ISOINDOLINE DERIVATIVE, INTERMEDIATE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF

Abstract

Provided are an isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof. The isoindoline derivative and the pharmaceutical composition thereof can regulate the production or activity of immunological cytokines, thus effectively treating cancer and inflammatory disease.

##STR00001##

Claims

1. An isoindoline derivative having a structure of general formula (I), a pharmaceutically acceptable salt, a solvate, a polymorph, a stereoisomer, a isotopic compound, a metabolite or a pr thereof ##STR00419## in the general formula (I), n1 is selected from 0 or 1; Z is ##STR00420## wherein the carbon atom labelled by * is an asymmetric center; each of R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 is independently selected from H or D; R.sub.2 is selected from H, D or a halogen; each of L.sub.1 and L.sub.2 is independently selected from CD.sub.2, CHD or CH.sub.2; X is selected from NH, ND or O; R.sub.10 is H, D or ##STR00421## wherein each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from H, D, a halogen, a cyano, a hydroxy, ##STR00422## a substituted or unsubstituted (C.sub.1-C.sub.12)alkyl, a substituted or unsubstituted (C.sub.2˜C.sub.20)alkoxy, a (C.sub.2˜C.sub.20)heterocycloalkyl or deuterated (C.sub.2˜C.sub.20)heterocycloalkyl; wherein each of R.sup.a and R.sup.b is independently H, a (C.sub.1-C.sub.12)alkyl, a (C.sub.1-C.sub.12)alkylacyl; each of R.sup.c and R.sup.d is independently H or a (C.sub.1-C.sub.12)alkyl; R.sup.e is ##STR00423## or a (C.sub.2˜C.sub.20)heterocycloalkyl; each of R.sup.e1 and R.sup.e2 is independently H or a (C.sub.1-C.sub.12)alkyl; the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from the group consisting of D, a halogen, a hydroxy, a (C.sub.1-C.sub.12)alkoxy, a (C.sub.2˜C.sub.20)heterocycloalkyl, a (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl, ##STR00424## wherein each of R.sup.f and R.sup.g is independently H or a (C.sub.1-C.sub.12)alkyl; R.sup.h is a (C.sub.2˜C.sub.20)heterocycloalkyl; the substituent contained in the substituted (C.sub.1-C.sub.12)alkyl is selected from the group consisting of D, a (C.sub.2˜C.sub.20)heterocycloalkyl, a deuterated (C.sub.2˜C.sub.20)heterocycloalkyl, a (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl, or a (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl; when more than one substituents are contained in the substituted (C.sub.1-C.sub.12)alkoxy or the substituted (C.sub.1-C.sub.12)alkyl, the substituents are the same or different; in each of the groups mentioned above, the heteroatom of the (C.sub.2˜C.sub.20)heterocycloalkyl contained in the (C.sub.2-C.sub.20)heterocycloalkyl, the deuterated (C.sub.2-C.sub.20)heterocycloalkyl, the (C.sub.2-C.sub.20)heteocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl or the (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl, is selected from consisting of O, N and S; provided that in the general formula (I), when n1 is 0, R.sub.1, R.sub.3 and R.sub.10 are H or D, X is NH or ND, R.sub.2 is a halogen; provided that in the general formula (I), when n1 is 1, R.sub.10 is ##STR00425##

2. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite or the prodrug thereof according to claim 1, wherein, in the general formula (I), the asymmetric center refers to an achiral carbon, (S) configuration carbon, enriched (S) configuration carbon, (R) configuration carbon, enriched (R) configuration carbon or racemate; and/or, in the general formula (I), Z is selected from the group consisting of ##STR00426## ##STR00427##

3. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite or the prodrug thereof according to claim 1, wherein, in the general formula (I), the (C.sub.2˜C.sub.20)heterocycloalkyl contained in the (C.sub.2˜C.sub.20)heterocycloalkyl, the deuterated (C.sub.2˜C.sub.20)heterocycloalkyl, the (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl, or the (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl is preferably a (C.sub.2-C.sub.6)heterocycloalkyl containing 1 or 2 heteroatom(s) selected from N or O; and/or, in the general formula (I), when R.sub.10 is ##STR00428## each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from ##STR00429## or a substituted (C.sub.1-C.sub.12)alkoxy, each of R.sup.a and R.sup.b is independently a (C.sub.1-C.sub.12)alkyl or a (C.sub.1-C.sub.12)alkylacyl, each of R.sup.c and R.sup.d is independently a (C.sub.1-C.sub.12)alkyl; R.sup.e is ##STR00430## each of R.sup.e1 and R.sup.e2 is independently a (C.sub.1-C.sub.12)alkyl; the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is ##STR00431## and each of R.sup.f and R.sup.g is independently a (C.sub.1-C.sub.12)alkyl, the structure of the (C.sub.1-C.sub.12)alkylacyl is ##STR00432## R.sup.a1 is a (C.sub.1-C.sub.12)alkyl; in the definition of R.sup.a, R.sup.b, R.sup.a1, R.sup.c, R.sup.d, R.sup.e1, R.sup.e2, R.sup.f or R.sup.g, the (C.sub.1-C.sub.12)alkyl is a (C.sub.1-C.sub.4)alkyl; and/or, in the general formula (I), when R.sub.10 is ##STR00433## each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted (C.sub.1-C.sub.12)alkoxy, and when the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from a (C.sub.1-C.sub.12)alkoxy, the (C.sub.1-C.sub.12)alkoxy is a (C.sub.1-C.sub.4)alkoxy; and/or, in the general formula (I), when R.sub.10 is ##STR00434## each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted C.sub.1-C.sub.12)alkoxy, and when the substituent in the substituted (C.sub.1-C.sub.12)alkoxy is selected from ##STR00435## in the general formula (I), when R.sub.10 is ##STR00436## each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted (C.sub.1-C.sub.12)alkoxy, and when the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from ##STR00437##

4. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite or the prodrug thereof according to claim 3, wherein, the (C.sub.2˜C.sub.6)heterocycloalkyl is pyrrolidine, morpholinyl or piperazinyl; the (C.sub.1-C.sub.12)alkyl contained in the (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl or the (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl is a (C.sub.1-C.sub.4)alkyl; the deuterated (C.sub.2˜C.sub.20)heterocycloalkyl is ##STR00438## the (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl is ##STR00439## the (C.sub.2˜C.sub.20)heteocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl is ##STR00440## and/or, each of R.sup.a, R.sup.b, R.sup.a1, R.sup.c, R.sup.d, R.sup.e1, R.sup.e2, R.sup.f or R.sup.g, the (C.sub.1-C.sub.12)alkyl is a (C.sub.1-C.sub.4)alkyl; the (C.sub.1-C.sub.4)alkyl is a methyl, an ethyl, a n-propyl, an iso-propyl, a n-butyl, an iso-butyl or a tert-butyl; and/or, in the general formula (I), when R.sub.10 is ##STR00441## each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted (C.sub.1-C.sub.12)alkoxy, and when the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from a (C.sub.1-C.sub.4)alkoxy, the (C.sub.1-C.sub.4)alkoxy is a methoxy, an ethoxy, a n-propoxy, an isopropoxy, a n-butoxy, an isobutoxy, or a tert-butoxy.

5. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite or the prodrug thereof according to claim 1, wherein, in the general formula (I), when R.sub.10 is ##STR00442## each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a halogen, the halogen is F, Cl, Br or I; and/or, in the general formula (I), when R.sub.10 is ##STR00443## and each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.12)alkyl, the substituted or unsubstituted (C.sub.1-C.sub.12)alkyl is a substituted or unsubstituted (C.sub.1-C.sub.4)alkyl; and/or, in the general formula (I), when R.sub.10 is ##STR00444## and each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.12)alkoxy, the substituted or unsubstituted (C.sub.1-C.sub.12)alkoxy is a substituted or unsubstituted (C.sub.1-C.sub.4)alkoxy; and/or, in the general formula (I), when R.sub.10 is ##STR00445## and each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from ##STR00446## and/or, in the general formula (I), when R.sub.10 is ##STR00447## each of R.sub.2′ R.sub.3′ R.sub.4′ and R.sub.5′ is independently selected from ##STR00448## and/or, in the general formula (I), when R.sub.10 is ##STR00449## and each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from ##STR00450##

6. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite or the prodrug thereof according to claim 5, wherein, in the general formula (I), when R.sub.10 ##STR00451## and each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.4)alkyl, the substituted or unsubstituted (C.sub.1-C.sub.4)alkyl is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted propyl, a substituted or unsubstituted isopropyl, a substituted or unsubstituted n-butyl, a substituted or unsubstituted isobutyl, or a substituted or unsubstituted tert-butyl; the substituted (C.sub.1-C.sub.12)alkyl is ##STR00452## and/or, in the general formula (I), when R.sub.10 is ##STR00453## and each of R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.4)alkoxy, the substituted or unsubstituted (C.sub.1-C.sub.4)alkoxy is a substituted or unsubstituted methoxy, a substituted or unsubstituted ethoxy, a substituted or unsubstituted n-propoxy, a substituted or unsubstituted n-butoxy, a substituted or unsubstituted isobutoxy, or a substituted or unsubstituted tert-butoxy, the substituted (C.sub.1-C.sub.12)alkoxy is ##STR00454##

7. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite or the prodrug thereof according to claim 1, wherein, in the definition of R.sub.10, the ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467##

8. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite or the prodrug thereof according to claim 1, wherein the compound having a structure of general formula (I) is selected from the group consisting of ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543## ##STR00544## ##STR00545## ##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550## ##STR00551## ##STR00552## ##STR00553## ##STR00554## ##STR00555## ##STR00556## ##STR00557## ##STR00558## ##STR00559## ##STR00560## ##STR00561## ##STR00562## ##STR00563## ##STR00564## ##STR00565## ##STR00566## ##STR00567## ##STR00568## ##STR00569## ##STR00570## ##STR00571## ##STR00572## ##STR00573## ##STR00574## ##STR00575## ##STR00576## ##STR00577## ##STR00578## ##STR00579## ##STR00580## ##STR00581## ##STR00582## ##STR00583## ##STR00584## ##STR00585## ##STR00586## ##STR00587## ##STR00588## ##STR00589## ##STR00590## ##STR00591## ##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596## ##STR00597## ##STR00598## ##STR00599## ##STR00600## ##STR00601## ##STR00602## ##STR00603## ##STR00604## ##STR00605## ##STR00606## ##STR00607## ##STR00608## ##STR00609## ##STR00610## ##STR00611## ##STR00612## ##STR00613## ##STR00614## ##STR00615## ##STR00616## ##STR00617## ##STR00618## ##STR00619## ##STR00620## ##STR00621## ##STR00622## ##STR00623## ##STR00624## ##STR00625## ##STR00626## ##STR00627## ##STR00628## ##STR00629## ##STR00630## ##STR00631## ##STR00632## ##STR00633## ##STR00634## ##STR00635## ##STR00636## ##STR00637## ##STR00638## ##STR00639## ##STR00640## ##STR00641##

9-16. (canceled)

17. A process for preparing the isoindoline derivative having a structure of general formula (I) according to claim 1, comprising: conducting a deprotection reaction with compound A-06(1) to give compound A-06(a1) and thereafter an amidation reaction with compound A-06(a1) to give the compound of general formula (I); ##STR00642## wherein in compound A-06(1), compound A-06(a1) or the general formula (I), L.sub.1, L.sub.2, X, Z, * , R.sub.1-R.sub.10 and n1 are as defined in claim 1; one of R.sup.a and R.sup.b is ##STR00643## and the other is ##STR00644## and one of R.sup.a1 and R.sup.b1 is ##STR00645## and the other i ##STR00646## wherein in ##STR00647## each of R.sup.a″ and R.sup.b″ is independently H or D;

18. A process for preparing an isoindoline derivative having a structure of general formula (I) according to claim 1 where n1 is 0, comprising: conducting a reduction reaction with compound I-RS to give the compound of general formula (I); ##STR00648## wherein in compound I-RS or the general formula (I), R.sub.2 is halogen, n1 is 0, X is NH or ND, R.sub.10 is H or D, and L.sub.1, Z, R.sub.1 and R.sub.3 are as defined in claim 1.

19. A process for preparing an isoindoline derivative having a structure of general formula (I) according to claim 1 where n1 is 1 and X is NH or HD, comprising: conducting a reductive amination reaction with compound P-01 and ##STR00649## to give the compound of general formula (I); ##STR00650## wherein in ##STR00651## R.sup.p3 is independently H or D and R.sub.10 is ##STR00652## where R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ are as defined in claim 1, in the compound P-01 each of R.sup.p1 and R.sup.p2 is independently H or D and L.sub.1, Z, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1, and in the general formula (I) X is NH or ND, n1 is 0, and L.sub.1, L.sub.2, Z, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1.

20. The process according to claim 17, further comprising conducting a reduction reaction with compound A-05(1) to give the compound A-06(1); ##STR00653## wherein in compound A-05(1) L.sub.1, R.sub.1-R.sub.8, and R.sup.a and R.sup.b are as defined in claim 17 and in compound A-06(1) L.sub.1, L.sub.2, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 17, X is NH or ND, n1 is 0, and R.sub.10 is H or D.

21. The process of claim 17, further comprising conducting a reductive amination reaction with compound A-05(2) and ##STR00654## to give compound A-06(1); ##STR00655## wherein in compound A-05(2) L.sub.1, R.sub.1-R.sub.9, R.sup.a and R.sup.b are as defined in claim 17 and in compound A-06(1) L.sub.1, L.sub.2, R.sub.1-R.sub.9, R.sup.a and R.sup.b are as defined in claim 17, X is NH or ND and n1 is 1, and in ##STR00656## R.sup.p3 is H or D and R.sub.10 is ##STR00657## wherein R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ are as defined in claim 17;

22. The process of claim 17, further comprising conducting a nucleophilic substitution reaction with compound A-05(3) and ##STR00658## to give compound A-06(1); ##STR00659## wherein in compound A-05(3) L.sub.1, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 17 and in compound A-06(1) L.sub.1, L.sub.2, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 17, X is O, and n1 is 1, and in ##STR00660## R.sub.10 is ##STR00661## where R.sub.2′, R.sub.3′, R.sub.4′ and R.sub.5′ are as defined in claim 17;

23. The process of claim 18, further comprising conducting a coupling reaction with compound A-03 and compound A-04(2) or salt thereof to give compound I-RS; ##STR00662## wherein in compound A-03 L.sub.1 and R.sub.1-R.sub.3 are as defined in claim 18 and Hal is a halogen, in compound A-04(2) * and R.sub.4-R.sub.9 are as defined in claim 18, and in compound I-RS L.sub.1, Z, *, and R.sub.1-R.sub.3 are as defined in claim 18.

24. The process of claim 18, further comprising conducting a deprotection and an amidation reaction sequentially with compound A-05(1) to give compound I-RS; ##STR00663## wherein in compound A-05(1) L.sub.1, *, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 18, in compound A-06(a2) L.sub.1 and R.sub.1-R.sub.8 are as defined in claim 18 and one of R.sup.a2 and R.sup.b2 is ##STR00664## and the other is ##STR00665## in ##STR00666## where each of R.sup.a″ and R.sup.b″ is independently H or D, and in compound I-RS L.sub.1, Z, and R.sub.1-R.sub.3 are as defined in claim 18.

25. The process of claim 19, further comprising conducting a reduction reaction with compound I-RS to give compound P-01; ##STR00667## wherein in compound I-RS R.sub.2 is H, D or a halogen and L.sub.1, Z, R.sub.1 and R.sub.3 are as defined in claim 19 and in P-01, R.sub.2 is H, D or a halogen, each of R.sup.p1 and R.sup.p2 is independently H or D, and L.sub.1, Z, R.sub.1 and R.sub.3 are as defined in claim 19.

26. An intermediate compound A-06(1), A-06(a1), I-RS or P-01 for preparing the isoindoline derivative having a structure of the general formula (I): ##STR00668## in compound A-06(1), A-06(a1), I-RS or P-01, the definitions of L.sub.1, L.sub.2, n1, Z, *, R.sub.1-R.sub.10 refer to those in claim 1; in compound A-06(1), one of R.sup.a and R.sup.b ##STR00669## the other is ##STR00670## in compound A-06(a1), one of R.sup.a1 and R.sup.b1 is ##STR00671## the other is ##STR00672## in ##STR00673## R.sup.a″ and R.sup.b″ is independently H or D; in compound P-01, each of R.sup.p1 and R.sup.p2 is independently H or D.

27. A pharmaceutical composition, which comprises a therapeutically effective and/or prophylactically effective amount of the substance selected from the group consisting of the isoindoline derivatives having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite and the prodrug thereof according to claim 1.

28. The pharmaceutical composition according to claim 27, wherein the composition comprises other therapeutic agent(s), the other therapeutic agent(s) is selected from the group consisting of elotuzumab, palbociclib, nivolumab, pembrolizumab, panobinostat, PD-I inhibitor, PD-L inhibitor, pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, dexamethasone, biaxin, vincristine, azacitidine, rituximab, trastuzumab, prednisone, docetaxel, clofarabine injection, Ublituximab, romidepsin, HDAC inhibitor, androgen receptor inhibitor, androgen biosynthesis inhibitor, BTK inhibitor, erythropoietin, eltrombopag, minocycline and melphalan.

29. A process for treating or preventing a disease, symptom or disorder caused by TNF-α or associated with abnormal regulation of TNF-α activity, wherein the process comprises administering to a subject a therapeutically or prophylactically effective amount of the substance selected from the group consisting of the compound having a structure of general formula (I), the pharmaceutically acceptable salt, the solvate, the polymorph, the stereoisomer, the isotopic compound, the metabolite and the prodrug thereof according to claim 1.

30. The process of claim 29, wherein the disease, symptom or disorder includes myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non Hodgkin's lymphoma, papillary and follicular thyroid carcinoma, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, type I complex regional pain syndrome, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, glioma sarcomatosum, malignant glioma, refractory plasma cell tumor, chronic myelomonocytic leukemia, follicular lymphoma, ciliary and chronic melanoma, iris melanoma, recurrent ocular melanoma, extraocular extension melanoma, solid tumor, T-cell lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia; myeloid leukemia, central nervous system lymphoma, brain tumors, meningiomas, spinal tumor, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, large cell lymphoma, diffuse large B cell lymphoma, astrocytoma, hepatocellular carcinoma, primary macroglobulinemia.

31. A process for treating or preventing a disease, symptom or disorder caused by TNF-α or associated with abnormal regulation of TNF-α activity, wherein the process comprises administering to a subject a therapeutically or prophylactically effective amount of the pharmaceutical composition according to claim 27.

Description

EXAMPLES

Example 1. Compound I-28

[0141] ##STR00327##

[0142] Step A. To a mixture of 5-fluoro-2-methylbenzoic acid (6.0 g, 39.0 mmol) in 98% H.sub.2SO.sub.4 (60 mL) was added 65% HNO.sub.3 (3.3 g, 50.7 mmol) at −5 to 0° C., then the resulting mixture was stirred for 1 h at this temperature. The mixture was poured into 200 g ice-water, then extracted by MTBE (150 mL×3). The combined organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness via rotary evaporation to afford 5-Fluoro-2-methyl-3nitro-benzoic acid (7.0 g, crude) as a yellow solid, which was used in the next step without further purification.

[0143] .sup.1H NMR (DMSO-d.sub.6. 300M Hz): δ 8.05 (dd, J=8.1 Hz, 3.0 Hz, 1H), 7.85 (dd, J=8.7, 3.0 Hz, 1H), 2.44 (s, 3H).

[0144] Step B. To a mixture of 5-Fluoro-2-methyl-3-nitro-benzoic acid (7.0 g, crude) in MeOH (70 mL) was added 98% H.sub.2SO.sub.4 (2 mL), then the resulting mixture was stirred for overnight at 70° C. The mixture was concentrated, then the residue was diluted by H.sub.2O (50 mL) and EtOAc (150 mL). The aqueous layer was extracted by EtOAc (100 mL×2), the combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness via rotary evaporation. The residue was purified by column chromatography on silica gel eluted with (PE:EtOAc=10:1 to 3:1) to afford methyl 5-fluoro-2-methyl-3-nitrobenzoate (3.5 g, yield 42%, two steps) as a light yellow solid.

