographic column, eluent, etc. In some embodiments, an asterisk (*) is used to indicate a chiral atom. In some embodiments, an asterisk “*” is used to indicate that the chiral atom is basically in a single stereochemical configuration and its absolute stereochemistry is not determined (even if the bond is specifically stereographically drawn). The chiral atom may be a chiral carbon atom, a chiral nitrogen atom, or a chiral phosphorus atom. The term “basically” means a difference in the range of 5%, 2%, 1%, or even 0.1% from the standard value. The term “single stereochemical configuration” may be a single R configuration or a single S configuration.

[0377] terminology

[0378] “Alkyl” is a branched or straight-chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl comprises 1 to about 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, and more typically comprises 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the alkyl comprises 1 to about 8 carbon atoms. In some embodiments, the alkyl is C1-C2, C1-C3, or C1-C6. Specific ranges used in the text represent alkyls having each of the values ​​of said ranges as independent classes. For example, the term C1-C6alkyl used in the text is intended to mean a straight-chain or branched-chain alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is described as an independent class. For example, the term C1-C4 alkyl used in the text is intended to mean that it refers to a straight-chain or branched-chain alkyl having 1, 2, 3, or 4 carbon atoms, and that each of these is described as an independent class. In the text, C0-C nWhen an alkyl is used with other groups such as (C3-C7 cycloalkyl)C0-C4 alkyl or -C0-C4 alkyl (C3-C7 cycloalkyl), the indicated group (in this case, cycloalkyl) is directly bonded by a single covalent bond (C0 alkyl) or connected by an alkyl chain (in this case, 1, 2, 3, or 4 carbon atoms). The alkyl may also be connected through other groups such as heteroatoms, such as -O-C0-C4 alkyl (C3-C7 cycloalkyl). Embodiments of the alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. In one embodiment, the alkyl group is optionally substituted as in the text.

[0379] “Alkenyl” is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable site of the chain. Non-limiting embodiments are C2-C8 alkenyls (e.g., C2, C3, C4, C5, C6, C7, C8), C2-C6 alkenyls, and C2-C4 alkenyls. Specific ranges used in the text represent alkenyls having each value of the said range as independent classes and are equivalent to the alkyl moiety according to the text. Embodiments of alkenyls include, but are not limited to, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl). In one embodiment, the alkenyl is optionally substituted as according to the text.

[0380] “Alkynyl” is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at a stable site of the chain. For example, it is a C2-C8 alkynyl (e.g., C2, C3, C4, C5, C6, C7, C8) or a C2-C6 alkynyl. Specific ranges used in the text represent alkynyls having each value of the said range as independent classes and are equivalent to the alkyl moiety according to the text. Embodiments of alkynyl include, but are not limited to, ethinyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexinyl, 2-hexinyl, 3-hexinyl, 4-hexinyl, and 5-hexinyl. In one embodiment, the alkynyl is optionally substituted as according to the text.

[0381] “Alkoxy” is an alkyl defined above having an indicated number of carbon atoms covalently bonded through an oxygen bridge (-O-). Embodiments of the alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentoxy. Similarly, the “alkylthio” or “thioalkyl” group is an alkyl defined above having an indicated number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, the alkoxy is optionally substituted as described in the text.

[0382] “Alkenyloxy” is an alkenyl defined above having the indicated number of carbon atoms covalently bonded to a substituted group through an oxygen bridge (-O-).

[0383] “Alkynyloxy” is the alkynyl defined above having the indicated number of carbon atoms covalently bonded to a group substituted through an oxygen bridge (-O-).

[0384] “Alkanoyle” is an alkyl group defined above having an indicated number of carbon atoms covalently bonded through a carbonyl (C=O) bridge. The number of carbons includes a carbonyl carbon, i.e., a C2 alkanoyle is a CH3(C=O)- group. In one embodiment, the alkanoyle is optionally substituted as described in the text.

[0385] “Alkyl ester” is an alkyl defined above having the indicated number of carbon atoms covalently bonded through ester bonds. The ester bonds can be alkyls of the formula -O(C=O) or -(C=O)O in any direction.

[0386] “Cycloalkyl” means a saturated or partially unsaturated cycloalkyl having a single or multiple ring, including condensed rings, bridge rings, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyls (i.e., ring groups having at least one double bond). As used in the text, C 3-8 Cycloalkyl has 3 to 8 cyclic carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 cyclic carbon atoms). Embodiments of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially unsaturated groups, e.g., cyclopentenyl and cyclohexenyl.

[0387] “Amid” or “carboxamide” is -C(O)NR c R d and, here R c and R d are each independently selected from hydrogen, alkyl, e.g., C1-C6 alkyl; alkenyl, e.g., C2-C6 alkenyl; alkynyl, e.g., C2-C6 alkynyl, -C0-C4 alkyl (C3-C7 cycloalkyl), -C0-C4 alkyl (C3-C7 heterocycloalkyl), -C0-C4 alkyl (aryl) and -C0-C4 alkyl (heteroaryl); or R c and R dIt can form a C3-C7 heterocycle with nitrogen bonded to them. In one embodiment, R c and R d Each is independently and selectively substituted as per the text.

[0388] “Carbocyclil,” “carbon ring group,” “carbon ring,” or “cycloalkyl” is a saturated or partially unsaturated (i.e., non-aromatic) group comprising all carbon ring atoms. The carbon ring group typically comprises one ring having 3 to 7 carbon atoms or two condensed rings each having 3, 4, 5, 6, or 7 carbon atoms. The cycloalkyl substituent may be a pendant from the substituted nitrogen atom or carbon atom, or the substituted carbon atom having two substituents may have a cycloalkyl connected by a spiro group. Embodiments of the carbon ring include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl rings. In one embodiment, the carbon ring is optionally substituted as described in the text. In one embodiment, the cycloalkyl is a partially unsaturated (i.e., non-aromatic) group comprising all carbon ring atoms. In another embodiment, the cycloalkyl is a saturated group containing all carbon ring atoms.

[0389] “Haloalkyl” refers to branched and straight-chain alkyls substituted by one or more halogen atoms up to the maximum allowable number of halogen atoms. Embodiments of haloalkyls include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0390] “Haloalkoxy” refers to a haloalkyl group defined in the text connected via an oxygen bridge (the oxygen of an alcohol radical).

[0391] “Thioalkyl” refers to branched and straight-chain alkyls substituted by one or more sulfur atoms up to the maximum allowable number of halogen atoms.

[0392] “Halo” or “halogen” independently represents any one of fluoro, chloro, bromo, and iodo.

[0393] “Aryl” represents an aromatic ring or an aromatic group in which the ring contains only carbon. In one embodiment, the aryl comprises one to three separate or condensed rings and is six to about 18 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms) that do not have heteroatoms as ring members. Where indicated, the aryl may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion into a 5- to 7-membered saturated ring group optionally comprising one or two heteroatoms independently selected from N, O, and S, for example, to form a 3,4-methylenedioxyphenyl group. The aryl includes naphthyl, fluorenyl, and anthryl, for example, phenyl, 1-naphthyl, and 2-naphthyl. In one embodiment, the aryl is a pendant. One embodiment of the pendant ring is a phenyl substituted by a phenyl. In one embodiment, the aryl is optionally substituted as described in the text.

[0394] The terms “heterocyclil,” “heterocyclic group,” or “heterocyclic” as used in the text refer to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds within a ring that is not aromatic) monocyclic or noncyclic radical of 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are C, wherein one or more ring atoms are optionally independently substituted by one or more of the substituents. In one embodiment, the only heteroatom is oxygen. The heterocycle may be a single ring having 4 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O and S), or a double ring having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O and S), for example, a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In one embodiment, the only heteroatom is sulfur. The heterocycle is Paquette, Leo A.; *Principles of Modern Heterocycle Chemistry* (WA Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7, and 9; It is described in “Chemistry of Heterocyclic Compounds, Paper Series” (John Wiley & Sons, New York, 1950–present), particularly volumes 13, 14, 16, 19 and 28; and in J. Am. Chem. Soc. (1960) 82: 5566.Examples of heterocyclic embodiments include pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomomorpholino, thioxanil, piperazinyl, homopiperazinyl, azetidinyl, oxetanil, tietanil, homopiperidinyl, oxephanil, tiefanil, oxazefinil, diazefinil, thiazefinil, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanil, 1,3-dioxolalanyl, pyrazolinyl, dithianil, dithiolanil, dihydropyranyl, dihydrothienyl, dihydrofuranyl, Includes dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinylimidazolidinyl, imidazolidinyl, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolinyl, quinolidinyl, N-pidilylurea, and pyrrolopyrimidine, but to It is not limited to spiromoiety. Spiro moiety is also included within the scope of this definition. Embodiments of a heterocyclic group in which one or two cyclic carbon atoms are substituted by an oxo (=O) moiety are pyrimidinonyl and 1,1-dioxo-thiomophorinyl. The heterocyclic group according to the text is optionally independently substituted by one or more substituents according to the text.

[0395] A “heterocyclic oxygroup” is the aforementioned monocyclic heterocyclic or noncyclic heterocyclic group connected to a substituted group via oxygen, -O-, and a linker.

[0396] “Heteroaryl” may be a stable monocyclic aromatic ring comprising 1-3 heteroatoms, or in some embodiments, 1-2 heteroatoms selected from N, O, and S, and the remaining ring atom is carbon, or a stable cyclic or tricyclic system comprising at least one 5-7-membered aromatic ring, said aromatic ring comprising 1-3 heteroatoms, or in some embodiments, 1-2 heteroatoms selected from N, O, and S, and the remaining ring atom is carbon. A 5-18-membered heteroaryl according to the text may comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryls typically have 5 to 7 ring atoms. In some embodiments, noncyclic heteroaryls are 9-10-membered heteroaryls, i.e., groups containing 9 or 10 ring atoms, wherein one 5-7-membered aromatic ring is fused to a second aromatic ring or a non-aromatic ring. If the total number of S and O atoms of the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms of the heteroaryl does not exceed 2. In another embodiment, the total number of S and O atoms of the aromatic hetero ring is not greater than 1.Embodiments of heteroaryl include pyridinyl (e.g., including 2-pyridinyl, 2-hydroxypyridinyl, 3-pyridinyl, 3-hydroxypyridinyl, 4-pyridinyl, 4-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (e.g., including 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furil, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, Triazinyl, isoindolyl, pteridinyl, furinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthiridinyl, tetrahydrofuranyl, and propyridinyl are included, but not limited thereto. Heteroaryls are optionally substituted with one or more substituents according to the text.

[0397] “Heteroaryloxy” is a heteroaryl connected to a substituted group through oxygen, -O-, and a linker.

[0398] “Heterocycloalkyl” is a saturated ring group. For example, it has 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, and the remaining ring atoms are carbon atoms. In a typical embodiment, the heteroatom is nitrogen. Monocyclic heterocycloalkyl typically has 3 to about 8 ring atoms or 4 to 6 ring atoms. Embodiments of heterocycloalkyl include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl.

[0399] The term “mono- and / or di-alkylamino” indicates a secondary or tertiary alkylamino, wherein the alkyl is independently selected from the alkyls defined in the text. The linkage point of the alkylamino is at nitrogen. Embodiments of mono- and di-alkylamino include ethylamino, dimethylamino, and methyl-propyl-amino.

[0400] As used in the text, the term “substitution” means that one or more hydrogens of a specified atom or group are replaced by a selected moiety from the indicated group, provided that the normal valence of the specified atom is not exceeded.

[0401] If a stereocenter is designated as “*R” or “*S,” this implies that the absolute stereochemistry for this stereocenter is not determined (even if the bond is specifically drawn stereochemically), despite it being essentially a single stereoconfiguration. That is, “*R” can be an absolute R configuration or an absolute S configuration. Similarly, “*S” can be an absolute R configuration or an absolute S configuration. “*R” or “*S” are randomly distributed for these molecules. A stereocenter designated as “*R” may be a single stereoconfiguration identical or different from another stereocenter designated as “*S”. A stereocenter designated as “*R” may be a single stereoconfiguration identical or different from another stereocenter designated as “*R”. A stereocenter designated as “*S” may be a single stereoconfiguration identical or different from another stereocenter designated as “*S”. For example, Compound 5 The absolute stereochemistry of is one of the following structural formulas, and compound 6 The absolute stereochemistry of is another of the following structural formulas:

[0402] or

[0403] The stereocenter designated as “(R)” signifies an absolute R arrangement. The stereocenter designated as “(S)” signifies an absolute S arrangement.

[0404] Where “*R” or “*S” for a first stereocenter appears simultaneously in the same molecule with a second stereocenter designated as “(R)” or “(S)” (known as the absolute stereochemistry for the second stereocenter), the absolute stereochemistry for the first stereocenter designated as “*R” or “*S” is not determined (even if the bond is specifically stereographically drawn), despite the first stereocenter being essentially a monosteric arrangement. For example, clearly, compound 82 Is or am.

[0405] The compound or its salt according to the text may be used for the treatment of proliferative diseases. The present invention provides a use of the compound according to the text or its pharmaceutically acceptable salt in the manufacture of a drug for the treatment of proliferative diseases. The present invention also provides a use of the compound according to the text or its pharmaceutically acceptable salt in the treatment of proliferative diseases. The present invention also provides a method for treating a proliferative disease comprising the step of administering a therapeutically effective amount of the compound according to the text or its pharmaceutically acceptable salt to a subject in need.

[0406] The applicant has discovered that the compound according to the text or its salt can effectively degrade CK1α. Therefore, the compound according to the text or its salt can be used for the treatment of proliferative diseases. Furthermore, the applicant has discovered that the compound according to the text or its salt does not simultaneously inhibit or degrade GSPT1 when degrading CK1α. That is, since the compound according to the text selectively degrades CK1α and reduces or does not affect other proteins / kinases, it has lower or no toxic side effects compared to conventional CK1α degraders / inhibitors.

[0407] The term “proliferative disease” or “cellular proliferative disease” refers to a disease associated with abnormal cell proliferation to some degree, whether malignant or benign. In some embodiments, the proliferative disease is cancer. In some aspects, the cancer is a solid tumor. In some aspects, the cancer is a hematological malignant tumor. The terms “proliferative disease,” “cellular proliferative disease,” “cancer,” “cancerous,” and “tumor” are not mutually exclusive as per the text.

[0408] “Cancer” includes cancer cells and / or benign or precancerous cells. Examples of cancer include breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, lymphoid organ cancer, and leukemia included in hematological malignancies (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute mononucleotic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), macrogranulocytic leukemia, adult T-cell leukemia), lymphoma (small lymphocytic lymphoma (SLL)), and Hodgkin lymphoma (nodular sclerosing type, mixed cell type, lymphocyte-rich type, lymphocyte-deficient or non-deficient type, and nodular lymphocyte-predominant type Hodgkin lymphoma), non-Hodgkin lymphoma (all subtypes), chronic lymphocytic leukemia / small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmocytic lymphoma (e.g., Waldenstrup macroglobulinemia), splenic marginal zone lymphoma, plasma cell tumors (plasmocytic myeloma, plasmacytoma, monoclonal immunoglobulin deposition disease, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), marginal zone B-cell lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, thymic large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell megagranular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma (nasal type), Enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, blastocytic NK-cell lymphoma, mycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorder, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulopathy, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (unspecified),Includes, but is not limited to, anaplastic giant cell lymphoma and multiple myeloma (plasma cell myeloma or Kaller's disease).

[0409] The present invention also provides a pharmaceutical composition comprising a compound according to the text or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier. The pharmaceutical composition according to the text may be a tablet, capsule, granule, syrup, suspension, solution, dispersant, sustained-release formulation for oral or parenteral administration, intravenous formulation, subcutaneous formulation, inhalation formulation, transdermal formulation, rectal or vaginal suppository.

[0410] The pharmaceutically acceptable carrier according to the text refers to a pharmaceutically acceptable carrier well known to those skilled in the art, and the pharmaceutically acceptable carrier of the present invention includes, but is not limited to, fillers, wetting agents, binders, disintegrants, lubricants, binders, lubricants, flavoring agents, surfactants, preservatives, etc. Fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, etc. Wetting agents and binders include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, sucrose, polyvinylpyrrolidone, etc. Disintegrants include, but are not limited to, sodium carboxymethylstarch, cross-linked polyvinylpyrrolidone, sodium croscarmellose, low-substituted hydroxypropylcellulose, etc. Lubricants include, but are not limited to, magnesium stearate, Aerosil, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, etc. Binders include, but are not limited to, gum arabic, alginate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, glucose, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, sorbitol, starch, syrup, and tragacanth gum. Lubricants include, but are not limited to, colloidal silica, powdered cellulose, magnesium trisilicate, silica, and talc. Flavoring agents include, but are not limited to, aspartame, stevioside, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, and glycyrrhizin. Surfactants include, but are not limited to, Tween-80 and poloxamer. Preservatives include, but are not limited to, parabens, sodium benzoate, potassium sorbate, etc.

[0411] Methods for preparing various pharmaceutical compositions containing various amounts of active ingredients based on the present invention are known or obvious to those skilled in the art and are as described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishers, 19th edition (1995). Methods for preparing pharmaceutical compositions include suitable pharmaceutical excipients, carriers, diluents, etc. Pharmaceutical compositions according to the text are prepared in a known manner and include general methods of mixing, dissolving, or freeze-drying.

[0412] In the pharmaceutical composition according to the text, the content of the active ingredient may vary from about 0.01% to about 99% based on the weight of a given unit formulation. In such a therapeutically useful pharmaceutical composition formulation, the content of the active ingredient may reach an effective dose level.

[0413] Tablets, capsules, etc. according to the text may include a binder such as tragacanth gum, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, or alginate; a lubricant such as magnesium stearate; and a sweetener such as sucrose, fructose, lactose, or aspartame; or a flavoring agent such as mint, wintergreen, or cherry flavor. If the unit formulation is a capsule, in addition to the materials of the above types, it may include a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be a coating or may otherwise alter the physical form of the solid unit formulation. For example, the tablet or capsule may be coated with gelatin, wax, shellac, or sugar, etc. The syrup may include an active ingredient, a sweetener such as sucrose or fructose, a preservative such as methylparaben or propylparaben, a dye, and a flavoring agent (e.g., cherry or orange flavor). Of course, any material used in the manufacture of any unit formulation must be pharmaceutically acceptable and non-toxic in the amount used. Additionally, the active ingredient may be contained in sustained-release formulations and sustained-release devices.

[0414] The active ingredient may be administered intravenously or intraperitoneally via infusion or injection. Optionally, an aqueous solution of the active ingredient or its salt may be prepared using a non-toxic surfactant. Dispersants of glycerol, liquid polyethylene glycol, triacetin and mixtures thereof, and oils may also be prepared. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0415] Pharmaceutical formulations suitable for injection or infusion may comprise sterile aqueous solutions or dispersants or sterile powders containing active ingredients suitable for the immediate preparation of sterile, injectable, or insoluble solutions or dispersants (optionally encapsulated in liposomes). In all cases, the final formulation must be sterile, liquid, and stable under production and storage conditions. The liquid carrier may be a solvent or a liquid dispersion medium and includes, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Suitable fluidity may be maintained, for example, through liposome formation, maintaining a desired particle size in the case of dispersion, or the use of surfactants. Microbial prevention may be achieved using various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, preferably, isotonic agents such as sugar, buffer, or sodium chloride are included. Long-term absorption of the injectable composition can be achieved by using a composition containing an absorption retardant (e.g., aluminum monostearate and gelatin).

[0416] Sterile injectable solutions are prepared by mixing the required amount of the active ingredient and the various other ingredients listed above in a suitable solvent, followed by filtration sterilization. For the sterile powder for the preparation of the sterile injectable solution, the preferred manufacturing method is vacuum drying and freeze-drying techniques to produce a powder of the active ingredient and any additional ingredients present in the sterile filtered solution.

