Substituted 1-oxo-isoindoline-5-carboxamide compounds, compositions thereof, and methods of treatment therewith

Abstract

Provided herein are 1-oxo-isoindoline-5-carboxamide compounds having the following structure of formula (I): wherein R1, R2, R3, R4 and n are as defined herein; provided are compositions comprising an effective amount of a 1-oxo-isoindoline-5-carboxamide compound, and methods for treating or preventing a condition. # imgabs0 #

Description

This application is a divisional application of the Chinese patent application with application number 202080040212.6 (application date: May 29, 2020, invention name: substituted 1-oxo-isoindoline-5-carboxamide compounds, compositions thereof, and methods of treatment therewith). Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 855,619, filed May 31, 2019, the disclosure of which is incorporated herein by reference in its entirety. [Technical field]

[0002] Provided herein are certain 1-oxo-isoindoline-5-carboxamide compounds, compositions comprising effective amounts of these compounds, and methods for treating or preventing acute myeloid leukemia (AML), comprising administering an effective amount of these 1-oxo-isoindoline-5-carboxamide compounds to an individual in need thereof. In addition, provided herein are these 1-oxo-isoindoline-5-carboxamide compounds and compositions comprising effective amounts of these compounds for use in these methods. [Prior Art]

[0003] Acute myeloid leukemia is the most commonly reported type of acute leukemia in adults in the United States (US). Based on estimates from the American Cancer Society, approximately 20,830 people in the United States will be diagnosed with AML and 10,460 patients will die from the disease in 2015 (American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015). The median age at diagnosis is approximately 67 years old.

[0004] Acute myeloid leukemia may occur de novo, secondary to prior cytotoxic chemotherapy, or by transformation of an existing myelodysplastic disorder. Therapy-related AML caused by exposure to environmental toxins, cytotoxic drugs, or radiation currently accounts for approximately 5% to 10% of all AML cases (Leone et al., Haematologica 1999; 84(10): 937-945). It is estimated that 35% to 40% of patients with myelodysplastic syndrome will go on to develop AML, and the disease is often refractory to current therapies (Silverman et al., Cancer Medicine, 5th ed., Hamilton, Canada: BC Decker; 2000, pp. 1931-1946). Preexisting myelodysplasia or myeloproliferative disorders are common in elderly AML patients, occurring in 24% to 40% of cases (Gajewski et al., J Clin Oncol 1989; 7: 1637-1645). Patients with secondary AML due to a previous blood disorder are less likely to respond to therapy than those with de novo disease.

[0005] The general treatment of AML is divided into two phases: induction of remission and consolidation therapy. For more than 30 years, the combination of cytarabine and anthracycline has been the mainstay of induction remission therapy (Lowenberg et al., N Engl J Med 1999; 341: 1051-1062; Tallman, Hematology Am Soc Hematol Educ Program 2005: 143-150). Induction remission therapy in leukemia is designed to produce rapid restoration of normal bone marrow function. The common induction regimen consists of 7 days of cytarabine combined with 3 days of daunorubicin, commonly referred to as the "7+3 regimen". A combination of cytarabine and daunorubicin or its analogs can achieve a CR in up to 70% to 80% of adults <60 years of age with de novo AML, usually defined morphologically by the presence of <5% blastocysts in the bone marrow and recovery of absolute neutrophil and platelet counts in the peripheral blood (Lowenberg et al., N Engl J Med 1999; 341: 1051-1062; Tallman, Hematology Am Soc Hematol Educ Program 2005: 143-150). If a CR is achieved, there are 3 basic treatment options for post-remission therapy: additional chemotherapy, stem cell transplantation from a donor (allogeneic stem cell transplantation), or stem cell transplantation using the patient's own stem cells (autologous stem cell transplantation). For post-remission chemotherapy, the same chemotherapy regimen used to induce remission or a higher dose regimen of cytarabine is usually repeated for one or more cycles, referred to as consolidation chemotherapy. When several consolidation courses are given, the survival rate at 2 to 3 years is 35% to 50% for young to middle-aged adults who have achieved CR (Milligan et al., BJ Hem 2006; 135:450-474). However, consolidation or post-remission chemotherapy has not been shown to be beneficial for elderly AML patients.

[0006] Given the poor overall prognosis and high treatment-related mortality rates for older AML patients, some physicians avoid aggressive induction therapy and opt for less aggressive treatments. For patients who choose not to receive intensive chemotherapy or who are deemed unsuitable (unfit) by their physicians, treatment options are limited. Treatment options for these patients include low-intensity therapy, such as low-dose cytarabine, or supportive care alone.

[0007] Due to extensive work involving sequencing of AML patient samples, a mutation spectrum associated with AML has been discovered, which has led to routine comprehensive sequencing in clinical care and the development of targeted therapies (Pollyea, Hematology 2018; 45-50, 2018; Michaelis, Hematology 2018; 51-62). Recently, several new treatments for AML have received FDA approval. In 2017, the FDA approved enasidenib For the treatment of relapsed / refractory AML with IDH2 mutation. In 2018, FDA approved ivosidenib For the treatment of relapsed / refractory AML with IDH1 mutation. In 2018, FDA approved gilteritinib For the treatment of patients with AML who test positive for the FLT3 gene mutation and glasdegib (Daurismo TM ) and venetoclax For the treatment of patients aged 75 or older with newly diagnosed AML, or patients with chronic health conditions or diseases that cannot be treated with standard intensive chemotherapy. All are targeted therapies, and except gilteritinib, are indicated for use in combination therapy (gragilib and low-dose cytarabine and venetoclax and azacitidine or decitabine or low-dose cytarabine). Despite these recent advances, the majority of patients treated with these agents will relapse or become refractory.

[0008] Casein kinase-1α (CK1α), also known as Csnk1a1, is a serine-threonine kinase and a central regulator of multiple pathways critical to normal and malignant stem cell biology, including the β-catenin and p53 pathways (Liu et al., Cell 2002; 108:837-847; Wang et al., Science 2010; 327:1650-1653; Zhao et al., Genes Dev. 2010; 24:1389-1402; Elyada et al., Nature 2011; 470:409-413; Luis et al., Cell Stem Cell 2011; 9:345-356). In addition, CK1α has been shown to play a key role in the biology of AML ( M et al., J Exp Med. 2014; 211(4):605-612). CK1α inhibitors have been reported, however, none has been approved for the treatment of AML.

[0009] There remains a significant need for safe and effective methods to treat, prevent and manage AML, particularly AML that is refractory to standard treatments such as surgery, radiation therapy, chemotherapy and biological therapy, while reducing or avoiding the toxicities and / or side effects associated with conventional therapies.

[0010] Citation or identification of any reference in this section of this application shall not be construed as an admission that such reference is prior art to the present application. [Summary of the invention]

[0011] Provided herein are compounds having the following formula (I): or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 and n is as defined herein.

[0012] The compound of formula (I) or its pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer (each referred to herein as an "isoindolinone carboxamide compound") is suitable for reducing CK1α protein concentration and treating or preventing AML.

[0013] In one aspect, provided herein are isoindolinonecarboxamide compounds as described herein, such as, for example, as described in Table 1, or pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof. In one aspect, provided herein are isoindolinonecarboxamide compounds as described in Table 1, or pharmaceutically acceptable salts thereof. In one aspect, provided herein are isoindolinonecarboxamide compounds as described in Table 1.

[0014] In one aspect, provided herein is a pharmaceutical composition comprising an effective amount of an isoindolinone carboxamide compound as described herein and a pharmaceutically acceptable carrier, excipient or vehicle. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, transmucosal, transdermal or topical administration.

[0015] In one aspect, provided herein are methods for treating or preventing AML, comprising administering to an individual in need thereof an effective amount of an isoindolinone carboxamide compound as described herein; and a pharmaceutically acceptable carrier, excipient, or vehicle. In one aspect, provided herein are methods for reducing CK1α protein concentrations, comprising administering to an individual in need thereof an effective amount of an isoindolinone carboxamide compound as described herein; and a pharmaceutically acceptable carrier, excipient, or vehicle. In another aspect, provided herein are isoindolinone carboxamide compounds for treating AML. In another aspect, provided herein are isoindolinone carboxamide compounds for reducing CK1α protein concentrations.

[0016] In another aspect, provided herein are methods for preparing the isoindolinonecarboxamide compounds as described herein.