[0145] .sup.1H NMR (DMSO-d.sub.6. 300M Hz): δ 8.10 (dd, J=8.1, 3.0 Hz, 1H), 7.88 (dd, J=8.7, 3.0 Hz, 1H), 3.86 (s, 3H), 2.41 (s, 3H).

[0146] Step C. To a mixture of methyl 5-fluoro-2-methyl-3-nitrobenzoate (3.5 g, 16.4 mmol) and benzoyl peroxide (388 mg, 1.6 mmol) in CCl.sub.4 (40 mL) was added NBS (3.2 g, 18.1 mmol), then the resulting mixture was stirred for overnight at 95° C. The mixture was cooled to room temperature and filtered, and the filtrate was washed wish brine (20 mL) dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness via rotary evaporation. The residue was purified by column chromatography on silica gel eluted with (PE:EtOAc=10:1-5:1) to afford methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate (3.7 g, yield 77%) as a light yellow oil.

[0147] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 8.21-8.25 (dd, J=8.1, 3.0 Hz, 1H), 7.99-8.03 (dd, J=8.7, 2.7 Hz, 1H), 4.97 (s, 2H), 3.93 (s, 3H).

[0148] Step D. To a mixture of 3-aminopiperidine-2,6-dione hydrochloride (2.5 g, 15.1 mmol) and KHCO.sub.3 (3.5 g, 34.2 mmol) in CH.sub.3CN (80 mL) was added methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate (4.0 g, 13.7 mmol), then the resulting mixture was stirred for overnight at 95° C. The mixture was concentrated, then poured into 100 g ice-water, then mixture was stirred for 0.5 h. The mixture was filtered and the solid was washed with H.sub.2O (50 mL×3), dried to afford compound I-28A [3-(6-fluoro-4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione] (3.8 g, yield 90%) as a yellow solid.

[0149] .sup.1H NMR (DMSO-d.sub.6. 400 MHz): δ 11.04 (s, 1H), 8.38 (dd, J=8.8, 2.4 Hz, 1H), 8.11 (dd, J=6.8, 2.4 Hz, 1H), 5.18 (dd, J=13.2, 5.2 Hz, 1H), 4.88 (d, J=19.2 Hz, 1H), 4.78 (d, J=19.2 Hz, 1H), 2.87-2.96 (m, 1H), 2.54-2.63 (m, 2H), 2.01-2.05 (m, 1H).

[0150] Step E. A mixture of compound I-28A (2.8 g, 9.1 mmol) and Pd/C (10%, 280 mg, 50% water) in DMF (30 mL) was stirred for 6 h under 50 Psi H.sub.2 at room temperature. The mixture was filtered and solid was washed with DMF (50 mL×1). The filtrate was concentrated then poured into H.sub.2O (100 mL) and stirred for 0.5 h. The mixture was filtered, the solid was washed with H.sub.2O (50 mL×3), dried, to afford a crude product (2.1 g, yield: 84%) as an off-white solid. 200 mg of the above crude product was purified by Prep-HPLC to afford I-28 [3-(4-amino-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione] (148.8 mg) as an off-white solid.

[0151] .sup.1H NMR (DMSO-d.sub.6. 400 MHz): 11.01 (s, 1H), 6.55-6.63 (m, 2H), 5.79 (s, 2H), 5.10 (dd, J=13.2, 4.8 Hz, 1H), 4.18 (d, J=17.2 Hz, 1H), 4.08 (d, J=17.2 Hz, 1H), 2.87-2.95 (m, 1H), 2.59-2.63 (m, 1H), 2.27-2.31 (m, 1H), 2.02-2.06 (m, 1H). LCMS: 278.1 ([M+1].sup.+).

[0152] Compounds I-01 to I-27 can be prepared according to the method described in Example 1.

Example 2. Synthesis of Compound I-29 and I-30

[0153] ##STR00328##

[0154] 800 mg of compound I-28 in 28 mL DMF was separated by chiral HPLC (Column: CHIRALPAK IA, 5 μm, 30×250 mm; Mobile Phase: CH.sub.3CN; Flow Rate: 21 mL/min; Temperature: 26-28° C.; Wave Length: 230 nm; Injection: 350 uL) to afford 300 mg I-29 and 260 mg I-30.

[0155] I-29: [Rt-4.81 min; >99% ee; .sup.1H NMR (DMSO-d.sub.6. 400 MHz): δ 11.01 (s, 1H), 6.55-6.63 (m, 2H), 5.80 (s, 2H), 5.07-5.12 (m, 1H), 4.18 (d, J=16.8 Hz, 1H), 4.08 (d, J=16.8 Hz, 1H), 2.87-2.93 (m, 1H), 2.59-2.63 (m, 1H), 2.27-2.31 (m, 1H), 2.02-2.07 (m, 1H). LCMS: 278.1 ([M+1].sup.+)].

[0156] I-30:[Rt=7.08 min; >97.5% ee; .sup.1H NMR (DMSO-d.sub.6. 400 MHz): δ 11.01 (s, 1H), 6.55-6.63 (m, 2H), 5.79 (s, 2H), 5.08-5.12 (m, 1H), 4.19 (d, J=17.2 Hz, 1H), 4.08 (d, J=17.2 Hz, 1H), 2.87-2.95 (m, 1H), 2.59-2.64 (m, 1H), 2.27-2.31 (m, 1H), 2.04-2.07 (m, 1H). LCMS: 278.1 ([M+1].sup.+)].

Example 3, Compound I-31 and I-32

[0157] ##STR00329##

[0158] Step A: To a solvent of (S)-2-amino-5-(benzyloxy)-5-oxopentanoic acid (50.0 g, 221 mmol) in CH.sub.3CO.sub.2D (150 mL) was added benzaldehyde (1.34 g, 12.6 mmol), the mixture was heated to 65° C. and stirred for 18 hours. The reaction mixture was concentrated and the resulted solid was triturated with MeOH (25 mL), CH.sub.3CN (50 mL) and t-BuOMe (200 mL) for 30 mins, the filtered cake was rinsed with t-BuOMe (200 mL) and dried. The product was subject to the same procedure to afford compound I-31A, (32.5 g, yield=65%).

[0159] .sup.1H NMR (CD.sub.3OD+D.sub.2O, 300 MHz): δ 7.33-7.42 (m, 5H), 5.14 (s, 2H), 3.70 (t, <0.05H), 2.58-2.63 (m, 2H), 2.13-2.17 (m, 2H).

[0160] Step B: To a mixture of THF (600 mL) and H.sub.2O (600 mL) was added compound I-31A (32.5 g, 137 mmol). NaHCO.sub.3 (12.6 g, 150 mmol) was added to the above mixture in ice-water bath, After 10 min, (BOC).sub.2O (32.7 g, 150 mmol) was added slowly, the reaction mixture was stirred for 4 hours at room temperature. THF was removed under reduced pressure (in vacuum), Sat. NaHCO.sub.3 solution was added to dissolve the residue, the mixture was extract with t-BuOMe (200 mL×2). The aqueous phase was cooled with ice-water bath and adjusted to PH=1 with 3N HCl, then extracted with EtOAc (300 mL×2), combined organic layers was dried over Na.sub.2SO.sub.4, filtrated and concentrated to afford I-31B (46.5 g, yield 100%) as white solid, which was used in the next step without further purification.

[0161] .sup.1H NMR (CD.sub.3OD, 300 MHz): δ 7.29-7.35 (m, 5H), 5.12 (s, 2H), 4.13 (br s, 0.05H), 2.45-2.50 (m, 2H), 2.12-2.21 (m, 1H), 1.85-1.94 (m, 1H), 1.42 (s, 9H).

[0162] Step C: To a solution of I-31B (46.5 g, 137 mmol) in THF (500 mL), cooled to 5° C., was added N-methyl morpholine (NMM) (16.5 g, 164 mmol) and Ethyl chlorocarbonate (17.8 g, 164 mmol) slowly. The reaction was stirred at 0-5° C. for 1 hour. 150 mL of saturated NH.sub.3.H.sub.2O was added to the reaction mixture and then stirred for 2 hours at room temperature. EtOAc (200 mL) was added and the organic phase was separated, aqueous layer was extracted with EtOAc (200 mL), the combined the organic phase was washed with NaHCO.sub.3 aqueous (200 mL×2) and brine (200 mL) as sequence, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford I-31C (41 g, 90%) as white solid.

[0163] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.30-7.41 (m, 5H), 7.24 (s, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 5.06 (s, 2H), 3.90 (m, <0.05H), 2.33-2.38 (m, 2H), 1.70-1.94 (m, 2H), 1.35 (s, 9H).

[0164] Step D: To a solution of I-31C (41.0 g, 121 mmol) in 1,4-dioxane (200 mL) was added a solution of 6N HCl in 1,4-dioxane (300 mL), the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure (in vacuum) to afford a solid, which was triturated with t-BuOMe (200 mL), and filtrated and dried to afford product I-31D (31.3 g, yield 95%) as a white solid.

[0165] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 8.37 (br s, 3H), 8.04 (s, 1H), 7.56 (s, 1H), 7.33-7.38 (m, 5H), 5.10 (s, 2H), 3.77 (t, <0.05H), 2.48-2.52 (m, 2H), 2.01-2.05 (m, 2H).

[0166] Step E: A mixture of methyl 2-(bromomethyl)-5-fluoro-3-nitrobenzoate (31.8 g, 108.9 mmol) and compound I-31D (29.7 g, 109 mmol) and Et.sub.3N (22.1 g, 218 mmol) in CH.sub.3CN (550 mL) was stirred at 75° C. for overnight. The mixture was concentrated. The residue was triturated with CH.sub.3CN (100 mL) to afford Compound I-31E (34.5 g, yield 76.2%) as a pale yellow solid.

[0167] .sup.1H NMR (DMSO-d.sub.6. 300 MHz): δ 8.33 (dd, J=8.7, 2.4 Hz, 1H), 8.04 (dd, J=6.9, 2.4 Hz, 1H), 7.66 (s, 1H), 7.26-7.36 (m, 6H), 4.82-5.05 (m, 4H), 2.20-2.39 (m, 3H), 2.06-2.15 (m, 1H).

[0168] Step F: Compound I-31E was subjected to chiral HPLC (Column: DAICEL CHIRALPAK IA, 10 μm, 25×250 mm; Mobile Phase: MeOH/DCM=80/20(V/V); Flow Rate: 30 mL/min; Temperature: 35° C.; Wave Length: 254 nm) separation to afford two compounds I-31F1 [.sup.1H NMR (DMSO-d.sub.6. 300 MHz): δ 8.31-8.35 (m, 1H), 8.03 (dd, J=7.2, 2.1 Hz, 1H), 7.66 (s, 1H), 7.29-7.35 (m, 6H), 4.83-5.04 (m, 4H), 2.22-2.40 (m, 3H), 2.06-2.16 (m, 1H)] and I-31F2 [.sup.1H NMR (DMSO-d.sub.6. 300 MHz): δ 8.33 (dd, J=9.3, 2.4 Hz, 1H), 8.03 (dd, J=7.2, 2.4 Hz, 1H), 7.67 (s, 1H), 7.29-7.36 (m, 6H), 4.83-5.05 (m, 4H), 2.20-2.42 (m, 3H), 2.09-2.16 (m, 1H).].

[0169] Compound I-32: A mixture of compound I-31F2, (2.2 g, 5.3 mmol) and Pd/C (10%, 200 mg, 50% water) in anhydrous MeOH (30 mL) was stirred for 4 h under 50 Psi H.sub.2 at room temperature. The mixture was filtered and filtrate was concentrated, the resulting solid was added into DCE (15 mL) and stirred for 5 mins, then the mixture was concentrated to afford an off-white solid residue (1.4 g). The above solid (1.1 g, 3.7 mmol) was dissolved in dry THF (10 mL) and DCE (40 mL), and then SOCl.sub.2 (0.74 g, 9.3 mmol) was slowly added to the mixture at −30° C., after stirring for 2 h, pyridine (1.1 g, 9.3 mmol) was added and stirred for 40 mins at this temperature, Et.sub.3N (1.3 g, 13 mmol) was added and then the mixture was stirred for 2 h. H.sub.2O (0.1 mL) was added, and then the mixture was concentrated to dryness, the residue was dissolved in H.sub.2O (5 mL) and extracted with EtOAc (70 mL×5), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-HPLC to afford I-32 (340 mg, yield 33%, ee: 99%) as a pale green solid.

[0170] .sup.1H NMR (DMSO-d.sub.6. 400 MHz): 11.00 (s, 1H), 6.56-6.61 (m, 2H), 5.78 (s, 2H), 5.05-5.11 (m, 0.05H), 4.17 (d, J=17.1 Hz, 1H), 4.05 (d, J=17.1 Hz, 1H), 2.84-2.96 (m, 1H), 2.56-2.62 (m, 1H), 2.20-2.32 (m, 1H), 1.98-2.05 (m, 1H). LCMS: 279.1 ([M+1].sup.+).

[0171] Compound I-31: Following the same synthetic method as compound I-32, compound I-31F1 was converted to 1-31 (99% ee). .sup.1H NMR (DMSO-d.sub.6. 400 MHz): 10.99 (s, 1H), 6.52-6.61 (m, 2H), 5.71 (br s, 2H), 5.08 (dd, J=18.0, 7.2 Hz, 0.04H) 4.17 (d, J=17.4 Hz, 1H), 4.06 (d, J=17.4 Hz, 1H), 2.83-2.96 (m, 1H), 2.47-2.62 (m, 1H), 2.21-2.32 (m, 1H), 1.98-2.05 (m, 1H). LCMS: 279.1 ([M+1].sup.+).

Example 4: Compound I-01

[0172] ##STR00330##

[0173] Following the procedure in above mentioned Example 3, compound I-01 of example 4 was obtained using racemic I-31E.

[0174] .sup.1H NMR (DMSO-d.sub.6. 300 MHz): δ 10.94 (br s, 1H), 6.52-6.61 (m, 2H), 5.78 (s, 2H), 5.05-5.11 (m, 0.05H), 4.16 (d, J=16.8 Hz, 1H), 4.05 (d, J=16.8 Hz, 1H), 2.84-2.96 (m, 1H), 2.54-2.62 (m, 1H), 2.21-2.31 (m, 1H), 1.98-2.04 (m, 1H). LCMS: 279.1 ([M+1].sup.+).

[0175] Compounds I-33 to I-56 can be prepared according to the synthetic method shown in Example 2 or 3 with appropriate starting material.

Example 5: Compound A195

3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A195

[0176] ##STR00331##

[0177] To a solution of A340D (40 mg, 0.096 mmol) in CH.sub.3CN (3 mL) was added CDI (20 mg, 0.13 mmol). The reaction mixture was stirred overnight at 90° C. under N2. After concentration under reduced pressure, the residue was dissolved in DCM (30 mL), washed with 0.1N HCl (10 mL), sat. aq. NaHCO.sub.3 (10 mL), and then sat. NaCl (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was then purified by prep-TLC (DCM/MeOH=25:1) 2 times to give compound A195 (46 mg, yield 81%) as white solid.

[0178] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.98 (s, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.11 (t, J=9.6 Hz, 1H), 6.90-6.95 (m, 2H), 6.78-6.84 (m, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.24 (t, J=5.7 Hz, 1H), 5.10 (dd, J=13.2, 5.4 Hz, 1H), 4.36 (d, J=5.4 Hz, 2H), 4.30 (d, J=17.7 Hz, 1H), 4.17 (d, J=17.7 Hz, 1H), 3.65 (s, 3H), 2.85-2.97 (m, 1H), 2.57-2.64 (m, 1H), 2.24-2.36 (m, 1H), 2.00-2.07 (m, 1H). LCMS: 398.1 ([M+1].sup.+).

[0179] Compounds of examples 6-7 were prepared according to the synthetic method shown in example 5 with corresponding starting materials to replace A340D.

Example 6: Compound A196

3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A196

[0180] ##STR00332##

[0181] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.00-7.04 (m, 2H), 6.90-6.95 (m, 2H), 6.62 (d, J=7.8 Hz, 1H), 6.30 (t, J=6.0 Hz, 1H), 5.10 (dd, J=13.2, 5.7 Hz, 1H), 4.40 (d, J=6.0 Hz, 2H), 4.28 (d, J=17.4 Hz, 1H), 4.16 (d, J=17.4 Hz, 1H), 3.81 (s, 3H), 2.85-2.97 (m, 1H), 2.56-2.63 (m, 1H), 2.26-2.32 (m, 1H), 1.99-2.07 (m, 1H). LCMS: 398.1 ([M+1].sup.+).

Example 7: Compound A197

3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A197

[0182] ##STR00333##

[0183] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.19-7.31 (m, 2H), 6.92 (d, J=7.2 Hz, 1H), 6.80 (dd, J=12.0, 2.4 Hz, 1H), 6.71 (dd, J=8.4, 2.4 Hz, 1H), 6.65 (d, J=7.8 Hz, 1H), 6.20 (t, J=5.7 Hz, 1H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.24-4.33 (m, 3H), 4.14 (d, J=17.1 Hz, 1H), 3.72 (s, 3H), 2.85-2.97 (m, 1H), 2.57-2.62 (m, 1H), 2.21-2.36 (m, 1H), 1.98-2.05 (m, 1H). LCMS: 398.1 ([M+1].sup.+).

Example 8: Compound A318

3-(6-fluoro-4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A318

[0184] ##STR00334##

[0185] Step A. To a mixture of compound I-28A (1.0 g, 3.3 mmol) in DMF (10 mL) was added Pd/C (0.18 g, 10%, 50% wet) and degassed with H.sub.2 3 times. The mixture was stirred at 25° C. for 5 hours under 50 psi H.sub.2 pressure. Then the reaction mixture was filtered and concentrated, then triturated with PE/EtOAc (5:1, 10 mL×3) to give 1-28 (crude, 0.9 g) as a green solid.

[0186] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.98 (s, 1H), 6.52-6.61 (m, 2H), 5.77 (s, 2H), 5.07 (dd, J=5.4, 13.2 Hz, 1H), 4.17 (d, J=17.1 Hz, 1H), 4.06 (d, J=17.1 Hz, 1H), 2.83-2.95 (m, 1H), 2.55-2.62 (m, 1H), 2.20-2.34 (m, 1H), 1.97-2.07 (m, 1H).

[0187] Step B. To a solution of compound I-28 and 2-fluoro-3-methoxybenzaldehyde (85 mg, 0.551 mmol) in AcOH (3 mL) was added dichloroethane (15 mL) and stirred for 1 hour. Then NaBH(OAc).sub.3 (235 mg, 1.09 mmol) was added and the mixture was stirred for 18 hours. Another portion of NaBH(OAc).sub.3 (50 mg, 0.236 mmol) was added and the mixture was heated to 30° C. for 8 hours. Then another portion of 2-fluoro-3-methoxybenzaldehyde (30 mg, 0.195 mmol) was added and the mixture was stirred at 40° C. for 16 hours. The mixture was concentrated and purified by prep-TLC to give crude product, which was triturated with MeOH (1 mL) to give A318 (30 mg, yield: 20%) as an off-white solid.

[0188] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.05-7.07 (m, 2H), 6.91-6.94 (m, 1H), 6.61-6.65 (m, 2H), 6.44 (dd, J=1.8, 12.9 Hz, 1H), 5.06-5.12 (m, 1H), 4.39 (d, J=5.7 Hz, 2H), 4.26 (d, J=17.1 Hz, 1H), 4.13 (d, J=17.1 Hz, 1H), 3.81 (s, 3H), 2.86-2.90 (m, 1H), 2.57-2.63 (m, 1H), 2.24-2.30 (m, 1H), 2.02-2.06 (m, 1H). LCMS:416.1 ([M+1].sup.+).

[0189] Compounds of Examples 9-10 were prepared according to the synthetic method shown in example 8 with corresponding starting material to replace 2-fluoro-3-methoxybenzaldehyde in step B.