[0417] Useful solid carriers include ground solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.). Useful liquid carriers include water, ethanol, or ethylene glycol or a water-ethanol / ethylene glycol mixture, and the pharmaceutical composition of the present invention may be dissolved or dispersed in an effective amount in the liquid carrier with the help of a non-toxic surfactant. The properties may be optimized for a given application by adding auxiliary agents (e.g., fragrances) and additional antimicrobial agents.

[0418] Thickeners (e.g., synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials) may be used together with a liquid carrier to form a coatable paste, gel, ointment, soap, etc., and are applied directly to the user's skin.

[0419] The therapeutically effective dose of the active ingredient depends not only on the selected specific salt but also on the route of administration, the characteristics of the disease to be treated, and the age and condition of the patient, and ultimately depends on the decision of the attending physician or clinician.

[0420] The above formulation may be provided in a unit formulation, and the unit formulation is a physical discrete unit containing a unit dose suitable for administration to the human and other mammalian bodies, and the unit formulation may be a capsule or a formulation. Depending on the specific treatment involved, the amount of the active ingredient within the unit dose may be changed or adjusted to about 0.01-1000 mg or more.

[0421] The term “treated / treating / treatment” as used in this text generally refers to the attainment of a desired pharmacological and / or physiological effect. The effect may be prophylactic depending on the prevention of the disease or its symptoms in whole or in part; or therapeutic depending on the partial or complete stabilization or treatment of the disease and / or adverse effects caused by the disease. As used in this text, “treated / treating / treatment” includes any treatment for a patient’s disease, including (a) prevention of the disease or disease in undiagnosed patients susceptible to the disease or disease; (b) suppression of disease symptoms, i.e., prevention of disease development; or (c) alleviation of disease symptoms, i.e., regression of the disease or symptoms in whole or in part.

[0422] The compound according to the text or a pharmaceutically acceptable salt thereof may be administered in combination with one or more additional therapeutic agents for the treatment of cancer. Such additional therapeutic agents include, but are not limited to, anthracyclines, cyclophosphamide, 5-fluorouracil, cisplatin, etc.

[0423] Unless otherwise specified, percentages, ratios, proportions, or quantities used in the present invention are calculated based on weight or volume. The quantities used in the present invention are weight or volume quantities. These can be easily determined by those skilled in the art.

[0424] The present invention illustrates beneficial effects through examples below. Those skilled in the art will recognize that these examples are exemplary and limiting. These examples do not limit the scope of the invention in any way. The experimental methods described in the following examples are all general methods unless otherwise specified; and the reagents and materials are all commercially available unless otherwise specified.

[0425] Preparation of isoindolinone carboxamide compounds

[0426] General Plan 1:

[0427]

[0428] Plan 1

[0429] As in Method 1, the isoindolinone compound represented by Formula (I) can be prepared using general organic synthesis methods and commercially available raw materials. Compound B is obtained by adding 2-methylpropane-2-sulfinamide in the presence of CuSO4 or Ti(OEt)4 to a solution of an organic solvent containing compound A (e.g., THF, DCM). Sulfinamide intermediate D is formed by applying a solvent containing an imine intermediate, e.g., THF, DCM, to Grignard reagent C. The sulfinamide is deprotected with an acidic reagent, such as a dioxane solution containing hydrochloric acid, to produce amine compound E. A carboxylic acid F is coupled in a solvent (e.g., DMF, THF, and DCM) in the presence of a coupling agent (e.g., T3P, HATU, and EDCI) and a base (e.g., DIEA and TEA) to produce the compound represented by Formula (I); wherein the W ring group and the Q ring group are as defined in the text. If necessary, the crude mixture is further purified by chiral HPLC or SFC to separate the optical isomers.

[0430] General Plan 2:

[0431]

[0432] Plan 2

[0433] An alternative route for the compound represented by Formula (I) is as in Scheme 2. The isoindolinone compound represented by Formula (I) can be prepared using general organic synthesis methods and commercially available starting materials. Compound B-2 is obtained by adding 2-methylpropane-2-sulfinamide in the presence of CuSO4 or Ti(OEt)4 to a solution of an organic solvent (e.g., THF, DCM) containing compound A-2. Sulfinamide intermediate D-2 is formed by applying a solvent containing an imine intermediate, e.g., THF, DCM, to Grignard reagent C-2. Amine compound E-2 is produced by deprotecting the sulfinamide with an acidic reagent, such as a dioxane solution containing hydrochloric acid. The compound represented by Formula (I) is produced by coupling carboxylic acid F in a solvent (e.g., DMF, THF, and DCM) in the presence of coupling agents (e.g., T3P, HATU, and EDCI) and bases (e.g., DIEA and TEA); Here, the W ring and Q ring are as defined in the text. If necessary, the crude mixture is further purified by chiral HPLC or SFC to separate the optical isomers.

[0434] chemistry

[0435] Several methods for preparing the compounds of the present invention are described below. Unless otherwise specified, all starting materials may be purchased from commercial suppliers and used without further purification.

[0436] Below, ACN: Acetonitrile, AcOH: Acetic acid, Boc: tert-butyloxycarbonyl, Bn: benzyl, calcd.: Calculation, Cbz: benzyloxycarbonyl, col.: Column, conc.: Concentration, DCM: Dichloromethane, DEA: Diethanolamine, DIPEA: N,N-diisopropylethylamine, DMF: Dimethylformamide, DMP: Des-martine oxidizing agent, DMSO: Dimethyl sulfoxide, DPPP: 1,3-bis(diphenylphosphine)propane, Et3N: Triethylamine, EtOAc: Ethyl acetate, ee: Enantiomer excess, ESI: Electrospray ionization, HATU: 2-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Hex: Hexane, HNMR: 1 1H NMR, HPLC: High Performance Liquid Chromatography, IPA: Isopropyl Alcohol, LC-MS or LCMS: Liquid Chromatography-Mass Spectrometry, LDA: Lithium Diisopropylamide, Ms: Methanesulfonyl, PE: Petroleum Ether, PMB: 4-Methoxybenzyl, PPTS: Pyridinium p-Toluenesulfonate, prep.: Preparation, Prep-HPLC: Preparative HPLC, tR or Rt: Retention Time, (s) or (s): Solid, sat.: Saturated, SFC: Supercritical Fluid Chromatography, TBAF: Tetrabutylammonium Fluoride, TBS: tert-Butyldimethylsilyl, TEA: Triethylamine, T3P: n-Propylphosphonic Acid Cyclic Anhydride, THF: Tetrahydrofuran, T or Temp: Temperature, TsCl: 4-Toluenesulfonyl Chloride, T-buok: Potassium tert-butoxide, W: wavelength.

[0437] Example 1:

[0438] Synthesis of Intermediate 1:

[0439] Preparation of intermediate 1: 2 -(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxylic acid

[0440]

[0441] Plan 3

[0442] In a 2 L high-pressure reaction vessel equipped with a magnetic stirring bar, the starting materials intermediate 1-1 (100 g, 0.31 mmol), DIPEA (140 g, 1.08 mol), DPPP (76.7 g, 0.186 mmol), Pd(OAc)2 (35.0 g, 0.155 mol), DMF (1200 mL), and water (50 mL) were added. The mixture was heated overnight at 80°C under a CO2 atmosphere (80 MPa). The mixture was cooled to room temperature, and the DMF was removed under vacuum. The residue was diluted with DCM (2.0 L) and stirred to form a slurry. The mixture was filtered, the filtrate was washed with a NaHCO3 solution, the aqueous layer was acidified with concentrated hydrochloric acid to pH = 1.0, and the resulting solid was filtered and collected.

[0443] The crude product of the filter cake was dissolved in a NaHCO3 solution, the resulting solution was filtered, the filtrate was acidified with concentrated hydrochloric acid to pH = 1.0, and the resulting solid was filtered and collected. The collected material was combined and dried to obtain a white solid 2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxylic acid (70.0 g, 78%).

[0444] 1 H NMR (400 MHz, CDCl3) δ 13.25 (brs, 1H), 11.02 (s, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 5.17-5.13 (m, 1H), 4.48 (d, J = 17.6 Hz, 1H), 4.42 (d, J = 17.6 Hz, 1H), 2.92-2.89 (m, 1H), 2.63-2.50 (m, 1H), 2.43-2.40 (m, 1H), 2.05-2.03 (m 1H). LCMS (ESI + ): m / z: 287 [MH]+

[0445] Synthesis of Intermediate 2:

[0446]

[0447] Plan 3-1

[0448] Step 1. Synthesis of tert-butyl(4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (Intermediate 2-3)

[0449]

[0450] A 900 mL solution of CH3CN containing (S)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride (139.68 g, 585.13 mmol, 1.06 eq) was stirred at 0°C for 0.5 hours. DIEA (142.69 g, 1.10 mol, 192.30 mL, 2 eq) was added dropwise to the mixture. 800 mL of CH3CN containing methyl 4-bromo-2-(bromomethyl)benzoate (170 g, 552.01 mmol, 1 eq) was added dropwise to the solution. The mixture was stirred at 60°C for 12 hours. LC-MS showed that the target compound was detected. The solvent was removed by concentrating the reaction mixture under reduced pressure. The residue was added to water (2000 mL) under ultrasound for 1 hour, and then the mixture was filtered. The filter cake was ground under ultrasound in PE:EtOAc (5:1, 500 mL) for 1 hour. The mixture was filtered and the filter cake was collected. The crude product was used in the next step without further purification. The compound tert-butyl(4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (220 g, 526.10 mmol, yield 95.3%, purity 95%) was obtained as a white solid.

[0451] LCMS (ESI) m / z 397.0 [M+H]

[0452] Step 2. Synthesis of 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-carboxylic acid (Intermediate 2)

[0453]

[0454] A mixture of DMF (450 mL) and H2O (125 mL) containing tert-butyl(4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (110 g, 276.89 mmol, 1 eq), TEA (224.15 g, 2.22 mol, 308.32 mL, 8 eq), DPPP (22.84 g, 55.38 mmol, 0.2 eq), and Pd(OAc)2 (9.95 g, 44.30 mmol, 0.16 eq) was degassed and purged three times with N2. The mixture was stirred at 80°C at 50 psi under CO gas for 12 hours. LC-MS showed that the target compound was detected. The mixture was concentrated under reduced pressure to obtain the residue, and 2 M aq. After pouring into Na2CO3 (dissolved in 6 L of water), a precipitate was formed. The solid was removed by filtration to obtain a yellow solution. The filtrate was extracted with ethyl acetate (1 L x 3), the organic layer was discarded, and the aqueous solution was collected. The aqueous solution was neutralized to pH = 4–5 with 6 N hydrochloric acid, extracted with ethyl acetate (3 L x 2), combined with the organic phase, dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was ground with MTBE (500 mL) while stirring for 2 hours. The target compound was obtained by filtration. Compound 2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxoisoindoline-5-carboxylic acid (76.3 g, 205.74 mmol, yield 74.3%, purity 97.8%) was obtained as a white solid.

[0455] LCMS (ESI) m / z 363.4 [M+H]

[0456] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 13.29 (br s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.79 (d, J= 7.9 Hz, 1H), 7.60 (br s, 1H), 7.22 (s, 1H), 4.75 (dd, J = 4.2, 10.4 Hz, 1H), 4.69-4.50 (m, 2H), 2.26-2.09 (m, 3H), 2.06-1.92 (m, 1H), 1.32 (s, 9H)

[0457] Example 2

[0458] Preparation of Compound 1: N-(cyclopropyl(2,4-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl) 1-oxoisoindolin-5-carboxamide

[0459]

[0460] Plan 4

[0461] Step 1: (R)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide 1-2

[0462] (R)-2-methylpropane-2-sulfinamide (768 mg, 6.34 mmol) was added to a mixture of DCM (10 mL) containing 2,4-difluorobenzaldehyde (1.00 g, 7.04 mmol), CuSO4 (2.25 g, 14.1 mmol), and PPTS (177 mg, 704 μmol) at 25°C, and the mixture was stirred at 25°C for 20 hours. The reaction mixture was filtered and concentrated under vacuum, and the resulting residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as gradient eluents to obtain the title product (1.59 g, yield 83%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.11-7.97 (m, 1H), 7.05-6.87 (m, 2H), 1.27 (s, 9H). LCMS (ESI + ): m / z 246.01 [M+H] + .

[0463] Step 2: (R)-N-(cyclopropyl(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide 1-3

[0464] At -50°C under N2 protection, cyclopropyl magnesium bromide (0.5 M, 6.52 mL) was added dropwise to a solution of THF (5 mL) containing (R)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide (400 mg, 1.63 mmol). After addition, the mixture was stirred at this temperature for 2 hours. The residue was poured into ice-saturated NH4Cl (10 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as gradient eluents to obtain the title product (165 mg, yield 28%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.42-7.32 (m, 1H), 6.91-6.77 (m, 2H), 3.90-3.83 (m, 1H), 3.59 (s, 1H), 1.45-1.38 (m, 1H), 1.22-1.17 (m, 9H), 0.77-0.64 (m, 1H), 0.59-0.36 (m, 3H). LCMS (ESI + ): m / z 288.04 [M+H] + .

[0465] Step 3: Cyclopropyl(2,4-difluorophenyl)methaneamine 1-4

[0466] A mixture of DCM (1 mL) containing (R)-N-((S)-cyclopropyl(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide (160 mg, 557 μmol) and hydrochloric acid / dioxane (4 N, 1 mL) was degassed and purged three times with N2. Then, the mixture was stirred for 1 hour at 20°C under N2 protection. The reaction mixture was concentrated under reduced pressure to obtain the title compound (180 mg, HCl salt, crude product) as a yellow solid, which was used directly in the next step without further purification.

[0467] Step 4: N-(cyclopropyl(2,4-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide compound 1

[0468] A mixture of DCM (2 mL) containing cyclopropyl-(2,4-difluorophenyl)methaneamine (50.0 mg, 228 μmol), 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxylic acid (54.6 mg, 190 μmol), Et3N (57.6 mg, 569 μmol), and T3P (181 mg, 285 μmol) was degassed, purged three times with N2, and stirred for 16 hours at 20°C under N2 protection. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography to obtain the title product (34.2 mg, yield 39.8%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.01 (s, 1H), 9.33-9.14 (m, 1H), 8.08 (s, 1H), 8.03-7.95 (m, 1H), 7.85-7.79 (m, 1H), 7.72-7.63 (m, 1H), 7.24-7.15 (m, 1H), 7.14-7.05 (m, 1H), 5.24-5.04 (m, 1H), 4.70-4.62 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.35 (m, 1H), 2.99-2.85 (m, 1H), 2.63 (br s, 1H), 2.45-2.39 (m, 1H), 2.07-1.96 (m, 1H), 1.43-1.31 (m, 1H), 0.64-0.27 (m, 4H). LCMS (ESI + ): m / z 454.1 [M+H] + .

[0469] Example 3

[0470] Compounds 10 and 11 were prepared through a condensation reaction similar to that of compound 1, and commercially available chiral amine and intermediate 1 were used.

[0471] number structure Compound Nomenclature and Characterization 10 N -((* S )-cyclopropyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (br.s., 1H), 9.30-9.17 (m, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 7.85-7.80 (m, 1H), 7.55-7.46 (m, 2H), 7.21-7.12 (m, 2H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 4.58-4.48 (m, 1H), 4.44-4.33 (m, 2H), 2.98-2.85 (m, 1H), 2.65-2.56 (m, 1H), 2.45-2.35 (m, 1H), 2.07-1.97 (m, 1H), 1.39-1.27 (m, 1H), 0.61-0.51 (m, 2H), 0.49-0.34 (m, 2H). LCMS (ESI + ): m / z 436.1 [M+H] + . 11 N -((* S )-cyclopropyl(2-fluorophenyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.04 (br. s., 1H), 9.28 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.36-7.11 (m, 3H), 5.15 (dd, J = 4.8, 13.2 Hz, 1H), 4.71 (t, J = 8.4 Hz, 1H), 4.58-4.34 (m, 2H), 2.99-2.85 (m, 1H), 2.67-2.57 (m, 1H), 2.47-2.35 (m, 1H), 2.10-1.98 (m, 1H), 1.43-1.32 (m, 1H), 0.65-0.30 (m, 4H); LCMS (ESI + ): m / z 436.1 [M+H] + .

[0472] Example 4

[0473] The preparation of the following compound is similar to the steps according to Compound 1, and the corresponding starting materials, aldehyde and Grignard reagent, were used. Compound 12, 13, 17, 18, 21, 24, 64 In the case of and 71, the corresponding major diastereomer intermediates were separated by preparative high-performance liquid chromatography or SFC prior to steps 3 and 4.