[0017] The embodiments herein may be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments. [Implementation Method] definition

[0018] As used herein, the term "or" should be interpreted as an inclusive "or", meaning any one or any combination. Thus, "A, B or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B and C". Exceptions to this definition occur only when a combination of elements, functions, steps or actions are inherently mutually exclusive to some extent.

[0019] As used herein and unless otherwise specified herein, "alkyl" is a saturated, partially saturated or unsaturated straight or branched chain acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbons, or in some embodiments, 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Typical alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched chain alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. "Alkenyl" is an alkyl group containing one or more carbon-carbon double bonds. "Alkynyl" is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), etc. The alkyl group may be substituted or unsubstituted. When alkyl groups described herein are said to be "substituted," they may be substituted with any substituent or substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocyclylalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocyclylalkylalkyloxy; oxo (═O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocyclylalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkyloxy, heteroarylalkyloxy, heterocyclylalkylalkyloxy; Cyclic alkylamino, heteroarylalkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkyloxyamino; hydrazine; hydrazide; hydrazono; azido; nitro; sulfenyl (-SH), alkylsulfenyl; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphino; acyl; formyl; carboxyl; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; sulfate; or -B(OH)2.

[0020] As used herein and unless otherwise specified herein, "cycloalkyl" is a saturated or partially saturated cycloalkyl group of 3 to 10 carbon atoms having a single annular ring or multiple fused or bridged rings that may be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms varies from 3 to 5, 3 to 6, or 3 to 7. These cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or polycyclic or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like. The cycloalkyl groups may be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.

[0021] As used herein and unless otherwise specified herein, "aryl" is an aromatic carbocyclic radical of 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl). In some embodiments, aryl contains 6 to 14 carbons in the ring portion of such radicals, and in other embodiments 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups may be substituted or unsubstituted. The phrase "aryl" also includes groups containing fused rings such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0022] As used herein and unless otherwise specified herein, "heteroaryl" is an aromatic ring system having from one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In some embodiments, heteroaryl contains 3 to 6 ring atoms in the ring portion of such groups, and in other embodiments 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-onyl), isoindolin-1-onyl, azaindolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[ The heteroaryl group may be substituted or unsubstituted.

[0023] As used herein and unless otherwise specified herein, "heterocyclyl" is an aromatic ring system (also known as heteroaryl) or a non-aromatic cycloalkyl (also known as heterocycloalkyl) in which one to four of the ring carbon atoms are independently replaced by heteroatoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In some embodiments, the heterocyclyl includes 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6 or 3 to 8 ring members. The heterocyclyl may also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocyclyl may be substituted or unsubstituted. The heterocyclyl includes unsaturated, partially saturated and saturated ring systems such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione). The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidine. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiolanyl, dioxy, dithianyl, pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridinyl, dihydrodihydropyranyl, 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazolyl-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolyl, benzothiazolyl, benzoxa ... Benzothiophene 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H-imidazolyl The non-aromatic heterocyclic groups include 3,4-dihydroisoquinolin-1(2H)-one, quinolinazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thiaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridinyl, tetrahydroimidazopyridinyl, tetrahydrotriazolopyridinyl, tetrahydropyrimidin-2(1H)-one and tetrahydroquinolinyl. Typical non-aromatic heterocyclic groups do not include fused ring types, which include fused aromatic groups. Examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Typical substituted heterocyclyl groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.

[0024] As used herein and unless otherwise specified herein, "cycloalkylalkyl" is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl may be substituted on the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the radical. Typical cycloalkylalkyls include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, and the like.

[0025] As used herein and unless otherwise specified herein, "aralkyl" is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are as defined above. Substituted aralkyl groups may be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the radical. Typical aralkyl groups include, but are not limited to, benzyl and phenethyl, and aralkyl groups in which the aryl group is fused to a cycloalkyl group, such as indan-4-ylethyl.

[0026] As used herein and unless otherwise specified herein, "heterocyclylalkyl" is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as defined above. "Heteroarylalkyl" is a radical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are as defined above. "Heterocycloalkylalkyl" is a radical of the formula: -alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl are as defined above. Substituted heterocyclylalkyl may be substituted at the alkyl, heterocyclyl, or both the alkyl and heterocyclyl portions of the radical. Typical heterocyclylalkyls include, but are not limited to, morpholin-4-ylethyl, morpholin-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0027] As used herein, and unless otherwise specified herein, "halogen" is fluoro, chloro, bromo, or iodo.

[0028] As used herein, and unless otherwise specified herein, "hydroxyalkyl" is an alkyl group as described above substituted with one or more hydroxy groups.

[0029] As used herein and unless otherwise specified herein, "alkoxy" is -O-(alkyl), wherein alkyl is as defined above. "Alkylthio" is -S-(alkyl), wherein alkyl is as defined above.

[0030] As used herein, and unless otherwise specified herein, "alkoxyalkyl" is -(alkyl)-O-(alkyl) where alkyl is as defined above.

[0031] As used herein, and unless otherwise specified herein, a "cycloalkoxy" group is -O-(cycloalkyl) where cycloalkyl is as defined above.

[0032] As used herein, and unless otherwise specified herein, "aryloxy" is -O-(aryl), wherein aryl is as defined above.

[0033] As used herein and unless otherwise specified herein, "heterocyclyloxy" is -O-(heterocyclyl), where heterocyclyl is as defined above. "Heteroaryloxy" is -O-(heteroaryl), where heteroaryl is as defined above. "Heterocycloalkoxy" is -O-(heterocycloalkyl), where heterocycloalkyl is as defined above.

[0034] As used herein, and unless otherwise specified herein, "amino" is a radical of the formula: -NH2, -NH(R # ) or -N(R # )2, where each R # is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) as defined above, each of which is independently substituted or unsubstituted.

[0035] In one embodiment, "amino" is "alkylamino", which is a radical of the formula: -NH-alkyl or -N(alkyl), wherein each alkyl is independently defined above. The term "cycloalkylamino", "arylamino", "heterocyclylamino", "heteroarylamino", "heterocycloalkylamino" or the like reflects the above description of "alkylamino", wherein the term "alkyl" is replaced by "cycloalkyl", "aryl", "heterocyclyl", "heteroaryl", "heterocycloalkyl" or the like, respectively.

[0036] As used herein, and unless otherwise specified herein, a "carboxy" group is a group of the formula: -C(O)OH.

[0037] As used herein, and unless otherwise specified herein, an "acyl" group is a group of the formula: -C(O)(R # ) or -C(O)H, where R # is as defined above. "Formyl" is a radical of the formula: -C(O)H.

[0038] As used herein, and unless otherwise specified herein, an "amide" group is a group of the formula: -C(O)-NH2, -C(O)-NH(R # )、-C(O)-N(R # )2、-NH-C(O)H、-NH-C(O)-(R # )、-N(R # )-C(O)H or -N(R # )-C(O)-(R # ), where each R # is independently defined above.

[0039] In one embodiment, "amide" is "aminocarbonyl", which is a radical of the formula: -C(O)-NH2, -C(O)-NH(R # )、-C(O)-N(R # )2, where each R # is independently defined above.

[0040] In one embodiment, "amido" is "acylamino", which is a radical of the formula: -NH-C(O)H, -NH-C(O)-(R # )、-N(R # )-C(O)H or -N(R # )-C(O)-(R # ), where each R # is independently defined above.

[0041] As used herein, and unless otherwise specified herein, a "sulfonylamino" group is a group of the formula: -NHSO2(R # ) or -N(R # )SO2(R # ), where each R # It is defined above.

[0042] As used herein, and unless otherwise specified herein, an "ester group" is a group of the formula: -C(O)-O-(R # ) or -OC(O)-(R # ), where R # It is defined above.

[0043] In one embodiment, "ester group" is "alkoxycarbonyl", which is a radical of the formula: -C(O)-O-(alkyl), wherein alkyl is as defined above. The term "cycloalkoxycarbonyl", "aryloxycarbonyl", "heterocyclyloxycarbonyl", "heteroaryloxycarbonyl", "heterocycloalkoxycarbonyl" or the like reflects the above description of "alkoxycarbonyl", wherein the term "alkoxy" is replaced by "cycloalkoxy", "aryloxy", "heterocyclyloxy", "heteroaryloxy", "heterocycloalkoxy" or the like, respectively.