Example 9: Compound A319

3-(6-fluoro-4-((2-fluoro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione, A319

[0190] ##STR00335##

[0191] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.30 (t, J=9.0 Hz, 1H), 6.71-6.84 (m, 2H), 6.55-6.64 (m, 2H), 6.47 (dd, J=2.1, 12.6 Hz, 1H), 5.05-5.11 (m, 1H), 4.31 (d, J=5.1 Hz, 2H), 4.24 (d, J=17.4 Hz, 1H), 4.11 (d, J=17.4 Hz, 1H), 3.73 (s, 3H), 2.84-2.96 (m, 1H), 2.57-2.62 (m, 1H), 2.19-2.34 (m, 1H), 2.03-2.06 (m, 1H). LCMS: 416.1 ([M+1].sup.+).

Example 10: Compound A320

3-(6-fluoro-4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A320

[0192] ##STR00336##

[0193] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.12 (t, J=9.3 Hz, 1H), 6.81-6.94 (m, 2H), 6.60-6.66 (m, 2H), 6.48 (dd, J=2.4, 12.6 Hz, 1H), 5.06-5.12 (m, 1H), 4.36 (d, J=5.4 Hz, 2H), 4.27 (d, J=17.7 Hz, 1H), 4.14 (d, J=17.7 Hz, 1H), 3.67 (s, 3H), 2.83-2.97 (m, 1H), 2.57-2.62 (m, 1H), 2.20-2.35 (m, 1H), 2.00-2.08 (m, 1H). LCMS: 416.1 ([M+1].sup.+).

Example 11: Compound A327

3-(6-fluoro-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione, A327

[0194] ##STR00337## ##STR00338##

[0195] Step A. To a mixture of (4-(morpholinomethyl)phenyl)methanol (1.5 g, 7.2 mmol) in DCM (20 mL) was added SOCl.sub.2 (2.6 g, 21.8 mmol) slowly at 0° C., then the resulting mixture was stirred overnight at 25° C. LCMS shown the reaction was finished. The reaction mixture was concentrated, to afford the crude product 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (1.9 g) as an off-white solid.

[0196] .sup.1H NMR (DMSO-d.sub.6. 400 M Hz): δ 11.70 (br s, 1H), 7.65-7.67 (m, 2H), 7.50-7.52 (m, 2H), 4.79 (s, 2H), 4.32-4.33 (m, 2H), 3.81-3.93 (m, 4H), 3.16-3.19 (m, 2H), 3.02-3.11 (m, 2H).

[0197] Step B. To a mixture of methyl 5-fluoro-2-methyl-3-nitrobenzoate (2.0 g, 9.4 mmol) and Pd/C (10%, 200 mg, 50% water) in MeOH (20 mL) was stirred at room temperature overnight under 50 Psi H.sub.2. TLC and LCMS shown the reaction was finished. The mixture was filtered and the solid was washed with MeOH (50 mL×1), the filtrate was concentrated to afford methyl 3-amino-5-fluoro-2-methylbenzoate (1.3 g crude) as a colorless oil.

[0198] .sup.1H NMR (DMSO-d.sub.6. 300 M Hz), δ 6.57-6.60 (m, 1H), 5.44 (s, 2H), 3.77 (s, 3H), 2.11 (s, 3H).

[0199] Step C. To a mixture of methyl 3-amino-5-fluoro-2-methylbenzoate (1.3 g crude) and 100/a H.sub.2SO.sub.4 (43 g, 42.6 mmol) in MeOH (20 mL) was added NaNO.sub.2 (750 mg, 10.87 mmol) at 0° C. under N.sub.2, then the resulting mixture was stirred for 1 h at this temperature. Then 50% H.sub.2SO.sub.4 (42.6 g, 213 mmol) was added to the reactor, the mixture was stirred for 1 h at 100° C. TLC shown the reaction was finished. The reaction mixture was concentrated, the residue was diluted with H.sub.2O (20 mL) and EtOAc (100 mL). The aqueous layer was extracted by EtOAc (100 mL×3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness via rotary evaporation. The residue was purified by column chromatography on silica gel eluted with (PE:EtOAc=50:1) to afford methyl 5-fluoro-3-hydroxy-2-methylbenzoate (660 mg, yield: 38% for two steps) as a light yellow solid.

[0200] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 10.25 (s, 1H), 6.93-6.96 (m, 1H), 6.78-6.82 (m, 1H), 3.81 (s, 3H), 2.23 (s, 3H).

[0201] Step D. A mixture of methyl 5-fluoro-3-hydroxy-2-methylbenzoate (1.2 g, 6.5 mmol) and imidazole (1.33 g, 19.5 mmol) in DCM (20 mL) was added TBDMSCl (1.96 g, 13.0 mmol) under N2 at 0° C., then the mixture was stirred for 10 minutes Then the mixture was stirred for 2 h at 25° C. TLC shown the reaction was finished. The mixture was washed with H.sub.2O (50 mL), the aqueous layer was extracted by DCM (150 mL×3), the combined organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness via rotary evaporation. The residue was purified by column chromatography on silica gel eluted with (PE:EtOAc=20:1-10:1) to afford methyl 3-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-methylbenzoate (1.4 g yield: 72%) as a light yellow oil.

[0202] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 7.12-7.15 (m, 1H), 6.84-6.87 (m, 1H), 3.82 (s, 3H), 2.26 (s, 3H), 0.98 (s, 9H), 0.23 (s, 6H).

[0203] Step E. To a mixture of methyl 3-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-methylbenzoate (1.4 g, 4.7 mmol) and NBS (1.0 g 5.6 mmol) in CCl.sub.4 (20 mL) was added benzoyl peroxide (0.12 g, 0.5 mmol) under N.sub.2, the mixture was stirred for overnight at 80° C. TLC shown the reaction was finished. The mixture was filtered then the solid was washed with DCM (50 mL), the organic phase was washed with H.sub.2O (50 mL), the aqueous layer was extracted by DCM (100 mL×3), the combined organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness via rotary evaporation. The residue was purified by column chromatography on silica gel eluted with (PE:EtOAc=100:1) to afford methyl 2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-5-fluorobenzoate (1.4 g, purity: 90%) as a white solid.

[0204] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 7.28-7.31 (m, 1H), 7.00-7.03 (m, 1H), 4.93 (s, 2H), 3.91 (s, 3H), 1.07 (s, 9H), 0.36 (s, 6H).

[0205] Step F. To a mixture of methyl 2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)-5-fluorobenzoate (500 mg, 1.33 mmol) and (S)-tert-butyl-4,5-diamino-5-oxopentanoate hydrochloride (349 mg, 1.46 mmol) and Et.sub.3N (405 mg, 4.0 mmol) in CH.sub.3CN (10 mL) was stirred for overnight under N.sub.2 at 80° C. TLC shown the reaction was finished. The mixture was concentrated, the residue was added to THF (10 mL), and then TBAF (4 mL, 1 M in THF) was added to the reactor dropwise. The mixture was stirred for 0.5 h at room temperature. TLC shown the reaction was finished. The mixture was concentrated, the residue was purified by column chromatography on silica gel eluted with (PE:EtOAc=5:1-1:1-EtOAc) to afford A327A (200 mg, yield: 34%, for 3 steps) as a light yellow solid.

[0206] .sup.1H NMR (MeOD, 400 MHz): δ 6.95-6.98 (m, 1H), 6.72-6.76 (m, 1H), 4.90-4.94 (m, 1H), 4.54 (d, J=17.6 Hz, 1H), 4.42 (d, J=17.6 Hz, 1H), 2.25-2.30 (m, 3H), 2.16-2.21 (m, 1H), 1.39 (s, 9H).

[0207] Step G. To a mixture of A327A (200 mg, 0.57 mmol) and 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (445 mg, crude) in dry DMF (10 mL), under N.sub.2 at room temperature, was added K.sub.2CO.sub.3 (393 mg, 2.90 mmol). The mixture was stirred at room temperature for overnight. LCMS shown the reaction was not finished. Another portion of 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (445 mg, crude) was added to the reactor, the reaction mixture was stirred for 6 h. The mixture was concentrated, then the residue was diluted by H.sub.2O (10 mL) and EtOAc (30 mL). The aqueous layer was extracted by EtOAc (10 mL×3), the combined organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness via rotary evaporation. The residue was purified by column chromatography on silica gel eluted with (PE: EtOAc=5:1˜1:1˜EtOAc) to afford A327B (250 mg, yield: 81%) as a white solid.

[0208] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 7.57 (s, 1H), 7.44-7.46 (m, 2H), 7.34-7.36 (m, 2H), 7.19-7.27 (m, 2H), 7.06-7.08 (m, 1H), 5.23 (s, 2H), 4.68-4.72 (m, 1H), 4.50 (d, J=17.6 Hz, 1H), 4.39 (d, J=17.6 Hz, 1H), 3.56-3.58 (m, 4H), 3.47 (s, 2H), 2.30-2.38 (m, 4H), 2.13-2.17 (m, 3H), 2.00-2.05 (m, 1H), 1.32 (s, 9H).

[0209] Step H. To a mixture of A327B (250 mg, 0.46 mmol) in dry DCM (10 mL) was added TFA (4 mL) under N.sub.2 at 0° C. The mixture was stirred for 4 h. TLC shown the reaction was finished. The mixture was concentrated to give A327C (230 mg crude) as a pale yellow solid.

[0210] Step I. To a mixture of A327C (230 mg crude) in CH.sub.3CN (15 mL) was added CDI (115 mg, 0.71 mmol) under N.sub.2 at room temperature. After finishing adding, the mixture was stirred for overnight at 95° C. LCMS shown the reaction was finished. The mixture was concentrated, The residue was purified by prep-HPLC to afford A327 (24 mg, yield: 11%, two steps) as a yellow solid.

[0211] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 10.98 (s, 1H), 7.43-7.45 (m, 2H), 7.28-7.35 (m, 3H), 7.11-7.13 (m, 1H), 5.23 (s, 2H), 5.08-5.13 (m, 1H), 4.39 (d, J=17.2 Hz, 1H), 4.23 (d, J=17.2 Hz, 1H), 3.55-3.58 (m, 4H), 3.47 (s, 2H), 2.87-2.91 (m, 1H), 2.54-2.59 (m, 1H), 2.42-2.45 (m, 1H), 2.35-2.41 (m, 4H), 1.97-1.99 (m, 1H). LCMS: 468.2 ([M+1].sup.+).

Example 12: Compound A329

3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A329

[0212] ##STR00339##

[0213] Step A. To a solution of 2-fluoro-4-methoxybenzaldehyde (1.0 g, 6.49 mmol) in MeOH (10 mL) were added NaBH.sub.4 (370 mg, 9.74 mmol) at room temperature, the mixture was stirred for 1 h. TLC shown the reaction was finished. HCl (1 N) was added to quench the reaction and pH was adjusted to 4-5. DCM (50 mL) and water (40 mL) was added and water layer was extracted with DCM (50 mL×2), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtration, concentrated to give the product (2-fluoro-4-methoxyphenyl)methanol (910 mg, yield: 90%) as a light yellow oil, without further purification for the next step.

[0214] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.31 (t, J=8.4 Hz, 1H), 6.72-6.76 (m, 2H), 5.08 (t, J=5.7 Hz, 1H), 4.43 (d, J=5.7 Hz, 2H), 3.73 (m, 3H).

[0215] Step B. To a solution of (2-fluoro-4-methoxyphenyl)methanol (400 mg, 2.56 mmol) in dry DCM (10 mL) was added SOCl.sub.2 (458 mg, 3.85 mmol) at room temperature, the mixture was stirred for 3h. LCMS shown the reaction was finished. The reaction mixture was concentrated to give 1-(chloromethyl)-2-fluoro-4-methoxybenzene (450 mg) as a light yellow oil which was used next step without further purification.

[0216] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.42 (t, J=8.7 Hz, 1H), 6.85 (dd, J=12.0, 2.7 Hz, 1H), 6.77 (dd, J=11.4, 2.7 Hz, 1H), 4.72 (s, 2H), 3.76 (s, 3H).

[0217] Step C. To a solution of A329B (200 mg, 0.68 mmol) in DMF (15 mL) were added K.sub.2CO.sub.3 (283 mg, 2.05 mmol) and [1-(chloromethyl)-2-fluoro-4-methoxybenzene] (239 mg, 1.37 mmol) at room temperature, the mixture was stirred overnight at room temperature. LCMS shown the reaction was not finished. Additional [1-(chloromethyl)-2-fluoro-4-methoxybenzene] (100 mg, 0.57 mmol) was added and stirred for 3 hr. LCMS shown the reaction was finished. The reaction mixture was concentrated and EtOAc (50 mL) and water (30 mL) was added and water layer was extracted with EtOAc (50 mL×2), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and then concentrated to give a residue. The residue was purified by prep-TLC (MeOH/DCM=1/20) to give A329A (190 mg, yield: 65%) as a white solid.

[0218] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.57 (br s, 1H), 7.45-7.54 (m, 2H), 7.36 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.17 (br s, 1H), 6.87-6.92 (m, 1H), 6.81-6.85 (m, 1H), 5.19 (s, 2H), 4.69-4.74 (m, 1H), 4.47 (d, J=17.7 Hz, 1H), 4.33 (d, J=17.7 Hz, 1H), 3.79 (s, 3H), 3.50 (s, 3H), 2.13-2.27 (m, 3H), 2.00-2.10 (m, 1H),

[0219] Step D. To a solution of A329A (190 mg, 0.44 mmol) in DMF (10 mL) were added K.sub.2CO.sub.3 (183 mg, 1.33 mmol), the mixture was stirred at 80° C. overnight under N.sub.2. LCMS shown the reaction was finished. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC and freeze-dried to give A329 (120 mg, yield: 68%) as a white solid.

[0220] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.79 (br s, 1H), 7.48-7.54 (m, 2H), 7.33-7.41 (m, 2H), 6.89 (dd, J=12.3, 2.4 Hz, 1H), 6.81 (dd, J=8.4, 2.4 Hz, 1H), 5.19 (s, 2H), 5.08-5.13 (m, 1H), 4.35 (d, J=17.7 Hz, 1H), 4.18 (d, J=17.7 Hz, 1H), 3.78 (s, 3H), 2.84-2.94 (m, 1H), 2.57-2.61 (m, 1H), 2.38-2.46 (m, 1H), 1.92-2.00 (m, 1H).

[0221] LCMS: 399.1 ([M+1].sub.+).

[0222] Compounds in example 13-14 were prepared according to the procedure described for example 12, with corresponding starting material to replace 2-fluoro-4-methoxybenzaldehyde in step A.

Example 13: Compound A331

3-(4-((2-fluoro-5-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A331

[0223] ##STR00340##

[0224] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.65 (br s, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.34-7.40 (m, 2H), 7.13-7.23 (m, 2H), 6.93-6.99 (m, 1H), 5.25 (s, 2H), 5.10 (dd, J=10.2, 5.1 Hz, 1H), 4.39 (d, J=17.7 Hz, 1H), 4.23 (d, J=17.7 Hz, 1H), 3.74 (s, 3H), 2.84-2.96 (m, 1H), 2.54-2.60 (m, 1H), 2.39-2.47 (m, 1H), 1.93-2.00 (m, 1H). LCMS: 399.1 ([M+1].sup.+).

Example 14: Compound A334

3-(4-((2-fluoro-3-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A334

[0225] ##STR00341##

[0226] .sup.1H NMR (DMSO-d.sub.6. 400 MHz): 10.96 (s, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.34-7.38 (m, 2H), 7.13-7.20 (m, 3H), 5.28 (s, 2H), 5.10 (dd, J=12.8, 4.4 Hz, 1H), 4.38 (d, J=17.6 Hz, 1H), 4.22 (d, J=17.6 Hz, 1H), 3.85 (s, 3H), 2.87-2.90 (m, 1H), 2.50-2.58 (m, 1H), 2.40-2.43 (m, 1H), 1.95-1.98 (m, 1H). LCMS: 399.1 ([M+1].sup.+).

Example 15: Compound A336

3-[4-(2-Fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione, A336

[0227] ##STR00342##

[0228] .sup.1H NMR (DMSO-d.sub.6. 400 MHz): 10.92 (s, 1H), 6.53-6.63 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.40-7.47 (m, 2H), 7.36 (t, J=8.0 Hz, 1H), 7.23-7.29 (m, 2H), 5.30 (s, 2H), 5.11 (dd, J=12.8, 5.2 Hz, 1H), 4.38 (d, J=17.6 Hz, 1H), 4.23 (d, J=17.6 Hz, 1H), 2.86-2.95 (m, 1H), 2.54-2.59 (m, 1H), 2.38-2.47 (m, 1H), 1.97-2.00 (m, 1H). LCMS: 369.1 ([M+1].sup.+).

Example 16: Compound A340

(S)-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A340

[0229] ##STR00343## ##STR00344##

[0230] Step A. To a solution of methyl 2-(bromomethyl)-3-nitrobenzoate (2.00 g, 7.30 mmol) in CH.sub.3CN (40 mL) were added (S)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride (1.91 g, 8.00 mmol) and Et.sub.3N (1.63 g, 16.1 mmol) under N.sub.2, the mixture was stirred at 75° C. overnight. TCL shown the reaction was finished. The reaction mixture was concentrated and EtOAc (50 mL) and water (50 mL) were added, the water layer was extracted with EtOAc (50 mL×2), the combined organic phases were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a crude product. The crude product was triturated with PE/EtOAc (4/1, v/v), then filtered to give A340A (2.2 g, 83% yield) as a white solid.

[0231] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 8.45 (dd, J=0.9, 8.1 Hz, 1H), 8.16 (dd, J=0.9, 8.1 Hz, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.65 (br s, 1H), 7.27 (br s, 1H), 5.05 (d, J=19.5 Hz, 1H), 4.90 (d, J=19.5 Hz, 1H), 4.75-4.80 (m, 1H), 2.14-2.27 (m, 3H), 2.00-2.10 (m, 1H), 1.33 (s, 9H).

[0232] Step B. To a solution of A340A (1.20 g, 3.30 mmol) in MeOH was added Pd/C (10%/o, 200 mg, 50% water), degassed with H.sub.2 3 times the mixture was stirred at 25° C. overnight under H.sub.2 (50 Psi). LCMS shown the reaction was finished. Pd/C was removed by filtration and the filtrate was concentrated to give A340B (1.19 g, crude) as a light yellow solid which was used for next step without further purification.

[0233] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.50 (br s, 1H), 7.11-7.16 (m, 2H), 6.85 (d, J=7.2 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 5.41 (br s, 2H), 4.68-4.73 (m, 1H), 4.38 (d, J=17.7 Hz, 1H), 4.16 (d, J=17.7 Hz, 1H), 2.09-2.19 (m, 3H), 1.92-2.01 (m, 1H), 1.32 (s, 9H).

[0234] Step C. To a solution of A340B (1.00 g, crude) and 2-Fluoro-5-methoxy-benzaldehyde (601 mg, 3.90 mmol) in MeOH (10 mL) was added AcOH (0.5 mL), the mixture was stirred at 25° C. for 3 hours. Pd/C (10%, 200 mg, 50% water) was added, degassed with H.sub.2 3 times and stirred at 25° C. overnight under H.sub.2 (balloon). LCMS shown the reaction was finished. Pd/C was removed by filtration and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on slica gel (PE/EtOAc=1/4) to give the desired product A340C (1.15 g, yield: 88%, for two steps) as a light yellow solid.

[0235] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.56 (br s, 1H), 7.09-7.24 (m, 3H), 6.91-6.96 (m, 2H), 6.80-6.85 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.34-6.38 (m, 1H), 4.74 (dd, J=10.2, 4.5 Hz, 1H), 4.50 (d, J=18.0 Hz, 1H), 4.37 (d, J=6.0 Hz, 2H), 4.28 (d, J=18.0 Hz, 1H), 3.67 (s, 3H), 2.12-2.21 (m, 3H), 1.91-2.02 (m, 1H), 1.33 (s, 9H).

[0236] Step D. To a solution of A340C (1.15 g, 2.44 mmol) in DCM (20 mL) cooled to 0° C. was added dropwise TFA (4 mL), the mixture was stirred overnight at 25° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 (40% acetonitrile in water) then was freeze-dried to afford A340D (800 mg, yield: 79%) as a light yellow solid.