[0474] number structure Compound Nomenclature and Characterization 12 N -((* S )-(2-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (br. s., 1 H), 9.19 (d, J = 7.6 Hz, 1 H), 7.95-8.15 (m, 2 H), 7.72-7.87 (m, 2 H), 7.23-7.47 (m, 3 H), 5.15 (dd, J =13.2, 4.8 Hz, 1 H), 4.96 (t, J = 8.4 Hz, 1 H), 4.35-4.58 (m, 2 H), 2.87-2.99 (m, 1 H), 2.59-2.72 (m, 1 H), 2.32-2.45 (m, 1 H), 1.98-2.07 (m, 1 H), 1.31-1.43 (m, 1 H), 0.39-0.63 (m, 4 H); LCMS (ESI + ): m / z 452.0 [M+H] + . 13 N -((* S )-(2-chloro-4-fluorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 9.33-9.14 (m, 1H), 8.08 (s, 1H), 8.03-7.95 (m, 1H), 7.85-7.79 (m, 1H), 7.72-7.63 (m, 1H), 7.24-7.15 (m, 1H), 7.14-7.05 (m, 1H), 5.24-5.04 (m, 1H), 4.70-4.62 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.35 (m, 1H), 2.99-2.85 (m, 1H), 2.63 (br s, 1H), 2.45-2.39 (m, 1H), 2.07-1.96 (m, 1H), 1.43-1.31 (m, 1H), 0.64-0.27 (m, 4H) ; LCMS (ESI + ): m / z 470.1 [M+H] + . 14 N -((4-chloro-2-fluorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 9.28 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.40 ( d, J = 10.4 Hz, 1H), 7.32 ( d, J = 8.4 Hz, 1H), 5.21-5.08 (m, 1H), 4.64 (t, J = 8.4 Hz, 1H), 4.57-4.47 (m, 1H), 4.44-4.34 (m, 1H), 3.00-2.83 (m, 1H), 2.65-2.57 (m, 1H), 2.45-2.36 (m, 1H), 2.07-1.98 (m, 1H), 1.41-1.30 (m, 1H), 0.64-0.56 (m, 1H), 0.56-0.47 (m, 1H), 0.46-0.38 (m, 1H), 0.37-0.28 (m, 1H). LCMS (ESI+): m / z 470.0 [M+H]+. 15 N -(cyclopropyl(2-methoxyphenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.03 (br. s, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.30-7.19 (m, 1H), 7.04-6.88 (m, 2H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 4.95 (t, J = 8.8 Hz, 1H), 4.58-4.34 (m, 2H), 3.81 (s, 3H), 3.00-2.86 (m, 1H), 2.63-2.59 (m, 1H), 2.46-2.35 (m, 1H), 2.09-1.96 (m, 1H), 1.37-1.20 (m, 1H), 0.54-0.26 (m, 4H); LCMS (ESI + ): m / z 448.1 [M+H] + . 16 N - ((3-chloropyridine-2-yl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.10-10.97 (m, 1H), 9.17 (d, J = 8.0 Hz, 1H), 8.57-8.52 (m, 1H), 8.10 (s, 1H), 8.03-7.97 (m, 1H), 7.94-7.90 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.38-7.33 (m, 1H), 5.18-5.10 (m, 1H), 5.00 (t, J = 8.0 Hz, 1H), 4.55-4.47 (m, 1H), 4.43-4.34 (m, 1H), 2.96-2.87 (m, 1H), 2.65-2.56 (m, 1H), 2.46-2.39 (m, 1H), 2.07-1.97 (m, 1H), 1.59-1.36 (m, 1H), 0.60-0.54 (m, 1H), 0.51-0.43 (m, 3H); LCMS (ESI + ): m / z 453.1 [M+H] + . 17 N -((* S )-cyclopropyl(2,6-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 9.34 (d, J = 6.8 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.39-7.28 (m, 1H), 7.13-7.01 (m, 2H), 5.18-5.10 (m, 1H), 4.55-4.46 (m, 2H), 4.42-4.34 (m, 1H), 2.98-2.86 (m, 1H), 2.68-2.58 (m, 1H), 2.45-2.32 (m, 1H), 2.06-1.97 (m, 1H), 1.65-1.54 (m, 1H), 0.69-0.61 (m, 1H), 0.57-0.49 (m, 1H), 0.49-0.41 (m, 1H), 0.29-0.21 (m, 1H); LCMS (ESI + ): m / z 454.1 [M+H] + . 18 N -((* S )-(3-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 8.90-8.81 (m, 1H), 8.56-8.47 (m, 1H), 8.11-8.03 (m, 1H), 8.01-7.94 (m, 1H), 7.93-7.88 (m, 1H), 7.81 -7.75 (m, 1H), 7.42-7.25 (m, 1H), 5.68-5.57 (m, 1H), 5.20-5.08 (m, 1H), 4.57-4.44 (m, 1H), 4.43-4.31 (m, 1H), 3.06-2.83 (m, 2H), 2.65-2.56 (m, 1H),2.45-2.35 (m, 1H), 2.12-1.89 (m, 3H), 1.88-1.67 (m, 4H). LCMS (ESI + ): m / z 467.1 [M+H] + 19 N -(2-chloro-4-fluorophenyl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1 H) 8.90 (d, J = 8.00 Hz, 1 H) 8.03 (s, 1 H) 7.95 (d, J = 8.00 Hz, 1 H) 7.81 (d, J = 8.00 Hz, 1 H) 7.59-7.66 (m, 1 H) 7.35-7.43 (m, 1 H) 7.20-7.28 (m, 1 H) 5.40-5.57 (m, 1 H) 5.02-5.23 (m, 1 H) 4.28-4.61 (m, 2 H) 2.78-2.97 (m, 2 H) 2.56-2.65 (m, 1 H) 2.35-2.44 (m, 1 H) 1.97-2.14 (m, 2 H) 1.73-1.93 (m, 5 H). LCMS (ESI + ): m / z 484.1 [M+H] + . 50 N -(( *S )-(2-chloro-4-fluorophenyl)(cyclobutyl)methyl)-2-(( *R )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65-7.59 (m, 1H), 7.43-7.35 (m, 1H), 7.28-7.18 (m, 1H), 5.55-5.41 (m, 1H), 5.22-4.99 (m, 1H), 4.56-4.45 (m, 1H), 4.44-4.33 (m, 1H), 2.94-2.80 (m, 2H), 2.62 (s, 1H),2.44-2.37 (m, 1H), 2.06-1.98 (m, 2H), 1.91-1.72 (m, 5H). LCMS (ESI + ): m / z 484.1 [M+H] + . Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 2.571 min, Chiral purity: 93% 51 N -(( *S )-(2-chloro-4-fluorophenyl)(cyclobutyl)methyl)-2-(( *S )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.66-7.59 (m, 1H),7.42-7.36 (m, 1H), 7.28-7.19 (m, 1H), 5.54-5.41 (m, 1H), 5.21-5.04 (m, 1H), 4.57-4.46 (m, 1H), 4.44-4.33 (m, 1H), 2.93-2.77 (m, 2H), 2.64-2.57(m, 1H), 2.42-2.38 (m, 1H), 2.14-1.97 (m, 2H), 1.86-1.65 (m, 5H). LCMS (ESI + ): m / z 484.1 [M+H] + Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 2.571 min, Chiral purity: 91% 52 N -(( *S )- (2-chloro-4-fluorophenyl)(cyclobutyl)methyl)-2-(( *R )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.66-7.59 (m, 1H),7.42-7.36 (m, 1H), 7.28-7.20 (m, 1H), 5.62-5.28 (m, 1H), 5.18-5.09 (m, 1H), 4.55-4.47 (m, 1H), 4.44-4.35 (m, 1H), 2.98-2.76 (m, 2H), 2.65-2.57(m, 1H), 2.45-2.37 (m, 1H), 2.12-1.97 (m, 2H), 1.93-1.71 (m, 5H). LCMS (ESI + ): m / z 484.1 [M+H] + Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 2.571 min, Chiral purity: 94% 53 N -(( *S )-(2-chloro-4-fluorophenyl)(cyclobutyl)methyl)-2-(( *S )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.00 (br s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.67-7.58 (m, 1H),7.42-7.36 (m, 1H), 7.28-7.19 (m, 1H), 5.53-5.41 (m, 1H), 5.19-5.07 (m, 1H), 4.56-4.46 (m, 1H), 4.43-4.33 (m, 1H), 2.93-2.77 (m, 2H), 2.64-2.58 (m, 1H), 2.45-2.37 (m, 1H), 2.13-1.98 (m, 2H), 1.97-1.68 (m, 5H). LCMS (ESI + ): m / z 484.1 [M+H] + . Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 2.571 min, Chiral purity: 88% 20 N -((4-chloro-2-fluorophenyl)(cyclobutyl)methyl)-2 -(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1 H), 8.90-9.05 (m, 1 H), 8.02-8.08 (m, 1 H), 7.93-7.99 (m, 1 H), 7.80-7.86 (m, 1 H), 7.50-7.58 (m, 1 H), 7.36- 7.44 (m, 1 H), 7.27-7.33 (m, 1 H), 5.23-5.35 (m, 1 H), 5.09-5.19 (m, 1 H), 4.35-4.55 (m, 2 H), 2.88-2.98 (m, 1 H), 2.77-2.86 (m, 1 H), 2.59-2.65 (m,1 H), 2.34-2.45 (m, 1 H), 2.07-2.15 (m, 1 H), 1.97-2.06 (m, 1 H), 1.63-1.86 (m, 5 H). LCMS (ESI+): m / z 484.0 [M+1] + . 54 N -(( *S )-(4-chloro-2-fluorophenyl)(cyclobutyl)methyl)-2-(( *R )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.01 (s, 1 H), 8.92-9.03 (m, 1 H), 8.04 (s, 1 H), 7.91-7.98 (m, 1 H), 7.82 (s, 1 H), 7.49-7.58 (m, 1 H), 7.34-7.43 (m, 1 H), 7.24-7.33 (m, 1 H), 5.22-5.32 (m, 1 H), 5.14-5.18 (m, 1 H), 4.35-4.56 (m, 2 H), 2.86-2.98 (m, 1 H), 2.75-2.85 (m, 1 H), 2.59-2.68 (m, 1 H), 2.35 -2.46 (m, 1 H), 2.07-2.15 (m, 1 H), 1.98-2.06 (m, 1 H), 1.63-1.89 (m, 5 H); LCMS (ESI + ): m / z 484.1 [M+1] + Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 2.571 min, Chiral purity: 98% 55 N -(( *S )-(4-chloro-2-fluorophenyl)(cyclobutyl)methyl)-2-(( *S )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1 H), 8.90-9.09 (m, 1 H), 8.04 (s, 1 H), 7.93-8.00 (m, 1 H), 7.80-7.86 (m, 1 H), 7.51-7.58 (m, 1 H), 7.37-7.43 (m, 1 H), 7.27-7.32 (m, 1 H), 5.23-5.33 (m, 1 H), 5.08-5.19 (m, 1 H), 4.34-4.58 (m, 2 H), 2.86-2.99 (m, 1 H), 2.75-2.85 (m, 1 H), 2.58-2.68(m, 1 H), 2.31-2.45 (m, 1 H), 2.07-2.16 (m, 1 H), 1.96-2.07 (m, 1 H), 1.53-1.90 (m, 5 H); LCMS (ESI+): m / z 484.1 [M+1] + . Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 3.06 min, chiral purity: 96% 56 N -(( *S )-(4-chloro-2-fluorophenyl)(cyclobutyl)methyl)-2-(( *R )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1H NMR (400 MHz, DMSO- d 6 ) δ 11.00 (s, 1 H), 8.87-9.07 (m, 1 H), 8.05 (s, 1 H), 7.96-8.01 (m, 1 H), 7.75-7.86 (m, 1 H), 7.51-7.61 (m, 1 H), 7.35-7.43 (m, 1 H), 7.26-7.32 (m, 1 H), 5.23-5.33 (m, 1 H), 5.10-5.18 (m, 1 H), 4.26-4.59 (m, 2 H), 2.87-3.03 (m, 1 H), 2.76-2.86 (m, 1 H), 2.56-2.69 (m, 1 H), 2.32-2.45 (m, 1 H), 2.07-2.17 (m, 1 H), 1.98-2.06 (m, 1 H), 1.61-1.88 (m, 5 H); LCMS (ESI+): m / z 484.1 [M+1] + . Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 4.34 min, Chiral purity: 100% 57 N -(( *S )-(4-chloro-2-fluorophenyl)(cyclobutyl)methyl)-2-(( *R )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (s, 1 H), 8.80-9.15 (m, 1 H), 8.05 (s, 1 H), 7.93-8.00 (m, 1 H), 7.78-7.85 (m, 1 H), 7.50-7.59 (m, 1 H), 7.36 -7.43 (m, 1 H), 7.25-7.32 (m, 1 H), 5.23-5.36 (m, 1 H), 5.05-5.20 (m, 1 H), 4.47-4.58 (m, 2 H), 2.87-2.98 (m, 1 H), 2.78-2.85 (m, 1 H), 2.58-2.69 (m, 1 H), 2.32-2.45 (m, 1 H), 2.08-2.16 (m, 1 H), 1.97-2.07 (m, 1 H), 1.59-1.93 (m, 5 H); LCMS (ESI+): m / z 484.1 [M+1] + . Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), tR: 5.47 min, Chiral purity: 100% 21 N -(( *S )-Cyclobutyl(4-(4-methylpiperazine-1-yl)phenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.09-8.00 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.25-5.06 (m, 1H), 5.00-4.83 (m, 1H), 4.63-4.31 (m, 2H), 3.09-3.00 (m, 4H), 2.97-2.88 (m, 1H), 2.82-2.75 (m, 1H), 2.58 (br s, 1H), 2.46-2.43 (m, 4H), 2.41-2.38 (m, 1H), 2.21 (s, 3H), 2.12-1.95 (m, 2H), 1.81-1.67 (m, 4H), 1.54-1.37 (m, 1H). LCMS (ESI + ): m / z 530.2 [M+H] + 22 N -(cyclobutyl(2,6-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 8.92 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.97-7.92 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.37-7.27 (m, 1H), 7.10-7.00 (m, 2H), 5.33-5.23 (m, 1H), 5.18-5.08 (m, 1H), 4.56-4.32 (m, 2H), 3.08-2.86 (m, 2H), 2.68-2.56 (m, 1H), 2.43-2.31 (m, 1H), 2.25-2.14 (m, 1H), 2.06-1.96 (m, 1H), 1.90-1.73 (m, 4H), 1.67-1.56 (m, 1H); LCMS (ESI + ): m / z 468.1 [M+H] + . 23 N -(cyclobutyl(3-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.03 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.42-7.33 (m, 1H), 7.25 (d, J = 7.6 Hz, 2H), 7.10-7.01 (m, 1H), 5.15 (dd, J = 4.8, 13.2 Hz, 1H), 5.07-4.93 (m, 1H), 4.58-4.46 (m, 1H), 4.45-4.33 (m, 1H), 3.01-2.87 (m, 1H), 2.83-2.74 (m, 1H), 2.66-2.56 (m, 1H), 2.45-2.36 (m, 1H), 2.12-1.99 (m, 2H), 1.86-1.71 (m, 5H); LCMS (ESI+): m / z 450.1 [M+H] + . 24 N -((* S )-Cyclobutyl(3-fluoropyridine-2-yl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.22 (s, 1 H), 8.85-9.02 (m, 1 H), 8.32-8.54 (m, 1 H), 8.07 (m, 1 H), 7.98 (m, 1 H), 7.81 (m, 1 H), 7.70 (m, 1 H), 7.27 -7.44 (m, 1) H), 5.35-5.53 (m, 1 H), 5.09-5.25 (m, 1 H), 4.27-4.57 (m, 2 H), 2.85-2.99 (m, 2 H), 2.56-2.70 (m, 2 H), 2.32-2.44 (m, 1 H), 1.98-2.14 (m,2 H), 1.68-1.86 (m, 4 H). LCMS (ESI+): m / z 451.1 [M+1] + . 64 N -((* S )-(2-cyanophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.03 (s, 1H), 9.46 (d, J = 8.0 Hz, 1H), 8.49 (s, 0.29H), 8.09 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.87-7.77 (m, 3H), 7.76-7.69 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 5.20-5.08 (m, 1H), 4.62 (t, J = 7.2 Hz, 1H), 4.56-4.48 (m, 1H), 4.44-4.35 (m, 1H), 2.97-2.87 (m, 1H), 2.65-2.56 (m, 1H), 2.44-2.36 (m, 1H), 2.07-1.97 (m, 1H), 1.43-1.32 (m, 1H), 0.72-0.39 (m, 4H). LCMS (ESI+): m / z 443.1 [M+H]+. 71 N -((* S )-(3-chloro-5-fluoropyridine-2-yl)methyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (br s, 1H), 9.22 (d, J = 7.2 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.13-8.05 (m, 2H), 8.03-7.97 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 5.18-5.10 (m, 1H), 4.98-4.90 (m, 1H), 4.55-4.46 (m, 1H), 4.42-4.33 (m, 1H), 2.99-2.85 (m, 1H), 2.60 (d, J = 15.6 Hz, 1H), 2.46-2.36 (m, 1H), 2.06-1.97 (m, 1H), 1.51-1.41 (m, 1H), 0.62-0.54 (m, 1H), 0.53-0.41 (m, 3H). LCMS (ESI + ): m / z 471.0 [M+H] + . 43 N -((2-chloro-3-fluorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1 H) 9.25 (d, J = 7.6 Hz, 1 H) 8.07 (s, 1 H) 7.99 (d, J = 8.0 Hz, 1 H) 7.82 (d, J = 8.0 Hz, 1 H) 7.58 (d, J = 7.7 Hz, 1 H) 7.41 (td, J = 8.0, 5.6 Hz, 1 H) 7.26-7.35 (m, 1 H) 5.14 (dd, J = 13.3, 5.0 Hz, 1 H) 4.90 (t, J = 8.3 Hz, 1 H) 4.28-4.59 (m, 2 H) 2.87-2.97 (m, 1 H) 2.61 (br d, J = 15.5 Hz, 1 H) 2.39-2.45 (m, 1 H) 1.96-2.09 (m, 1 H) 1. LCMS (ESI + ): m / z 470.1 [M+H] + . 44 N -(3-cyanophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.03 (br s, 1H), 9.30 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.88-7.79 (m, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.61-7.53 (m, 1H), 5.22-5.08 (m, 1H), 4.57-4.46 (m, 1H), 4.46-4.35 (m, 2H), 2.95-2.87 (m, 1H), 2.63 (br s, 1H), 2.45-2.39 (m, 1H), 2.08-1.95 (m, 1H), 1.34 (d, J = 4.4 Hz, 1H), 0.67-0.37 (m, 4H)LCMS (ESI) + ): m / z 443.1 [M+H] + . 45 N -(2-chloro-6-fluorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 9.33 (d, J = 6.0 Hz, 1H), 8.06 (s, 1H), 7.98 (br d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.37-7.25 (m, 2H), 7.24-7.15 (m, 1H), 5.21-5.07 (m, 1H), 4.74-4.60 (m, 1H), 4.57-4.47 (m, 1H), 4.45-4.32 (m, 1H), 2.91 (t, J = 12.8 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.44-2.36 (m, 1H), 2.08-1.92 (m, 1H), 1.63 (br s, 1H), 0.73-0.28 (m, 4H).LCMS (ESI + ): m / z 470.1 [M+H] + . 39 N -((* S )-Cyclopropyl(o-tolyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 9.05 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.25-7.17 (m, 1H), 7.14 (d, J = 4.0 Hz, 2H), 5.18-5.08 (m, 1H), 4.75 (t, J = 8.0 Hz, 1H), 4.56-4.46 (m, 1H), 4.43-4.33 (m, 1H), 2.99-2.85 (m, 1H), 2.64-2.58 (m, 1H), 2.45-2.38 (m, 1H), 2.34 (s, 3H), 2.07-1.96 (m, 1H), 1.45-1.34 (m, 1H), 0.62-0.45 (m, 2H), 0.45-0.37 (m, 1H), 0.32-0.23 (m, 1H).LCMS (ESI + ): m / z 432.1 [M+H] + .

[0475] Example 5

[0476] Preparation of Compound 2 and Compound 3:

[0477] N-((*R)-(4-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide and N-((*S)-(4-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide

[0478]

[0479] Plan 5

[0480] Step 1: (R)-N-(4-chlorobenzylidene)-2-methylpropane-2-sulfinamide 2-2

[0481] 2-2 The preparation of is similar to steps 1-2 according to compound 1.

[0482] 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 1.19 (s, 9H); LCMS (ESI + ): m / z 244.1 [M+H] + .

[0483] Step 2: (R)-N-((*R)-(4-chlorophenyl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide(2-3-1) and (R)-N-((*S)-(4-chlorophenyl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide(2-3-2)

[0484] At -78°C, cyclopropyl magnesium bromide (1 M, 36.9 mL) was added dropwise to a solution of THF (15 mL) containing (R)-N-(4-chlorobenzylidene)-2-methylpropane-2-sulfinamide 2-2 (3 g, 12.3 mmol). After addition, the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL x 3). The combined organic phase was washed with water (5 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (SiO2, PE / EtOAc = 1:0–3:1), and then purified by SFC (DAICEL CHIRALPAK AS (250mm*30mm, 10um), 0.1% NH3·H2O ETOH, B: 10%, flow rate: 60 mL / min) to obtain the title product 2-3-1 (500 mg, yield 13%) as a white solid, 2-3-2 (200 mg, yield 5%) was obtained as a colorless oil.

[0485] 2-3-1 : 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.29-7.07 (m, 4H), 5.52 (d, J = 7.2 Hz, 1H), 3.35-3.23 (m, 1H), 0.87 (s, 10H), 0.40-0.28 (m, 1H), 0.25-0.14 (m, 2H), 0.10-0.01 (m, 1H); LCMS (ESI + ): m / z 286.01 [M+H] + .

[0486] 2-3-2 : 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.20-7.09 (m, 4H), 5.13 (d, J = 5.6 Hz, 1H), 3.28 (dd, J= 5.6, 9.2 Hz, 1H), 0.97-0.82 (m, 10H), 0.37-0.31 (m, 1H), 0.25 -0.09 (m, 3H); LCMS (ESI + ): m / z 286.2 [M+H] + .

[0487] Step 3: (*R)-(4-chlorophenyl)(cyclopropyl)methaneamine 2-4-1

[0488] Hydrochloric acid / dioxane (2 mL, 4 M) was added to a mixture of N-[(*R)-(4-chlorophenyl)(cyclopropyl)methyl)-2-methyl-propane-2-sulfinamide (150 mg, 525 μmol) and DCM (2 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product (150 mg, yield 69%, HCl salt) as a white solid. LCMS (ESI + ): m / z 164.93 [M-NH2]+.

[0489] (*S)-(4-chlorophenyl)(cyclopropyl)methaneamine 2-4-2

[0490] intermediate 2-3-2 Using as a raw material, and an intermediate 2-4-1 Intermediate 2-4-2 was prepared according to a similar process.