[0044] As used herein and unless otherwise specified herein, a "carbamate" is a radical of the formula: -OC(O)-NH2, -OC(O)-NH(R # )、-OC(O)-N(R # )2、-NH-C(O)-O-(R # ) or -N(R # )-C(O)-O-(R # ), where each R # is independently defined above.

[0045] As used herein and unless otherwise specified herein, "urea" is a radical of the formula: -NH(CO)NH2, -NHC(O)NH(R # )、-NHC(O)N(R # )2、-N(R # )C(O)NH2、-N(R #)C(O)NH(R # ) or -N(R # )C(O)N(R # )2, where each R # is independently defined above.

[0046] As used herein, and unless otherwise specified herein, a "sulfinyl" group is a group of the formula: -S(O)R # , where R # It is defined above.

[0047] As used herein, and unless otherwise specified herein, a "sulfonyl" group is a group of the formula: -S(O)2R # , where R # It is defined above.

[0048] As used herein, and unless otherwise specified herein, "aminosulfonyl" is a radical of the formula: -SO2NH2, -SO2NH(R # ) or -SO2N(R # )2, where each R # is independently defined above.

[0049] When a group described herein (other than an alkyl group) is said to be "substituted," it may be substituted with any suitable substituent. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, and halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, heterocyclylalkylalkyl, optionally further substituted; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocyclylalkyloxy, cycloalkylalkoxy, aralkyloxy, heterocyclylalkoxy, heteroarylalkoxy, heterocyclylalkylalkoxy; oxo (═O); oxide (e.g., a nitrogen atom substituted with an oxide is referred to as an N-oxide); amino, alkylamino, cycloalkylamino, arylamino alkylamino; imino; acylimino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrous urea; oxime; hydroxyamino; alkoxyamino; aralkyloxyamino; hydrazine; hydrazide; hydrazono; azido; nitro; sulfenyl (-SH), alkylsulfenyl; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphino; acyl; formyl; carboxyl; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or -B(OH)2.

[0050] As used herein, the term "isoindolinone carboxamide compound" refers to a compound of formula (I), such as formula (II) to (XI), and other embodiments provided herein. In one embodiment, the "isoindolinone carboxamide compound" is a compound listed in Table 1. The term "isoindolinone carboxamide compound" includes pharmaceutically acceptable salts, tautomers, isotopomers and stereoisomers of the compounds provided herein.

[0051] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isoacetic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfonic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid and methanesulfonic acid. Therefore, embodiments of specific salts include hydrochloride and mesylate. Others are well known in the art, see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton PA (1995).

[0052] As used herein and unless otherwise indicated herein, the term "stereoisomer" or "stereoisomerically pure" means one stereoisomer of an isoindolinonecarboxamide compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The isoindolinone carboxamide compounds may have chiral centers and may occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

[0053] The use of stereoisomerically pure forms of these isoindolinone carboxamide compounds and the use of mixtures of those forms are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular isoindolinone carboxamide compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral optical resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268 (ed. by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: APractical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0054] It should also be noted that the isoindolinone carboxamide compounds may include E and Z isomers, or mixtures thereof, and cis and trans isomers, or mixtures thereof. In certain embodiments, the isoindolinone carboxamide compounds may be separated into E or Z isomers. In other embodiments, the isoindolinone carboxamide compounds are a mixture of E and Z isomers.

[0055] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is found and may be different, depending, for example, on whether the compound is a solid or an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0056] As those skilled in the art readily appreciate, various functional groups and other structures may exhibit tautomerism and all tautomers of the compounds of formula (I) are within the scope of the present invention.

[0057] It should also be noted that the isoindolinonecarboxamide compounds may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be irradiated with radioactive isotopes such as, for example, tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C) can be radiolabeled, or can be labeled with deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N) isotope enrichment. As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition in addition to the natural isotopic composition of the atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition in addition to the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are suitable for use as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding analytical reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the isoindolinone carboxamide compounds described herein (whether or not radioactive) are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopologues of such isoindolinone carboxamide compounds are provided, e.g., such isotopologues are isoindolinone carboxamide compounds enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterated" means a compound in which at least one hydrogen (H) has been replaced with deuterium (by D or 2 H indicates), i.e., the compound is enriched in deuterium at at least one position.

[0058] It will be appreciated that, independently of the stereo or isotopic composition, each of the isoindolinone carboxamide compounds mentioned herein may be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Likewise, it will be appreciated that the isotopic composition may vary independently of the stereo composition of each of the isoindolinone carboxamide compounds mentioned herein. Furthermore, the isotopic composition, while limited to those elements present in the individual isoindolinone carboxamide compounds or their salts, may also vary independently of the choice of the pharmaceutically acceptable salt of the individual isoindolinone carboxamide compounds.

[0059] It should be noted that if there is a discrepancy between a structure depicted herein and the name of the structure, the structure depicted herein will be given greater weight.

[0060] As used herein, "treating" means the complete or partial relief of a disorder, disease or condition, or one or more of the symptoms associated with the disorder, disease or condition, or the slowing or cessation of further progression or worsening of those symptoms, or the alleviation or eradication of the cause of the disorder, disease or condition itself. In one embodiment, the disorder is AML or a symptom thereof as described herein.

[0061] As used herein, "prevention" means a method of completely or partially delaying and / or preventing the onset, recurrence, or spread of a disorder, disease, or condition; preventing a subject from having a disorder, disease, or condition; or reducing the risk of a subject having a disorder, disease, or condition. In one embodiment, the disorder is AML or a symptom thereof, as described herein.

[0062]

[00136] The term "effective amount" in conjunction with an isoindolinonecarboxamide compound means an amount disclosed herein that can treat or prevent a disorder, disease or condition, or a symptom thereof.

[0063] As used herein, the term "CK1α" refers to casein kinase 1α, a kinase in humans encoded by the CSNK1A1 gene. CK1α has been shown to play a key role in the biology of AML ( M et al., J Exp Med. 2014; 211(4):605-612).

[0064] As used herein, the term "degradation" means the degradation of a protein mediated by an E3 ligase (eg, CRBN), resulting in a decrease in the concentration of the protein. In one embodiment, the protein is CK1α.

[0065] The term "subject" includes animals, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, in one embodiment, mammals, in another embodiment, humans. In one embodiment, the subject is a human having or at risk of having AML or a symptom thereof. Isoindolinone carboxamide compounds

[0066] Provided herein are compounds having the following formula (I): or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, in: R 1 It is C 1-3 Alkyl or C 1-3 Fluoroalkyl; R 2 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl; R 3 It is H; R 4 is a halogen; and n is 0 to 3.

[0067] In some embodiments of the compound of formula (I), the compound is a compound of formula (II): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0068] In other embodiments of the compound of formula (I), the compound is a compound of formula (III): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0069] In yet other embodiments of the compound of formula (I), the compound is a compound of formula (IV): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0070] In yet other embodiments of the compound of formula (I), the compound is a compound of formula (V): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0071] In some embodiments of the compound of formula (I), the compound is a compound of formula (VI): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0072] In other embodiments of the compound of formula (I), the compound is a compound of formula (VII): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0073] In yet other embodiments of the compound of formula (I), the compound is a compound of formula (VIII): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0074] In yet other embodiments of the compound of formula (I), the compound is a compound of formula (IX): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0075] In other embodiments of the compound of formula (I), the compound is a compound of formula (X): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0076] In yet other embodiments of the compound of formula (I), the compound is a compound of formula (XI): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

[0077] In some embodiments of the compound of Formula (I)-(XI), R 1 is methyl, ethyl, n-propyl, isopropyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH3, CF2CH3 or CF2CF3. In other embodiments, R 1 It is methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3 or CF2CH3.