[0237] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 12.14 (br s, 1H), 7.57 (br s, 1H), 7.10-7.23 (m, 3H), 6.91-6.96 (m, 2H), 6.81-6.85 (m, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.35 (t, J=6.0 Hz, 1H), 4.72-4.76 (m, 1H), 4.51 (d, J=17.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 4.31 (d, J=17.6 Hz, 1H), 3.67 (s, 3H), 2.18-2.23 (m, 3H), 1.96-2.02 (m, 1H).

[0238] Step E. A solution of A340D (700 mg, 1.69 mmol) in dry DCM (70 mL) was cooled to −40° C. under N.sub.2, SOCl.sub.2 (1.00 g, 8.40 mmol) was slowly added to the mixture at −40° C., then a solution of DMF (10 mg) in DCM (1 mL) was added and stirred for 2 h, and then pyridine (666 mg, 8.42 mmol) was added dropwise and stirred for 40 mins at this temperature, Et.sub.3N (852 mg, 8.42 mmol) was added and then the mixture was stirred for 2 h. LCMS shown the reaction was finished. H.sub.2O (10 mL) was added to quench the reaction, the water layer was extracted with DCM (20 mL×2), the combined organic phase was washed with brine (50 mL×1), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The residue was purified by Prep-HPLC to give A340 (460 mg, yield: 68%, ee: 98%) as a pale green solid.

[0239] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (br s, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.11 (t, J=9.6 Hz, 1H), 6.90-6.95 (m, 2H), 6.78-6.84 (m, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.26 (t, J=6.0 Hz, 1H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.37 (d, J=6.0 Hz, 2H), 4.30 (d, J=17.1 Hz, 1H), 4.17 (d, J=17.1 Hz, 1H), 3.65 (s, 3H), 2.85-2.96 (m, 1H), 2.56-2.63 (m, 1H), 2.24-2.37 (m, 1H), 2.00-2.07 (m, 1H). LCMS: 398.1 ([M+1].sup.+).

Example 17: Compound A341

(R)-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A341

[0240] ##STR00345## ##STR00346##

[0241] Step A. To a solution of 2-Bromomethyl-3-nitro-benzoic acid methyl ester (1.00 g, 3.65 mmol) in CH.sub.3CN (50 mL) were added (R)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride (955 mg, 4.00 mmol) and Et.sub.3N (815 mg, 8.05 mmol), the mixture was stirred 75° C. overnight under N.sub.2. TLC shown the reaction was finished. The reaction mixture was concentrated and EtOAc (50 mL) and water (50 mL) were added, the water layer was extracted with EtOAc (50 mL×2), the combined organic phase was washed with brine (50 mL), dried over NaZSO.sub.4, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography on slica gel (PE/EtOAc=1/4), to give A341A (800 mg, yield: 60%) as a white solid.

[0242] .sup.1H NMR (DMSO-d, 300 MHz): δ 8.45 (d, J=6.0 Hz, 1H), 8.16 (d, J=5.4 Hz, 1H), 7.82 (t, J=6.0 Hz, 1H), 7.64 (br s, 1H), 7.27 (br s, 1H), 5.05 (d, J=14.4 Hz, 1H), 4.91 (d, J=14.4 Hz, 1H), 4.76-4.80 (m, 1H), 2.15-2.25 (m, 3H), 2.02-2.11 (m, 1H), 1.33 (s, 9H).

[0243] Step B. To a solution of A341A (800 mg, 2.20 mmol) in MeOH was added Pd/C (100%, 80 mg, 50(955 m water), the mixture was stirred at 25° C. overnight under Hz (50 Psi). LCMS showed the reaction completed. Pd/C was removed by filtration and the filtrate was concentrated to give a crude product A341C (680 rag, 93% yield) as a light yellow solid. The crude product was used for next step without further purification.

[0244] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.54 (br s, 1H), 7.13-7.18 (m, 2H), 6.88 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 5.44 (br s, 2H), 4.70-4.75 (m, 1H), 4.41 (d, J=17.7 Hz, 1H), 4.18 (d, J=17.7 Hz, 1H), 2.09-2.21 (m, 3H), 1.92-2.06 (m, 1H), 1.34 (s, 9H).

[0245] Step C. To a solution of A341C (680 mg, 2.04 mmol) and 2-Fluoro-5-methoxy-benzaldehyde (472 mg, 3.06 mmol) in MeOH was added AcOH (0.5 mL), the mixture was stirred at 25° C. for 3 hours. Pd/C (10%, 50 mg, 50% water) was added, degassed with H.sub.2 3 times and stirred at 25° C. overnight under H.sub.2 (balloon). LCMS showed the reaction completed. Pd/C was removed by filtration and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on slica gel (PE/EtOAc=1/4) to give the desired product A341E (650 mg, yield: 68%) as a light yellow solid.

[0246] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 7.56 (br s, 1H), 7.18-7.23 (m, 2H), 7.12 (t, J=9.2 Hz, 1H), 6.91-6.95 (m, 2H), 6.81-6.85 (m, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.36 (t, J=5.6 Hz, 1H), 4.72-4.76 (m, 1H), 4.50 (d, J=17.6 Hz, 1H), 4.37 (d, J=6.0 Hz, 2H), 4.29 (d, J=17.6 Hz, 1H), 3.67 (s, 3H), 2.14-2.22 (m, 3H), 1.94-2.04 (m, 1H), 1.33 (s, 9H).

[0247] Step D. To a solution of A341E (650 mg, 1.38 mmol) in DCM (20 mL) cooled to 0° C. was added dropwise TFA (4 mL), the mixture was warmed slowly to 25° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure (in vacuum) to remove solution. The residue was purified by flash chromatography on C18 (40% acetonitrile in water) then was freeze-dried to afford A341G (450 mg, yield: 79%) as a light yellow solid.

[0248] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.56 (br s, 1H), 7.07-7.22 (m, 3H), 6.89-6.94 (m, 2H), 6.78-6.83 (m, 1H), 6.61 (d, J=7.8 Hz, 1H), 6.34 (t, J=6.3 Hz, 1H), 4.69-4.73 (m, 1H), 4.50 (d, J=17.7 Hz, 1H), 4.35 (d, J=5.7 Hz, 2H), 4.29 (d, J=17.7 Hz, 1H), 3.65 (s, 3H), 2.12-2.19 (m, 3H), 1.93-1.98 (m, 1H).

[0249] Step E. To a solution of A341G (450 mg, 1.08 mmol) dissolved in dry DCM (50 mL) cooled to −40° C. under N.sub.2, SOCl.sub.2 (644 mg, 5.41 mmol) was slowly added to the mixture at −40° C. under N.sub.2, then a solution of DMF (10 mg) in DCM (1 mL) was added and stirred for 2 hrs, pyridine (428 mg, 5.41 mmol) was added dropwise and stirred for 40 mins at this temperature, Et.sub.3N (547 mg, 5.41 mmol) was added and then the mixture was stirred for 2 h. LCMS showed the reaction completed. H.sub.2O (10 mL) was added to quench the reaction, the water layer was extracted with DCM (30 mL×2), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The residue was purified by Prep-HPLC to give A341 (260 mg, yield: 61%, ee: 96%) as a pale green solid.

[0250] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.98 (br s, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.11 (t, J=9.3 Hz, 1H), 6.90-6.95 (m, 2H), 6.78-6.84 (m, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.26 (t, J=6.0 Hz, 1H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.36 (d, J=5.7 Hz, 2H), 4.30 (d, J=17.1 Hz, 1H), 4.17 (d, J=17.1 Hz, 1H), 3.65 (s, 3H), 2.85-2.97 (m, 1H), 2.56-2.63 (m, 1H), 2.22-2.35 (m, 1H), 2.00-2.07 (m, 1H). LCMS: 398.1 ([M+1].sup.+).

Example 18: Compound A342

(R)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A342

[0251] ##STR00347## ##STR00348##

[0252] Step A. To a solution of A343F (31.7 g, 115.7 mmol) in CH.sub.3CN (560 mL) were added A343G (31.5 g, 115.1 mmol) and Et.sub.3N (23.3 g, 231.0 mmol), the mixture was stirred at 75° C. overnight under N.sub.2. The reaction mixture was concentrated and EtOAc (50 mL) and 4N HCl aqueous solution (150 mL) were added, the mixture was filtered and the cake was washed with water (30 mL) and dried, while the filtrate was extracted with EtOAc (250 mL×2), the combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtration, concentrated to give a crude product. The combined solid was triturated with CH.sub.3CN (40 mL×2), filtered to give A343E (37 g, 81% yield) as a white solid. Compound A343E was subjected to chiral separation to afford Peak 1 A343E(S) (14.4 g, yield: 77.8%, Rt=7.30 min, 100% ee) and Peak 2 A342E(R) (14.8 g, yield: 80%, Rt=11.87 min, 100% ee) as a white solid.

[0253] Chiral Separation conditions: Column: CHIRALPAK IE, Particle size: 10 μm, Dimensious: 50×250 mm: Wave Length: 254 nm; Mobile Phase: MeOH/DCM=80/20 (V/V); Injection: 48 mL; Flow Rate: 60 mL/min; Temperature: 35° C. Solvent: Mobile Phase, 17.1 mg/mL.

[0254] A343E(S): .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 8.43 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.79 (t, J=8.1 Hz, 1H), 7.66 (br s, 1H), 7.26-7.35 (m, 6H), 4.86-5.07 (m, 4H), 2.42-2.21-2.43 (m, 3H), 2.06-2.16 (m, 1H).

[0255] A342E(R): .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 8.43 (d, J=8.4 Hz, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.77-7.82 (m, 1H), 7.65 (br s, 1H), 7.35-7.23-7.35 (m, 6H), 4.86-5.07 (m, 4H), 2.20-2.42 (m, 3H), 2.06-2.15 (m, 1H).

[0256] Step B. To a solution of A342E(R) (2.5 g, 6.3 mmol) in MeOH (150 mL) and THF (150 mL) was added Pd/C (10%, 500 mg, 50% water), the mixture was stirred overnight under H.sub.2 (50 Psi) at 25° C. LCMS showed the reaction completed. Pd/C was removed by filtration and the filtrate was concentrated to give a crude product which was co-evaporated with CH.sub.3CN/DCE (50 mL/150 mL), and then the solid was dissolved in THF (300 mL) and concentrated to give A342C (1.68 g, 97% yield) as a white solid, which was used in the next step without further purification.

[0257] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 12.11 (br s, 1H), 7.54 (s, 1H), 7.11-7.16 (m, 2H), 6.85 (d, J=7.8 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 5.43 (br s, 2H), 4.68-4.73 (m, 0.02H), 4.41 (d, J=17.4 Hz, 1H), 4.17 (d, J=17.4 Hz, 1H), 2.10-2.18 (m, 3H), 1.94-1.97 (m, 1H).

[0258] Step C: To a solution of A342C and 2-Fluoro-5-methoxy-benzaldehyde (831 mg, 5.39 mmol) in MeOH was added AcOH (0.5 mL), the mixture was stirred at 25° C. for 20 hours. Pd/C (10%, 100 mg, 50% water) was added, degassed with H.sub.2 3 times and stirred at 25° C. overnight under H.sub.2 (balloon). LCMS showed the reaction completed. Pd/C was removed by filtration and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography on C18 (CH.sub.3CN: H.sub.2O=5%-35%, 30 min; 35%-45%, 30 min; 45%-55% 20 min) then was freeze-dried to afford A342A (800 mg, yield: 53%) as a light yellow solid.

[0259] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 12.10 (br s, 1H), 7.56 (br s, 1H), 7.07-7.22 (m, 3H), 6.89-6.94 (m, 2H), 6.78-6.83 (m, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.34 (t, J=6.0 Hz, 1H), 4.70-4.74 (m, 0.03H), 4.50 (d, J=17.7 Hz, 1H), 4.35 (d, J=5.7 Hz, 2H), 4.28 (d, J=17.7 Hz, 1H), 3.65 (s, 3H), 2.10-2.21 (m, 3H), 1.92-2.02 (m, 1H).

[0260] Step D: To a solution of A342A (450 mg, 1.10 mmol) in dry DCM (50 mL) cooled to −40° C. under N.sub.2, SOCl.sub.2 (572 mg, 4.81 mmol) was slowly added to the mixture at −40° C. under N.sub.2, then a solution of DMF (10 mg) in DCM (1 mL) was added, stirring for 2 hr, then pyridine (380 mg, 4.80 mmol) was added dropwise at this temperature, stirring for 40 mins, then Et.sub.3N (486 mg, 4.80 mmol) was added and then the mixture was stirred for 2 h. LCMS showed the reaction completed. H.sub.2O (10 mL) was added to quench the reaction, the water layer was extracted with DCM (30 mL×2), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The residue was purified by flash chromatography on C18 (CH.sub.3CN: H.sub.2O=5%-35%, 30 min; 35%-45%, 30 min; 45%-55% 20 min) to give A342 (220 mg, yield: 58%, ee: 99%) as a light yellow solid.

[0261] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (br s, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.11 (t, J=9.6 Hz, 1H), 6.90-6.95 (m, 2H), 6.79-6.84 (m, 1H), 6.65 (d, J=7.8 Hz, 1H), 6.26 (t, J=5.4 Hz, 1H), 5.07-5.14 (m, 0.01H), 4.36 (d, J=5.7 Hz, 2H), 4.30 (d, J=17.1 Hz, 1H), 4.17 (d, J=17.1 Hz, 1H), 3.65 (s, 3H), 2.85-2.97 (m, 1H), 2.57-2.63 (m, 1H), 2.24-2.34 (m, 1H), 2.00-2.06 (m, 1H).

[0262] LCMS: 399.1 ([M+1].sup.+).

[0263] Compound of example 19 was prepared according to the synthetic method described for example 18, with corresponding starting material to replace A342E(R) in step B.

Example 19: A343

(S)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A343

[0264] ##STR00349##

[0265] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (br s, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.11 (t, J=9.6 Hz, 1H), 6.90-6.95 (m, 2H), 6.78-6.84 (m, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.26 (t, J=6.3 Hz, 1H), 5.07-5.13 (m, 0.02H), 4.36 (d, J=5.7 Hz, 2H), 4.29 (d, J=17.1 Hz, 1H), 4.17 (d, J=17.1 Hz, 1H), 3.65 (s, 3H), 2.85-2.97 (m, 1H), 2.56-2.64 (m, 1H), 2.24-2.34 (m, 1H), 2.00-2.05 (m, 1H). LCMS: 399.1 ([M+1].sup.+).

Example 20: Compound A346

(S)-3-(4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl) piperidine-2,6-dione, A346

[0266] ##STR00350##

[0267] A346A (119 mg, 0.58 mmol) and compound A308A (100 mg, 0.39 mmol) was dissolved in AcOH (2.5 mL) and DCM (2.5 mL) and the solution was stirred for 1 hour at 30° C. NaBH(OAc).sub.3 (246 mg, 1.16 mmol) was added and the reaction mixture was stirred for 18 hours under N.sub.2. TCL showed the reaction completed. The solvent was removed and sat aq NaHCO.sub.3 (5 mL) was added to adjust pH to 8. The mixture was extracted with DCM (25 mL×5) and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated and triturated with PE/EtOAc (1/1) (25 mL×2) to give 250 mg crude product, which was purified by prep-HPLC to give A346 (140 mg, 80% yield) as a white solid.

[0268] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 0.7.16-7.33 (m, 5H), 6.90 (d, J=7.2 Hz, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.33 (t, J=5.7 Hz, 1H), 5.07-5.13 (m, 1H), 4.35 (d, J=5.4 Hz, 2H), 4.29 (d, J=17.1 Hz, 1H), 4.16 (d, J=17.1 Hz, 1H), 3.53 (t, J=4.5 Hz, 4H), 3.39 (s, 2H), 2.85-2.93 (m, 1H), 2.58-2.63 (m, 1H), 2.28-2.31 (m, 5H), 2.01-2.06 (m, 1H).

[0269] LCMS: 449.2 ([M+1].sup.+).

[0270] Compounds in examples 12-45 was prepared according to the procedure described for example 20, with corresponding starting materials to replace A346A.

Example 21: Compound A359

3-(4-((2-fluoro-3-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A359

[0271] ##STR00351##

[0272] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.96 (br, 1H), 9.79 (br, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.73-6.93 (m, 4H), 6.63 (d, J=7.8 Hz, 1H), 6.25 (t, J=6.0 Hz, 1H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.37 (d, J=5.7 Hz, 2H), 4.28 (d, J=17.4 Hz, 1H), 4.15 (d, J=17.4 Hz, 1H), 2.85-2.97 (m, 1H), 2.57-2.63 (m, 1H), 2.22-2.36 (m, 1H), 2.01-2.05 (m, 1H). LCMS: 384.1 ([M+1].sup.+).

Example 22: Compound A360

3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzonitrile, A360

[0273] ##STR00352##

[0274] .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.03 (s, 1H), 7.81-7.86 (m, 1H), 7.71-7.76 (m, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.41 (t, J=5.7 Hz, 1H), 5.13, (dd, J=12.9, 5.1 Hz, 1H), 4.50 (d, J=5.7 Hz, 1H), 4.32 (d, J=17.1 Hz, 1H), 4.19 (d, J=17.1 Hz, 1H), 2.87-2.95 (m 1H), 2.50-2.65 (m 1H), 2.29-2.34 (m 1H), 2.02-2.07 (m 1H).

Example 23: Compound A361

3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzamide, A361

[0275] ##STR00353##

[0276] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.45-7.53 (m, 2H), 7.16-7.27 (m, 2H), 6.96 (d, J=7.2 Hz, 1H), 6.64 (d, J=8.1 Hz, 1H), 6.35-6.38 (m, 1H), 5.13 (dd, J=13.2, 4.8 Hz, 1H), 4.46 (d, J=5.4 Hz, 2H), 4.33 (d, J=17.4 Hz, 1H), 4.20 (d, J=17.4 Hz, 1H), 2.87-2.98 (m, 1H), 2.60-2.65 (m, 1H), 2.25-2.39 (m, 1H), 2.03-2.07 (m, 1H). LCMS: 411.1 ([M+1].sup.+).

Example 24: Compound A362

3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluoro-N-methylbenzamide, A362

[0277] ##STR00354##

[0278] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.01 (s, 1H), 8.28 (d, J=3.3 Hz, 1H), 7.46 (t, J=7.2 Hz, 2H), 7.15-7.26 (m, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.37 (t, J=5.7 Hz, 1H), 5.12 (dd, J=13.5, 4.8 Hz, 1H), 4.45 (d, J=5.1 Hz, 2H), 4.32 (d, J=17.4 Hz, 1H), 4.20 (d, J=17.4 Hz, 1H), 2.87-2.99 (m, 1H), 2.78 (d, J=4.8 Hz, 3H), 2.60-2.65 (m, 1H), 2.25-2.39 (m, 1H), 1.99-2.11 (m, 1H). LCMS: 425.1 ([M+1].sup.+).

Example 25: Compound A363

3-(4-((5-(2-(Dimethylamino)ethoxy)-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A363

[0279] ##STR00355##

[0280] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.11 (t, J=9.3 Hz, 1H), 6.90-6.96 (m, 2H), 6.80-6.86 (m, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.29 (t, J=6.0 Hz, 1H), 5.12 (dd, J=13.2, 4.8 Hz, 1H), 4.29-4.39 (m, 3H), 4.19 (d, J=17.1 Hz, 1H), 3.94 (t, J=5.7 Hz, 2H), 2.87-2.99 (m, 1H), 2.51-2.65 (m, 3H), 2.24-2.38 (m, 1H), 2.15 (s, 6H), 2.00-2.10 (m, 1H). LCMS: 455.2 ([M+1].sup.+).

Example 26: Compound A364

3-(4-((2-fluoro-5-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A364

[0281] ##STR00356##

[0282] .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.01 (s, 1H), 9.24 (s, 1H), 7.22 (t, J=7.8 Hz, 1H), 6.92-6.99 (m, 2H), 6.70-6.73 (m, 1H), 6.55-6.60 (m, 2H), 6.31 (t, J=5.7 Hz, 1H), 5.11, (dd, J=13.2, 5.1 Hz, 1H), 4.27-4.34 (m, 3H), 4.17 (d, J=17.1 Hz, 1H), 2.86-2.96 (m 1H), 2.57-2.64 (m 1H), 2.24-2.33 (m 1H), 2.02-2.06 (m 1H).