[0491] Preparation of Compound 2: N-((*R)-(4-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide

[0492] intermediate 2-3-1 Compound 2 was prepared using [material] as a raw material and following a similar process to that of Compound 1. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (br. s., 1H), 9.26 (d, J= 8.0 Hz, 1H), 8.10 (s, 1H), 8.05-7.99 (m, 1H), 7.86-7.80 (m, 1H), 7.53-7.46 (m, 2H), 7.44-7.36 (m, 2H), 5.23-5.09 (m, 1H), 4.60-4.48 (m, 1H), 4.47-4.30 (m, 2H), 3.00-2.84 (m, 1H), 2.74-2.58 (m, 1H), 2.46-2.29 (m, 1H), 2.11-1.96 (m, 1H), 1.42-1.25 (m, 1H), 0.65-0.51 (m, 2H), 0.49-0.33 (m, 2H). LCMS (ESI + ): m / z 452.0 [M+H] + .

[0493] Preparation of Compound 3: N-((*S)-(4-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide

[0494] intermediate 2-3-1 Using as a raw material, and a compound 2 Compounds according to a similar process 3 Manufactured. 1 ¹H NMR (400 MHz, DMSO- d 6): δ 11.03 (br. s., 1H), 9.31 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 8.03-7.95 (m, 1H), 7.86-7.78 (m, 1H), 7.51-7.44 (m, 2H), 7.42-7.34 (m, 2H), 5.18-5.05 (m, 1H), 4.58-4.48 (m, 1H), 4.45-4.26 (m, 2H), 2.98-2.81 (m,1H), 2.71-2.57 (m, 1H), 2.48-2.31 (m, 1H), 2.09-1.97 (m, 1H), 1.40-1.24 (m, 1H), 0.63-0.49 (m, 2H), 0.47-0.31 (m, 2H). LCMS (ESI + ): m / z 452.0 [M+H] + .

[0495] Example 6

[0496] The preparation of the following compound is a compound 2 Similar to the steps according to, corresponding starting materials aldehyde and Grignard reagent were used ( Example 5 ).

[0497] number structure Compound Nomenclature and Characterization 25 N -((* R )-cyclopropyl(3-fluorophenyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (br. s., 1 H), 9.19-9.34 (m, 1 H), 8.10 (s, 1 H), 7.98-8.05 (m, 1 H), 7.79-7.85 (m, 1 H),7.35-7.42 (m, 1 H), 7.27- 7.34 (m, 2 H), 7.04-7.11 (m, 1 H), 5.11-5.19 (m, 1 H), 4.35-4.58 (m, 3 H), 2.84-2.97 (m, 1 H), 2.52-2.68 (m, 2 H), 1.97-2.08 (m, 1 H), 1.27-1.38(m, 1 H), 0.51-0.59 (m, 2 H), 0.36-0.50 (m, 2 H); LCMS (ESI + ): m / z 436.1.0 [M+H] + . 26 N -((* S )-cyclopropyl(3-fluorophenyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (br. s.1 H), 9.26 (s, 1 H), 8.11 (s, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 7.81-7.88 (m, 1 H), 7.38 (s, 1 H), 7.24-7.34 (m, 2H), 7.07-7.08 (m, 1 H), 5.10-5.23 (m, 1 H), 4.47-4.57 (m, 3 H), 2.86-3.02 (m, 1 H), 2.56-2.72 (m, 2 H), 1.98-2.09 (m, 1 H), 1.29-1.41 (m, 1 H), 0.54 -0.65 (m, 2 H), 0.45-0.52 (m, 1 H), 0.36-0.45 (m, 1 H); LCMS (ESI + ): m / z 436.1 [M+H] + . 27 N -((* R) -(3-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 9.27 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.46-7.29 (m, 3H), 5.15 (dd, J = 4.8, 13.2 Hz, 1H), 4.58-4.49 (m, 1H), 4.46-4.33 (m, 2H), 3.00-2.86 (m, 1H), 2.62 (d, J = 16.8 Hz, 1H), 2.46-2.35 (m, 1H), 2.09-1.97 (m, 1H), 1.41-1.29 (m, 1H), 0.63-0.53 (m, 2H), 0.51-0.37 (m, 2H); LCMS (ESI + ): m / z 454.1 [M+H] + . 28 N -((* S) -(3-chlorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1H), 9.26 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.45-7.27 (m, 3H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 4.59-4.50 (m, 1H), 4.41-4.35 (m, 1H), 3.00-2.85 (m, 1H), 2.60-2.59 (m, 1H), 2.45-2.43 (m, 1H), 2.13-1.92 (m, 1H), 1.39-1.36 (m, 1H), 0.60-0.55 (m, 2H), 0.50-0.39 (m, 2H) ; LCMS (ESI + ): m / z 454.0 [M+H] + . 29 N -((* R) -cyclopropyl(m-tolyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br. s., 1H), 9.25-9.12 (m, 1H), 8.11 (s, 1H), 8.08-7.99 (m, 1H), 7.89-7.77 (m, 1H), 7.34-7.18 (m, 3H), 7.12-7.02 (m, 1H), 5.15 (dd, J = 4.8, 13.2 Hz, 1H), 4.58-4.32 (m, 3H), 3.00-2.86 (m, 1H), 2.66-2.57 (m, 1H), 2.46-2.37 (m, 1H), 2.31 (s, 3H), 2.10-1.96 (m, 1H), 1.40-1.28 (m, 1H), 0.62-0.50 (m, 2H), 0.47-0.34 (m, 2H); LCMS (ESI + ): m / z 432.1 [M+H] + . 30 N -((* S) -cyclopropyl(m-tolyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.00 (br. s., 1H), 9.25-9.08 (m, 1H), 8.10 (s, 1H), 8.05-7.99 (m, 1H), 7.84-7.79 (m, 1H), 7.30-7.18 (m, 3H), 7.09-7.01 (m, 1H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 4.57-4.31 (m, 3H), 2.99-2.83 (m, 1H), 2.67-2.57 (m, 1H), 2.48-2.36 (m, 1H), 2.30 (s, 3H), 2.10-1.97 (m, 1H), 1.42-1.28 (m, 1H), 0.62-0.47 (m, 2H), 0.45-0.32 (m, 2H); LCMS (ESI + ): m / z 432.1 [M+H] + . 31 N -((* R) -cyclopropyl(3-methoxyphenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 9.18 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.30-7.19 (m, 1H), 7.10-6.97 (m, 2H), 6.87-6.76 (m, 1H), 5.19-5.10 (m, 1H), 4.57-4.48 (m, 1H), 4.44-4.30 (m, 2H), 3.74 (s, 3H), 2.99-2.84 (m, 1H), 2.65-2.56 (m, 1H), 2.45-2.37 (m, 1H), 2.08-1.95 (m, 1H), 1.38-1.27 (m, 1H), 0.60-0.50 (m, 2H), 0.48-0.33 (m, 2H). LCMS (ESI+): m / z 448.1 [M+H] + . 32 N -((* S) -cyclopropyl(3-methoxyphenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (br. s, 1H), 9.18 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.29-7.20 (m, 1H), 7.09-6.99 (m, 2H), 6.86-6.78 (m, 1H), 5.22-5.08 (m, 1H), 4.57-4.48 (m, 1H), 4.45-4.31 (m, 2H), 3.74 (s, 3H), 2.99-2.84 (m, 1H), 2.68-2.58 (m, 1H), 2.44-2.32 (m, 1H), 2.08-1.98 (m, 1H), 1.38-1.26 (m, 1H), 0.58-0.49 (m, 2H), 0.47-0.33 (m, 2H). LCMS (ESI+): m / z 448.1 [M+H] + . 33 N -((* R) -Cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.03 (br. s., 1H), 9.36 (d, J = 7.6 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.89-7.81 (m, 2H), 7.78 (d, J = 6.8 Hz, 1H), 7.66-7.55 (m, 2H), 5.21-5.08 (m, 1H), 4.58-4.35 (m, 3H), 2.99-2.85 (m, 1H), 2.65-2.57 (m, 1H), 2.45-2.35 (m, 1H), 2.08-1.96 (m, 1H), 1.42-1.28 (m, 1H), 0.65-0.35 (m, 4H). LCMS (ESI+): m / z 486.1 [M+H] + . 34 N -((* S) -Cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.03 (br. s., 1H), 9.41-9.28 (m, 1H), 8.10 (s., 1H), 8.06-7.98 (m, 1H), 7.89-7.81 (m, 2H), 7.80-7.71 (m, 1H), 7.67-7.52 (m, 2H), 5.23-5.07 (m, 1H), 4.60-4.34 (m, 3H), 2.99-2.85 (m, 1H), 2.66-2.56 (m, 1H), 2.44-2.35 (m, 1H), 2.10-1.95 (m, 1H), 1.45-1.30 (m, 1H), 0.66-0.36 (m, 4H). LCMS (ESI+): m / z 486.1 [M+H] + . 72 N -((* R) -(2-chloro-4-fluorophenyl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.67-7.56 (m, 1H), 7.47-7.31 (m, 1H), 7.28-7.20 (m, 1H), 5.53-5.43 (m, 1H), 5.18-5.10 (m, 1H), 4.55-4.35 (m, 2H), 2.98-2.77 (m, 2H), 2.65-2.58 (m, 1H), 2.43-2.35 (m, 1H), 2.13-1.98 (m, 2H), 1.93-1.70 (m, 5H). LCMS (ESI+): m / z 484.1 [M+H] + . 73 N -((* S) -(2-chloro-4-fluorophenyl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65-7.59 (m, 1H), 7.45-7.34 (m, 1H), 7.30-7.18 (m, 1H), 5.52-5.44 (m, 1H), 5.17-5.10 (m, 1H), 4.55-4.35 (m, 2H), 2.97-2.79 (m, 2H), 2.64-2.58 (m, 1H), 2.44 -2.41 (m, 1H), 2.15-1.97 (m, 2H), 1.95-1.54 (m, 5H). LCMS (ESI+): m / z 484.1 [M+H] + . 74 N -((* R) -(2-chloro-4-fluorophenyl)(cyclopropyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1H), 9.17 (d, J = 7.6 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.86-7.75 (m, 2H), 7.40 (dd, J = 2.8, 8.8 Hz, 1H), 7.32-7.22 (m, 1H), 5.18-5.09 (m, 1H), 4.95-4.86 (m, 1H), 4.57-4.46 (m, 1H), 4.44-4.33 (m, 1H), 2.98-2.85 (m, 1H), 2.65-2.56 (m, 1H), 2.45-2.36 (m, 1H), 2.08-1.97 (m, 1H), 1.41-1.28 (m, 1H), 0.63-0.55 (m, 1H), 0.54-0.47 (m, 1H), 0.46-0.36 (m, 2H). LCMS (ESI+): m / z 470.1 [M+H] + . 75 N -((* R) -cyclobutyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 5.6, 8.4 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 5.05-4.95 (m, 1H), 4.60-4.34 (m, 2H), 2.98-2.87 (m, 1H), 2.84-2.72 (m, 1H), 2.62-2.59 (m, 1H), 2.46-2.36 (m, 1H), 2.15-1.97 (m, 2H), 1.86-1.71 (m, 5H); LCMS (ESI + ): m / z 450.1 [M+H] + . 66 N -((* R) -Cyclobutyl(2,6-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d6 ) δ 11.02 (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.03-7.99 (m, 1H), 7.97-7.91 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.37-7.28 (m, 1H), 7.09-6.99 (m, 2H), 5.34-5.21 (m, 1H), 5.17-5.10 (m, 1H), 4.55-4.33 (m, 2H), 3.10-2.84 (m, 2H), 2.64-2.57 (m, 1H), 2.43-2.35 (m, 1H), 2.25-2.12 (m, 1H), 2.06-1.96 (m, 1H), 1.91-1.71 (m, 4H), 1.68-1.53 ​​(m, 1H); LCMS (ESI + ): m / z 468.1 [M+H] + . 67 N -((* R) -Cyclobutyl(2,6-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1H), 8.92 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.97-7.91 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.37-7.26 (m, 1H), 7.09-6.99 (m, 2H), 5.33-5.22 (m, 1H), 5.17-5.09 (m, 1H), 4.55-4.31 (m, 2H), 3.06-2.86 (m, 2H), 2.63-2.56 (m, 1H), 2.44-2.39 (m, 1H), 2.25-2.14 (m, 1H), 2.07-1.96 (m, 1H), 1.89-1.74 (m, 4H), 1.66-1.57 (m, 1H); LCMS (ESI + ): m / z 468.1 [M+H] + . 41 N -((* S) -Cyclobutyl(2,4-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (br s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.61-7.52 (m, 1H), 7.24-7.15 (m, 1H), 7.13-7.04 (m, 1H), 5.33-5.23 (m, 1H), 5.18-5.11 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.34 (m, 1H), 3.00-2.86 (m, 1H), 2.86-2.76 (m, 1H), 2.66-2.56 (m, 1H), 2.45-2.36 (m, 1H), 2.17-1.98 (m, 2H), 1.91-1.63 (m, 5H)LCMS (ESI + ): m / z 468.1 [M+H] + . 42 N -((* R) -Cyclobutyl(2,4-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 8.92 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.63-7.50 (m, 1H), 7.23-7.14 (m, 1H), 7.12-7.04 (m, 1H), 5.34-5.23 (m, 1H), 5.20-5.10 (m, 1H), 4.56-4.47 (m, 1H), 4.44-4.33 (m, 1H), 2.97-2.86 (m, 1H), 2.85-2.75 (m, 1H), 2.65-2.56 (m, 1H), 2.44-2.35 (m, 1H), 2.15-1.96 (m, 2H), 1.88-1.62 (m, 5H)LCMS (ESI + ): m / z 468.1 [M+H] + . 40 N -(cyclobutyl(3,4-difluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.54-7.44 (m, 1H), 7.42-7.33 (m, 1H), 7.32-7.21 (m, 1H), 5.21-5.09 (m, 1H), 5.03-4.94 (m, 1H), 4.56-4.48 (m, 1H), 4.44-4.35 (m, 1H), 2.95-2.86 (m, 1H), 2.75 (br d, J = 10.5 Hz, 1H), 2.61 (br d, J = 14.9 Hz, 1H), 2.44-2.35 (m, 1H), 2.11-1.96 (m, 2H), 1.87-1.67 (m, 6H).LCMS (ESI + ): m / z 468.1 [M+H] + .

[0498] Example 7

[0499] Preparation of Compound 4: N-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide

[0500]

[0501] Plan 6

[0502] Step 1: 3,3-Difluorocyclobutanecarbaldehyde 4-2

[0503] DMP (9.00 g, 21.2 mmol) was added to a solution of DCM (30 mL) containing (3,3-difluorocyclobutyl)methanol (2.00 g, 16.4 mmol). The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM and quenched with aq. Na2S2O3 (100 mL) and sat. NaHCO3 (100 mL). The mixture was extracted with DCM (150 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried with Na2SO4, filtered to obtain the filtrate, and concentrated at 15°C. Intermediate 4-2 Contains DCM (DCM 21 g, Intermediate 4-2 A solution of 14.4 mmol (yield 88%) was obtained and used directly in the next step without further purification.

[0504] Step 2: (S)-N-((3,3-difluorocyclobutyl)methylene)-2-methylpropane-2-sulfinamide 4-3

[0505] 3,3-Difluorocyclobutanecarbaldehyde (DCM containing 21 g, 14.4 mmol Intermediate 4-2(S)-2-methylpropane-2-sulfinamide (1.74 g, 14.4 mmol) and Ti(OEt)4 (7.22 g, 31.7 mmol) were added to a solution of DCM (20 mL) containing ). The mixture was stirred at 45°C for 16 hours. The reaction mixture was cooled to 0°C, the reaction mixture was quenched by adding H2O (16 mL), and the solution was filtered through Celite. The phases were separated, the organic phase was washed with brine (20 mL), dried with Na2SO4, and the residue obtained by concentration was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain the title product (912 mg, yield 28%) as a yellow oil.

[0506] 1 H NMR (400 MHz, CDCl3) δ 8.21-8.09 (m, 1H), 3.29-3.13 (m, 1H), 2.96-2.62 (m, 4H), 1.21 (s, 9H). LCMS (ESI + ): m / z 224.01 [M+H] + .

[0507] Step 3: (S)-N-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide 4-4

[0508] At -48℃, (S)-N-((3,3-difluorocyclobutyl)methylene)-2-methyl-propane-2-sulfinamide Intermediate 4-34-fluorophenylmagnesium bromide (1 M, 3.54 mL) was added dropwise to a solution of DCM (2.4 mL) containing (316 mg, 1.42 mmol). After addition, the mixture was stirred at this temperature for 5 hours. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched by adding saturated NH4Cl at 25°C and extracted with DCM (10 mL x 2). The combined organic layer was washed with brine (15 mL x 2), dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, PE / EtOAc = 5 / 1-0 / 1) and further purified by preparative high-performance liquid chromatography to obtain the title product (340 mg, yield 75%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.49-7.42 (m, 1H), 7.42-7.35 (m, 1H), 7.15 (t, J = 8.8 Hz, 2H), 5.82-5.56 (m, 1H), 4.31-4.09 (m, 1H), 2.74-2.51 (m, 3H), 2.39-2.20 (m, 2H), 1.17-1.06 (m, 6H), 1.04 (s, 3H). LCMS (ESI + ): m / z 319.98 [M+H] + .

[0509] Step 4: (3,3-Difluorocyclobutyl)(4-fluorophenyl)methaneamine 4-5

[0510] (S)-N-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide Intermediate 4-4 Hydrochloric acid / dioxane (4 M, 2.0 mL) was added to a solution of DCM (2 mL) containing (100 mg, 313 μmol). The mixture was stirred at 25°C for 4 hours, then concentrated under reduced pressure to obtain the title product (90 mg, crude product, HCl salt) as a white solid, which was used directly in the next step without further purification.

[0511] 1¹H NMR (400 MHz, DMSO- d 6) δ 8.60 (s, 2H), 7.72 - 7.50 (m, 2H), 7.29 (t, J = 8.8 Hz, 2H), 4.36 (s, 1H), 3.57 (s, 1H), 2.78 - 2.68 (m, 2H), 2.42 - 2.22 (m, 2H). LCMS (ESI + ): m / z 215.99 [M+H] + .

[0512] Step 5: N-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide compound 4

[0513] (3,3-difluorocyclobutyl)(4-fluorophenyl)methaneamine Intermediate 4-5 (40.0 mg, 159 μmol) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxylic acid Intermediate 1 TEA (42.0 mg, 416 μmol) and T3P (177 mg, 278 μmol) were added to a 2 mL solution of DCM containing (40.0 mg, 139 μmol). The mixture was stirred at 25°C for 16 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by preparative high-performance liquid chromatography to obtain the title product. Compound 4 (50.0 mg, yield 74%) was obtained as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.01 (s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.55-7.45 (m, 2H), 7.18 (t, J = 8.4 Hz, 2H), 5.22-5.03 (m, 2H), 4.56-4.48 (m, 1H), 4.44-4.36 (m, 1H), 3.02-2.84 (m, 1H), 2.71 (s, 2H), 2.61 (d, J= 16.8 Hz, 1H), 2.47-2.30 (m, 4H), 2.11-1.96 (m, 1H); LCMS (ESI + ): m / z 486.1 [M+H] + .

[0514] Example 8

[0515] Preparation of Compounds 5 and 6: N-((*R)-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide and N-((*S)-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide

[0516]

[0517] Plan 7

[0518] N-[(3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide Compound 4 (40.0 mg, 82.4 μmol) was purified with SFC (separation conditions: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 µm); mobile phase: A: supercritical CO2, B: EtOH, 40% B at 80 mL / min) Compound 5 ( t R = 0.686 min, 13 mg) and Compound 6 ( t R = 0.894 min, 25 mg) was obtained as a white solid.