[0078] In some embodiments of the compound of Formula (I)-(XI), R 2 is substituted by one or more substituents selected from the following: halogen, CN, OR', substituted or unsubstituted C 1-3 Alkyl and substituted or unsubstituted -(C0-3 alkyl) (3 to 6 membered heterocyclic group); wherein each R' is independently selected from H, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 In some of these embodiments, R 2 is substituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, OCH3, OCF3, OCH2CH3, O-n-propyl, O-isopropyl, O-n-butyl, O-sec-butyl, O-tert-butyl, O-cyclopropyl, O-cyclobutyl, O-phenyl, CH3, CH2CH3, CF3, CH2CF3, CH2NHCH3, CH2N(CH3)2, and -(C 0-3 alkyl) (3 to 6 membered heterocyclic group) selected from piperidinyl, piperazinyl, morpholinyl, CH2-aziridine, CH2-pyrrolidinyl, CH2-piperazinyl, CH2-piperidinyl, CH2-morpholinyl, CH2 (2-oxa-6-azaspiro [3.3] heptyl), wherein the - (C 0-3 alkyl) (3 to 6 membered heterocyclyl) is optionally substituted with one or more F, Cl or CH3. For example, in some embodiments of compounds of formula (I)-(XI), R 2 is substituted with one or more substituents selected from the group consisting of F, Cl, CN, OH, OCH3, OCF3, O-isopropyl, O-cyclopropyl, O-phenyl, CH3, CF3, CH2CF3, CH2N(CH3)2, and -(C 0-3 alkyl)(3 to 6 membered heterocyclic group) selected from morpholinyl, piperazinyl, CH2-aziridine, CH2-pyrrolidinyl, CH2-piperazinyl, CH2-morpholinyl and CH2(2-oxa-6-azaspiro[3.3]heptyl), wherein the -(C 0-3 alkyl) (3 to 6 membered heterocyclyl) is optionally substituted with one or more F or CH3.

[0079] In some embodiments of the compound of Formula (I)-(XI), R 2 It is C 1-6 Alkyl, which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CN and OR'; C 3-10 Cycloalkyl, which is unsubstituted or substituted by one or more substituents independently selected from the following: halogen, OR' and substituted or unsubstituted C 1-3 alkyl; a 3- to 6-membered heterocyclic group which is unsubstituted or substituted with one or more substituted or unsubstituted C 1-3 Alkyl substitution; C 6-10 Aryl, which is unsubstituted or substituted with one or more substituents independently selected from the following: halogen, CN, OR', substituted or unsubstituted C 1-3Alkyl and substituted or unsubstituted -(C 0-3 alkyl) (3 to 6 membered heterocyclyl); or 5 to 10 membered heteroaryl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, OR' and substituted or unsubstituted C 1-3 wherein each R' is independently selected from H, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 In some embodiments of the compounds of Formula (I)-(XI), R 2 It is C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, CN, and OH. In some of these embodiments, R 2 is CH3, isopropyl, tert-butyl, C(CH3)2CH2OH, C(CH3)2CN or C(CH3)2CF3. In some other embodiments of compounds of formula (I)-(XI), R 2 It is C 3-10 Cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, OH, CH3, C(CH3)2OH and CF3. In some of these embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.5]nonyl, bicyclo[1.1.1]pentyl or spiro[2.5]octyl. In yet other embodiments of the compounds of Formula (I)-(XI), R 2 is a 3- to 6-membered heterocyclyl group which is unsubstituted or substituted with one or more CH3, and CH2CF3. In some of these embodiments, R 2 is oxetanyl, tetrahydropyranyl or piperidinyl. In yet other embodiments of compounds of formula (I)-(XI), R 2 It is C 6-10 Aryl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, Cl, CN, OH, OCH3, OCF3, O-isopropyl, O-cyclopropyl, O-phenyl, CH3, CF3, and CH2N(CH3)2; and -(C 0-3 alkyl) (3 to 6 membered heterocyclic group) selected from piperazinyl, morpholinyl, CH2-aziridine, CH2-pyrrolidinyl, CH2-piperazinyl, CH2-morpholinyl, CH2 (2-oxa-6-azaspiro [3.3] heptyl), wherein the - (C 0-3 alkyl) (3 to 6 membered heterocyclyl) is optionally substituted with one or more F or CH3. In some of these embodiments, R 2 In yet other embodiments of compounds of formula (I)-(XI), R 2is a 5- to 10-membered heteroaryl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, Cl, OCH3, CH3, CF3, and CH2N(CH3)2. In some of these embodiments, R 2 is pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl.

[0080] In some embodiments of the compound of Formula (I)-(XI), R 4 It is F or Cl.

[0081] In some embodiments of compounds of Formula (I)-(XI), n is 0, 1 or 2.

[0082] In some embodiments of the compound of Formula (I)-(XI), R 1 is methyl, ethyl, n-propyl, isopropyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFCH3, CF2CH3 or CF2CF3, and R 2 It is C 1-6 Alkyl, which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CN and OR'; C 3-10 Cycloalkyl, which is unsubstituted or substituted by one or more substituents independently selected from the following: halogen, OR' and substituted or unsubstituted C 1-3 alkyl; a 3- to 6-membered heterocyclic group which is unsubstituted or substituted with one or more substituted or unsubstituted C 1-3 Alkyl substitution; C 6-10 Aryl, which is unsubstituted or substituted with one or more substituents independently selected from the following: halogen, CN, OR', substituted or unsubstituted C 1-3 Alkyl and substituted or unsubstituted -(C 0-3 alkyl) (3 to 6 membered heterocyclyl); or 5 to 10 membered heteroaryl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, OR' and substituted or unsubstituted C 1-3 wherein each R' is independently selected from H, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 In other embodiments of the compounds of formula (I)-(XI), R 1 is methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3 or CF2CH3, and R 2 It is C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, CN, and OH. In some of these embodiments, R 2is CH3, isopropyl, tert-butyl, C(CH3)2CH2OH, C(CH3)2CN or C(CH3)2CF3. In some other embodiments of compounds of Formula (I)-(XI), R 1 is methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3 or CF2CH3, and R 2 It is C 3-10 Cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, OH, CH3, C(CH3)2OH and CF3. In some of these embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.5]nonyl, bicyclo[1.1.1]pentyl or spiro[2.5]octyl. In other embodiments of the compounds of formula (I)-(XI), R 1 is methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3 or CF2CH3, and R 2 is a 3- to 6-membered heterocyclyl group which is unsubstituted or substituted with one or more CH3, and CH2CF3. In some of these embodiments, R 2 is oxetane, tetrahydropyranyl or piperidinyl. In yet other embodiments of compounds of formula (I)-(XI), R 1 is methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3 or CF2CH3, and R 2 It is C 6-10 Aryl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, Cl, CN, OH, OCH3, OCF3, O-isopropyl, O-cyclopropyl, O-phenyl, CH3, CF3, and CH2N(CH3)2; and -(C 0-3 alkyl) (3 to 6 membered heterocyclic group) selected from piperazinyl, morpholinyl, CH2-aziridine, CH2-pyrrolidinyl, CH2-piperazinyl, CH2-morpholinyl, CH2 (2-oxa-6-azaspiro [3.3] heptyl), wherein the - (C 0-3 alkyl) (3 to 6 membered heterocyclyl) is optionally substituted with one or more F or CH3. In some of these embodiments, R 2 In yet other embodiments of compounds of formula (I)-(XI), R 1 is methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3 or CF2CH3, and R 2 is a 5- to 10-membered heteroaryl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, Cl, OCH3, CH3, CF3, and CH2N(CH3)2. In some of these embodiments, R 2 is pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl.

[0083] Other embodiments provided herein include combinations of one or more of the specific embodiments set forth above.

[0084] Typical compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) and (XI) are described in Table 1.

[0085] The isoindolinone carboxamide compounds described in Table 1 were tested and found to be active in the assays described herein. In one embodiment, the isoindolinone carboxamide compound is a compound as described herein, wherein the compound degrades CK1α protein by at least about 50% or more at a concentration of 1 μM. Method for producing isoindolinone carboxamide compounds

[0086] Isoindolinone carboxamide compounds can be prepared using conventional organic synthesis and commercially available starting materials. By way of illustration and not limitation, isoindolinone carboxamide compounds of formula (I) can be prepared as outlined in Schemes 1 and 2 shown below and in the Examples described herein. It should be noted that methods are known to those skilled in the art to modify the procedures described in the illustrative schemes and Examples to achieve the desired products.