Example 27: Compound A367

3-(4-((2-fluoro-3-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A367

[0283] ##STR00357##

[0284] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.03 (s, 1H), 7.14-7.26 (m, 3H), 6.93-7.04 (m, 2H), 6.64 (d, J=7.5 Hz, 1H), 6.30 (br s, 1H), 5.09-5.16 (m, 1H), 4.42 (s, 2H), 4.31 (d, J=17.4 Hz, 1H), 4.18 (d, J=17.4 Hz, 1H), 2.89-2.98 (m, 1H), 2.59-2.65 (m, 1H), 2.25-2.46 (m, 4H), 2.02-2.07 (m, 1H). LCMS: 382.2 ([M+1].sup.+).

Example 28: Compound A368

3-(4-((2-fluoro-5-(2-morpholinoethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A368

[0285] ##STR00358##

[0286] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.98 (s, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.09 (t, J=9.6 Hz, 1H), 6.79-6.95 (m, 3H), 6.64 (d, J=7.5 Hz, 1H), 6.24 (br, 1H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.36 (d, J=5.7 Hz, 2H), 4.30 (d, J=17.1 Hz, 1H), 4.18 (d, J=17.1 Hz, 1H), 3.97 (t, J=5.7 Hz, 2H), 3.51 (t, J=4.5 Hz, 4H), 2.85-2.97 (m, 1H), 2.56-2.63 (m, 3H), 2.27-2.39 (m, 5H), 2.00-2.05 (m, 1H). LCMS: 497.2 ([M+1].sup.+).

Example 29: Compound A369

3-(4-((2-fluoro-5-(3-morpholinopropoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A369

[0287] ##STR00359##

[0288] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.09 (t, J=9.3 Hz, 1H), 6.88-6.95 (m, 2H), 6.77-6.83 (m, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.27 (t, J=5.7 Hz, 1H), 5.11 (dd, J=13.2, 5.4 Hz, 1H), 4.36 (d, J=5.7 Hz, 2H), 4.30 (d, J=17.4 Hz, 1H), 4.17 (d, J=17.4 Hz, 1H), 3.88 (t, J=6.3 Hz, 2H), 3.52 (t, J=3.9 Hz, 4H), 2.85-2.96 (m, 1H), 2.57-2.63 (m, 1H), 2.22-2.41 (m, 7H), 1.99-2.05 (m, 1H), 1.73-1.84 (m, 2H). LCMS: 511.2 ([M+1].sup.+).

Example 30: Compound A370

3-(4-((2-fluoro-5-(2-methoxyethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A370

[0289] ##STR00360##

[0290] .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 10.98 (s, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.06-7.12 (m, 1H), 6.90-6.95 (m, 2H), 6.79-6.84 (m, 1H), 6.64 (d, J=8.1 Hz, 1H), 6.24 (t, J=5.4 Hz, 1H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.28-4.38 (m, 3H), 4.19 (d, J=17.1 Hz, 1H), 3.96-3.99 (m, 2H), 3.55-3.58 (m, 2H), 3.23 (s, 3H), 2.85-2.95 (m 1H), 2.57-2.64 (m 1H), 2.24-2.36 (m 1H), 1.98-2.09 (m 1H).

Example 31: Compound A371

3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenyl methylcarbamate, A371

[0291] ##STR00361##

[0292] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.52-7.56 (m, 1H), 7.15-7.25 (m, 2H), 6.93-7.06 (m, 3H), 6.63 (d, J=7.8 Hz, 1H), 6.28-6.32 (m, 1H), 5.10 (dd, J=13.5, 4.5 Hz, 1H), 4.40 (d, J=4.8 Hz, 2H), 4.30 (d, J=17.4 Hz, 1H), 4.18 (d, J=17.4 Hz, 1H), 2.84-2.97 (m, 1H), 2.59-2.69 (m, 4H), 2.23-2.37 (m, 1H), 1.99-2.08 (m, 1H). LCMS: 441.1 ([M+1].sup.+).

Example 32: Compound A372

3-(4-((2-fluoro-3-(methylamino)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A372

[0293] ##STR00362##

[0294] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.99 (s, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.85-6.92 (m, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.48-6.55 (m, 2H), 6.21 (t, J=5.4 Hz, 1H), 5.48-6.49 (m, 1H), 5.09 (dd, J=13.2, 5.1 Hz, 1H), 4.35 (d, J=5.4 Hz, 2H), 4.27 (d, J=17.4 Hz, 1H), 4.15 (d, J=17.4 Hz, 1H), 2.85-2.97 (m, 1H), 2.69 (d, J=4.5 Hz, 3H), 2.49-2.63 (m, 1H), 2.21-2.35 (m, 1H), 1.98-2.05 (m, 1H). LCMS=397.1 ([M+1].sup.+)

Example 33: Compound A375

3-(4-((2-fluoro-5-(2-hydroxyethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A375

[0295] ##STR00363##

[0296] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 9.35 (br s, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.10 (t, J=9.3 Hz, 1H), 6.88-6.95 (m, 2H), 6.78-6.83 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.31 (t, J=6.0 Hz, 1H), 5.11 (dd, J=13.5, 5.1 Hz, 1H), 4.82 (br s, 1H), 4.37 (d, J=5.7 Hz, 2H), 4.30 (d, J=17.1 Hz, 1H), 4.17 (t, J=17.1 Hz, 1H), 3.85 (t, J=4.8 Hz, 2H), 3.62 (t, J=4.8 Hz, 2H), 2.85-2.97 (m, 1H), 2.55-2.65 (m, 1H), 2.24-2.36 (m, 1H), 2.01-2.05 (m, 1H). LCMS: 428.1 [(M+1).sup.+].

Example 34: Compound A376

3-(4-((2-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A376

[0297] ##STR00364##

[0298] .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.02 (s, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.06-7.13 (m, 1H), 6.89-6.95 (m, 2H), 6.78-6.84 (m, 1H), 6.63 (d, J=7.8 Hz, 1H), 6.29 (t, J=5.7 Hz, 1H), 5.11, (dd, J=13.2, 5.1 Hz, 1H), 4.27-4.37 (m, 3H), 4.17 (d, J=17.1 Hz, 1H), 3.94 (t, J=6.0 Hz, 1H), 2.85-2.97 (m 1H), 2.57-2.69 (m 3H), 2.22-2.42 (m 5H), 1.98-2.06 (m 1H), 1.56-1.66 (m 4H).

Example 35: Compound A377

3-(4-((2-fluoro-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A377

[0299] ##STR00365##

[0300] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.03 (s, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.09 (t, J=9.6 Hz, 1H), 6.91-6.95 (m, 2H), 6.79-6.89 (m, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.29 (t, J=6.0 Hz, 1H), 5.11 (dd, J=13.5, 4.8 Hz, 1H), 4.27-4.37 (m, 3H), 4.17 (d, J=17.4 Hz, 1H), 3.94 (t, J=5.7 Hz, 2H), 2.85-2.98 (m, 1H), 2.55-2.62 (m, 4H), 2.20-2.42 (m, 8H), 2.12 (s, 3H), 1.98-2.07 (m, 1H). LCMS: 510.2 ([M+1].sup.+).

Example 36: Compound A378

3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenyl dimethylcarbamate, A378

[0301] ##STR00366##

[0302] .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.00 (s, 1H), 7.17-7.26 (m, 2H), 7.08-7.11 (m, 1H), 6.94-7.04 (m, 2H), 6.78-6.84 (m, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.30 (t, J=5.9 Hz, 1H), 5.11, (dd, J=13.2, 5.4 Hz, 1H), 4.40 (d, J=5.7 Hz, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.18 (d, J=17.4 Hz, 1H), 2.84-2.96 (m 7H), 2.57-2.63 (m 1H), 2.23-2.37 (m 1H), 2.00-2.05 (m 1H).

Example 37: Compound A382

3-(4-((2-fluoro-5-(3-morpholinopropoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A382

[0303] ##STR00367##

[0304] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.05-7.13 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.64 (d, J=7.8 Hz, 1H), 6.28 (t, J=6.3 Hz, 1H), 5.07-5.13 (m, 1H), 4.38 (d, J=5.7 Hz, 2H), 4.28 (d, J=17.4 Hz, 1H), 4.16 (d, J=17.4 Hz, 1H), 3.54 (t, J=4.5 Hz, 4H), 3.42 (s, 2H), 2.85-2.97 (m, 1H), 2.57-2.63 (m, 1H), 2.26-2.38 (m, 5H), 2.00-2.09 (m, 1H). LCMS: 467.2 ([M+1].sup.+).

Example 38: Compound A383

3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A383

[0305] ##STR00368##

[0306] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.98 (br s, 1H), 7.34 (d, J=0.9 Hz, 1H), 7.10-7.32 (m, 3H), 6.95 (d, J=7.5 Hz, 1H), 6.64 (d, J=7.8 Hz, 1H), 6.27 (br s, 1H), 5.12 (dd, J=13.5, 5.1 Hz, 1H), 4.43 (d, J=5.7 Hz, 2H), 4.32 (d, J=17.1 Hz, 1H), 4.21 (d, J=17.1 Hz, 1H), 3.45-3.48 (m, 4H), 3.38 (s, 2H), 2.87-2.99 (m, 1H), 2.30-2.36 (m, 1H), 2.23-2.25 (m, 4H), 2.22-2.36 (m, 1H), 2.01-2.09 (m, 1H). LCMS=467.2 [(M+1).sup.+].

Example 39: Compound A381

3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A381

[0307] ##STR00369##

[0308] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.20-7.31 (m, 3H), 7.10 (t, J=7.8 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.31 (t, J=5.7 Hz, 1H), 5.12 (dd, J.sub.1=13.8 Hz, J.sub.2=5.4 Hz, 1H), 4.43 (d, J=5.4 Hz, 2H), 4.31 (d, J=17.4 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 3.53-3.58 (m, 6H), 2.87-2.99 (m, 1H), 2.57-2.66 (m, 1H), 2.24-2.39 (m, 5H), 2.00-2.10 (m, 1H). LCMS=467.2 [(M+1).sup.+].

Example 40: Compound A384

3-(4-((3-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A384

[0309] ##STR00370##

[0310] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 9.76 (br s, 1H), 7.23 (t, J=8.1 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.77 (t, J=7.8 Hz, 1H), 6.61-6.67 (m, 2H), 6.49-6.54 (m 1H), 6.22 (t, J=5.7 Hz, 1H), 5.09-5.15 (m, 3H), 4.35 (d, J=5.4 Hz, 2H), 4.29 (d, J=17.4 Hz, 1H), 4.17 (d, J=17.4 Hz, 1H), 2.87-2.99 (m, 1H), 2.58-2.67 (m, 1H), 2.23-2.36 (m, 1H), 2.00-2.10 (m, 1H). LCMS=383.1 ([M+1].sup.+).

Example 41: Compound A388

N-(3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorophenyl)acetamide, A388

[0311] ##STR00371##

[0312] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.96 (br s, 1H), 9.71 (s, 1H), 7.74 (t, J=6.9 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.02-7.13 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.64 (d, J=7.8 Hz, 1H), 6.31 (t, J=6.0 Hz, 1H), 5.10 (dd, J=12.9, 5.1 Hz, 1H), 4.42 (d, J=5.4 Hz, 2H), 4.29 (d, J=17.1 Hz, 1H), 4.16 (d, J=17.1 Hz, 1H), 2.85-2.95 (m, 1H), 2.55-2.64 (m, 1H), 2.22-2.36 (m, 1H), 1.99-2.07 (m, 4H). LCMS=425.1 [(M+1).sup.+].

Example 42: Compound A389

3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzenesulfonamide, A389

[0313] ##STR00372##

[0314] .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.02 (s, 1H), 7.85-7.88 (m, 1H), 7.73-7.78 (m, 1H), 7.39-7.45 (m, 3H), 7.24 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.43 (t, J=6.0 Hz, 1H), 5.11, (dd, J=13.2, 5.1 Hz, 1H), 4.46 (d, J=5.4 Hz, 2H), 4.29 (d, J=17.4 Hz, 1H), 4.18 (d, J=17.4 Hz, 1H), 2.85-2.97 (m 1H), 2.58-2.63 (m 1H), 2.24-2.36 (m 5H), 2.02-2.07 (m 1H).

Example 43: Compound A387

3-(4-((2-fluoro-5-(methylamino)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A387

[0315] ##STR00373##

[0316] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.22 (t, J=7.5 Hz, 1H), 6.87-6.93 (m, 2H), 6.62 (d, J=8.1 Hz, 1H), 6.50-6.53 (m, 1H), 6.31-6.36 (m, 1H), 6.25 (t, J=5.7 Hz, 1H), 5.47-5.52 (m, 1H), 5.11 (dd, J=4.8, 13.2 Hz, 1H), 4.25-4.30 (m, 3H), 4.15 (d, J=17.4 Hz, 1H), 2.85-2.97 (m, 1H), 2.54-2.63 (m, 4H), 2.22-2.37 (m, 1H), 1.99-2.06 (m, 1H). LCMS: 397.21 ([M+1].sup.+).

Example 44: Compound A396

3-(4-((2-fluoro-4-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A396

[0317] ##STR00374##

[0318] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (br s, 1H), 9.74 (br s, 1H), 7.14-7.25 (m, 2H), 6.92 (d, J=7.2 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 6.52-6.55 (m, 2H), 6.13 (t, J=6.0 Hz, 1H), 5.07-5.13 (m, 1H), 4.24-4.29 (m, 3H), 4.14 (d, J=17.1 Hz, 1H), 2.87-2.97 (m, 1H), 2.56-2.65 (m, 1H), 2.21-2.36 (m, 1H), 1.98-2.06 (m, 1H). LCMS: 384.1 [(M+1).sup.+]

Example 45: Compound A391

[3-(4-((5-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione], A391

[0319] Step A: compound A391G was prepared according to the synthetic method shown in Example 20, with corresponding starting material to replace A346A.

[0320] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 11.03 (s, 1H), 9.31 (s, 1H), 7.37-7.44 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.09 (t, J=9.2 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.33 (t, J=5.6 Hz, 1H), 5.11-5.16 (m, 1H), 4.36 (t, J=5.2 Hz, 2H), 4.29 (d, J=16.8 Hz, 1H), 4.19 (d, J=17.2 Hz, 1H), 2.89-2.98 (m, 1H), 2.60-2.64 (m, 1H), 2.26-2.37 (m, 1H), 2.03-2.06 (m, 1H), 1.42 (s, 9H).

##STR00375##

[0321] Step B: To a solution of A391G (400 mg, 0.83 mmol) in DCM (12 mL) was added CF.sub.3COOH (4 m L), and the solution was stirred for 0.5 hours at 35° C. The solvent was removed and the residue was dissolved with 4 mL CH.sub.3CN and 100 mg Et.sub.3N, then purified by prep-HPLC to give A391 (130 mg, yield: 41%) as a white solid.

[0322] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 10.83 (s, 1H), 9.37 (t, J=5.6 Hz, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.78-7.86 (m, 3H), 7.58 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.17 (s, 1H), 4.64 (d, J=5.6 Hz, 2H), 4.50-4.54 (m, 1H), 2.37-2.41 (m, 1H), 2.21-2.26 (m, 1H), 1.89-1.93 (m, 2H). LCMS: 523.1 ([M+1].sup.+).

Example 46: Compound A397

3-(4-((5-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A397

[0323] Step A: Compound A397A was prepared according to the synthetic method shown in Example 20, with corresponding starting material to replace A346A.

[0324] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 11.04 (br s, 1H), 9.54 (br s, 1H), 7.38 (d, J=12.8 Hz, 1H), 7.22-7.28 (m, 2H), 7.13 (d, J=8.4 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H), 6.24 (t, J=5.6 Hz, 1H), 5.10-5.14 (m, 1H), 4.27-4.34 (m, 3H), 4.17 (d, J=17.2 Hz, 1H), 2.89-2.97 (m, 1H), 2.64-2.67 (m, 1H), 2.25-2.36 (m, 1H), 2.03-2.06 (m, 1H), 1.46 (s, 9H).

##STR00376##

[0325] Step B: To a solution of compound A397A (100 mg, 0.21 mmol) in dioxane (20 mL) was added a solution of 6 N HCl in dioxane, the mixture was stirred for 2.5 h. The reaction mixture was concentrated and the residue was dissolved in DMF (10 mL) and adjust pH=7-8 with Sat. NaHCO.sub.3, filtered. The filtrate was concentrated and the residue was purified by Prep-HPLC to give the desired product A397 (35 mg, yield: 44%) as a light yellow solid.

[0326] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 11.02 (br s, 1H), 7.24 (t, J=8.4 Hz, 1H), 7.02 (t, J=8.4 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.04 (t, J=5.6 Hz, 1H), 5.30 (br s, 2H), 5.09-5.14 (m, 1H), 4.25 (d, J=17.2 Hz, 1H), 4.20 (d, J=5.6 Hz, 1H), 4.14 (d, J=17.2 Hz, 1H), 2.88-2.97 (m, 1H), 2.59-2.64 (m, 1H), 2.24-2.35 (m, 1H), 2.02-2.08 (m, 4H). LCMS: 383.2 [(M+1).sup.+].

Example 47: Compound A373

(S)-3-deuterium-3-(4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A373

[0327] ##STR00377##

[0328] Step A: To a solution of A373C [4-(morpholinomethyl)benzaldehyde] (0.8 g, 3.9 mmol) and A356C (0.7 g, 2.5 mmol) in MeOH (100 mL) was added AcOH (1 mL) and the mixture was stirred overnight at 40° C. under N.sub.2. Then Pd/C (50% wet, 10%, 150 mg) was added to the reaction mixture and degassed with H.sub.2 3 times. The mixture was stirred for 5 hours at 1 atm hydrogen pressure. The reaction mixture was filtered and the filtrate was concentrated and purified by RP-HPLC to give A373A (1.0 g, yield: 86%) as a light yellow solid.

[0329] .sup.1H NMR (DMSO-d6, 300 MHz): δ 9.96 (br, 1H), 7.59 (s, 1H), 7.41-7.49 (m, 4H), 7.11-7.18 (m, 2H), 6.87 (d, J=7.2 Hz, 1H), 6.54 (d, J=8.1 Hz, 1H), 4.25-4.55 (m, 7H), 3.93 (d, J=12.0 Hz, 2H), 3.58 (t, J=12.3 Hz, 2H), 3.01-3.24 (m, 4H), 2.13-2.21 (m, 3H), 1.93-2.00 (m, 1H).

[0330] Step B: To a solution of A373A (200 mg, 0.428 mmol) in THF (12 mL) and DCM (12 mL) was added SOCl.sub.2 (204 mg, 1.71 mmol in 1.7 mL DCM) at −40° C. and the mixture was stirred at −40° C. for 2 hours under N.sub.2. Then pyridine (135 mg, 1.71 mmol) was added to the reaction mixture and stirred for 30 minutes. Then Et.sub.3N (173 mg, 1.71 mmol) was added and the reaction mixture was allowed to warm to room temperature. Water (0.5 mL) was added to quench the reaction and the mixture was concentrated and purified by reversed-phase Prep-HPLC (mobile phase:water/acetonitrile) 2 times to give A373 (20 mg, yield: 10%) as a white solid.

[0331] .sup.1H NMR (DMSO-d6, 300 MHz): δ 11.02 (s, 1H), 7.15-7.34 (m, 5H), 6.89 (d, J=7.2 Hz, 1H), 6.61 (d, J=7.8 Hz, 1H), 6.38 (t, J=4.8 Hz, 1H), 5.08-5.14 (m, 0.04H), 4.35 (d, J=5.1 Hz, 2H), 4.29 (d, J=17.4 Hz, 1H), 4.16 (d, J=17.4 Hz, 1H), 3.55 (br s, 4H), 3.42 (br.s, 2H), 2.85-2.98 (m, 1H), 2.57-2.63 (m, 1H), 2.24-2.34 (m, 5H), 1.99-2.05 (m, 1H).

[0332] LCMS: 450.2 ([M+1].sup.+).