[0519] Compound 5 : 1 HNMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.54-7.45 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.19-5.04 (m, 2H), 4.56-4.46 (m, 1H), 4.43-4.33 (m, 1H), 2.98-2.85 (m, 1H), 2.69 (s, 2H), 2.60 (d, J= 17.6 Hz, 1H), 2.47-2.35 (m, 4H), 2.07-1.95 (m, 1H). LCMS (ESI + ): m / z 486.1 [M+H] + .

[0520] Compound 6 : 1 H NMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 9.06 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.57-7.41 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.22-4.99 (m, 2H), 4.61-4.30 (m, 2H), 3.00-2.83 (m, 1H), 2.79-2.68 (m, 2H), 2.60 (d, J = 18.8 Hz, 1H), 2.33 (s, 4H), 2.12-1.91 (m, 1H). LCMS (ESI + ): m / z 486.1 [M+H] + .

[0521] Example 9

[0522] Preparation of Compound 7: N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide

[0523]

[0524] 방안 8

[0525] Step 1: Synthesis of (S)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide 7-2

[0526] A portion of Ti(OEt)4 (1.36 g, 5.94 mmol) was added to a solution of THF (10 mL) containing cyclobutanecarbaldehyde (500 mg, 5.94 mmol) and (S)-2-methylpropane-2-sulfinamide (720 mg, 5.94 mmol) under N2 protection at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0–50% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound (S)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide Intermediate 7-2 (600 mg, 3.20 mmol) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) 8.04 (d, J = 4.8 Hz, 1H), 3.37-3.25 (m, 1H), 2.23-1.82 (m, 6H), 1.13 (s, 9H).

[0527] Step 2: Synthesis of (S)-N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide 7-3

[0528] (S)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide at -78°C under N2 protection Intermediate 7-21 M bromo-(4-fluorophenyl)magnesium (9.61 mL, 9.61 mmol) was added to a 10 mL THF solution containing 600 mg (3.20 mmol), and the mixture was stirred at 25°C under N2 protection for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with water (5 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0–100% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound (S)-N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide Intermediate 7-3 (90 mg, yield 9%) was obtained as white oil. LCMS (ESI + ): m / z 284.3 [M+H] + .

[0529] Step 3: Synthesis of (*S)-Cyclobutyl(4-fluorophenyl)methaneamine 7-4

[0530] (S)-N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-methyl-propane-2-sulfinamide at -78°C under N2 protection Intermediate 7-3 Hydrochloric acid / dioxane (4 M, 1.59 mL) was added to a solution of DCM (20 mL) containing (90.0 mg, 318 μmol). The mixture was stirred at 25°C for 0.5 hours, and then concentrated under reduced pressure. Compound (*S)-cyclobutyl(4-fluorophenyl)methaneamine Intermediate 7-4 (65 mg, crude product, HCl salt) was obtained as a white solid. LCMS (ESI + ): m / z 180.2 [M+H] + .

[0531] Step 4: N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide compound 7

[0532] (*S)-Cyclobutyl(4-fluorophenyl)methaneamine Intermediate 7-4 (65.0 mg, 301 μmol) and 2-(2,6-dioxo-3-piperidyl)-1-oxoisoindolin-5-carboxylic acid Intermediate 1 TEA (192 mg, 301 μmol) and T3P (30.5 mg, 301 μmol) were added to a 2 mL solution of DCM containing 95.6 mg, 331 μmol. The mixture was stirred at 25°C for 16 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by preparative high-performance liquid chromatography to obtain the compound N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide Compound 7 (80.9 mg, yield 60%) was obtained as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.04 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.44 (dd, J = 5.6, 8.4 Hz, 2H), 7.19-7.11 (m, 2H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 5.05-4.95 (m, 1H), 4.58-4.34 (m, 2H), 2.98-2.87 (m, 1H), 2.84-2.72 (m, 1H), 2.68-2.59 (m, 1H), 2.47-2.33 (m, 1H), 2.13-1.98 (m, 2H), 1.86-1.69 (m, 5H); LCMS (ESI + ): m / z 450.1 [M+H] + .

[0533] Example 10

[0534] Preparation of Compounds 8 and 9: N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-((R)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide and N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-((S)-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide

[0535]

[0536] Plan 9

[0537] N-((*S)-cyclobutyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide Compound 7 (60.0 mg, 133 μmol) was purified using preparative SFC (chromatography column: DAICEL CHIRALPAK OD (250 mm x 30 mm, 10 µm); conditions: 0.1% NH3H2O, EtOH, starting B: 45%, flow rate: 80 mL / min). Compound 8 (14.8 mg, 100% purity) as a white solid, Compound 9 (14.2 mg, 100% purity) was obtained as a white solid.

[0538] Compound 8 : 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.04 (br. s., 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 5.6, 8.4 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 5.03-4.96 (m, 1H), 4.56-4.35 (m, 2H), 2.98-2.86 (m, 1H), 2.85-2.73 (m, 1H), 2.66-2.57 (m, 1H), 2.45-2.36 (m, 1H), 2.13-1.98 (m, 2H), 1.86-1.68 (m, 5H); LCMS (ESI + ): m / z 450.1 [M+H] + ;

[0539] Compound 9 : 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 8.91 (d, J= 8.4 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.50-7.37 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 5.15 (dd, J = 4.8, 13.2 Hz, 1H), 4.99 (t, J = 9.2 Hz, 1H), 4.58-4.36 (m, 2H), 2.98-2.86 (m, 1H), 2.84-2.73 (m, 1H), 2.68-2.58 (m, 1H), 2.45-2.35 (m, 1H), 2.14-1.98 (m, 2H), 1.86-1.70 (m, 5H); LCMS (ESI + ): m / z 450.1 [M+H] + .

[0540] Example 11

[0541] The preparation of the following compounds is Compound 4 Similar to the steps according to, corresponding starting materials aldehyde and Grignard reagent were used ( Example 7 ).

[0542] compound 35, 36, 38, 58, 59, 66, 67, 69 and 70 In this case, the corresponding major diastereomer intermediates were separated by preparative high-performance liquid chromatography or SFC prior to steps 3 and 4.

[0543] number structure Compound Nomenclature and Characterization 35 N -((* S )-(4-chlorophenyl)(3,3-difluorocyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 10.99 (s, 1H), 9.08 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.53-7.44 (m, 2H), 7.44-7.38 (m, 2H), 5.19-5.03 (m, 2H), 4.57-4.47 (m, 1H), 4.44-4.34 (m, 1H), 2.98-2.85 (m, 1H), 2.78-2.56 (m, 3H), 2.48-2.34 (m, 4H), 2.08-1.96 (m, 1H). LCMS (ESI+): m / z 502.02 [M+H]+. 36 N -((* S )-(4-chlorophenyl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.02 (br. s, 1H), 8.92 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45-7.36 (m, 4H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 5.03-4.93 (m, 1H), 4.56-4.36 (m, 2H), 2.98-2.85 (m, 1H), 2.80-2.76 (m, 1H), 2.63-2.59 (m, 1H), 2.44-2.40 (m, 1H), 2.13-1.99 (m, 2H), 1.83-1.71 (m, 5H); LCMS (ESI + ): m / z 466.1 [M+H] + . 37 N -(cyclopentyl(4-fluorophenyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d6 ) δ 11.01 (br s, 1H), 9.20-8.90 (m, 1H), 8.03 (s, 1H), 7.99-7.91 (m, 1H), 7.85-7.77 (m, 1H), 7.51-7.42 (m, 2H), 7.19-7.09 (m, 2H), 5.20 -5.08 (m, 1H), 4.84-4.70 (m, 1H), 4.59-4.44 (m, 1H), 4.42-4.27 (m, 1H), 3.05-2.84 (m, 1H), 2.65-2.56 (m, 1H), 2.45-2.34 (m, 2H), 2.07-1.95 (m, 1H), 1.93-1.81(m, 1H), 1.69-1.41 (m, 4H), 1.40-1.21 (m, 2H), 1.18-1.05 (m, 1H). LCMS (ESI+): m / z 464.1 [M+H]+ 38 2-(2,6-dioxopiperidin-3-yl)- N -((* S )-(4-fluorophenyl)(tetrahydro-2 H -pyran-4-yl)methyl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.03 (br. s, 1H), 9.08-8.94 (m, 1H), 8.09-7.78 (m, 3H), 7.53-7.39 (m, 2H), 7.22-7.11 (m, 2H), 5.21-5.08 (m, 1H), 4.86-4.69 (m, 1H), 4.58-4.32 (m, 2H), 3.90-3.78 (m, 2H), 3.25-3.16 (m, 2H), 3.00-2.83 (m, 1H), 2.64-2.59 (m, 1H), 2.43-2.40 (m, 1H), 2.04-2.00 (m, 1H), 1.90-1.76 (m, 1H), 1.36-1.12 (m, 3H), 1.06-0.98 (m, 1H). LCMS (ESI+): m / z 480.1 [M+H] + . 46 N -((* R )-cyclobutyl(3,4-difluorophenyl)methyl)-2-((* S )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53-7.43 (m, 1H), 7.43-7.30 (m, 1H), 7.29-7.17 (m, 1H), 5.21-5.08 (m, 1H), 5.06-4.91 (m, 1H), 4.59-4.45 (m, 1H), 4.45-4.30 (m, 1H), 3.02-2.83 (m, 1H), 2.82-2.69 (m, 1H), 2.64-2.57 (m, 1H), 2.41-2.38 (m, 1H), 2.15-1.95 (m, 2H), 1.92-1.61 (m, 6H). LCMS (ESI+): m / z 468.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 1.80 min, Chiral purity: 95% 47 N -((* R )-cyclobutyl(3,4-difluorophenyl)methyl)-2-((* R )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 8.87 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.54-7.43 (m, 1H), 7.42-7.31 (m, 1H), 7.29-7.19 (m, 1H), 5.23-5.07 (m, 1H), 5.06-4.92 (m, 1H), 4.59-4.46 (m, 1H), 4.44-4.29 (m, 1H), 3.01-2.84 (m, 1H), 2.81-2.70 (m, 1H), 2.61-2.57 (m, 1H), 2.45-2.38 (m, 1H), 2.10-2.01 (m, 2H), 1.89-1.67 (m, 6H). LCMS (ESI+): m / z 468.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, Gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 2.13 min, Chiral purity: 66% 48 N -((* S )-cyclobutyl(3,4-difluorophenyl)methyl)-2-(( S )-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53-7.43 (m, 1H), 7.42-7.32 (m, 1H), 7.29-7.20 (m, 1H), 5.21-5.09 (m, 1H), 5.06-4.92 (m, 1H), 4.58-4.47 (m, 1H), 4.44-4.34 (m, 1H), 2.98-2.85 (m, 1H), 2.82-2.69 (m, 1H), 2.65-2.57 (m, 1H), 2.44-2.38 (m, 1H), 2.14-1.95 (m, 2H), 1.90-1.64 (m, 6H). LCMS (ESI+): m / z 468.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, Gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 3.82 min, Chiral purity: 100% 49 N -((* S )-cyclobutyl(3,4-difluorophenyl)methyl)-2-(( R )-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.54-7.43 (m, 1H), 7.42-7.32 (m, 1H), 7.29-7.20 (m, 1H), 5.20-5.09 (m, 1H), 5.06-4.93 (m, 1H), 4.59-4.46 (m, 1H), 4.44-4.32 (m, 1H), 3.00-2.83 (m, 1H), 2.81-2.70 (m, 1H), 2.64-2.58 (m, 1H), 2.45-2.35 (m, 1H), 2.14-1.96 (m, 2H), 1.87-1.67 (m, 6H). LCMS (ESI+): m / z 468.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, Gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 4.89 min, Chiral purity: 98% 58 2-(2,6-dioxo-3-piperidyl)- N -[(* S )-(4-fluorophenyl)-(oxetane-3-yl)methyl)-1-oxo-isoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1H), 9.03 (d, J = 8.4 Hz, 1H), 8.44 (br s, 0.28H), 8.04 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.49-7.40 (m, 2H), 7.21-7.12 (m, 2H), 5.51-5.36 (m, 1H), 5.20-5.07 (m, 1H), 4.72-4.66 (m, 1H), 4.55-4.46 (m, 2H), 4.45-4.35 (m, 2H), 4.30 (t, J = 6.4 Hz, 1H), 2.98-2.85 (m, 2H), 2.60 (d, J = 16.8 Hz, 1H), 2.46-2.37 (m, 1H), 2.07-1.91 (m, 1H); LCMS (ESI + ): m / z 452.1 [M+H] + . 59 2-(2,6-dioxopiperidin-3-yl)- N -[(* R )-(4-fluorophenyl)-(oxetane-3-yl)methyl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.01 (br s, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.46 (s, 0.19H), 8.04 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.51-5.40 (m, 1H), 5.21-5.07 (m, 1H), 4.69 (t, J = 7.6 Hz, 1H), 4.55-4.46 (m, 2H), 4.45-4.35 (m, 2H), 4.30 (t, J = 6.4 Hz, 1H), 3.59-3.45 (m, 1H), 2.97-2.85 (m, 1H), 2.61 (d, J = 16.8 Hz, 1H), 2.40 (d, J = 4.0 Hz, 1H), 2.06-1.97 (m, 1H) ; LCMS (ESI + ): m / z 452.1 [M+H] + . 60 N -((* R )-cyclopentyl(4-fluorophenyl)methyl)-2-(( S )-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 9.06-8.92 (m, 1H), 8.03 (s, 1H), 7.97-7.92 (m, 1H), 7.84-7.78 (m, 1H), 7.49-7.42 (m, 2H), 7.17-7.09 (m, 2H), 5.19-5.04 (m, 1H), 4.81-4.69 (m, 1H), 4.57-4.45 (m, 1H), 4.43-4.32 (m, 1H), 2.93-2.90 (m, 1H), 2.64-2.61 (m, 1H), 2.47-2.35 (m, 2H), 2.07-1.96 (m, 1H), 1.93-1.82 (m, 1H), 1.67-1.42 (m, 4H), 1.30-1.21 (m, 2H), 1.17-1.09 (m, 1H). LCMS (ESI+): m / z 464.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 2.04 min, Chiral purity: 58% 61 N -((* R )-cyclopentyl(4-fluorophenyl)methyl)-2-(( R )-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 9.06-8.92 (m, 1H), 8.03 (s, 1H), 7.97-7.92 (m, 1H), 7.84-7.78 (m, 1H), 7.49-7.42 (m, 2H), 7.17-7.09 (m, 2H), 5.19-5.04 (m, 1H), 4.81-4.69 (m, 1H), 4.57-4.45 (m, 1H), 4.43-4.32 (m, 1H), 2.93-2.90 (m, 1H), 2.64-2.61 (m, 1H), 2.47-2.35 (m, 2H), 2.07- 1.96 (m, 1H), 1.93-1.82 (m, 1H), 1.65-1.49 (m, 4H), 1.30-1.21 (m, 2H), 1.17-1.11 (m, 1H). LCMS (ESI+): m / z 464.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 2.42 min, Chiral purity: 76% 62 N -((* S )-cyclopentyl(4-fluorophenyl)methyl)-2-(( R )-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 9.08-8.90 (m, 1H), 8.03 (s, 1H), 7.97-7.92 (m, 1H), 7.83-7.78 (m, 1H), 7.51-7.41 (m, 2H), 7.19-7.10 (m, 2H), 5.18-5.09 (m, 1H), 4.81-4.72 (m, 1H), 4.55-4.46 (m, 1H), 4.43-4.33 (m, 1H), 2.99-2.82 (m, 1H), 2.65-2.57 (m, 1H), 2.45-2.38 (m, 2H), 2.10-1.96 (m, 1H), 1.93-1.82 (m, 1H), 1.64-1.42 (m, 4H), 1.36-1.23 (m, 2H), 1.18-1.08 (m, 1H). LCMS (ESI+): m / z 464.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 5.30 min, Chiral purity: 91% 63 N -((* S )-cyclopentyl(4-fluorophenyl)methyl)-2-(( S )-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (br s, 1H), 9.05-8.95 (m, 1H), 8.02 (s, 1H), 7.98-7.91 (m, 1H), 7.84-7.77 (m, 1H), 7.53-7.42 (m, 2H), 7.19-7.09 (m, 2H), 5.19-5.07 (m, 1H), 4.81-4.71 (m, 1H), 4.57-4.47 (m, 1H), 4.44-4.33 (m, 1H), 2.96-2.86 (m, 1H), 2.65-2.53 (m, 1H), 2.45-2.39 (m, 2H), 2.06-1.96 (m, 1H), 1.94-1.81 (m, 1H), 1.66-1.46 (m, 4H), 1.38-1.23 (m, 2H), 1.15-1.08 (m, 1H). LCMS (ESI+): m / z 464.1 [M+H]+. Separation of compounds with corresponding racemic mixtures by SFC: Chiral column: (S,S)Whelk-01, 100*4.6 mm ID, 5 µm, gradient mobile phase: CO2:MeOH (0.05% DEA), t R: 5.22 min, Chiral purity: 97% 68 N -((3-chlorophenyl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d6 ) δ 11.02 (br s, 1H), 8.92 (d, J =8.0 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J =8.0 Hz, 1H), 7.82 (d, J =8.0 Hz, 1H), 7.47 (s, 1H), 7.37-7.32 (m, 1H), 7.37-7.32 (m, 1H), 7.31-7.27 (m, 1H), 5.18-5.11 (m, 1H), 5.02-4.95 (m, 1H), 4.57-4.47 (m, 1H), 4.43-4.35 (m, 1H), 2.97 2.87 (m, 1H), 2.82-2.72 (m, 1H), 2.65-2.55 (m, 1H), 2.44-2.36 (m, 1H), 2.13-1.96 (m, 2H), 1.84-1.70 (m, 5H). LCMS (ESI + ): m / z 466.1 [M+H] + . 69 N -((* S )-(2-chloro-6-fluorophenyl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.01 (br s, 1H), 8.90 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.97-7.91 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.35-7.25 (m, 2H), 7.22-7.12 (m, 1H), 5.55-5.44 (m, 1H), 5.22-5.07 (m, 1H), 4.56-4.45 (m, 1H), 4.43-4.30 (m, 1H), 3.16-3.03 (m, 1H), 2.99-2.84 (m, 1H), 2.60 (d, J = 15.6 Hz, 1H), 2.46-2.35 (m, 1H), 2.29-2.15 (m, 1H), 2.07-1.96 (m, 1H), 1.91-1.63 (m, 5H). LCMS (ESI + ): m / z 484.0 [M+H] + . 70 N -((* R )-(2-chloro-6-fluorophenyl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (br s, 1H), 8.90 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.35-7.25 (m, 2H), 7.22-7.11 (m, 1H), 5.53-5.44 (m, 1H), 5.18-5.09 (m, 1H), 4.57-4.46 (m, 1H), 4.43-4.32 (m, 1H), 3.09 (d, J = 9.2 Hz, 1H), 2.98-2.85 (m, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.45-2.37 (m, 1H), 2.23 (br s, 1H), 2.08-1.96 (m, 1H), 1.92-1.64 (m, 5H). LCMS (ESI + ): m / z 484.1 [M+H] + .

[0544] Example 12

[0545] Preparation of Compound 65: 2-(2,6-dioxopiperidine-3-yl)-N-((R)-(4-fluorophenyl)(1-hydroxycyclopropyl)methyl)-1-oxoisoindolin-5-carboxamide

[0546]

[0547] Plan 10

[0548] Step 1: Synthesis of (R)-methyl-2-(dibenzylamino)-2-(4-fluorophenyl)acetate 65-2

[0549] DIPEA (4.23 g, 32.8 mmol) and bromomethylbenzene (5.60 g, 32.8 mmol) were added to a solution of MeCN (15 mL) containing methyl(2R)-2-amino-2-(4-fluorophenyl)acetate (1.50 g, 8.19 mmol). The mixture was stirred at 90°C for 21 hours. The reaction mixture was concentrated under vacuum to collect the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain the compound methyl(2R)-2-(dibenzylamino)-2-(4-fluorophenyl)acetate (1.73 g, yield 58%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 7.36-7.29 (m, 10H), 7.27 (s, 2H), 7.15-6.93 (m, 2H), 4.60 (s, 1H), 3.80 (s, 3H), 3.77-3.70 (m, 4H). LCMS (ESI + ): m / z 364.01 [M+H] + .