[0087] As shown in Scheme 1, the isoindolinone carboxamide compound of formula (I) (wherein R 1 , R 2 , R 3 , R 4 and n is as defined herein) can be prepared by reacting an appropriately derivatized alkyl benzoate (wherein Hal is Br or I, and R is C 1-3alkyl) with 3-aminopiperidine-2,6-dione in a solvent such as ACN, THF, DCM, DMF, DMA or NMP in the presence of a base such as DIPEA, TEA or NMM at a temperature from room temperature to about 80° C. to obtain the halogenated 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione intermediate a. The intermediate is carbonylated by treatment with carbon monoxide and water in the presence of 1,3-bis(diphenylphosphino)propane and a palladium catalyst such as palladium acetate in a solvent such as DMF, DMA or NMP in the presence of a base such as DIPEA, TEA or NMM at a temperature from room temperature to about 80° C. to provide the derivatized 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxylic acid b, wherein X is OH. Intermediate b can also be obtained by reductive amination of an appropriately derivatized benzaldehyde (wherein Hal is Br or I) with 3-aminopiperidine-2,6-dione in the presence of a reducing agent such as 2-MePyBH3, NaBH4, NaBH3CN, (CH3COO)3BHNa or decaborane in a solvent such as ACN, MeOH or EtOH in the presence of an acid such as acetic acid or sodium acetate to provide intermediate c. Intermediate c is then treated with carbon monoxide and water in the presence of 1,3-bis(diphenylphosphino)propane and a palladium catalyst such as palladium acetate in a solvent such as DMF, DMA or NMP in the presence of a base such as DIPEA, TEA or NMM at a temperature from room temperature to about 80°C to provide intermediate b. In an alternative approach, intermediate c can also be obtained by treating an appropriately derivatized benzyl halide (wherein Hal is Br or I) with 3-aminopiperidine-2,6-dione in a solvent such as ACN, THF, DCM, DMF, DMA or NMP in the presence of a base such as DIPEA, TEA or NMM at a temperature from room temperature to about 80°C.

[0088] Carboxylic acid b and amine NH2(CR 1 R 2 R 3 ), in a solvent such as DMF, DMA, DCM, THF or NMP, in the presence of a coupling agent such as HOBT, EDCI, HATU or T3P and a base such as DIPEA, TEA or NMM, at a temperature from room temperature to about 50° C., to provide a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 and n is as defined herein.

[0089] Scheme 2 shows an alternative synthesis of one of the compounds of formula (I), wherein R1 , R 2 , R 3 , R 4 and n is as defined herein. A suitably derivatized carboxy-protected 5-amino-5-oxo-4-(1-oxoisoindolin-2-yl)pentanoic acid (wherein Hal is Br or I and P O is a carboxyl protecting group such as tert-butyl) by carbonylation with carbon monoxide and water in the presence of dicyclohexyl (3-dicyclohexylphosphonopropyl) bisphosphonium tetrafluoroborate and a palladium catalyst (e.g., palladium acetate) in a solvent such as DMF, DMA or NMP in the presence of a base such as DIPEA, TEA, NMM, K2CO3 or Na2CO3 at room temperature to about 80°C to provide intermediate d, wherein X is OH. Intermediate d is reacted with an amine NH2 (CR 1 R 2 R 3 ), in a solvent such as DMF, DMA, DCM, THF or NMP, in the presence of a coupling agent such as HOBT, EDCI, HATU or T3P and a base such as DIPEA, TEA or NMM, at a temperature from room temperature to about 50°C, to provide a carboxyl protected intermediate e. Deprotection and cyclization are achieved by treating the intermediate e with an acid such as benzenesulfonic acid, methanesulfonic acid or p-toluenesulfonic acid in a solvent such as ACN, THF, DMF, DMA or NMP at a temperature from room temperature to about 80°C to provide a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 and n is as defined herein.

[0090] In some embodiments, chiral separation of a mixture of diastereomers of a compound of formula (I) prepared as described above (by standard methods and as described herein) can be used to provide compounds of formula (II) to (IX). Alternatively, the method described in Scheme 2 can be used starting from an appropriately derivatized chiral starting material (R)-2-(1-amino-4-carboxy-1-oxobutan-2-yl)-1-oxoisoindoline-5-carboxylic acid or (S)-2-(1-amino-4-carboxy-1-oxobutan-2-yl)-1-oxoisoindoline-5-carboxylic acid to provide compounds of formula (II), (III) and (VI) to (IX).

[0091] The term "protected" with respect to functional groups refers to forms of these functional groups that are protected from undesired reactions by protecting groups known to those skilled in the art (such as those listed in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (5th edition, 2014)), which can be added or removed using the procedures described therein. Examples of protecting groups for carboxyl groups as used herein include tert-butyl protecting groups.

[0092] In one aspect, provided herein are methods for preparing compounds of formula (I): The methods comprise treating a compound of formula (b): Where X is OH, with NH2(CR 1 R 2 R 3 ), in a solvent, in the presence of a coupling agent and a base, under conditions suitable for providing a compound of formula (I), wherein: R 1 It is C 1-3 Alkyl or C 1-3 Fluoroalkyl; R 2 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl; R 3 It is H; R 4 is a halogen; and n is 0 to 3.

[0093] In one embodiment, the solvent is DMF, DMA, DCM, THF or NMP. In another embodiment, the coupling agent is HOBT, EDCI, HATU or T3P. In another embodiment, the base is DIPEA, TEA or NMM. In some embodiments, the contacting is carried out at a temperature of room temperature to about 50°C.

[0094] In some embodiments, the methods further comprise preparing a compound of formula b: The methods comprise treating a compound of formula C: wherein Hal is Br or I, is contacted with carbon monoxide and water in the presence of 1,3-bis(diphenylphosphino)propane and a palladium catalyst in a solvent in the presence of a base under conditions suitable to provide a compound of formula b.

[0095] In one embodiment, the palladium catalyst is palladium acetate. In one embodiment, the solvent is DMF, DMA or NMP. In another embodiment, the base is DIPEA, TEA or NMM. In some embodiments, the contacting is carried out at a temperature of room temperature to about 80°C.

[0096] In some embodiments, the methods further comprise preparing a compound of formula C: The methods comprise treating a benzyl halide of the formula: wherein Hal is Br or I, is contacted with 3-aminopiperidine-2,6-dione in a solvent in the presence of a base under conditions appropriate to provide a compound of formula c.

[0097] In one embodiment, the solvent is ACN, THF, DCM, DMF, DMA or NMP. In another embodiment, the base is DIPEA, TEA or NMM. In some embodiments, the contacting is performed at a temperature of room temperature to about 80°C.

[0098] In some other embodiments, the methods further comprise preparing a compound of formula C: The methods comprise reacting a benzaldehyde of the formula: wherein Hal is Br or I, is contacted with 3-aminopiperidine-2,6-dione in the presence of a reducing agent in a solvent in the presence of an acid under conditions appropriate to provide a compound of formula c.

[0099] In one embodiment, the reducing agent is 2-MePyBH3, NaBH4, NaBH3CN, (CH3COO)3BHNa or decaborane. In one embodiment, the solvent is ACN, MeOH or EtOH. In one embodiment, the acid is acetic acid or sodium acetate.

[0100] In some embodiments, the methods further comprise preparing a compound of formula b: The methods comprise treating a compound of formula a: wherein Hal is Br or I, is contacted with carbon monoxide and water in the presence of 1,3-bis(diphenylphosphino)propane and a palladium catalyst in a solvent in the presence of a base under conditions suitable to provide a compound of formula b.

[0101] In one embodiment, the palladium catalyst is palladium acetate. In one embodiment, the solvent is DMF, DMA or NMP. In another embodiment, the base is DIPEA, TEA or NMM. In some embodiments, the contacting is carried out at a temperature of room temperature to about 80°C.

[0102] In some embodiments, the methods further comprise preparing a compound of formula a: The methods comprise reacting an alkyl benzoate of the formula: Where Hal is Br or I and R is C 1-3 An alkyl group is contacted with 3-aminopiperidine-2,6-dione in a solvent in the presence of a base under conditions suitable to provide a compound of formula a.

[0103] In one embodiment, the solvent is ACN, THF, DCM, DMF, DMA or NMP. In another embodiment, the base is DIPEA, TEA or NMM. In some embodiments, the contacting is performed at a temperature of room temperature to about 80°C.

[0104] In another aspect, provided herein are methods for preparing compounds of formula (I): The methods comprise treating a compound of formula e: Where P O is a carboxyl protecting group, and is contacted with an acid, in a solvent, under conditions suitable for providing a compound of formula (I), wherein: R 1 It is C 1-3 Alkyl or C 1-3 Fluoroalkyl; R 2 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl; R3 It is H; R 4 is a halogen; and n is 0 to 3.