Example 48: Compound A374

2-(3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenoxy)ethyl pyrrolidine-1-carboxylate, A374

[0333] ##STR00378##

[0334] Step A. A mixture of pyrrolidine (3.77 g 53 mmol), 2-bromoethanol (6.25 g, 50 mmol) and K.sub.2CO.sub.3 (6.9 g 50 mmol) in CH.sub.3CN (70 mL) was heated to reflux and stirred overnight under N.sub.2. The reaction mixture was filtered and concentrated, and purified via column chromatography on silica gel (DCM:MeOH=100:1 to 10:1) to give A374A (4 g, 50% yield) as a light yellow oil.

[0335] .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 4.25-4.28 (m, 2H), 3.80-3.85 (m, 2H), 3.36-3.43 (m, 4H), 2.92 (t, J=5.7, 1H), 1.88-1.92 (m, 4H).

[0336] Step B. To a solution of A374A (2.3 g, 14.4 mmol) in CHCl.sub.3 (50 mL) was added SOCl.sub.2 (3.6 g, 30.0 mmol) and the reaction mixture was stirred for 1.5 h under reflux. The reaction mixture was concentrated to give crude A374C (2.0 g, yield: 78%) as a white solid.

[0337] .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 4.21 (t, J=5.7, 2H), 3.77 (t, J=5.7, 2H), 3.21-3.32 (m, 4H), 1.75-1.83 (m, 4H).

[0338] Step C. A mixture of A374C (802 mg, 4.52 mmol), 2-fluoro-5-hydroxybenzaldehyde (280 mg, 2.0 mmol) and K.sub.2CO.sub.3 (828 mg, 6.0 mmol) in DMF (10 mL) was heated to 90° C. and stirred overnight under N.sub.2. The reaction mixture was poured into ice water (100 mL), stirred and filtered. The cake was washed with water (20 mL) and then dissolved in EtOAc (50 mL), dried and concentrated to give product A374E (560 mg) as a white solid which was used in next step without purification.

[0339] .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 10.32 (s, 1H), 7.31-7.34 (m, 1H), 7.09-7.17 (m, 2H), 4.42 (t, J=5.1 Hz, 2H), 4.20 (t, J=5.1 Hz, 2H) 3.30-3.41 (m, 4H), 1.85 (br s, 4H).

[0340] Step D. A solution of A374E (206 mg, 0.732 mmol), A308A (150 mg, 0.578 mmol) and AcOH (6 mL) in dichloromethane (6 mL) was stirred for 4 hours at room temperature. NaBHCN (109 mg, 1.74 mmol) was added and the reaction mixture was stirred at room temperature overnight under N.sub.2. The solvent was removed and the residue was dissolved in CH.sub.3CN and purified by prep-HPLC to give A374 (105 mg, 35% yield) as a white solid.

[0341] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.20-7.25 (m, 1H), 7.11 (t, J=9.3 Hz, 1H), 6.93-6.95 (m, 2H), 6.82-6.87 (m, 1H), 6.64 (d, J=8.1 Hz, 1H), 6.24-6.29 (m, 1H), 5.11 (dd, J=13.5, 5.1 Hz, 1H), 4.33-4.37 (m, 2H), 4.20-4.27 (m, 4H), 4.08-4.14 (m, 2H), 3.12-3.22 (m, 4H), 2.86-2.97 (m, 1H), 2.62-2.71 (m, 1H), 2.24-2.33 (m, 1H), 2.01-2.06 (m, 1H), 1.69-1.77 (m, 4H). LCMS: 525.2 ([M+1].sup.+).

Example 49: Compound A349

[3-(4-((3,4-dimethoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione], A349

[0342] ##STR00379##

[0343] To a solution of compound A349A (100 mg, 0.23 mmol) in DMF (5 mL) were added K.sub.2CO.sub.3 (47.0 mg, 0.34 mmol), the mixture was stirred 80° C. (oil bath) overnight under N.sub.2. TCL showed the reaction was finished. The reaction mixture was filtrated and the filtrate was concentrated to give a residue. The residue was purified by RP-HPLC to give A349 (40 mg, 43% yield) as a white solid.

[0344] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.01 (s, 1H), 6.85-6.92 (m, 3H), 6.68 (d, J=7.8 Hz, 1H), 6.24-6.28 (m, 1H), 5.08-5.14 (m, 1H), 4.25-4.33 (m, 3H), 4.18 (d, J=17.1 Hz, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 2.87-2.99 (m, 1H), 2.59-2.65 (m, 1H), 2.24-2.37 (m, 1H), 2.00-2.08 (m, 1H). LCMS: 410.2([M+1].sup.+)

Example 50: Compound A350

3-(4-((3,4-dimethylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A350

[0345] ##STR00380##

[0346] To a solution of A350A (100 mg, 0.25 mmol) in CH.sub.3CN (5 mL) were added CDI (62.0 mg, 0.38 mmol), the mixture was stirred 95° C. (oil bath) overnight under N.sub.2. TCL showed the reaction was finished. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by RP-HPLC to give A350 (61 mg, yield: 65%) as a white solid.

[0347] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.01 (s, 1H), 7.15-7.21 (m, 2H), 7.04-7.10 (m, 2H), 6.91 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.27-6.31 (m, 1H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 4.28-4.33 (m, 3H), 4.18 (d, J=17.7 Hz, 1H), 2.87-2.99 (m, 1H), 2.60-2.65 (m, 1H), 2.24-2.37 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 2.02-2.07 (m, 1H). LCMS: 378.2([M+1].sup.+).

[0348] Compounds in examples 51-55 were prepared according to the procedure described in example 50, with corresponding starting materials to replace A350A.

Example 51: Compound A351

3-(4-((4-fluoro-3-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A351

[0349] ##STR00381##

[0350] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.29 (d, J=6.0 Hz, 1H), 7.18-7.23 (m, 2H), 7.06 (t, J=9.6 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 6.63 (d, J=7.8 Hz, 1H), 6.34 (t, J=6.0 Hz, 1H), 5.12 (dd, J=13.2, 5.1 Hz, 1H), 4.28-4.33 (m, 3H), 4.18 (d, J=17.4 Hz, 1H), 2.87-2.99 (m, 1H), 2.59-2.65 (m, 1H), 2.26-2.37 (m, 1H), 2.21 (s, 3H), 2.01-2.08 (m, 1H). LCMS: 382.1 ([M+1].sup.+).

Example 52: Compound A352

3-(4-((3-chloro-4-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A352

[0351] ##STR00382##

[0352] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.01 (s, 1H), 7.41 (s, 1H), 7.17-7.30 (m, 3H), 6.92 (d, J=7.5 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.39 (t, J=6.0 Hz, 1H), 5.12 (dd, J=13.2, 5.4 Hz, 1H), 4.29-4.37 (m, 3H), 4.18 (d, J=17.1 Hz, 1H), 2.87-2.99 (m, 1H), 2.59-2.65 (m, 1H), 2.25-2.39 (m, 4H), 2.02-2.07 (m, 1H). LCMS: 398.1([M+1].sup.+).

Example 53: Compound A353

3-(4-((3-fluoro-4-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A353

[0353] ##STR00383##

[0354] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.11-7.24 (m, 4H), 6.92 (d, J=7.2 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 6.36-6.40 (m, 1H), 5.12 (dd, J=13.5, 5.1 Hz, 1H), 4.29-4.37 (m, 3H), 4.19 (d, J=17.4 Hz, 1H), 2.86-2.99 (m, 1H), 2.59-2.65 (m, 1H), 2.24-2.39 (m, 1H), 2.18 (s, 3H), 2.01-2.07 (m, 1H). LCMS: 382.1([M+1].sup.+).

Example 54: Compound A354

3-(4-((3-chloro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A354

[0355] ##STR00384##

[0356] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.32 (dd, J=8.4, 1.8 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.35 (t, J=5.9 Hz, 1H), 5.09-5.15 (m, 1H), 4.28-4.33 (m, 3H), 4.18 (d, J=16.8 Hz, 1H), 3.81 (s, 3H), 2.87-2.99 (m, 1H), 2.58-2.67 (m, 1H), 2.24-2.37 (m, 1H), 2.01-2.09 (m, 1H). LCMS: 414.1([M+1].sup.+).

Example 55: Compound A355

3-(4-((3,5-dimethoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A355

[0357] ##STR00385##

[0358] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.03 (s, 1H), 7.18-7.24 (m, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.55 (d, J=2.1 Hz, 2H), 6.31-6.35 (m, 2H), 5.12 (dd, J=13.2, 4.8 Hz, 1H), 4.28-4.34 (m, 3H), 4.19 (d, J=16.8 Hz, 1H), 3.33 (s, 6H), 2.87-2.99 (m, 1H), 2.58-2.67 (m, 1H), 2.26-2.37 (m, 1H), 2.02-2.08 (m, 1H). LCMS: 410.2([M+1].sup.+).

Example 56: Compound A356

(S)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A356

[0359] ##STR00386##

[0360] Step A. To a solution of A356C (300 mg, 1.08 mmol) and 2-Fluoro-4-methoxy-benzaldehyde (249 mg, 1.62 mmol) in MeOH (30 mL) was added glacial AcOH (0.5 mL), the mixture was stirred at 30° C. (oil bath) for 5 hours. Pd/C (10%, 100 mg, 50% water) was added and stirred at 30° C. (oil bath) overnight under H.sub.2 (balloon). Pd/C was removed by filtration and the filtrate was concentrated to give a residue. The residue was purified by flash chromatography on C18 (CH.sub.3CN: H.sub.2O=5%-35%, 30 min; 35%-45%, 30 min; 45%-55% 20 min) then was freeze-dried to afford A356A (160 mg, yield: 35%) as a light yellow solid.

[0361] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 12.06 (br s, 1H), 7.55 (br s, 1H), 7.29 (t, J=9.0 Hz, 1H), 7.16-7.22 (m, 2H), 6.88 (d, J=7.5 Hz, 1H), 6.80 (dd, J=12.6, 2.4 Hz, 1H), 6.71 (dd, J=8.7, 2.7 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.28 (t, J=6.0 Hz, 1H), 4.68-4.74 (m, 0.01H), 4.48 (d, J=17.7 Hz, 1H), 4.23-4.31 (m, 3H), 3.72 (s, 3H), 2.10-2.19 (m, 3H), 1.93-2.01 (m, 1H).

[0362] Step B. To a solution of A356A (160 mg, 0.39 mmol) in dry DCM (20 mL) cooled to −40° C. under N.sub.2, SOCl.sub.2 (229 mg, 1.92 mmol) was slowly added to the mixture at −40° C. under N.sub.2, then a solution of DMF (5 mg) in DCM (1 mL) was added. The reaction mixture was stirred at −40° C. for 2 hr, pyridine (152 mg, 1.92 mmol) was added dropwise, stirred for 40 minutes at this temperature, Et.sub.3N (195 mg, 1.92 mmol) was added and then the reaction mixture was stirred at −40° C. for 2 h. LCMS showed the reaction was finished. H.sub.2O (10 mL) was added to quench the reaction, the water layer was extracted with DCM (30 mL×2), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The residue was purified by flash chromatography on C18 (CH.sub.3CN: H.sub.2O=5%-35%, 30 min; 35%-45%, 30 min; 45%-55% 20 min) to give A356 (70 mg, yield: 46%, ee: 97%) as a white solid.

[0363] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.99 (br s, 1H), 7.31 (t, J=9.0 Hz, 1H), 7.24 (t, J 7.8 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.82 (dd, J=12.3, 2.7 Hz, 1H), 6.71-6.75 (m, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.20 (t, J=6.0 Hz, 1H), 5.08-5.14 (m, 0.04H), 4.26-4.35 (m, 3H), 4.17 (d, J=16.8 Hz, 1H), 3.74 (s, 3H), 2.87-2.97 (m, 1H), 2.57-2.66 (m, 1H), 2.25-2.34 (m, 1H), 2.00-2.09 (m, 1H). LCMS: 399.1 ([M+1].sub.+).

[0364] Compound in example 57 was prepared according to the procedure described in example 56, with corresponding starting material to replace 2-Fluoro-4-methoxy-benzaldehyde in step A.

Example 57: Compound A357

(S)-3-deuterium-3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A357

[0365] ##STR00387##

[0366] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (br s, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.00-7.07 (m, 2H), 6.89-6.93 (m, 2H), 6.78-6.84 (m, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.30 (t, J=5.4 Hz, 1H), 5.07-5.13 (m, 0.03H), 4.40 (d, J=5.7 Hz, 2H), 4.28 (d, J=17.1 Hz, 1H), 4.16 (d, J=17.1 Hz, 1H), 3.81 (s, 3H), 2.85-2.97 (m, 1H), 2.57-2.63 (m, 1H), 2.24-2.34 (m, 1H), 2.00-2.06 (m, 1H). LCMS: 399.1 ([M+1].sup.+).

Example 58: Compound A379

(S)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A379

[0367] ##STR00388##

[0368] Step A. To a mixture of A379A1 (10.0 g, 27.8 mmol) and A379A2 (8.01 g, 33.4 mmol) in CH.sub.3CN (250 mL) were added DIPEA (7.92 g, 61.3 mmol), the mixture was stirred 45° C. overnight under N.sub.2. The reaction mixture was concentrated and DCM (300 mL) and H.sub.2O (100 mL) were added, the water phase was extracted with DCM (200 mL×1), the combined organic phase was washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a crude product A379A (12.3 g) as a yellow solid.

##STR00389##

[0369] Step B. To a solution of A379A (12.3 g, crude) in THF (100 mL) was added 1N TBAF in THF (100 mL), the mixture was stirred overnight at 25° C. LCMS showed the reaction was finished. EtOAc (200 mL) and H.sub.2O (200 mL) were added, the water phase was extracted with EtOAc (200 mL×2), the combined organic phase was washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The residue was triturated with EtOAc (20 mL), filtered, washed with EtOAc (10 mL), then dried to give A379B (5.7 g) as white solid. The filtrate was concentrated and purified by column chromatography on silica gel (PE/EtOAc=1:4) to give additional 1.5 g A379B as a white solid; (overall yield: 77%, for two steps).

[0370] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.01 (s, 1H), 7.54 (br s, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.12-7.16 (m, 2H), 6.96 (dd, J=8.1, 0.6 Hz, 1H), 4.66-4.71 (m, 0.01H), 4.47 (d, J=17.7 Hz, 1H), 4.29 (d, J=17.7 Hz, 1H), 2.08-2.17 (m, 3H), 1.95-2.02 (m, 1H), 1.31 (s, 9H).

##STR00390##

[0371] Step C. To a solution of A379B (1.18 g, 3.52 mmol) and 2-(chloromethyl)-1-fluoro-4-methoxybenzene (1.23 g, 7.04 mmol) in DMF (20 mL) was added K.sub.2CO.sub.3 (972 mg, 7.03 mmol), the mixture was stirred overnight at room temperature. LCMS showed the reaction was finished. The reaction mixture was concentrated and EtOAc (50 mL) and H.sub.2O (30 mL) were added, the water phase was extracted with EtOAc (50 mL), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The residue was purified by column chromatography on silica gel (MeOH/DCM=1/30) to give a white product (1.46 g, 87% yield). The white solid was subjected to chiral separation to give A379C (650 mg) and A379D (650 mg).

[0372] Conditions of Chiral Separation:

[0373] Mobile Phase: Hexane/EtOH=40/60 (V/V), sample concentration: 100 mg/ml in Mobile Phase; Column: CHIRALPAK IC; 20 mm(I.D)×250 mm(L); 5 um; temperature: 35° C.; Injection Volume: 250 μL; Flow Rate: 10 mL/min; Wave Length: 205 nm. A379C: .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.55 (br s, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.28-7.34 (m, 2H), 7.11-7.21 (m, 3H), 6.92-6.97 (m, 1H), 5.22 (s, 2H), 4.49 (d, J=18.0 Hz, 1H), 4.36 (d, J=18.0 Hz, 1H), 3.73 (s, 3H), 2.05-2.13 (m, 3H), 1.96-2.02 (m, 1H), 1.30 (s, 9H).

##STR00391##

[0374] Step D. To a solution of A379C (650 mg, 1.37 mmol) in DCM (20 mL) at 0° C. was added dropwise TFA (10 mL), the mixture was warmed to room temperature and stirred for overnight. The reaction mixture was concentrated under reduced pressure (in vacuum). The residue was dissolved in CH.sub.3CN (4 mL) and purified by flash chromatography on C18 (40% acetonitrile in water) then was freeze-dried to afford A379E (566 mg, yield: 99%) as a light yellow solid.

[0375] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 12.08 (br s, 1H), 7.58 (br s, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.28-7.35 (m, 2H), 7.11-7.21 (m, 3H), 6.92-6.97 (m, 1H), 5.22 (s, 2H), 4.51 (d, J=17.7 Hz, 1H), 4.37 (d, J=17.7 Hz, 1H), 3.73 (s, 3H), 2.08-2.20 (m, 3H), 1.96-2.05 (m, 1H).

##STR00392##

[0376] Step E: To a solution of A379E (366 mg, 0.88 mmol) in dry DCM (35 mL) and THF (5 mL) under N.sub.2 at −40° C., was slowly added SOCl.sub.2 (522 mg, 4.39 mmol), and then a solution of DMF (5 mg) in DCM (1 mL). The reaction mixture was stirred at −40° C. for 1 h, pyridine (347 mg, 4.39 mmol) was added, after 40 mins Et.sub.3N (444 mg, 4.39 mmol) was added and then the mixture was stirred for 1 h at −40° C. LCMS showed the reaction was finished. H.sub.2O (10 mL) was added to quench the reaction, the water layer was extracted with DCM (50 mL), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The crude product was purified by C18 to give A379 (270 mg, yield: 77%, ee: 100%) as a white solid.

[0377] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.96 (br s, 1H), 7.49 (t, J=8.1 Hz, 1H), 7.32-7.38 (m, 2H), 7.11-7.21 (m, 2H), 6.91-6.97 (m, 1H), 5.23 (s, 2H), 5.06-5.12 (m, 0.01H), 4.37 (d, J=17.4 Hz, 1H), 4.21 (d, J=17.4 Hz, 1H), 3.72 (s, 3H), 2.82-2.94 (m, 1H), 2.57-2.60 (m, 1H), 2.38-2.48 (m, 1H), 1.92-1.97 (m, 1H). LCMS=400.1 ([M+1].sup.+).

[0378] Compound in example 59 was prepared according to the procedure described for example 58, with corresponding starting material to replace 2-(chloromethyl)-1-fluoro-4-methoxybenzene in step C.

Example 59: Compound A380

(S)-3-deuterium-3-(4-((2-fluoro-3-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A380

[0379] ##STR00393##

[0380] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.95 (br s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.31-7.37 (m, 2H), 7.07-7.19 (m, 3H), 5.26 (s, 2H), 5.05-5.11 (m, 0.01H), 4.36 (d, J=17.4 Hz, 1H), 4.20 (d, J=17.4 Hz, 1H), 3.83 (s, 3H), 2.82-2.94 (m, 1H), 2.51-2.60 (m, 1H), 2.37-2.46 (m, 1H), 1.92-1.99 (m, 1H). LCMS=400.1 ([M+1].sup.+).

Example 60: Compound A393

(S)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A393

[0381] ##STR00394##

[0382] Step A: To a solution of A379B (2.0 g, 6.0 mmol) in DCM (30 mL) was added TFA (5 mL), after stirring for 3 hours at 25° C., the reaction mixture was concentrated to afford a residue (1.7 g). The residue (1.7 g) was dissolved in DMF (5 mL) and treated with 2-(trimethylsilyl)ethanol (3.55 g, 30 mmol), EDCI (2.3 g, 12.0 mmol) and DMAP (733 mg, 6.0 mmol). The reaction mixture was stirred overnight at 35° C., and then concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=40:1) to give A393A (1.6 g, 70%).

[0383] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 9.99 (s, 1H), 7.54 (s, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.11-7.14 (m, 2H), 6.96 (d, J=7.8 Hz, 1H), 4.47 (d, J=18.0 Hz, 1H), 4.28 (d, J=18.0 Hz, 1H), 3.92-3.99 (m, 2H), 2.00-2.25 (m, 4H), 0.80-0.85 (m, 2H), 0.04 (s, 9H).