[0550] Step 2: (R)-1-((dibenzylamino)(4-fluorophenyl)methyl)cyclopropanol 65-3

[0551] Ti(i-PrO)4 (193 mg, 678 µmol) was added to a solution of THF (5 mL) containing (2R)-2-(dibenzylamino)-2-(4-fluorophenyl)acetate (500 mg, 1.38 mmol) at 20°C. Then, EtMgBr (3 M, 1.67 mL) was added to the reaction mixture over 1.5 hours. After addition, the reaction mixture was quenched with a saturated NH4Cl solution. After stirring for 30 minutes at room temperature, the mixture was filtered through a Celite pad, transferred to a separatory funnel, and diluted with ethyl acetate (250 mL). The layers were separated, and the aqueous solution was extracted with ethyl acetate (50 mL x 3). The combined organic extract was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (TFA conditions). Compound 1-[(R)-(dibenzylamino)-(4-fluorophenyl)methyl]cyclopropanol (269 mg, yield 32%) was obtained as a colorless oil. LCMS (ESI + ): m / z 362.10 [M+H] + .

[0552] Step 3: (R)-1-(amino(4-fluorophenyl)methyl)cyclopropanol 65-4

[0553] Pd / C (10%, 50 mg) was added to a solution of EtOH (3 mL) containing 1-[(R)-(dibenzylamino)-(4-fluorophenyl)methyl]cyclopropanol (80 mg, 221 μmol) under N2 protection. The suspension was degassed and purged three times with H2. The mixture was stirred for 20 hours at 25°C under H2 (35 Psi). After 20 hours, Celite was added and the slurry was filtered. The filter cake was washed with ethanol (25 mL x 5), 4.0 M hydrochloric acid / dioxane (0.12 mL) was added to the combined filtrate to concentrate it, and the residue was ground with ethyl acetate (1 mL). Compound 1-[(R)-amino-(4-fluorophenyl)methyl]cyclopropanol (22 mg, crude product, hydrochloric acid) was obtained as a white solid. LCMS (ESI + ): m / z 182.1 [M+H]+ .

[0554] Step 4: 2-(2,6-dioxopiperidine-3-yl)-N-((R)-(4-fluorophenyl)(1-hydroxycyclopropyl)methyl)-1-oxoisoindolin-5-carboxamide compound 65

[0555] The preparation of the compound is similar to the steps according to compound 1.

[0556] Compound 65 :

[0557] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.02 (br s, 1H), 8.86 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.55-7.47 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 5.55 (s, 1H), 5.18-5.10 (m, 1H), 4.85 (d, J = 8.8 Hz, 1H), 4.60-4.48 (m, 1H), 4.45-4.36 (m, 1H), 2.98-2.85 (m, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.41 (d, J = 4.4 Hz, 1H), 2.08-1.97 (m, 1H), 0.86-0.75 (m, 1H), 0.72-0.60 (m, 3H)). LCMS (ESI + ): m / z 452.1 [M+H] + .

[0558] Example 13

[0559] Preparation of Compounds 76 and 77: N-((*S)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide and N-((*R)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide

[0560]

[0561] Plan 11

[0562] Step 1: Synthesis of N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide

[0563]

[0564] A solution of DCM (10 mL) containing cyclobutanecarbaldehyde (4.00 g, 47.6 mmol), 2-methylpropane-2-sulfinamide (5.19 g, 42.8 mmol), CuSO4 (15.2 g, 95.1 mmol), and PPTS (1.20 g, 4.76 mmol) was degassed and purged three times with N2. The mixture was stirred at 20°C for 3 hours under N2 protection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the DCM. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent 0–10% ethyl acetate / petroleum ether gradient @ 40 mL / min). Compound N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide (8.00 g, yield 89.8%) was obtained as a colorless oil.

[0565] 1 HNMR (400 MHz, DMSO- d 6) δ 7.99 (d, J = 4.4 Hz, 1H), 3.43-3.35 (m, 1H), 2.26-2.02 (m, 5H), 1.90-1.79 (m, 1H), 1.11 (s, 9H).

[0566] Step 2: Synthesis of N-((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide

[0567]

[0568] Bromo(isopropyl)magnesium (2.8 M, 17.2 mL) was added to a solution of THF (15 mL) containing 2-bromo-5-chloro-pyridine (9.25 g, 48.1 mmol) under N2 protection at -65°C, and the mixture was stirred at 20°C for 2 hours. Under N2 protection at -78°C, the crude product (5-chloropyridine-2-yl)magnesium bromide solution was added dropwise to a solution of THF (20 mL) containing N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide (2.00 g, 10.7 mmol), and the mixture was stirred at 20°C for 2 hours. At 0°C, the reaction mixture was quenched with saturated NH4Cl (15 mL) and extracted with EA (25 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0–40% ethyl acetate / petroleum ether gradient @ 15 mL / min). Compound N-((5-chloropiperidin-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide (600 mg, yield 18.7%) was obtained as a colorless oil. LCMS (ESI + ): m / z 301.3 [M+H] + .

[0569] Step 3: Synthesis of (5-chloropyridine-2-yl)(cyclobutyl)methaneamine

[0570]

[0571] Hydrochloric acid / dioxane (4 M, 5.00 mL) was added to a solution of DCM (3 mL) containing N-((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide (150 mg, 499 μmol). The mixture was stirred at 20°C for 1 hour, and the mixture was concentrated under reduced pressure. The compound (5-chloropyridine-2-yl)(cyclobutyl)methaneamine (78 mg, crude product, HCl salt) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI +): m / z 197.2 [M+H] + .

[0572] Step 4: Synthesis of N-((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide

[0573]

[0574] TEA (67.3 mg, 669 µmol) was added to a mixture of DCM (5 mL) containing (5-chloropyridine-2-yl)(cyclobutyl)methanolamine (78 mg, 334 µmol, HCl salt), 2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxylic acid (106 mg, 368 µmol), and T3P (212 mg, 334 µmol). The mixture was stirred for 12 hours at 20°C under N2 protection. The mixture was concentrated under reduced pressure to remove the DCM. The crude product was purified by preparative high-performance liquid chromatography (FA conditions). Compound N-((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (60 mg, yield 26.0%) was obtained as a white solid. LCMS (ESI + ): m / z 467.13 [M+H] + .

[0575] Step 5: N-((*S)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (Compound 76, Peak 1) and N-((*R)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (Compound 77, Peak 2)

[0576]

[0577] N-((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (60 mg, 129 µmol) was purified by SFC (column: (s,s) WHELK-O1 (250 mm x 30 mm, 5 µm); mobile phase: Neu-ETOH; B%: 50%, flow rate 80 mL / min). During the SFC separation process, the first elution peak was designated as compound 76 and the second elution peak was designated as compound 77. Compound N-((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (Compound 76, Peak 1) (15.62 mg, 26.0% yield) was obtained as a white solid. (R t = 3.577 min and 4.993 min; de%:100.00%); 1 HNMR (400 MHz, DMSO- d 6) 11.03 (br. s., 1H), 9.04-8.79 (m, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 8.03-7.97 (m, 1H), 7.90 (dd, J = 2.4, 8.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 5.19-5.07 (m, 2H), 4.61-4.24 (m, 2H), 3.00-2.80 (m, 2H), 2.64-2.58 (m, 1H), 2.47-2.37 (m, 1H), 2.14-1.97 (m, 2H), 1.95-1.71 (m, 5H); LCMS (ESI + ): m / z 467.3 [M+H] + .

[0578] Compound N-((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (Compound 77, Peak 2) (12.14 mg, yield 20.23%) was obtained as a white solid. (R t = 2.184 min and 2.833 min; de%: 100%). 1 HNMR (400 MHz, DMSO- d 6) δ 11.03 (br. s., 1H), 8.98-8.86 (m, 1H), 8.61-8.49 (m, 1H), 8.08 (s, 1H), 8.02-7.97 (m, 1H), 7.93-7.87 (m, 1H), 7.84-7.79 (m, 1H), 7.53-7.48 (m, 1H), 5.20-5.05 (m, 2H), 4.57-4.34 (m, 2H), 2.97-2.81 (m, 2H), 2.65-2.58 (m, 1H), 2.45-2.37 (m, 1H), 2.11-1.99 (m, 2H), 1.92-1.72 (m, 5H); LCMS (ESI + ): m / z 467.2 [M+H] + .

[0579] ( reference Compound 76 can be further separated by optimized SFC conditions to yield two stereoisomers. Therefore, Compound 76 is a mixture of two isomers with unknown stereochemistry.

[0580] Example 14

[0581] The preparation of the following compounds is similar to the steps according to compounds 76 and 77, using the corresponding starting materials aldehyde and Grignard reagent and the following coupling step ( Example 13 ).

[0582] compound 77, 78, 79, 80 and 81 In the case of, the corresponding major diastereomer intermediate was separated by preparative high-performance liquid chromatography or SFC prior to the following step.

[0583] 78 N -(( *S )-Cyclobutyl(5-fluoropyridine-2-yl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72-7.65 (m, 1H), 7.55 -7.49 (m, 1H), 5.17-5.08 (m, 2H), 4.55-4.48 (m, 1H), 4.43-4.34 (m, 1H), 2.98-2.92 (m,1H), 2.57 (d, J = 6.4 Hz, 2H), 2.47-2.45 (m, 1H), 2.13-1.96 (m, 2H), 1.90-1.71 (m, 5H).LCMS (ESI+): m / z 451.3[M+H] + , Duration: 2.706 min;SFC: Duration of stay: 2.888 min, 3.661 min. 79 N -(( *S )-Cyclobutyl(3,5-dichloropyridine-2-yl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 8.90 (d, J = 7.6 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 3.6, 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 5.55 (d, J = 7.6, 9.6 Hz, 1H), 5.13 (d, J = 5.2, 13.2 Hz, 1H), 4.48 (s, 1H), 4.44-4.33 (m, 1H), 3.06-2.85 (m, 2H), 2.44-2.42 (m, 2H), 2.15-1.93 (m,3H), 1.86-1.76 (m, 4H).LCMS (ESI+): m / z 451.3[M+H] + , Duration: 1.711 min; SFC : Duration: 1.413 min, 1.702 min. 80 N -(( *S )-(5-chloro-3-fluoropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 HNMR (400 MHz, DMSO- d 6) δ 11.03 (br. s., 1H), 9.02-8.92 (m, 1H), 8.51-8.48 (m, 1H), 8.11-8.04 (m, 2H), 8.00-7.95 (m, 1H), 7.82-7.77 (m, 1H), 5.39-5.31 (m, 1H), 5.18-5.11 (m, 1H), 4.54-4.35 (m, 2H), 3.02-2.87 (m, 2H), 2.64-2.57 (m, 1H), 2.46-2.36 (m, 1H), 2.20-2.09 (m, 1H), 2.07-1.98 (m, 1H), 1.95-1.66 (m, 5H);LCMS (ESI + ): m / z 485.2 [M+H] + , duration of stay: 1.910 min; SFC duration of stay: 1.251 min and 1.500 min. 81 N -(( *S )-(3-chloro-5-fluoropyridine-2-yl)(cyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 HNMR (400 MHz, DMSO- d 6) δ 11.01 (br. s., 1H), 8.87 (d, J = 7.6 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.10-8.04 (m, 2H), 8.00-7.93 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 5.64-5.52 (m, 1H), 5.22-5.06 (m, 1H), 4.58-4.30 (m, 2H), 3.02-2.87 (m, 2H), 2.64-2.60 (m, 1H), 2.45-2.40 (m, 1H), 2.11-1.94 (m, 3H), 1.86-1.75 (m, 4H);LCMS (ESI + ): m / z 485.3 [M+H] + , duration of stay: 3.298 min; SFC duration of stay: 3.341 min and 4.428 min.

[0584] Example 15

[0585] Preparation of Compound 82: N-((*S)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-((S)-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide

[0586]

[0587] Plan 12

[0588] Step 1: Synthesis of (R)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide

[0589]

[0590] Cesium carbonate (44.5 g, 0.137 mol) was added to a solution of DCM (100 mL) containing cyclobutanecarbaldehyde (10 g, 0.119 mol) and (R)-2-methylpropane-2-sulfinamide (14.4 g, 0.119 mol). The mixture was stirred for 12 hours at 20°C under N2 protection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the DCM. The residue was purified by silica gel chromatography eluted with petroleum ether:ethyl acetate (0–10%) to obtain (R)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide (19 g, yield 85.0%) as a colorless oil.

[0591] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.15-7.82 (m, 1H), 3.44-3.36 (m, 1H), 2.53-2.45 (m, 1H), 2.24-1.94 (m, 5H), 1.11 (s, 9H).

[0592] Step 2: Synthesis of (R)-N-(*S)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide

[0593]

[0594] Bromo(isopropyl)magnesium (3 M, 50 mL) was added to a solution of THF (100 mL) containing 2-bromo-5-chloropyridine (28.9 g, 0.150 mmol) at -65°C under N2 protection. The mixture was stirred at 20°C for 2 hours. THF (100 mL) containing (R)-N-(cyclobutylmethylene)-2-methyl-propane-2-sulfinamide (10 g, 53.4 mmol) was added to the mixture at -65°C under N2 protection. The mixture was stirred at 20°C for 30 minutes. At 0°C, the reaction mixture was quenched with saturated NH4Cl (150 mL) and extracted with EA (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography eluted with petroleum ether:ethyl acetate (50%–100%). The crude product was purified by recrystallization from PE (20 mL) at 0°C, removing minor by-products during the recrystallization process. The results were confirmed by chiral analysis (CHIRALPAK IC-3 AS (150 mm x 4.6 mm, 3 µm), A: CO2, B: isopropyl alcohol (0.05% DEA), flow rate: 2.5 mL / min), and the compound 82-3 The de value exceeded 98%. Compound (R)-N-((*S)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide (12.1 g, yield 31%) was obtained as a white solid.

[0595] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.51 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 2.4, 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 5.38 (d, J = 6.8 Hz, 1H), 4.24 (dd, J= 6.8, 9.6 Hz, 1H), 2.80-2.65 (m, 1H), 2.12-2.00 (m, 1H), 1.95-1.83 (m, 1H), 1.79-1.61 (m, 4H), 1.04 (s, 9H).

[0596] Step 3: Synthesis of (*S)-(5-chloropyridine-2-yl)(cyclobutyl)methaneamine

[0597]

[0598] ( R )-N-(( *S )- N Hydrochloric acid / dioxane (4 M, 30 mL) was added to a solution of DCM (20 mL) containing -((5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-methylpropane-2-sulfinamide (11 g, 36.6 mmol). The mixture was stirred at 20°C for 4 hours, and the mixture was concentrated under reduced pressure. The crude product was purified by recrystallizing it from DCM (60 mL) at 20°C, and compound (*S)-(5-chloro-2-pyridyl)-cyclobutyl-methaneamine (9 mg, crude product, HCl salt) was obtained as a white solid.

[0599] LCMS (ESI + ): m / z 197.1 [M+H] + .

[0600] Step 4: Synthesis of tert-butyl(S)-5-amino-4-(5-((*S))-(5-chloropyridine-2-yl)(cyclobutyl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0601] HATU (5.6 g, 14.7 mmol) was added to a mixture of DMAC (50 mL) containing (*S)-(5-chloro-2-pyridyl)-cyclobutyl-methaneamine (3.25 g, 12.3 mmol, HCl salt), (S)-2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-carboxylic acid (4.67 g, 12.9 mmol), and NMM (6.2 g, 61.3 mmol). The mixture was degassed and purged three times with N2. The mixture was stirred for 12 hours under N2 protection at 25°C. The mixture was poured into saturated NaCl (100 mL), filtered, and washed with water (100 mL). The filter cake was dissolved in DCM (200 mL), washed with saturated NaHCO3 (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The compound tert-butyl(S)-5-amino-4-(5-((*S))-(5-chloropyridine-2-yl)(cyclobutyl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (6.5 g, yield 95.0%) was obtained as a white solid.

[0602] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.96 (d, J = 8.0 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.96 (dd, J = 2.4, 8.4 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 5.30-5.11 (m, 1H), 4.81 (m, 1H), 4.75-4.52 (m, 2H), 2.98-2.86 (m, 1H), 2.27-2.12 (m, 4H), 1.98-1.78 (m, 6H), 1.39 (s, 9H); LCMS (ESI+ ): m / z 541.4 [M+H] + .

[0603] Step 5: Synthesis of Compound 82: N-((*S)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide

[0604]

[0605] Benzenesulfonic acid (1.1 g, 7.21 mmol) was added to a solution of CH3CN (13 mL) containing tert-butyl(S)-5-amino-4-(5-((*S))-(5-chloropyridine-2-yl)(cyclobutyl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.3 g, 2.4 mmol). The mixture was stirred for 14 hours at 70°C under N2 protection. The mixture was diluted with DCM (60 mL), washed twice with saturated NaHCO3 (30 mL x 2), washed with water (30 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was ground with EA (5 mL) and MTBE (5 mL) at 25°C for 0.5 hours. Compound N-((*S)-(5-chloropyridine-2-yl)(cyclobutyl)methyl)-2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (0.79 g, yield 87%, purity 99%) was obtained as a white solid.

[0606] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.01 (s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.57-8.52 (m, 1H), 8.06 (s, 1H), 8.02-7.95 (m, 1H), 7.91-7.87 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.49 (d, J= 8.4 Hz, 1H), 5.19-5.05 (m, 2H), 4.57-4.34 (m, 2H), 2.97-2.81 (m, 2H), 2.65-2.56 (m, 1H), 2.45-2.35 (m, 1H), 2.12-1.97 (m, 2H), 1.91-1.71 (m, 5H); LCMS (ESI + ): m / z 467.2 [M+H] + , Duration of stay: 4.028 min; SFC Duration of stay: 4.593 min.

[0607] Example 16

[0608] Preparation of Compound 83: N-((*S)-cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methyl)-2-((S)-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide

[0609]

[0610] Plan 13

[0611] Step 1: Synthesis of 3-(4-fluorophenyl)-picolinealdehyde

[0612]

[0613] A mixture of H2O (6 mL) and CH3CN (30 mL) containing 3-chloropicolinaldehyde (3.00 g, 21.2 mmol), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.65 g, 25.4 mmol), Na2CO3 (6.74 g, 63.6 mmol), and Pd(dppf)Cl2 (1.55 g, 2.12 mmol) was degassed and purged three times with N2, then stirred for 12 hours at 100°C under N2 protection. At 20°C, the reaction mixture was poured into water (10 mL) and extracted with EA (25 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0–100% ethyl acetate / petroleum ether gradient @ 40 mL / min). Compound 3-(4-fluorophenyl)pyridine-2-carbaldehyde (4.20 g, yield 98.5%) was obtained as a colorless oil. 1 HNMR (400 MHz, DMSO- d 6) δ 10.06-9.93 (m, 1H), 8.83 (dd, J = 1.6, 4.4 Hz, 1H), 7.92 (dd, J = 1.2, 7.6 Hz, 1H), 7.73 (dd, J = 4.4, 7.6 Hz, 1H), 7.57-7.46 (m, 2H), 7.36-7.28 (m, 2H).

[0614] Step 2: Synthesis of (S)-N-((3-(4-chlorophenyl)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide

[0615]

[0616] A mixture of DCM (40 mL) containing 3-(4-fluorophenyl)picolinealdehyde (4.20 g, 21.0 mmol), (S)-2-methylpropane-2-sulfinamide (2.29 g, 18.9 mmol), PPTS (527 mg, 2.10 mmol), and CuSO4 (6.70 g, 41.9 mmol) was degassed and purged three times with N2, then stirred for 12 hours under N2 protection at 20°C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the DCM. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, 0–50% ethyl acetate / petroleum ether gradient eluent @ 20 mL / min). The compound SN-((3-(4-chlorophenyl)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.20 g, yield 18.8%) was obtained as a colorless oil.