[0105] In one embodiment, P O is tert-butyl. In one embodiment, the acid is benzenesulfonic acid, methanesulfonic acid or p-toluenesulfonic acid. In one embodiment, the solvent is ACN, THF, DMF, DMA or NMP. In some embodiments, the contacting is carried out at a temperature of room temperature to about 80°C.

[0106] In some embodiments, the methods further comprise preparing a compound of formula e: The methods comprise treating a compound of formula d: Where X is OH, with NH2(CR 1 R 2 R 3 ), in a solvent, in the presence of a coupling agent and a base, under conditions suitable to provide a compound of formula e.

[0107] In one embodiment, the solvent is DMF, DMA, DCM, THF or NMP. In another embodiment, the coupling agent is HOBT, EDCI, HATU or T3P. In another embodiment, the base is DIPEA, TEA or NMM. In some embodiments, the contacting is carried out at a temperature of room temperature to about 50°C.

[0108] In some embodiments, the methods further comprise preparing a compound of formula d: The methods comprise reacting a compound of the formula: wherein Hal is Br or I, is contacted with carbon monoxide and water in the presence of dicyclohexyl(3-dicyclohexylphosphonopropyl)bisphosphonium tetrafluoroborate and a palladium catalyst in a solvent in the presence of a base under conditions suitable to provide a compound of formula d.

[0109] In one embodiment, the palladium catalyst is palladium acetate. In one embodiment, the solvent is DMF, DMA or NMP. In another embodiment, the base is DIPEA, TEA, NMM, K2CO3 or Na2CO3. In some embodiments, the contacting is carried out at a temperature of room temperature to about 80°C. Methods of use and compounds or pharmaceutical compositions for use in these methods

[0110] Isoindolinone carboxamide compounds can be used as drugs to treat, prevent or improve animal or human conditions. Therefore, provided herein are isoindolinone carboxamide compounds or pharmaceutical compositions comprising such isoindolinone carboxamide compounds for use as drugs, including the treatment or prevention of those diseases described below. The methods provided herein include administering an effective amount of one or more isoindolinone carboxamide compounds to an individual in need thereof.

[0111] In one aspect, provided herein are methods for treating or preventing AML, comprising administering to an individual in need thereof an effective amount of an isoindolinone carboxamide compound. For example, the isoindolinone carboxamide compound is a compound from Table 1. Provided herein are methods for treating or preventing AML, comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition as provided herein, the pharmaceutical composition comprising the isoindolinone carboxamide compound.

[0112] In another aspect, provided herein are compounds for treating or preventing AML, comprising administering an effective amount of an isoindolinone carboxamide compound to an individual in need thereof. In some embodiments, provided herein are compounds for treating AML, comprising administering an effective amount of an isoindolinone carboxamide compound as described herein to an individual in need thereof. Provided herein are pharmaceutical compositions for treating or preventing AML, comprising administering an effective amount of a pharmaceutical composition as provided herein to an individual in need thereof, the pharmaceutical composition comprising the isoindolinone carboxamide compound. Provided herein are pharmaceutical compositions for treating AML, comprising administering an effective amount of a pharmaceutical composition as provided herein to an individual in need thereof, the pharmaceutical composition comprising the isoindolinone carboxamide compound.

[0113] In some embodiments, the AML is a newly diagnosed AML. In some embodiments, the AML is a primary AML. In other embodiments, the AML is a relapsed AML. In yet other embodiments, the AML is a refractory AML. In some embodiments, the AML is a relapsed / refractory AML. In one embodiment, the AML is refractory to one or more of cytarabine, daunorubicin, idarubicin, midostaurin, cladribine, gemtuzumab ozogamicin, fludarabine, mitoxantrone, gilteritinib, glasdegib, and venetoclax.

[0114] In certain embodiments, the methods provided herein include treating an individual who has not been previously treated for AML. In some embodiments, the individual has not undergone an allogeneic bone marrow transplant. In some embodiments, the individual has not undergone a stem cell transplant. In some embodiments, the individual has not received hydroxyurea treatment. In some embodiments, the individual has not undergone systemic glucocorticoid treatment.

[0115] In other embodiments, the methods include treating an individual who has been previously treated or is currently being treated for AML. For example, the individual may have been previously treated for AML or is currently being treated with a standard treatment regimen. The individual may be familiar with any standard AML treatment regimen known to practitioners in the art. In certain embodiments, the individual has previously been treated with at least one induction / re-induction or consolidation AML regimen. In some embodiments, the individual has undergone autologous bone marrow transplantation or stem cell transplantation as part of a consolidation regimen. In some embodiments, the individual has undergone hydroxyurea treatment. In some embodiments, the individual has undergone a previous induction or consolidation therapy using cytarabine (Ara-C). In some embodiments, the individual has undergone treatment using systemic glucocorticoids. In other embodiments, the methods include treating an individual who has been previously treated for AML but has not responded to standard therapy.

[0116] Also included herein are methods for treating individuals with relapsed or refractory AML. In some embodiments, the individual has been diagnosed with a relapsed or refractory AML subtype as defined by the World Health Organization (WHO). Relapsed or refractory disease can be de novo AML or secondary AML, e.g., therapy-related AML (t-AML).

[0117] The method for treating, preventing or managing AML in an individual comprises the step of administering to the individual an amount of an isoindolinone carboxamide compound provided herein, which is effective for treating, preventing or managing AML alone or in combination with a standard of care. In some of these embodiments, the standard of care is treatment with one or more of cytarabine, daunorubicin, idarubicin, midostaurin, cladribine, monoclonal antibody ozogamicin, fludarabine, mitoxantrone, gilteritinib, gelagib and venetoclax.

[0118] Provided herein are methods for reducing CK1α protein concentrations, comprising administering an effective amount of an isoindolinone carboxamide compound to an individual. Also provided herein are methods for reducing CK1α protein concentrations in cells in vivo, in vitro, or in vitro using isoindolinone carboxamide compounds, comprising contacting the cells with an effective amount of an isoindolinone carboxamide compound. In one embodiment, the cell line is in a patient. Provided herein are methods for reducing CK1α protein concentrations in cells in vitro or in vitro using isoindolinone carboxamide compounds, comprising contacting the cells with an effective amount of an isoindolinone carboxamide compound. In one embodiment, the cells are not in a patient. In some embodiments, the CK1α protein concentrations are reduced compared to the CK1α protein concentrations before administration of the isoindolinone carboxamide compound. In some embodiments, the CK1α protein concentration is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the CK1α protein concentration before administration of the isoindolinone carboxamide compound.

[0119] In certain embodiments of the methods provided herein, the individual is an animal, preferably a mammal, more preferably a non-human primate. In a specific embodiment, the individual is a human. The individual can be a male or female individual. Pharmaceutical compositions and routes of administration

[0120] Isoindolinone carboxamide compounds can be administered orally, topically or parenterally to a subject in the conventional form of preparations such as capsules, microcapsules, tablets, granules, powders, tablets, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by commonly used methods using conventional organic or inorganic additives such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or citrate). The composition may be a pharmaceutical composition comprising a preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a suspending agent (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), a dispersant (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water) and a base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the isoindolinone carboxamide compound in the pharmaceutical composition may be at a level that will exert the desired effect; for example, in a unit dose for both oral or parenteral administration, about 0.005 mg / kg of subject body weight to about 10 mg / kg of subject body weight.