##STR00395##

[0384] Step B: To a solution of A393A (1.02 g, 2.70 mmol) in DMF (20 mL) was added K.sub.2CO.sub.3 (750 mg, 5.40 mmol) and 1-Chloromethyl-2-fluoro-4-methoxy-benzene (720 mg, 4.10 mmol), this mixture was warm to 30° C. and stirred for 17 hours, then this mixture was filtered and concentrated to afford a crude oil, which was purified by column chromatography on silica gel (DCM/MeOH=60/1) to afford A393C (1.0 g, 72%).

[0385] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.43-7.54 (m, 3H), 7.26-7.35 (m, 2H), 7.14 (s, 1H), 6.80-6.90 (m, 2H), 5.16 (s, 2H), 4.45 (d, J=17.4 Hz, 1H), 4.30 (d, J=17.4 Hz, 1H), 3.92-3.98 (m, 2H), 3.77 (s, 3H), 2.01-2.22 (m, 4H), 0.79-0.84 (m, 2H).

[0386] Step C: Chiral Separation

##STR00396##

[0387] Chiral Separation Conditions:

[0388] Mobile Phase: MeOH/EtOH=50/50 (V/V); Sample: 120 mg/mL in Mobile Phase; Column: IF; 20 mm(I.D)×250 mm(L); 5 um; Temperature: 35° C.; Injection volume: 300 L; Flow Rate: 9 mL/min; Wave length: 205 nm.

[0389] A393E

[0390] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.59 (s, 1H), 7.45-7.54 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.20 (s, 1H), 6.80-6.92 (m, 2H), 5.18 (s, 2H), 4.47 (d, J=17.4 Hz, 1H), 4.32 (d, J=17.4 Hz, 1H), 3.92-4.01 (m, 2H), 3.78 (s, 3H), 2.01-2.20 (m, 4H), 0.80-0.85 (m, 2H), 0.04 (s, 9H).

##STR00397##

[0391] Step D: To a solution of A393E (500 mg, 0.97 mmol) in THF (5 mL) was added TBAF (1N/THF, 5 mL), this mixture was stirred at 50° C. overnight, filtered and concentrated, the residue was purified by column chromatography (C 18) to afford an intermediate (420 mg), To a solution of this intermediate (300 mg) in DCM (15 mL) and DMF (1 mL) at −40° C. was added SOCl.sub.2 (428 mg, 3.60 mmol). The reaction mixture was stirred for 2 hours, pyridine (281 mg, 3.60 mmol) was added, the mixture was stirred for another 30 min and then Et.sub.3N (363 mg, 3.60 mmol) was added and stirred for additional 1 hr at −40° C. The reaction mixture was treated with water (80 mL) and extracted with DCM (80 mL×3), combined organic layers and was dried over Na.sub.2SO.sub.4, filtered and concentrated and purified by Prep-HPLC to give A393 (200 mg, 72%, for two steps).

[0392] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.95 (s, 1H), 7.48-7.53 (m, 2H), 7.32-7.40 (m, 2H), 6.80-6.91 (m, 2H), 5.19 (s, 2H), 4.35 (d, J=17.4 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 3.78 (s, 3H), 2.84-2.96 (m, 1H), 2.37-2.59 (m, 2H), 1.93-1.99 (m, 1H). LCMS: 400.1 ([M+1].sup.+).

[0393] Compound of example 61 was prepared according to the procedure described for example 60, with corresponding starting material to replace compound A393E.

Example 61: Compound A392

(R)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A392

[0394] ##STR00398##

[0395] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.95 (s, 1H), 7.48-7.53 (m, 2H), 7.32-7.40 (m, 2H), 6.80-6.91 (m, 2H), 5.19 (s, 2H), 5.07-5.13 (m, 0.05H), 4.35 (d, J=17.7 Hz, 1H), 4.19 (d, J=17.7 Hz, 1H), 3.78 (s, 3H), 2.84-2.96 (s, 1H), 2.36-2.59 (m, 2H), 1.93-1.98 (m, 1H). LCMS: 400.1 ([M+1].sup.+).

Example 62: Compound A385

3-(4-((2-fluoro-3-(methylamino)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A385

[0396] ##STR00399##

[0397] Step A. To a solution of (2-fluoro-3-(methylamino)phenyl)methanol in DCM (10 mL) was added SOCl.sub.2 (0.5 mL), the mixture was stirred for 4 h. The reaction mixture was concentrated to give crude product 3-(chloromethyl)-2-fluoro-N-methylaniline hydrochloride (430 mg) as a yellow solid which was used in the next step without further purification.

[0398] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 9.97 (br s, 2H), 7.05 (t, J=8.1 Hz, 1H), 6.84-6.92 (m, 2H), 4.72 (s, 2H), 2.74 (s, 3H).

[0399] Step B. To a solution of A329B (300 mg, 1.03 mmol) in DMF (10 mL) was added 3-(chloromethyl)-2-fluoro-N-methylaniline hydrochloride (259 mg) and K.sub.2CO.sub.3 (355 mg, 2.57 mmol), the mixture was stirred overnight. LCMS showed the reaction was not finished. Additional 3-(chloromethyl)-2-fluoro-N-methylaniline hydrochloride (150 mg) and K.sub.2CO.sub.3 (100 mg, 0.72 mmol) were added and the mixture was stirred overnight. The reaction mixture was concentrated and EtOAc (20 mL) and H.sub.2O (10 mL) was added. The water layer was extracted by EtOAc (20 mL×2), the combined organic layer was washed by brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The residue was purified by Prep-TLC (petroleum ether/EtOAc=1/4) to give compound A385A (242 mg, 55% yield) as a white solid.

[0400] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.55 (br s, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.27-7.33 (m, 2H), 7.15 (br s, 1H), 6.99 (t, J=8.1 Hz, 1H), 6.61-6.71 (m, 2H), 5.59 (br s, 1H), 5.20 (s, 2H), 4.70 (dd, J=10.5, 4.5 Hz, 1H), 4.47 (d, J=17.7 Hz, 1H), 4.33 (d, J=17.7 Hz, 1H), 3.48 (s, 3H), 2.71 (d, J=4.2 Hz, 3H), 2.12-2.25 (m, 3H), 1.99-2.09 (m, 1H).

[0401] Step C. To a solution of A385A (242 mg, 0.56 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (234 mg, 1.69 mmol), the mixture was stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC then freeze-dried to give A385 (100 mg, 45% yield) as a white solid.

[0402] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.71 (br s, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.32-7.38 (m, 2H), 7.00 (t, J=7.8 Hz, 1H), 6.63-6.72 (m, 2H), 5.61-5.62 (m, 1H), 5.23 (s, 2H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.37 (d, J=17.7 Hz, 1H), 4.21 (d, J=17.7 Hz, 1H), 2.84-2.96 (m, 1H), 2.72 (d, J=4.8 Hz, 3H), 2.51-2.60 (m, 1H), 2.37-2.47 (m, 1H), 1.93-2.00 (m, 1H). LCMS=398.1 ([M+1].sup.+)

[0403] Compounds in examples 63-66 were prepared according to the procedure described for example 62, with corresponding starting materials to replace 3-(chloromethyl)-2-fluoro-N-methylaniline hydrochloride in step B.

Example 63: Compound A390

3-(4-((2-fluoro-5-(methylamino)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A390

[0404] ##STR00400##

[0405] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.97 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.33 (t, J=7.2 Hz, 2H), 6.96 (t, J=9.3 Hz, 1H), 6.63-6.66 (m, 1H), 6.46-6.51 (m, 1H), 5.58-5.63 (m, 1H), 5.16 (s, 2H), 5.06-5.12 (m, 1H), 4.35 (d, J=17.4 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 2.83-2.95 (m, 1H), 2.54-2.62 (m, 4H), 2.34-2.45 (m, 1H), 1.91-1.99 (m, 1H). LCMS: 398.1 ([M+1].sup.+).

Example 64: Compound A398

3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione, A398

[0406] ##STR00401##

[0407] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.92 (br s, 1H), 7.46-7.51 (m, 2H), 7.31-7.37 (m, 3H), 7.16-7.22 (m, 1H), 5.27 (s, 2H), 5.05-5.11 (m, 1H), 4.35 (d, J=17.4 Hz, 1H), 4.20 (d, J=17.4 Hz, 1H), 3.50-3.53 (m, 4H), 3.43 (s, 2H), 2.82-2.92 (m, 1H), 2.53-2.60 (m, 1H), 2.34-2.44 (m, 1H), 2.23-2.29 (m, 4H), 1.90-2.00 (m, 1H). LCMS=468.2 [(M+1).sup.+].

Example 65: Compound A399

3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A399

[0408] ##STR00402##

[0409] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.98 (s, 1H), 7.49-7.54 (m, 2H), 7.34-7.45 (m, 3H), 7.19-7.24 (m, 1H), 5.29 (s, 2H), 5.08-5.14 (m, 1H), 4.39 (d, J=17.7 Hz, 1H), 4.22 (d, J=17.7 Hz, 1H), 3.50-3.57 (m, 6H), 2.84-2.98 (m, 1H), 2.54-2.60 (m, 1H), 2.34-2.47 (m, 5H), 1.92-2.01 (m, 1H). LCMS: 468.2 ([M+1].sup.+).

Example 66: Compound A407

3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A407

[0410] ##STR00403##

[0411] Step A: To a solution of A327A (300 mg, 0.85 mmol) and 4-(4-(chloromethyl)-3-fluorobenzyl)morpholine hydrochloride (359 mg, 1.28 mmol) in DMF (15 mL) was added K.sub.2CO.sub.3 (352 mg, 2.55 mmol), the mixture was stirred overnight at 40° C. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by Prep-TLC (MeOH/DCM=1/15) to give a white solid A407B (430 mg, 90% yield).

[0412] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.51-7.56 (m, 2H), 7.33 (dd, J=11.4, 1.5 Hz, 1H), 7.17-7.21 (m, 3H), 7.07 (dd, J=7.5, 1.5 Hz, 1H), 5.24 (s, 2H), 4.66-4.69 (m, 1H), 4.44 (d, J=17.7 Hz, 1H), 4.32 (d, J=17.7 Hz, 1H), 3.55-3.58 (m, 4H), 3.48 (s, 2H), 2.29-2.39 (m, 4H), 2.05-2.18 (m, 3H), 1.95-2.01 (m, 1H), 1.29 (s, 9H).

[0413] Step B: To a solution of A407B (430 mg, 0.77 mmol) in DCM (20 mL) was added dropwise TFA (5 mL) at room temperature, the mixture was stirred for 3 hours at 25° C. LCMS showed the reaction was finished. The reaction mixture was concentrated under reduced pressure (in vacuum) to afford A407C (387 mg, yield 100%) as a yellow solid.

[0414] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.33 (br s, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.33-7.47 (m, 3H), 7.19 (s, 1H), 7.09-7.11 (m, 1H), 5.31 (s, 2H), 4.69-4.72 (m, 1H), 4.48 (d, J=17.7 Hz, 1H), 4.38 (s, 2H), 4.35 (d, J=17.7 Hz, 1H), 3.89-3.99 (m, 2H), 3.57-3.67 (m, 2H), 3.14-3.34 (m, 4H), 2.10-2.17 (m, 3H), 1.95-2.01 (m, 1H).

[0415] Step C: To a solution of A407C (215 mg, 0.39 mmol) in CH.sub.3CN (15 mL) was added CDI (190 mg, 1.17 mmol), the mixture was refluxed overnight under N.sub.2. LCMS showed the reaction was finished. The reaction mixture was concentrated to give a residue and purified by Prep-HPLC to give A407 (80 mg, yield: 43%) as a white solid.

[0416] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.96 (br s, 1H), 7.51-7.56 (m, 1H), 7.34-7.39 (m, 1H), 7.11-7.21 (m, 3H), 5.25 (s, 2H), 5.05-5.11 (m, 1H), 4.33 (d, J=18.0 Hz, 1H), 4.16 (d, J=18.0 Hz, 1H), 3.54-3.57 (m, 4H), 3.48 (s, 2H), 2.82-2.94 (m, 1H), 2.49-2.56 (m, 1H), 2.30-2.44 (m, 5H), 1.91-1.99 (m, 1H). LCMS=486.2 ([M+1].sup.+).

Example 67: A403

(S)-3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A403

[0417] ##STR00404##

[0418] Step A: To a solution of compound A379B (1.0 g, 3.59 mmol) and 4-(3-(chloromethyl)-4-fluorobenzyl)morpholine hydrochloride (1.23 g, 7.05 mmol) in DMF (20 mL) was added K.sub.2CO.sub.3 (972 mg, 7.04 mmol), the mixture was stirred overnight at 25° C. Filtration and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel to give a white solid A403A (1.3 g, 80% yield).

[0419] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.54 (br s, 1H), 7.43-7.49 (m, 2H), 7.28-7.34 (m, 3H), 7.14-7.22 (m, 2H), 5.26 (s, 2H), 4.67-4.72 (m, 0.05H), 4.50 (d, J=17.4 Hz, 1H), 4.33 (d, J=17.4 Hz, 1H), 3.49-3.56 (m, 4H), 3.44 (s, 2H), 2.25-2.34 (m, 4H), 2.09-2.15 (m, 3H), 1.94-2.03 (m, 1H), 1.29 (s, 9H).

[0420] Step B: Chiral Separation

[0421] A403A was chiral separated to give A403C (500 mg) and A403E (500 mg).

[0422] Chiral Separation conditions: Mobile Phase: Hexane/IPA=70/30(V/V); Sample concentration: 100 mg/mL; Column: CHIRALPAK IA; 30 mm (I.D)×250 mm(L); 5 μm, Temperature: 35° C.; Wave Length: 205 nm; Injection: 250 uL; Flow Rate: 50 mL/min.

[0423] A403C:

(S)-tert-butyl 5-amino-4-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0424] ##STR00405##

[0425] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.55 (br s, 1H), 7.43-7.49 (m, 2H), 7.28-7.34 (m, 3H), 7.16-7.22 (m, 2H), 5.26 (s, 2H), 4.66-4.71 (m, 1H), 4.49 (d, J=17.4 Hz, 1H), 4.33 (d, J=17.4 Hz, 1H), 3.51-3.53 (m, 4H), 3.43 (s, 23H), 2.26-2.33 (m, 4H), 2.02-2.16 (m, 3H), 1.94-1.99 (m, 1H), 1.29 (s, 9H).

##STR00406##

[0426] Step C: To a solution of A403C (500 mg, 1.0 mmol) in DCM (12 mL) cooled to 0° C. was added TFA (3 mL) dropwise, the mixture was warmed slowly to 25° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure (in vacuum). The residue was dissolved in CH.sub.2Cl.sub.2 (20 mL) and sat. NaHCO.sub.3 was added to adjust pH=8-9, the mixture was concentrated and the residue was purified by flash chromatography on C18 (CH.sub.3CN: H.sub.2O=5-40%, 40 min) to afford A403D (400 mg, yield: 82%) as a light yellow solid.

[0427] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.93 (br s, 1H), 7.41-7.49 (m, 2H), 7.26-7.32 (m, 3H), 7.16-7.22 (m, 1H), 7.06 (br s, 1H), 5.25 (s, 2H), 5.05-5.13 (m, 0.00H), 4.60 (d, J=17.7 Hz, 1H), 4.30 (d, J=17.7 Hz, 1H), 3.50-3.52 (m, 4H), 3.42 (s, 2H), 2.22-2.32 (m, 4H), 2.03-2.10 (m, 1H), 1.81-1.94 (m, 3H).

[0428] Step D: To a solution of A403D (400 mg, 0.82 mmol) in dry DMF (1 mL), dry DCM (40 mL) and THF (20 mL) cooled to −40° C. under N.sub.2, SOCl.sub.2 (488 mg, 4.1 mmol) was slowly added to the mixture at −40° C. The reaction mixture was stirred for 1 h, and then pyridine (324 mg, 4.1 mmol) was added, after 40 mins Et.sub.3N (415 mg, 4.1 mmol) was added, and then the mixture was stirred for 1 h. LCMS showed the reaction was finished. DCM (50 mL) and H.sub.2O (2 mL) was added to quench the reaction, the water layer was extracted with DCM (50 mL×2), the combined organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated to give a residue. The crude product was purified by C18 (CH.sub.3CN: H.sub.2O=5%-45%, 40 min) to give A403 (300 mg, yield: 78%, ee: 99%) as a white solid.

[0429] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.96 (br s, 1H), 7.46-7.51 (m, 2H), 7.31-7.37 (m, 3H), 7.16-7.22 (m, 1H), 5.27 (s, 2H), 5.05-5.13 (m, 0.04H), 4.35 (d, J=17.7 Hz, 1H), 4.19 (d, J=17.7 Hz, 1H), 3.5.-3.53 (m, 4H), 3.43 (s, 2H), 2.82-2.94 (m, 1H), 2.49-2.58 (m, 1H), 2.36-2.41 (m, 1H), 2.26-2.32 (m, 4H), 1.91-1.98 (m, 1H). LCMS=469.2 ([M+1].sup.+).

[0430] Compounds in examples 68 and 69 were prepared according to the procedure described for example 67, with corresponding starting materials to replace 4-(3-(chloromethyl)-4-fluorobenzyl)morpholine hydrochloride.

Example 68: Compound A404

(S)-3-deuterium-3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A404

[0431] ##STR00407##

[0432] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.94 (s, 1H), 7.45-7.53 (m, 2H), 7.31-7.42 (m, 3H), 7.17-7.21 (m, 1H), 5.28 (s, 2H), 4.37 (d, J=18.0 Hz, 1H), 4.21 (d, J=18.0 Hz, 1H), 3.51-3.62 (m, 6H), 2.82-2.95 (m, 1H), 2.57-2.62 (m, 1H), 2.28-2.42 (m, 5H), 1.91-2.01 (m, 1H). LCMS: 469.2 ([M+1].sup.+).

Example 69: Compound A406

(S)-3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A406

[0433] ##STR00408##

[0434] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.98 (s, 1H), 7.47-7.55 (m, 2H), 7.31-7.38 (m, 2H), 7.16-7.20 (m, 2H), 5.24 (s, 2H), 5.06-5.12 (m, 0.04H), 4.35 (d, J=18.0 Hz, 1H), 4.19 (d, J=18.0 Hz, 1H), 3.55 (br, 4H), 3.47 (s, 2H), 2.82-2.94 (m, 1H), 2.48-2.57 (m, 1H), 2.33-2.42 (m, 5H), 1.91-1.96 (m, 1H). LCMS: 469.2 ([M+1].sup.+).

Example 70: Compound A400

(S)-3-deuterium-3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A400

[0435] ##STR00409##

[0436] Step A: To a solution of compound A356C (400 mg, 1.44 mmol) in MeOH (30 mL) was added 2-fluoro-3-(morpholinomethyl)benzaldehyde (481 mg, 2.16 mmol) and AcOH (0.5 mL). The reaction mixture was stirred overnight at 30° C., then Pd/C (150 mg, 10%, 50% water) was added under H.sub.2 atmosphere, the mixture was stirred for 3 hours, filtered and concentrated to afford product A400A (580 mg).

[0437] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 7.57 (br s, 1H), 7.06-7.31 (m, 5H), 6.88-6.90 (m, 1H), 6.58-6.60 (m, 1H), 6.37 (s, 1H), 4.26-4.54 (m, 4H), 3.47-3.66 (m, 6H), 2.23-2.37 (m, 4H), 2.07-2.15 (m, 3H), 1.85-1.97 (m, 1H).

[0438] Step B: To a solution of crude A400A (480 mg, 0.99 mmol) in DCM (20 mL) cooled to −40° C., was added DMF (1 mL), then SOCl.sub.2 (589 mg, 4.95 mmol) was added and stirred for 2 hours, pyridine (383 mg, 4.95 mmol) was added, the mixture was stirred for 30 min, and then Et.sub.3N (501 mg, 4.95 mmol) was added. The reaction mixture was stirred for another 1 hour at −40° C. and then quenched with water (80 mL), extracted with DCM (80 mL×3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to afford a crude oil, which was purified by column chromatographer on silica gel (DCM/MeOH=40/1) to give product A400 (251 mg, 54%).