[0617] 1 HNMR (400 MHz, DMSO- d 6) δ 8.80 (dd, J = 1.6, 4.4 Hz, 1H), 8.53-8.37 (m, 1H), 7.89 (dd, J = 1.6, 7.6 Hz, 1H), 7.65 (dd, J = 4.4, 7.6 Hz, 1H), 7.51-7.41 (m, 2H), 7.37-7.25 (m, 2H), 1.06 (s, 9H).

[0618] Step 3: Synthesis of (*S)-N-(cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide

[0619]

[0620] Bromo(cyclobutyl)magnesium (0.5 M, 15.4 mL) was added to a solution of THF (10 mL) containing (S)-N-(3-(4-fluorophenyl)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.17 g, 3.84 mmol). The mixture was stirred for 3 hours at -70°C under N2 protection. At 0°C, the reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0–50% ethyl acetate / petroleum ether gradient eluent @ 40 mL / min) to obtain the desired elution peak 2, which was compound 83-5, and the retention time of the isomer was determined by detecting it by chiral HPLC. Compound (*S)-N-(cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (45 mg, yield 3.25%) was obtained as a white solid.

[0621] LCMS (ESI + ): m / z 363.3 [M+H] + .

[0622] Step 4: Synthesis of Cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methaneamine

[0623]

[0624] Hydrochloric acid / dioxane (4 M, 665 μL) was added to a solution of DCM (10 mL) containing (*S)-N-(cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (40 mg, 111 μol). The mixture was stirred at 20°C for 1 hour, and the reaction mixture was concentrated under reduced pressure. The compound (*S)-cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methaneamine (32 mg, HCl salt, crude product) was obtained as a white solid and used directly in the next step without further purification.

[0625] Step 5: N-((*S)-cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide(compound 83)

[0626]

[0627] TEA (22.1 mg, 219 µmol) was added to a mixture of DCM (5 mL) containing cyclobutyl (3-(4-fluorophenyl)pyridine-2-yl)methaneamine (32.0 mg, 109 µmol, HCl salt), 2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolinone-5-carboxylic acid (34.7 mg, 120 µmol), and T3P (69.6 mg, 109 µmol). The mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the DCM. The residue was purified by preparative high-performance liquid chromatography (FA conditions). Compound N-((*S)-cyclobutyl(3-(4-fluorophenyl)pyridine-2-yl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (9.66 mg, yield 16.8%) was obtained as a white solid.

[0628] 1 HNMR (400 MHz, DMSO- d 6) δ 11.03 (br. s., 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.58 (d, J = 4.2 Hz, 1H), 8.08 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 7.6 Hz,1H), 7.72 (dd, J = 5.6, 8.4 Hz, 2H), 7.61 (dd, J = 1.6, 7.6 Hz, 1H), 7.42-7.31 (m, 3H), 5.40-5.29 (m, 1H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 4.57-4.31 (m, 2H), 2.98-2.88 (m, 1H), 2.82-2.74 (m, 1H), 2.66 (d, J= 17.2 Hz, 1H), 2.43-2.37 (m, 1H), 2.07-1.93 (m, 2H), 1.70-1.48 (m, 4H), 1.27-1.21 (m, 1H); LCMS (ESI + ): m / z 527.3 [M+H] + .

[0629] Example 17

[0630] Preparation of Compound 84: N-((*S)-cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)-2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide

[0631]

[0632] Plan 14

[0633] Step 1: Synthesis of 3-(1-methyl-1H-pyrazole-4-yl)picolinealdehyde

[0634]

[0635] Pd(dppf)Cl2 (517 mg, 706 µmol) was added to a mixture of water (7 mL) and dioxane (35 mL) containing 3-chloropyridine-2-carbaldehyde (2.00 g, 14.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.53 g, 17.0 mmol), and K2CO3 (3.91 g, 28.3 mmol) under N2 protection at 25°C. The mixture was stirred for 6 hours at 80°C under N2 protection. The reaction mixture was poured into water (20 mL) and extracted with EA (40 mL x 2). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0–100% ethyl acetate / petroleum ether gradient @ 40 mL / min). Compound 3-(1-methylpyrazole-4-yl)pyridine-2-carbaldehyde (1.7 g, yield 64.28%) was obtained as a brown solid.

[0636] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 10.18-10.05 (m, 1H), 8.69 (dd,J = 1.6, 4.4 Hz, 1H), 8.12 (s, 1H), 8.00 (dd, J = 1.2, 7.6 Hz, 1H), 7.78 (s, 1H), 7.66 (m, 1H), 3.91 (m, 3H).

[0637] Step 2: Synthesis of 2-methyl-N-((3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methylene)propane-2-sulfinamide

[0638]

[0639] 2-methylpropane-2-sulfinamide (1.55 g, 12.8 mmol) was added to a mixture of DCM (10 mL) containing 3-(1-methylpyrazole-4-yl)pyridine-2-carbaldehyde (1.60 g, 8.55 mmol), CuSO4 (2.73 g, 17.1 mmol), and PPTS (215 mg, 855 μmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0–20% ethyl acetate / petroleum ether gradient @ 20 mL / min). The compound 2-methyl-N-((3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methylene)propane-2-sulfinamide (1.70 g, yield 94.44%) was obtained as a yellow oil.

[0640] 1 HNMR (400 MHz, DMSO- d 6) δ 8.73-8.61 (m, 1H), 8.73-8.61 (m, 1H), 8.01 (s, 1H), 7.93 (dd, J = 1.6, 8.0 Hz, 1H), 7.66-7.47 (m, 2H), 3.91 (s, 3H), 1.17 (s, 9H).

[0641] Step 3: Synthesis of N-(cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide

[0642]

[0643] Bromo(cyclobutyl)magnesium (0.5 M, 9.12 mL) was added to a solution of THF (10 mL) containing 2-methyl-N-((3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methylene)propane-2-sulfinamide (1.26 g, 3.04 mmol) under N2 protection at -70°C. The mixture was stirred at 20°C for 2 hours. At 0°C, the reaction mixture was quenched with water (10 mL) and extracted with EA (25 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0–30% ethyl acetate / petroleum ether gradient @ 20 mL / min) to obtain N-(cyclobutyl-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (150 mg, yield 14.2%) as a colorless oil.

[0644] 1 H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.52 (dd, J = 5.6, 7.6 Hz, 1H), 5.79 (d, J = 8.4 Hz, 1H), 4.79-4.51 (m, 1H), 4.00 (s, 3H), 2.88-2.69 (m, 1H), 2.12-2.02 (m, 1H), 1.84-1.72 (m, 2H), 1.70-1.45 (m, 3H), 1.19 (s, 9H).

[0645] Step 4: Synthesis of cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methaneamine

[0646]

[0647] Hydrochloric acid / dioxane (4 M, 1.08 mL) was added to a DCM (3 mL) solution containing N-(cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (100 mg, 288 μmol). The mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure. The compound cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methaneamine (150 mg, crude product, HCl salt) was obtained as a white solid and used directly in the next step without further purification. LCMS (ESI + ): m / z 242.9 [M+H] + .

[0648] Step 5: Synthesis of tert-butyl(4S)-5-amino-4-(5-((cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0649]

[0650] TEA (109 mg, 1.08 mmol) and T3P (342 mg, 538 μmol) were added to a solution of DCM (10 mL) containing cyclobutyl (3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methaneamine (150 mg, 538 μmol, HCl salt) and (S)-2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-carboxylic acid (214 mg, 592 μmol). The mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0–100% ethyl acetate / petroleum ether gradient @ 15 mL / min). The compound tert-butyl(4S)-5-amino-4-(5-((cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (120 mg, yield 38.01%) was obtained as a white solid. LCMS (ESI + ): m / z 586.9 [M+H] + .

[0651] Step 6: tert-butyl(S)-5-amino-4-(5-(((*S)-cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0652]

[0653] tert-butyl(4S)-5-amino-4-(5-((cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (120 mg, 256 μmol) was purified using a preparative SFC (column: Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 μm); mobile phase: 0.1% NH3H2O ​​MeOH; starting B%: 50%, flow rate 80 mL / min). The compound tert-butyl(S)-5-amino-4-(5-(((*R)-cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (75 mg, yield 50%) was obtained as a white solid, and peak 1 (R t = 2.295 min; de%: 100%); the compound tert-butyl(S)-5-amino-4-(5-(((*S)-cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (70 mg, yield 46.67%) was obtained as a white solid, and peak 2(R t = 3.495 min; de%: 99.4%).

[0654] Step 7: N-((*S)-cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)-2-((S)-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide(compound 84)

[0655]

[0656] A mixture of CH3CN (10 mL) containing tert-butyl(S)-5-amino-4-(5-(((*S)-cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (70 mg, 119 μmol) and benzenesulfonic acid (56.6 mg, 358 μmol) was degassed and purged three times with N2. The mixture was stirred at 90°C for 3 hours under N2 protection. The mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase high-performance liquid chromatography (FA conditions). Compound N-((*S)-cyclobutyl(3-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)methyl)-2-((S)-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (18.09 mg, yield 29.6%, purity 100%) was obtained as a white solid.

[0657] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.01 (br. s., 1H), 8.78 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 3.6 Hz, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 8.03-7.99 (m, 1H), 7.88 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.69-7.62 (m, 1H), 7.33-7.24 (m, 1H), 5.70-5.60 (m, 1H), 5.18-5.08 (m, 1H), 4.57-4.34 (m, 2H), 3.95 (s, 3H), 2.99-2.80 (m, 2H), 2.68-2.56 (m, 1H), 2.47-2.36 (m, 1H), 2.08-1.92 (m, 2H), 1.86-1.75 (m, 1H), 1.74-1.55 (m, 3H), 1.47-1.35 (m, 1H); LCMS (ESI + ): m / z 513.4 [M+H] +, Duration of stay: 2.221 min; SFC Duration of stay: 3.581 min.

[0658] Example 18

[0659] Preparation of Compound 85: N-((*R)-(3-chloro-5-fluoropyridine-2-yl)(1-fluorocyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide

[0660]

[0661] Plan 15

[0662] Step 1: Synthesis of 1-Fluorocyclobutane-1-Carbaldehyde

[0663]

[0664] DIBAL-H (1 M, 49.3 mL) was added dropwise to a mixture of DCM (40 mL) and THF (40 mL) containing ethyl 1-fluorocyclobutanecarboxylate (4.00 g, 27.4 mmol) under N2 protection at -78°C. The mixture was stirred for 10 minutes under N2 protection at -78°C. The mixture was quenched with water (2 mL), 15% NaOH (2 mL), and water (5 mL). It was stirred at 0°C for 0.5 hours, dried with anhydrous Na2SO4, and filtered to obtain the crude residue. The compound 1-fluorocyclobutanecarbaldehyde (4 g, crude product) was obtained as a yellow liquid and used in the next step without further purification.

[0665] Step 2: Synthesis of (R)-N-(1-fluorocyclobutyl)methylene)-2-methylpropane-2-sulfinamide

[0666]

[0667] PPTS (98.5 mg, 39.0 µmol) and CuSO4 (1.25 g, 7.83 mmol) were added to a 10 mL DCM solution containing 1-fluorocyclobutanecarbaldehyde (400 mg, 3.92 mmol, crude product) and (R)-2-methylpropane-2-sulfinamide (950 mg, 7.83 mmol). The mixture was stirred at 20°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 20 g eluent, 0–100% ethyl acetate / petroleum ether gradient @ 20 mL / min). Compound (R)-N-(1-fluorocyclobutyl)methylene)-2-methylpropane-2-sulfinamide (600 mg, yield 74.6%) was obtained as a colorless oil. LCMS (ESI + ): m / z 206.9 [M+H] +

[0668] Step 3: Synthesis of (R)-N-((*R)-(3-chloro-5-fluoropyridine-2-yl)(1-fluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide

[0669]

[0670] Bromo(isopropyl)magnesium (2.8 M, 686 μL) was added to a solution of THF (5 mL) containing 2-bromo-3-chloro-5-fluoro-pyridine (404 mg, 1.92 mmol) at -78°C under N2 protection. The mixture was stirred at 20°C for 2 hours. The crude product was added to a mixture of THF (5 mL) containing (R)-N-(1-fluorocyclobutyl)methylene)-2-methylpropane-2-sulfinamide (90.0 mg, 438 μmol) at -65°C under N2 protection. The mixture was stirred at 20°C for 2 hours. At 0°C, the reaction mixture was quenched with water (15 mL) and extracted with EA (25 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purifying the residue by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0–50% ethyl acetate / petroleum ether gradient @ 20 mL / min), the retention time was determined by SFC to obtain the target compound 85-4, and only one compound was obtained. Compound (R)-N-((*R)-(3-chloro-5-fluoropyridine-2-yl)(1-fluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide (60 mg, yield 42.93%) was obtained as a colorless oil.

[0671] 1 HNMR (400 MHz, DMSO- d 6) δ 8.65 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 2.4, 8.8 Hz, 1H), 5.85 (d, J = 10.4 Hz, 1H), 5.10-4.88 (m, 1H), 2.63-2.55 (m, 2H), 2.30-2.11 (m, 3H), 1.84-1.77 (m, 1H), 1.04 (s, 9H).

[0672] Step 4: Synthesis of (*R)-(3-chloro-5-fluoropyridine-2-yl)(1-fluorocyclobutyl)methaneamine

[0673]

[0674] Hydrochloric acid / dioxane (4 M, 5 mL) was added to a solution of DCM (3 mL) containing (R)-N-((*R)-(3-chloro-5-fluoropyridine-2-yl)(1-fluorocyclobutyl)methyl)-2-methylpropane-2-sulfinamide (60.0 mg, 178 μmol). The mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure. The compound (*R)-(3-chloro-5-fluoro-2-pyridyl)(1-fluorocyclobutyl)methaneamine (45 mg, crude product, hydrochloric acid) was obtained as a white solid. LCMS (ESI + ): m / z 235 [M+H] + .

[0675] Step 5: Synthesis of N-((*R)-(3-chloro-5-fluoropyridine-2-yl)(1-fluorocyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (Compound 85):

[0676]

[0677] T3P (106 mg, 167 µmol) was added to a mixture of DCM (5 mL) containing (*R)-(3-chloro-5-fluoro-2-pyridyl)(1-fluorocyclobutyl)methaneamine (45.0 mg, 167 µmol), 2-(2,6-dioxopiperidin-3-alkanoyl)-1-oxoisoindolin-5-carboxylic acid (53.0 mg, 184 µmol), and TEA (33.9 mg, 334 µmol), and the mixture was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to remove the DCM. The crude product was purified by reverse-phase high-performance liquid chromatography (FA conditions). Compound N-((*R)-(3-chloro-5-fluoropyridine-2-yl)(1-fluorocyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide (39.29 mg, yield 46.72%) was obtained as a white solid.

[0678] 1 ¹H NMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 9.00 (d, J= 8.4 Hz, 1H), 8.65 (s, 1H), 8.19-8.13 (m, 1H), 8.10 (s, 1H), 8.04-7.94 (m, 1H), 7.80 (d, J = 7.6 Hz, 1H), 6.03 (dd, J = 8.4, 17.6 Hz, 1H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 4.57-4.33 (m, 2H), 2.98-2.86 (m, 1H), 2.67-2.59 (m, 2H), 2.47-2.37 (m, 2H),2.33-2.19 (m, 2H), 2.07-1.99 (m, 1H), 1.90-1.78 (m, 1H), 1.56-1.44 (m, 1H); LCMS (ESI + ): m / z 503.3 [M+H] + , duration of stay: 3.162 min; SFC duration of stay: 1.279 min and 1.422 min.

[0679] Example 19

[0680] The preparation of the following compound is similar to the steps according to compound 84, using the corresponding starting materials aldehyde and Grignard reagent and the following coupling step ( Example 18 ).

[0681] compound 86, 87, 88 and 89 In the case of, the corresponding sulfonimide diastereomer intermediate was separated by preparative high-performance liquid chromatography or SFC prior to the following step.

[0682] 86 2-(2,6-dioxopiperidin-3-yl)- N -(( *R )-(1-fluorocyclobutyl)(5-fluoropyridine-2-yl)methyl)-1-oxoisoindolin-5-carboxamide 1 HNMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 9.18 (d, J = 8.8 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.79-7.71 (m, 2H), 5.68-5.52 (m, 1H), 5.16 (dd, J = 5.2, 13.2 Hz, 1H), 4.58-4.35 (m, 2H), 2.99-2.86 (m, 1H), 2.71-2.58 (m, 1H), 2.46-2.42 (m, 1H), 2.40-2.22 (m, 3H), 2.18-2.00 (m, 2H), 1.90-1.75 (m, 1H), 1.62-1.48 (m, 1H); LCMS (ESI + ): m / z 469.3 [M+H] + ; Duration of stay: 3.483 min; SFC Duration of stay: 1.991 min and 2.121 min. 87 N -[( *R )-(3-chloro-2-pyridyl)-(1-fluorocyclobutyl)methyl]-2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-carboxamide 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 10.96 (s, 1H), 8.97-8.85 (m, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.46-8.40 (m, 0.156H), 8.16-8.07 (m, 1H), 8.03-7.91 (m, 2H), 7.84-7.72 (m, 1H), 7.49 -7.37 (m, 1H), 6.14-5.97 (m, 1H), 5.21-5.05 (m, 1H), 4.57-4.45 (m, 1H), 4.45-4.29 (m, 1H), 2.98-2.83 (m, 1H), 2.66-2.57 (m, 2H), 2.45-2.34 (m, 2H), 2.31-2.18 (m, 2H), 2.08 -1.97 (m, 1H), 1.90-1.74 (m, 1H), 1.52-1.37 (m, 1H).LCMS (ESI+): m / z 485.3 [M+H] + , Duration of stay: 1.778 min. SFC: Duration of stay: 1.367 min, 1.629 min. 88 2-(2,6-dioxopiperidin-3-yl)- N -(( *R )-(1-fluorocyclobutane)(3-fluoropyridine-2-yl)methyl)-1-oxoisoindolin-5-carboxamide 1 HNMR (400 MHz, DMSO- d 6) δ 11.02 (s, 1H), 9.16-8.90 (m, 1H), 8.51-8.43 (m, 1H), 8.16-8.06 (m, 1H), 8.03-7.96 (m, 1H), 7.85-7.73 (m, 2H), 7.53-7.44 (m, 1H), 5.92-5.77 (m, 1H), 5.20-5.03 (m, 1H), 4.57-4.33 (m, 2H), 3.02-2.85 (m, 1H), 2.64-2.57 (m, 1H), 2.49-2.35 (m, 3H), 2.30-2.16 (m, 2H), 2.06-1.98 (m, 1H), 1.89-1.75 (m, 1H), 1.53-1.41 (m, 1H);LCMS (ESI + ): m / z 469.3 [M+H] + , duration of stay: 2.033 min; SFC duration of stay: 4.040 min and 5.320 min. 89 N -(( *R )-(5-chloro-3-fluoropyridine-2-yl)-(1-fluorocyclobutyl)methyl)-2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindolin-5-carboxamide 1 HNMR (400 MHz, DMSO- d 6) δ 11.03 (s, 1H), 9.15 (d, J = 8.4 Hz, 1H), 8.64-8.52 (m, 1H), 8.16 (dd, J = 2.0, 9.6 Hz, 1H), 8.11 (s, 1H), 8.00 (dd, J = 2.4, 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 5.86-5.75 (m, 1H), 5.15 (dd, J = 5.2, 13.2 Hz, 1H), 4.56-4.36 (m, 2H), 2.98-2.87 (m, 1H), 2.63-2.59 (m, 1H), 2.47-2.35 (m, 3H), 2.30-2.19 (m, 2H), 2.07-2.00 (m, 1H), 1.89-1.80 (m, 1H), 1.58-1.49 (m, 1H);LCMS (ESI + ): m / z 503.2 [M+H] + , duration of stay: 3.210 min; SFC duration of stay: 12.397 min and 12.704 min.