[0121] The dosage of the isoindolinone carboxamide compound to be administered to a subject can vary widely and can be at the discretion of a healthcare practitioner. Generally speaking, the isoindolinone carboxamide compound can be administered one to four times a day at a dosage of about 0.001 mg / kg of subject body weight to about 10 mg / kg of subject body weight, but the above dosage can be appropriately varied depending on the age, weight and medical condition of the subject and the type of administration. In one embodiment, the dosage is about 0.001 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.01 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.05 mg / kg of subject body weight to about 1 mg / kg of subject body weight, about 0.1 mg / kg of subject body weight to about 0.75 mg / kg of subject body weight or about 0.25 mg / kg of subject body weight to about 0.5 mg / kg of subject body weight. In one embodiment, the dosage is about 0.001 mg / kg of subject body weight to about 5 mg / kg of subject body weight. In one embodiment, the dosage is from about 0.01 mg / kg of individual body weight to about 5 mg / kg of individual body weight. In one embodiment, the dosage is from about 0.05 mg / kg of individual body weight to about 1 mg / kg of individual body weight. In one embodiment, the dosage is from about 0.1 mg / kg of individual body weight to about 0.75 mg / kg of individual body weight. In one embodiment, the dosage is from about 0.25 mg / kg of individual body weight to about 0.5 mg / kg of individual body weight. In one embodiment, one dose is given per day. In any given case, the amount of the isoindolinone carboxamide compound administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0122] In another embodiment, provided herein are methods for treating or preventing a disease or condition, comprising administering to a subject in need thereof from about 0.01 mg / day to about 750 mg / day, from about 0.1 mg / day to about 375 mg / day, from about 0.1 mg / day to about 150 mg / day, from about 0.1 mg / day to about 75 mg / day, from about 0.1 mg / day to about 50 mg / day, from about 0.1 mg / day to about 25 mg / day, or from about 0.1 mg / day to about 10 mg / day of an isoindolinone carboxamide compound. In one embodiment, the method for treating or preventing a disease or condition comprises administering to a subject in need thereof from about 0.01 mg / day to about 750 mg / day of an isoindolinone carboxamide compound. In one embodiment, the method for treating or preventing a disease or condition comprises administering to a subject in need thereof from about 0.1 mg / day to about 375 mg / day of an isoindolinone carboxamide compound. In one embodiment, the method for treating or preventing a disease or condition comprises administering to an individual in need thereof from about 0.1 mg / day to about 150 mg / day of an isoindolinone carboxamide compound. In one embodiment, the method for treating or preventing a disease or condition comprises administering to an individual in need thereof from about 0.1 mg / day to about 75 mg / day of an isoindolinone carboxamide compound. In one embodiment, the method for treating or preventing a disease or condition comprises administering to an individual in need thereof from about 0.1 mg / day to about 50 mg / day of an isoindolinone carboxamide compound. In one embodiment, the method for treating or preventing a disease or condition comprises administering to an individual in need thereof from about 0.1 mg / day to about 25 mg / day of an isoindolinone carboxamide compound. In one embodiment, the method for treating or preventing a disease or condition comprises administering to an individual in need thereof from about 0.1 mg / day to about 10 mg / day of an isoindolinone carboxamide compound.

[0123] In another embodiment, provided herein are unit dose formulations comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise about 0.1 mg to 500 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise about 1 mg to 250 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise about 1 mg to about 100 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise about 1 mg to about 50 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise about 1 mg to about 25 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain from about 1 mg to about 10 mg of the isoindolinonecarboxamide compound.

[0124] In a specific embodiment, provided herein is a unit dosage formulation comprising about 0.1 mg or 100 mg of an isoindolinonecarboxamide compound.

[0125] In another embodiment, provided herein are unit dose formulations comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise 0.5 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise 1 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise 5 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations comprise 10 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 15 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 20 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 30 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 35 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 50 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 70 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 100 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 125 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 140 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 175 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 200 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 250 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 280 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 350 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 500 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 560 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 700 mg of an isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 750 mg of an isoindolinone carboxamide compound.In one embodiment, the unit dose formulations contain 1000 mg of the isoindolinone carboxamide compound. In one embodiment, the unit dose formulations contain 1400 mg of the isoindolinone carboxamide compound.

[0126] The isoindolinone carboxamide compound can be administered once, twice, three times, four times or more per day. In a specific embodiment, a dose of 100 mg or less is administered as a once-daily dose and a dose greater than 100 mg is administered twice daily in an amount equal to half of the total daily dose.

[0127] For convenience, the isoindolinone carboxamide compound can be administered orally. In one embodiment, when administered orally, the isoindolinone carboxamide compound is administered with a meal and water. In another embodiment, the isoindolinone carboxamide compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a solution or suspension.

[0128] The isoindolinone carboxamide compounds may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the nose, eyes, or skin. The mode of administration is left to the discretion of the health care practitioner and may depend in part on the site of the medical condition.

[0129] In one embodiment, provided herein are capsules containing an isoindolinonecarboxamide compound without additional carriers, excipients, or vehicles.

[0130] In another embodiment, provided herein is a composition comprising an effective amount of an isoindolinone carboxamide compound and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0131] The composition can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions and the like. The composition can be formulated to contain a daily dose or a convenient portion of a daily dose in a dosage unit, which can be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solutions are prepared from water-soluble salts (such as hydrochlorides). In general, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules can be prepared by mixing the isoindolinone carboxamide compound with a suitable carrier or diluent and filling an appropriate amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch, powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), cereal flours and similar edible powders.

[0132] Tablets can be prepared by direct compression, by wet granulation or by dry granulation. Its formulations are usually incorporated with diluents, binders, lubricants and disintegrants and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride and powdered sugar). Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including gum arabic, alginate, methylcellulose, polyvinyl pyrrolidine and the like. Polyethylene glycol, ethyl cellulose and waxes can also serve as binders.

[0133] Lubricants are necessary in tablet formulations to prevent the tablet and punch from adhering to the dye. The lubricant can be selected from smooth solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet to break down the tablet and release the compound. They include starch, clay, cellulose, seaweed and gum. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose and sodium lauryl sulfate can be used. Tablets can be coated with such as flavorings and sealants, or with film-forming protective agents to modify the dissolution properties of the tablet. The composition can also be formulated into a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0134] When it is desired to administer the isoindolinone carboxamide compound as a suppository, a typical base may be used. Cocoa butter is a typical suppository base, which may be modified by the addition of waxes to slightly raise its melting point. Water-miscible suppository bases are widely used and include, among others, polyethylene glycols of various molecular weights.

[0135] The effect of isoindolinone carboxamide compounds can be delayed or prolonged by appropriate formulations. For example, slowly dissolving pellets of isoindolinone carboxamide compounds can be prepared and incorporated into tablets or capsules, or as a sustained-release implantable device. The technology also includes making several pellets with different dissolution rates and filling capsules with a mixture of such pellets. Tablets or capsules can be coated with films that resist dissolution over a predictable time. Even parenteral preparations can be made long-acting by dissolving or suspending the isoindolinone carboxamide compound in an oily or emulsified vehicle that allows it to be slowly dispersed in serum. Example

[0136] The following examples are presented by way of illustration and not limitation. Compounds were named using the automatic name generation tool provided in ChemBiodrawUltra (Cambridgesoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art may modify the procedures described in the illustrative examples to achieve the desired product.

[0137] Abbreviations used in this article: Compound synthesis Example 1: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-1-phenylethyl)isoindoline-5-carboxamide

[0138] A. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-1-phenylethyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (S)-1-phenylethylamine (1.0 equiv), DIPEA (3.0 equiv) and DMF (0.17 M) were stirred for 5 min. HATU (1.1 equiv) was added and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-1-phenylethyl)isoindoline-5-carboxamide (78.0% yield). 1 H NMR (500MHz, DMSO-d6) δ11.01(s,1H),9.00(d,J=7.88Hz,1H),8.10(d,J=0.63Hz,1H),8.02(dd,J=1 .26,7.88Hz,1H),7.83(d,J=7.57Hz,1H),7.40-7.44(m,2H),7.31-7.37(m,2H),7.22-7.26(m,1H), 5.11-5.24(m,2H),4.49-4.56(m,1H),4.37-4.44(m,1H),2.93(ddd,J=5.36,13.64,17.58Hz,1H),2 .58-2.66(m,1H),2.38-2.48(m,1H),2.04(dtd,J=2.05,5.32,12.53Hz,1H),1.51(d,J=7.25Hz,3H). LCMS(ESI)m / z 392.3[M+H] + . Example 2: N-((S)-1-cyclohexylethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.