[0439] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.20-7.31 (m, 3H), 7.10 (t, J=7.8 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.65 (d, J=7.8 Hz, 1H), 6.29-6.32 (m, 1H), 5.09-5.15 (m, 0.05H), 4.43 (d, J=5.1 Hz, 2H), 4.31 (d, J=17.1 Hz, 1H), 4.19 (d, J=17.1 Hz, 1H), 3.49-3.64 (m, 6H), 2.87-2.99 (m, 1H), 2.58-2.65 (m, 1H), 2.25-2.44 (m, 5H), 2.01-2.06 (m, 1H). LCMS: 468.2 ([M+1].sup.+).

[0440] Compounds in example 71 and 72 were prepared according to the procedure described for example 70, with corresponding starting materials to replace 2-fluoro-3-(morpholinomethyl)benzaldehyde in step A.

Example 71: Compound A401

(S)-3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A401

[0441] ##STR00410##

[0442] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 11.03 (br s, 1H), 7.32 (d, J=6.8 Hz, 1H), 7.12-7.23 (m, 3H), 6.94 (d, J=7.6 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.34 (t, J=6.0 Hz, 1H), 5.11-5.16 (m, 0.4H), 4.42 (d, J=5.6 Hz, 2H), 4.31 (d, J=16.8 Hz, 1H), 4.20 (d, J=17.2 Hz, 1H), 3.42-3.49 (m, 4H), 3.37 (s, 2H), 2.89-2.98 (m, 1H), 2.58-2.67 (m, 1H), 2.28-2.35 (m, 1H), 2.18-2.26 (m, 4H), 2.02-2.06 (m, 1H). LCMS: 468.2 [(M+1).sup.+].

Example 72: Compound A402

(S)-3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A402

[0443] ##STR00411##

[0444] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.01 (s, 1H), 7.30-7.35 (m, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.05-7.13 (m, 2H), 6.92 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.1 Hz, 1H), 6.27-6.31 (m, 1H), 5.08-5.14 (m, 0.05H), 4.38 (d, J=5.4 Hz, 2H), 4.28 (d, J=17.4 Hz, 1H), 4.16 (d, J=17.4 Hz, 1H), 3.54 (br s, 4H), 3.42 (s, 2H), 2.85-2.97 (m, 1H), 2.56-2.62 (m, 1H), 2.24-2.31 (m, 5H), 1.98-2.06 (m, 1H). LCMS: 468.2 ([M+1].sup.+).

Example 73: Compound A405

3-(6-fluoro-4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A405

[0445] ##STR00412##

[0446] Step A: To a solution of DMSO (156 mg, 2.0 mmol) in DCM (10 mL) at −70° C. under N.sub.2 was added (COCl).sub.2 (152 mg, 1.2 mmol). The reaction mixture was stirred for 30 minutes at −70° C. A solution of (4-(morpholinomethyl)phenyl) methanol (207 mg, 1.0 mmol) in DCM (3 mL) was added and the reaction mixture was stirred for 1 hour. Et.sub.3N (405 mg, 4.0 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 1 hour at −70° C., then the temperature was allowed to warm up to 25° C., the reaction mixture was quenched with H.sub.2O (10 mL) and NaHCO.sub.3 solution (5 mL) was added. The mixture was separated and the aqueous layer was extracted with 10 mL DCM. The combined organic layer was concentrated, and purified via column chromatography (PE:EtOAc=2:1) to give A405A (180 mg, yield: 88%) as a light yellow oil.

[0447] .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 9.99 (s, 1H), 7.84 (d, J=7.8 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 3.70-3.73 (m, 4H), 3.57 (s, 2H), 2.46 (t, J=4.2 Hz, 4H).

[0448] Step B: To a solution of A405A (111 mg, 0.54 mmol) and I-28 (100 mg, 0.36 mmol) in DCM (6 mL) was added HOAc (6 mL) and the reaction mixture was stirred for 3 hour at 25° C. NaBH.sub.3CN (45 mg, 0.72 mmol) was added and the reaction mixture was stirred at room temperature overnight. Additional A405A (40 mg, 0.14 mmol) was added and the mixture was stirred at 40° C. for 6 hours. The solvent was removed and NaHCO.sub.3 solution (10 mL) and DCM (25 mL) was added and separated. The aqueous layer was extracted with DCM (20 mL×2). The combined organic layer was concentrated and purified by prep-HPLC then freeze-dried to give a solid, which was added to 5 mL sat. NaHCO.sub.3 solution to adjust pH=8 and then extracted with DCM (5 mL×5), the organic solution was combined, concentrated to give A405 (50 mg, 30% yield) as a white solid.

[0449] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.01 (s, 1H), 7.23-7.33 (m, 4H), 6.72 (br s, 1H), 6.60 (dd, J=1.8 Hz, 7.5 Hz, 1H), 6.42 (dd, J=2.1 Hz, 12.6 Hz, 1H), 5.09 (dd, J=5.1 Hz, 13.2 Hz, 1H), 4.35 (d, J=5.4 Hz, 2H), 4.27 (d, J=17.4 Hz, 1H), 4.14 (d, J=17.4 Hz, 1H), 3.53 (br s, 4H), 3.41 (s, 2H), 2.84-2.96 (m, 1H), 2.57-2.63 (m, 1H), 2.21-2.31 (m, 5H), 2.01-2.05 (m, 1H). LCMS: 467.2 ([M+1].sup.+).

Example 74: Compound A386

3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A386

[0450] ##STR00413## ##STR00414##

[0451] Step A: A solution of (2-fluoro-4-(morpholinomethyl)phenyl)methanol (1.0 g, 4.4 mmol) in chloroform (25 mL) was added SOCl.sub.2 (1.1 g, 9.2 mmol) and the mixture was heated to reflux for 2 hours. The solvent was removed in vacuum and co-evaporated with chloroform (25 mL×2) to give A386A (1.2 g, yield: 97%) as a white solid.

[0452] .sup.1H NMR (DMSO-d6, 400 MHz): δ 11.98 (br s, 1H), 7.70 (d, J=10.8 Hz, 1H), 7.63 (t, J 8.0 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 4.82 (s, 2H), 4.37 (d, J=4.8 Hz, 2H), 3.86-3.93 (m, 4H), 3.07-3.21 (m, 4H).

[0453] Step B: A mixture of A386A and A386B (0.8 g, 2.4 mmol), K.sub.2CO.sub.3 (1.3 g, 9.6 mmol) in DMF (20 mL) was degassed with N.sub.2 and heated to 40° C. and stirred for 18 hours. The reaction mixture was poured into 100 mL ice water and extracted with EtOAc (20 mL×5). The combined organic layer was washed with 20 mL water, 20 mL brine and dried over Na.sub.2SO.sub.4, filtered, concentrated, and purified by column chromatography on silica gel (PE: EtOAc=2:1 to 1:1) to give A386C (1.2 g, yield: 92%) as a white solid.

[0454] .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 7.37-7.47 (m, 3H), 7.10-7.16 (m, 3H), 6.30 (br s, 1H), 5.33 (br s, 1H), 5.18 (s, 2H), 4.86-4.91 (m, 1H), 4.36-4.51 (m, 2H), 3.71-3.74 (m, 4H), 3.51 (s, 2H), 2.45-2.48 (m, 4H), 2.09-2.40 (m, 4H), 1.42 (s, 9H).

[0455] Step C: A solution of A386C (1.2 g, 2.2 mmol) in DCM (30 mL) was added TFA (15 mL) and stirred at 35° C. for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC to give A386E (1.4 g, yield: 64%) as a light yellow solid.

[0456] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 12.05 (br s, 1H), 7.56 (br s, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.29-7.36 (m, 4H), 7.15-7.22 (m, 1H), 5.25 (s, 2H), 4.68-4.73 (m, 1H), 4.50 (d, J=17.7 Hz, 1H), 4.36 (d, J=17.7 Hz, 1H), 3.56-3.60 (m, 6H), 2.26-2.45 (m, 2H), 1.94-2.16 (m, 4H), 1.72-1.77 (m, 2H).

[0457] Step D: To a solution of A386E (421 mg, 0.867 mmol) in DCM/THF (50 mL/5 mL) at −40° C. was added SOCl.sub.2 (516 mg, 4.33 mmol, as solution in 10 mL DCM). The mixture was stirred at −40° C. to −20° C. for 2 hours and pyridine (339 mg, 4.33 mmol) was added and the reaction mixture was stirred at −40° C. for 0.5 hours. Et.sub.3N (438 mg, 4.33 mmol) was added and the mixture was allowed to warm to 25° C. slowly. H.sub.2O (0.5 mL) was added and then filtered. The filter cake was dissolved with CH.sub.3CN (5 mL) and un-dissolved solid was filtered off, and CH.sub.3CN was removed to give crude product. The DCM layer of the reaction mixture was washed with water (25 mL×2) and brine (25 mL) and concentrated to give additional crude product. The combined crude product was purified by prep-HPLC twice to give A386 (105 mg, yield: 26%) as a white solid.

[0458] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.95 (s, 1H), 7.49-7.58 (m, 2H), 7.34-7.40 (m, 2H), 7.17-7.21 (m, 2H), 5.26 (s, 2H), 5.07-5.13 (m, 1H), 4.38 (d, J=17.7 Hz, 1H), 4.22 (d, J=17.7 Hz, 1H), 3.58 (br s, 4H), 3.49 (br s, 2H), 2.84-2.96 (m, 1H), 2.56-2.60 (m, 1H), 2.30-2.43 (m, 5H), 1.92-2.02 (m, 1H).

Example 75: Compound A425

3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A425

[0459] ##STR00415##

[0460] Compound A425 in Example 75 was prepared according to the procedure described in example 67, with racemic A403A as appropriate starting material.

[0461] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.95 (s, 1H), 7.49-7.57 (m, 2H), 7.33-7.40 (m, 2H), 7.18-7.22 (m, 2H), 5.26 (s, 2H), 4.37 (d, J=17.7 Hz, 2H), 4.21 (d, J=17.7 Hz, 1H), 3.58-3.62 (m, 4H), 3.49 (s, 2H), 2.84-2.96 (m, 1H), 2.27-2.58 (m, 6H), 1.93-1.99 (m, 1H). LCMS=469.2 ([M+1].sup.+).

Example 76: Compound A427

3-deuterium-3-(4-((4-((2,6-dimethylmorpholino)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A427

[0462] ##STR00416##

[0463] Compound A427 in Example 76 was prepared according to the procedure described in example 67, with appropriate starting material to replace 4-(3-(chloromethyl)-4-fluorobenzyl)morpholine hydrochloride.

[0464] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 10.97 (s, 1H), 7.49-7.58 (m, 2H), 7.34-7.41 (m, 2H), 7.17-7.21 (m, 2H), 5.26 (s, 2H), 4.38 (d, J=17.7 Hz, 1H), 4.21 (d, J=17.7 Hz, 1H), 3.54-3.61 (m, 2H), 3.47 (s, 2H), 2.84-2.96 (m, 1H), 2.53-2.68 (m, 3H), 2.38-2.44 (m, 1H), 1.93-1.99 (m, 1H), 1.66 (t, J=10.5 Hz, 2H), 1.02 (d, J=6.0 Hz, 6H). LCMS: 497.2 ([M+1].sup.+).

Example 77: Compound A426

3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A426

[0465] ##STR00417##

[0466] Compound A426 in Example 77 was prepared according to the procedure described in example 70, with racemic A400A as appropriate starting material.

[0467] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.00 (s, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.05-7.13 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.1 Hz, 1H), 6.27 (t, J=6.0 Hz, 1H), 5.07-5.13 (m, 0.01H), 4.38 (d, J=5.4 Hz, 2H), 4.28 (d, J=17.1 Hz, 1H), 4.16 (d, J=17.1 Hz, 1H), 3.52-3.55 (m, 4H), 3.42 (s, 2H), 2.85-2.97 (m, 1H), 2.56-2.65 (m, 1H), 2.23-2.35 (m, 5H), 1.99-2.06 (m, 1H). LCMS: 468.2 ([M+1].sup.+).

Example 78: Compound A428

3-deuterium-3-(4-((4-((2,6-dimethylmorpholino)methyl)-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A428

[0468] ##STR00418##

[0469] Compound A428 in Example 78 was prepared according to the procedure described in example 70, with appropriate starting material to replace 2-fluoro-3-(morpholinomethyl)benzaldehyde in step A.

[0470] .sup.1H NMR (DMSO-d.sub.6, 300 MHz): δ 11.02 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H) 7.06-7.13 (m, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.28 (t, J=5.7 Hz, 1H), 4.40 (d, J=5.1 Hz, 2H), 4.30 (d, J=17.1 Hz, 1H), 4.18 (d, J=17.1 Hz, 1H), 3.52-3.61 (m, 2H), 3.42 (s, 2H), 2.87-2.99 (m, 1H), 2.59-2.65 (m, 3H), 2.35-2.25 (m, 1H), 2.01-2.06 (m, 1H), 1.63 (t, J=10.5 Hz, 2H), 1.01 (d, J=6.0 Hz, 6H). LCMS: 496.2 ([M+1]+).

EFFECT EXAMPLES

TNF-α Activity Inhibiting Assay

[0471] Peripheral blood from healthy volunteers was collected and collected with EDTA anticoagulant tubes. After being diluted 5-fold with 1640 medium (Gibco, catalog number 11875-093, USA), the blood was added to 96-well cell culture plates (Costar, catalog number 3599, USA) and then treated with 10 μL solution of the compound of general formula (I) of the present invention in DMSO (Sigma, catalog number D2650, USA). The final concentration of the compound was 100 nM, and the final concentration of DMSO was 0.2%. After incubation for 60 minutes in an incubator at 37° C. under 5% CO.sub.2, 10 μL LPS (Sigma, catalog number L-2880, USA) was added to the reaction system, and the final concentration was 10 ng/mL. After further culturing for 6 hours in the incubator at 37° C. under 5% CO.sub.2, the supernatant was collected. The content of TNF-α was determined by ELISA (BD Biosciences, catalog number 555212, USA). Absorbance was detected at OD.sub.450 nm with a microplate reader, with OD 650 nm as reference. The control, a solution containing 0.2% DMSO medium, was as 0% inhibition. Raw data and standard curves were recorded. The four-parameter drug inhibition curve was plotted by XL-fit software and the inhibition rate of each compound was calculated, as shown in Table 1.

TABLE-US-00001 TABLE 1 Inhibitory Inhibitory Inhibitory Rate on Rate on Rate on Com- TNF-α Com- TNF-α TNF-α pound (%) pound (%) Compound (%) I-01 >50 I-28 >50 I-29 >50 I-31 >50 I-32 >50 A386 ≧50 A196 ≧50 A360 <50 A387 ≧50 A197 ≧50 A361 ≧50 A388 ≧50 A318 <50 A362 <50 A389 <50 A319 <50 A363 <50 A390 ≧50 A320 <50 A364 <50 A391 ≧50 A327 <50 A367 ≧50 A392 ≧50 A329 ≧50 A368 ≧50 A393 <50 A331 ≧50 A369 ≧50 A396 <50 A334 ≧50 A370 <50 A397 <50 A340 <50 A371 ≧50 A398 ≧50 A341 <50 A372 ≧50 A399 ≧50 A342 <50 A373 ≧50 A400 ≧50 A343 ≧50 A374 ≧50 A401 ≧50 A346 ≧50 A375 <50 A402 ≧50 A349 <50 A376 ≧50 A403 ≧50 A350 <50 A377 <50 A404 ≧50 A351 <50 A378 <50 A405 <50 A352 <50 A379 <50 A406 ≧50 A353 <50 A380 <50 A407 <50 A354 <50 A381 ≧50 A425 ≧50 A355 <50 A382 ≧50 A426 ≧50 A356 ≧50 A383 ≧50 A427 ≧50 A357 ≧50 A384 ≧50 A428 ≧50 A359 ≧50 A385 ≧50 Lenalidomide <50

Cell Proliferation Assay

[0472] MM.1S cells (myeloma cells) (ATCC, catalog number CRL-2974) were seeded at 1.8×10.sup.3 per well to a 96-well culture plate containing RPMI-1964 medium (Gibco, catalog number A10491-01), and were incubated in an incubator for 24 hours at 37° C. under 5% CO.sub.2. Compounds were prepared as 20 mM stock solutions with DMSO (Sigma, catalog number D2650), and were diluted with the medium to the desired concentration (the final concentration of DMSO was 0.5%) and then were added to each well, incubated in an incubator for 72 hours at 37° C. under 5% CO.sub.2. Then, 20 μL MTS (Promega, catalog number G3581) was added to each well, and further incubated for 1-4 hours in an incubator at 37° C. under 5% CO.sub.2. OD.sub.490 nm was detected with OD.sub.650 nm as reference. The control, a solution containing 0.5% DMSO medium, was as 0% inhibition. GraphPad Prism 5 was used, slope was allowed to change to make the dose-effect curve and IC.sub.50 values were calculated, shown in table 2 for details.

TABLE-US-00002 TABLE 2 IC.sub.50 IC.sub.50 IC.sub.50 values values values Com- of MMIS Com- of MMIS of MMIS pound Inhibition pound Inhibition Compound Inhibition I-28 A I-30 A I-29 A I-31 A I-32 B A386 A A195 A A359 A A387 A A196 A A360 A A388 A A197 A A361 A A389 A A318 B A362 B A390 B A319 B A363 B A391 B A320 B A364 A A392 A A327 A A367 A A393 A A329 A A368 A A396 B A331 A A369 A A397 A A334 A A370 B A398 A A336 A A371 A A399 A A340 A A372 A A400 A A341 A A373 A A401 A A342 B A374 A A402 A A343 A A375 B A403 A A346 A A376 A A404 A A349 B A377 B A405 B A350 A A378 B A406 A A351 A A379 A A407 A A352 A A380 A A425 A A353 A A381 A A426 A A354 A A382 A A427 A A355 B A383 A A428 A A356 A A384 A Lenalidomide B A357 A A385 A / / Note: A: <300 nM; B:: ≧300 nM

CTG Cell Proliferation Assay

[0473] Rec-1 cells (Mantle cell lymphoma cells) (ATCC, catalog number CRL-3004), Namalwa.CSN/70 cells (Burkitt lymphoma cells) (DSMZ, catalog number ACC-70), and WSU-DLCL-2 cells (diffuse large B cell lymphoma cells) (DSMZ, catalog number ACC-575) were seeded at (5-15)×10.sup.3 per well to a 96-well plate with transparent bottom and white wall (Corning, catalog number CLS3903) containing specific medium. The plate was placed in an incubator and incubated for 24 hours at 37° C. under 5% CO.sub.2. Compounds were prepared as 150 mM stock solutions with DMSO (Sigma, catalog number 276855), and were diluted with the medium to the desired concentration (the final concentration of DMSO was 0.2%) and then were added to each well, incubated in an incubator for 72-120 hours at 37° C. under 5% CO.sub.2. Then, 100 μl CellTiter-Glo® cell activity assay reagent (Promega, catalog number G7570) was added to each well. Mixing proceeded for 10 minutes on a shaker to induce cytolysis. The 96-well plate was placed at room temperature for 10 minutes to make the luminous signal stable. A white base film was pasted at the bottom of the culture plate. EnSpire was used to test the plate. Data were processed by XLfit software, and IC.sub.50 values were obtained and shown in table 3 for details.

TABLE-US-00003 TABLE 3 IC.sub.50 Value of IC.sub.50 Value of WSU-DLCL2 IC.sub.50 Value of Namalwa.CSN/70 Compound Inhibition Rec-1 Inhibition Inhibition Lenalidomide D B D I-28 D A D I-29 D A D I-30 D A D I-31 C A D I-32 D B D A195 D A D A324 B B D A329 D A C A334 D A D A356 C A B A357 C A B A381 C A D A382 A A D A383 C B D A386 A A D A399 C A D A400 C B D A402 A A D A403 C A D A404 C A D A406 A A D A407 C A D A427 C A D A428 D A C Note: A: <100 nM; B: 100-400 nM; C: 401 nM-300 μM; D: >300 μM.

[0474] It is to be understood that the foregoing description of the preferred embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited other than expressly set forth in the following claims.