[0683] Example 20

[0684] Example 20

[0685] CK1a and GSPT1 Decomposition Analysis (HiBiT Analysis)

[0686] The following is an example of an assay that can be used to determine the dose-dependent CK1a and GSPT1 degradation activities of a test compound in human cell lines such as HT-1080 (ATCC Cat# CRL-9591).

[0687] Wild-type CRBN, GSPT1Δ(1-138) / G575N mutants, and HT-1080 cells stably overexpressing CK1α or GSPT1 tagged with HiBiT were seeded into 384-well plates (Cat# 3764, Corning) pre-dropped with DMSO or the test compound. Using an Echo Acoustic Liquid Handler (Beckman Coulter), increasing concentrations of the test compound (3.162 x 10⁶) were applied. -4 CK1α or DMSO (in a 3.16-fold increasing range from μM to 10 μM) or DMSO was dispensed into empty 384-well plates. Approximately 10,000 cells in full DMEM cell culture medium were seeded per well. After incubating the assay plates at 37°C and 5% CO2 for 20 hours, CK1α or GSPT1 degradation was evaluated using the Nano-Glo HiBiT solubility detection reagent (Cat# N3050, Promega) according to the manufacturer's instructions. Then, luminescence was measured using an EnVision plate reader (PerkinElmer) or a PHERAstar plate reader (BMG Labtech). All CK1α or GSPT1 degradation curves were processed using Collaborative Drug Discovery Vault software (Burlingame, CA., www.collaborativedrug.com).

[0688] The levels of CK1α or GSPT1 in the compound-treated wells were normalized with respect to the levels in the DMSO control and expressed as the percentage PoC (y) of the control. The EC of the compound was determined using a 4-parameter logical regression model. 50 and DC 50 Determine , and the calculation formula is as follows:

[0689] y = (A+((BA) / (1+((C / x) A D))))

[0690] A = Lowest CK1α or GSPT1 levels normalized to the DMSO control in response to compound treatment as determined by curve fitting

[0691] B = CK1α or GSPT1 levels in DMSO control group

[0692] C = EC 50

[0693] D = Hill slope

[0694] x = concentration of the compound

[0695] EC 50 Concentration of the compound when y = (BA) / 2

[0696] DC 50 = y = Concentration of the compound at 50% of the DMSO control (50% CK1α or GSPT1 degradation)

[0697] y = CK1α or GSPT1 protein levels normalized to the DMSO control group

[0698] D max = (1- A / B) * 100%

[0699] D max represents the maximum CK1α or GSPT1 protein degradation % achievable by compound treatment at the highest compound concentration in the analysis.

[0700] result:

[0701] Using the above analysis, D of the representative compound in Table 7 max and DC 50 The data was determined:

[0702] Compound number HiBiT CK1a: DC 50 (μM) HiBiT CK1a: D max (%) HiBiT GSPT1: D max (%) Compound number HiBiT CK1a: DC 50 (μM) HiBiT CK1a: D max (%) HiBiT GSPT1: D max (%) 1 0.221 66.2 37 39 0.363 61 32.5 2 0.18 67 33.6 40 0.416 57.5 30.6 3 5.19 50.6 73.1 41 0.0824 70.5 24.9 4 0.183 63.4 31.1 42 1.15 57.7 40.8 5 0.243 75.9 30.3 43 0.0496 69.8 58.2 6 0.234 60.9 30.1 44 NA 49.5 22.5 7 0.0817 71.8 28.6 45 0.0578 73.8 42.4 8 0.16 72.9 23.4 46 1.3 54.6 32.4 9 0.116 71.6 22.6 47 2.96 56.1 29.7 10 0.706 60.8 36 48 0.13 66.2 26.2 11 0.308 64.7 23.4 49 0.112 68.6 28.6 12 0.14 64.7 36.8 50 0.237 63.1 42.7 13 0.293 65.9 37 51 0.142 62.3 46 14 0.284 67.1 45.5 52 0.095 73.9 28.5 15 0.0666 73.2 24.5 53 0.118 70.2 24.2 16 0.303 62.2 44.9 54 1.11 56.5 47.9 17 0.123 68.1 49.3 55 0.948 57.8 48 18 0.137 66 58.5 56 0.0937 63.6 15.3 19 0.0659 69.6 43 57 0.128 64.4 19.1 20 0.0364 71.2 42 58 NA 49.7 16.5 21 0.132 60.6 20.6 59 NA 32.2 7.93 22 0.0797 70.7 48.3 60 < 0.0471 49 27.4 23 0.198 61.3 32 61 NA 49.5 29.3 24 0.363 63.2 63.1 62 0.0777 69.8 27.5 25 1.58 54.5 48.4 63 0.0535 72.2 29 26 0.417 58.4 30.7 64 0.162 66.7 27.9 27 0.345 59.3 40.3 65 0.721 59.6 23.1 28 1.15 60.1 70.8 66 0.118 67.9 55.3 29 0.553 58.8 22 67 0.04 76.4 31.7 30 NA 47.9 62.1 68 0.789 55.4 48.3 31 NA 48.1 60 69 0.0627 74 26 32 0.198 59.3 36.3 70 0.0503 73.9 58 33 1.3 56.3 66.3 71 0.455 61.7 19.1 34 0.446 59.5 25.8 72 0.132 65.5 45.2 35 0.0947 67 14.8 73 0.0735 71.4 30.4 36 0.0667 65.8 24.6 74 0.233 59.2 62.3 37 0.0727 70.8 36.2 75 3.88 50.4 24.1 38 0.218 64.1 19.9 76 0.219 64.4 23.5 77 NA 41.1 23.5 84 0.0741 72.4 15.2 78 0.198 67.2 14.4 85 0.0939 65.3 16.2 79 0.274 65.9 20.4 86 0.193 63 18.2 80 0.652 61.1 14.2 87 0.279 59.8 25 81 0.153 62.1 18.4 88 0.394 55.4 14.9 82 0.105 66.3 16.2 89 0.148 69 17.3 83 0.115 66 14.4 CC-885 0.653 53.7 92.5

[0703]

[0704] The reference compound CC-885 was synthesized according to the published literature (Hanson et al., J Med Chem (2018) 61:492503). Compared to other test compounds, CC-885 exhibited similar CK1α degradation activity (Table 7). However, CC-885 can also effectively degrade GSPT1. Those skilled in the art are well aware that the degradation of GSPT1 causes serious toxicity to humans (Uy et al., Blood (2019) 134 (Supplement 1):232).

[0705] NA: Cannot calculate.

[0706] Example 21

[0707] MV4-11 Cell Proliferation Analysis

[0708] The following is an example of an assay that can be used to determine the dose-dependent antiproliferative activity of CK1α degradation compounds in AML cell lines such as MV4-11 (ATCC Cat# CRL-9591).

[0709] MV4-11 cells were seeded into 384-well plates (Cat# 3764, Corning) pre-dropped with DMSO or the test compound. Using a D300e digital dispenser (Tecan) or an Echo acoustic liquid handler (Beckman Coulter), increasing concentrations of the test compound (1 x 10 in a 10-point dose-response assay) were administered. -3 3.162-fold increase range from μM to 10 μM; 3.162x10 in 11-point dose-response analysis -4DMSO (ranging from μM to 10 μM in a 3.162-fold increase) or DMSO was dispensed into empty 384-well plates. Approximately 2,000 cells in 50 μL of culture medium (IMDM + 10% heat-inactivated FBS) were seeded per well. After incubating the assay plates at 37°C and 5% CO2 for 120 hours, 20 μL of CellTiter-Glo luminescence cell viability assay reagent (Cat# G7573, Promega) was added to each well and incubated at room temperature for 30 minutes. Then, luminescence was measured using an EnVision plate reader (PerkinElmer) or a PHERAstar plate reader (BMG Labtech). All cell growth inhibition curves were processed using Collaborative Drug Discovery Vault software (Burlingame, CA., www.collaborativedrug.com).

[0710] The cell viability readings of the compound-treated wells were normalized with respect to the DMSO control readings and expressed as a percentage of the control (PoC, y). The EC of the compound was determined using a 4-parameter logical regression model. 50 and DC 50 Determine , and the calculation formula is as follows:

[0711] y = (A+((BA) / (1+((C / x) A D))))

[0712] A = Lowest cell viability reading normalized to the DMSO control in response to compound treatment as determined by curve fitting

[0713] B = Cell viability readings in the DMSO control group

[0714] C = EC 50

[0715] D = Hill slope

[0716] x = concentration of the compound

[0717] EC 50Concentration of the compound when y = (BA) / 2

[0718] DC 50 = y = Concentration of the compound at 50% of the DMSO control

[0719] y = Cell viability readings normalized for the DMSO control group

[0720] Y min = A / B * 100%

[0721] Y min % represents the lowest cell viability that can be achieved by compound treatment in the analysis.

[0722] Compound number CTG Cell Viability Analysis MV4-11: IC 50 (μM) Compound number CTG Cell Viability Analysis MV4-11: IC 50 (μM) 7 0.112 76 0.071 8 0.205 78 0.176 9 0.172 79 0.176 4 0.262 82 0.060 5 0.363 83 0.027 6 0.691 84 0.024 35 0.198 85 0.102 41 0.115 86 0.142 42 0.42 87 0.133 36 0.128 89 0.198

[0723] KG-1a cell proliferation analysis While maintaining the underlying mechanism of the antitumor response to CK1α inactivation in AML (Jaras et al., J Exp Med (2014) 211(4):605-612), we found that AML cell lines with loss of function in p53 are insensitive to CK1α degradation. Additionally, most AML cell lines have been reported to be sensitive to GSPT1 degradation induced by CC-885 or CC-90009, regardless of p53 mutation status (Matyskiela et al., Nature (2016) 535:252-257; Surka et al., Blood (2021) 137(5): 661-677). Since mild to moderate degradation of GSPT1 induced by CK1α degraders with weak activity against GSPT1 can still cause toxicity in humans, a counter screen was performed using AML cell lines carrying p53 mutations such as KG-1a (ATCC Cat# CCL-246.1) to determine in vitro GSPT1-mediated cytotoxicity.

[0724] The following is an example of an assay that can be used to determine the potential GSPT1-dependent cytotoxicity of a test compound that degrades GSPT1.

[0725] KG-1a cells were seeded into 384-well plates (Cat# 3764, Cormning) pre-dropped with DMSO or the test compound. Using a D300e digital dispenser (Tecan) or an Echo acoustic liquid handler (Beckman Coulter), increasing concentrations of the test compound (1 x 10 in a 10-point dose-response assay) were administered. -3 3.162-fold increase range from μM to 10 μM; 3.162x10 in 11-point dose-response analysis -4 DMSO (ranging from μM to 10 μM in a 3.162-fold increase) or DMSO was dispensed into empty 384-well plates. Approximately 2,000 cells in 50 μL of culture medium (IMDM + 10% heat-inactivated FBS) were seeded per well. After incubating the assay plates at 37°C and 5% CO2 for 120 hours, 20 μL of CellTiter-Glo luminescence cell viability assay reagent (Cat# G7573, Promega) was added to each well and incubated at room temperature for 30 minutes. Then, luminescence was measured using an EnVision plate reader (PerkinElmer) or a PHERAstar plate reader (BMG Labtech). All cell growth inhibition curves were processed using Collaborative Drug Discovery Vault software (Burlingame, CA., www.collaborativedrug.com).

[0726] The cell viability readings of the compound-treated wells were normalized with respect to the DMSO control readings and expressed as a percentage of the control (PoC, y). The EC of the compound was determined using a 4-parameter logical regression model. 50 and DC 50 Determine , and the calculation formula is as follows:

[0727] y = (A+((BA) / (1+((C / x) A D))))

[0728] A = Lowest cell viability reading normalized to the DMSO control in response to compound treatment as determined by curve fitting

[0729] B = Cell viability readings in the DMSO control group

[0730] C = EC 50

[0731] D = Hill slope

[0732] x = concentration of the compound

[0733] EC 50 Concentration of the compound when y = (BA) / 2

[0734] DC 50 = y = Concentration of the compound at 50% of the DMSO control

[0735] y = Cell viability readings normalized for the DMSO control group

[0736] Y min = A / B * 100%

[0737] Y min represents the lowest cell viability % achievable by compound treatment at the highest compound concentration in the analysis.

[0738] No. CTG Cell Viability Analysis KG-1a: Y min (%) 7 91.7 4 90.9 35 92.1

[0739] *Note: In the KG-1a cell proliferation assay, the highest concentration used was 10 μM. All of these compounds induced less than 10% inhibition of cell proliferation at 10 μM of the tested compounds.

[0740] Example 22

[0741] Pharmacokinetic study of single intravenous and oral administration in mice

[0742] Sample Collection and Preparation: Blood samples were collected after intravenous injection or oral administration of the test compound, and the time of blood collection was recorded. Immediately after collecting the blood samples, they were transferred to a labeled centrifuge tube containing K2-EDTA and centrifuged to collect plasma. The plasma was then transferred to a pre-chilled centrifuge tube, rapidly frozen over dry ice, and stored in an ultra-low temperature refrigerator at -70±10℃ until LC-MS / MS analysis was performed.

[0743] Pharmacokinetic Data Analysis: Plasma drug concentration data of the compound in a non-compartment model were processed using pharmacokinetic software. Peak concentration (C max ), peak time (T max ) and quantifiable termination time can be obtained directly from the plasma concentration-time diagram. Using the log-linear trapezoidal method, the half-life (T1 / 2) and apparent volume of distribution (V dss ) and clearance (Cl), area under the time-plasma concentration curve from zero to the endpoint (AUC 0-inf Pharmacokinetic parameters such as ) were calculated.

[0744] parameters Compound 41 Compound 82 Compound 86 Mouse (2 mg / kg, intravenous injection) CL(mL / min / kg) 23 10.5 7.85 CO(ng / mL) 1856 6796 4912 t 1 / 2 (hr) 2.84 1.34 3.62 V ss (L / kg) 3.20 0.85 0.87 Mouse (10 mg / kg, oral) C max (ng / mL) 1573 6080 5690 T max (hr) 0.83 0.67 0.5 T 1 / 2 (hr) 2.72 2.03 2.12 AUC (0-inf) (mg / mL) 5867 13264 14940 F (%) 76.8 85 70.4

[0745] Experimental Conclusion: The compound of the present invention exhibited a low clearance rate, good oral exposure, and high oral bioavailability.

Claims

Claim 1 Compound represented by structural formula (I): (I), or as a pharmaceutically acceptable salt thereof, in the above structural formula (I): Moiety is 1-2 Rs a C selectively substituted by 3-7 Cycloalkyl, or 1-2 R a It is a 4-7-membered monocyclic heterocyclyl having 1-3 heteroatoms selected from N, O, and S, selectively substituted by; and each R a is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; Moiety is 1-2 Rs b A 6-membered aryl selectively substituted by, or 1-2 R b It is a 5-6-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S that are selectively substituted by, and each R b C0-C4 alkyl-(4-7-membered heterocycloalkyl) having one, two, or three heteroatoms independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, N, O, and S, and -C0-C4 alkylNR 11 R 12 Selected from, but R 11 and R 12 is a compound independently selected from hydrogen or C1-C6 alkyl. Claim 2 In claim 1, the compound is a compound represented by structural formula (I-1) or (I-2). (I-1), (I-2), or a pharmaceutically acceptable salt thereof; in the above structural formula, Moiety and Moiety is a compound as defined in paragraph 1. Claim 3 In Article 1, Moiety , , , and Selected from a group consisting of, wherein in each case, n is independently 0, 1, or 2; and in each case, X 1 is independently C, N, O, or S; in each case, X 2 is independently C, N, O, or S; in each case, X 3 is independently C, N, O, or S; in each case, X 4 is independently C, N, O, or S; in each case, X 5 is independently C, N, O, or S; in each case, X 6 is independently C, N, O, or S;R a is a compound as defined in paragraph 1. Claim 4 In Paragraph 3, Moiety is, and Selected from; in each case, n is independently 0, 1, or 2 and; R a is a compound as defined in Paragraph 3. Claim 5 In Article 1, Moiety ..., provided that, in each case, m is independently 0, 1, or 2; and in each case, Y 1 is independently C or N; in each case, Y 2 is independently C or N; in each case, Y 3 is independently C or N; in each case, Y 4 is independently C or N; in each case, Y 5 is independently C or N; R b is a compound as defined in paragraph 1. Claim 6 In Paragraph 5, Moiety , , , , and Selected from, wherein in each case, m is independently 0, 1, or 2; R b is a compound as defined in paragraph 5. Claim 7 In claim 1, the compound is a compound represented by a structural formula selected from the group consisting of structural formulas (II), (III), (IV), (V) and (VI): (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt thereof, wherein in the above structural formula, in each case, m is independently 0, 1, or 2; in each case, n is independently 0, 1, or 2; in each case, X 1 is independently C, N, O, or S; in each case, X 2 is independently C, N, O, or S; in each case, X 3 is independently C, N, O, or S; in each case, X 4 is independently C, N, O, or S; in each case, X 5 is independently C, N, O, or S; in each case, X 6 is independently C, N, O, or S; in each case, Y 1 is independently C or N; in each case, Y 2 is independently C or N; in each case, Y 3 is independently C or N; in each case, Y 4 is independently C or N; in each case, Y 5 is independently C or N and;R a and R b is a compound as defined in paragraph 1. Claim 8 In claim 7, the above compound is a compound represented by structural formula (I-7) or (I-8): (I-7), (I-8) or a pharmaceutically acceptable salt thereof; in the above structural formula, m, n, R a and R b is a compound as defined in paragraph 7 Claim 9 In claim 7, the above compound is a compound represented by structural formula (I-9) or (I-10): (I-9), (I-10) or a pharmaceutically acceptable salt thereof; in the above structural formula, m, n, R a and R b is a compound as defined in Paragraph 7. Claim 10 In Paragraph 1, each R a A compound independently selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. Claim 11 In Paragraph 1, each R b ... is a C0-C4 alkyl-(4-7-membered heterocycloalkyl) having one, two, or three heteroatoms independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, N, O, and S, and -C0-C4 alkylNR 11 R 12 Selected from, but R 11 and R 12 is a compound independently selected from hydrogen or C1-C6 alkyl. Claim 12 In claim 1, the compound or a pharmaceutically acceptable salt thereof is a compound selected from the following: Claim 13 In claim 1, the above compound is , A compound selected from. Claim 14 In claim 1, the above compound is A compound selected from. Claim 15 A pharmaceutical composition for treating proliferative diseases comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the proliferative disease comprises breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, lymphoid organ cancer, and hematological malignancies. Claim 16 A pharmaceutical composition according to claim 15, wherein the hematological malignant tumors include leukemia, lymphoma, and multiple myeloma. Claim 17 In paragraph 15, the above-mentioned hematological malignancies are acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, acute mononucleosis, hairy cell leukemia, T-cell prolymphocytic leukemia, macrogranulocytic leukemia, adult T-cell leukemia, small lymphocytic lymphoma (SLL), Hodgkin lymphoma, non-Hodgkin lymphoma, B-cell prolymphocytic leukemia, lymphoplasmocytic lymphoma, splenic marginal zone lymphoma, plasma cell tumor, extranodal marginal zone B-cell lymphoma, nodular marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, T-cell prolymphocytic leukemia, T-cell macrogranulocytic leukemia, aggressive NK cells A pharmaceutical composition comprising leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, blastocytic NK-cell lymphoma, mycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disease, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, plasma cell myeloma, and Callers' disease. Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete

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