[0139] N-((S)-1-cyclohexylethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (S)-1-cyclohexylethan-1-amine (1.25 equiv), DIPEA (3.0 equiv), HOBt (1.5 equiv), EDCI (1.5 equiv) and DMF (1.0 M) were combined and the resulting mixture was stirred at ambient temperature for 12 h. The reaction mixture was purified by standard methods to provide N-((S)-1-cyclohexylethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (71.7% yield). 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.32(d,J=8.8Hz,1H),8.04(s,1H),7.96(d,J=7.6Hz,1H),7. 80(d,J=8.0Hz,1H),5.14(dd,J=5.2,13.2Hz,1H),4.52(dd,J=2.8,17.6Hz,1H),4.40(dd,J=2.8,17. 6Hz,1H),4.92-3.82(m,1H),2.96-2.87(m,1H),2.65-2.57(m,1H),2.45-2.36(m,1H),2.07-1.98(m, 1H),1.82-1.67(m,4H),1.65-1.57(m,1H),1.44-1.39(m,1H),1.18-1.11(m,6H),0.97-0.94(m,2H). LCMS(ESI)m / z 398.1[M+H] + . Example 3: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-1-phenylpropyl)isoindoline-5-carboxamide.

[0140] A. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-1-phenylpropyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (S)-1-phenylpropan-1-amine (1.0 equiv), DIPEA (3.0 equiv), HOBt (1.5 equiv), EDCI (1.5 equiv) and DMF (0.27 M) were combined and the resulting mixture was stirred at ambient temperature for 12 h. The reaction mixture was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-1-phenylpropyl)isoindoline-5-carboxamide (59.5% yield). 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.93(d,J=8.4Hz,1H),8.07(s,1H),7.99(d,J=8.0Hz,1H),7.8 1(d,J=7.6Hz,1H),7.40(d,J=7.6Hz,2H),7.32(t,J=7.2Hz,2H),7.22(t,J=7.2Hz,1H),5.13(dd,J=5 .2,8.0Hz,1H),4.95-4.89(m,1H),4.51(d,J=17.6Hz,1H),4.39(d,J=17.2Hz,1H),2.96-2.86(m,1H) ,2.62-2.58(m,1H),2.43-2.39(m,1H),2.03-2.01(m,1H),1.88-1.79(m,2H),0.91(t,J=7.2Hz,3H). LCMS(ESI)m / z 406.2[M+H] + . Example 4: N-((R)-1-cyclohexylethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.

[0141] A.2 N-((R)-1-cyclohexylethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (R)-1-cyclohexylethan-1-amine, DIPEA (3.0 equiv), HOBt (1.2 equiv), EDCI (1.2 equiv) and DMF (0.3 M) were combined and the resulting mixture was stirred at ambient temperature for 12 h. The reaction mixture was purified by standard methods to provide N-((R)-1-cyclohexylethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (50.2% yield). 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.31(d,J=8.8Hz,1H),8.04(s,1H),7.96(d,J=8.0Hz,1H),7. 80(d,J=8.0Hz,1H),5.14(dd,J=6.0,12.8Hz,1H),4.57-4.45(m,1H),4.44-4.32(m,1H),3.92-3.79 (m,1H),2.97-2.87(m,1H),2.61(d,J=17.2Hz,1H),2.47-2.36(m,1H),2.10-1.97(m,1H),1.81-1.6 5(m,4H),1.65-1.54(m,1H),1.48-1.37(m,1H),1.25-1.06(m,6H),1.01-0.91(m,2H). LCMS(ESI)m / z 398.1[M+H] + . Example 5: N-((R)-1-cyclohexyl-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide.

[0142] N-((R)-1-cyclohexyl-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (R)-1-cyclohexyl-2,2,2-trifluoroethan-1-amine hydrochloride (1.0 equiv), DIPEA (4.0 equiv) and DMF (0.17 M) were combined and stirred for 5 min. HATU (1.1 equiv) was added and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide (59.7% yield). 1 H NMR (400MHz, DMSO-d6) δ10.99-11.04(m,1H),8.91-8.98(m,1H),8.09(s,1H),7.97-8.02(m,1H),7.82-7.88(m,1H),5.11-5.18(m,1H),4.57-4. 70(m,1H),4.38-4.57(m,2H),2.87-2.98(m,1H),2.57-2.65(m,1H),2.3 6-2.46(m,1H),1.99-2.08(m,1H),1.59-1.95(m,6H),1.07-1.33(m,5H). LCMS(ESI)m / z 452.2[M+H] + . Example 6: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide.

[0143] A. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (R)-2,2,2-trifluoro-1-phenylethylamine (1.0 equiv), DIPEA (3.0 equiv) and DMF (0.17 M) were combined and stirred for 5 min. HATU (1.1 equiv) was added and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide (60.5% yield). 1HNMR(400MHz,DMSO-d6)δ10.97-11.04(m,1H),9.66-9.77(m,1H),8.10-8 .14(m,1H),7.99-8.05(m,1H),7.82-7.88(m,1H),7.68-7.74(m,2H),7.39 -7.50(m,3H),6.02-6.15(m,1H),5.11-5.19(m,1H),4.36-4.58(m,2H),2. 85-2.98(m,1H),2.57-2.65(m,1H),2.36-2.47(m,1H),1.99-2.08(m,1H). LCMS (ESI) m / z 446.2 [M+H] + . Example 7: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-3,3,3-trifluoro-1-phenylpropyl)isoindoline-5-carboxamide.

[0144] A. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-3,3,3-trifluoro-1-phenylpropyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (S)-3,3,3-trifluoro-1-phenylpropan-1-amine (1.0 equiv), DIPEA (3.0 equiv) and DMF (0.17 M) were combined and stirred for 5 min. HATU (1.1 equiv) was added and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((S)-3,3,3-trifluoro-1-phenylpropyl)isoindoline-5-carboxamide (44.7% yield). 1 HNMR (400 MHz, DMSO-d6) δ 10.98-11.04 (m, 1H), 9.20 to 9.27 (m, 1H), 8.03-8.07 (m, 1H), 7.95-8.00 (m, 1H), 7.82-7.88 (m, 1H), 7.45-7.51 (m, 2H), 7.34-7.41 (m, 2H), 7.26 -7.32 (m, 1H), 5.43-5.51 (m, 1H), 5.10 to 5.18 (m, 1H), 4.50 to 4.57 (m, 1H), 4.37-4.44 (m, 1H), 2.79-3.08 (m, 3H), 2.57-2.65 (m, 1H), 2.35-2.47 (m, 1H), 1.98-2.07 (m, 1H). LCMS (ESI) m / z 452.2 [M+H]+ . Example 8: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide.

[0145] A. (S,E)-N-(4-fluorobenzylidene)-2-methylpropane-2-sulfenamide. A mixture of 4-fluorobenzaldehyde (1.0 equiv.) and 2-methylpropane-2-sulfenamide (1.0 equiv.) in titanium tetraglycolate (2.0 equiv.) was stirred at 60 °C for 12 h. The mixture was diluted with EtOAc and saturated aqueous sodium chloride solution was added. The mixture was filtered through celite and washed with EtOAc. The combined filtrates were concentrated under reduced pressure to provide (S,E)-N-(4-fluorobenzylidene)-2-methylpropane-2-sulfenamide (quantitative yield). LCMS (ESI) m / z: 228.1 [M+H] + .

[0146] B. (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)propane-2-sulfinamide. To a solution of (S,E)-N-(4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (1.0 equiv) in THF (0.3 M) was added tetrabutylammonium difluorotriphenylsilicate (0.2 equiv) at -60 °C. The mixture was then stirred for 0.5 h and (trifluoromethyl)trimethylsilane (2.0 equiv) was added dropwise to the solution. The mixture was stirred at -60 °C for 2.5 h and then at -20 °C for 12 h. The reaction was quenched with aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to 10:1 petroleum ether:EtOAc) to provide (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)propane-2-sulfenamide as a white solid (79.8% yield). 1 H NMR (400MHz, CDCl3) δ7.45-7.41 (m, 2H), 7.13-7.08 (m, 2H), 4.87-4.80 (m, 1H), 3.61 (d, J = 6.0Hz, 1H), 1.26 (s, 9H). LCMS(ESI)m / z:298.1[M+H] + .

[0147] C. (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride. To a solution of (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)propane-2-sulfenamide (1.0 equiv) in DCM (0.24 M) was added a 4 M solution of hydrochloric acid in EtOAc (19.5 equiv) at 0°C. The solution was stirred at 25°C for 48 h. The solution was concentrated to provide (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride (97.9% yield). LCMS (ESI) m / z: 194.0 [M+H] + .

[0148] D. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide. To a solution of 2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-carboxylic acid (1.0 equiv) in DMF (0.73 M) was added HATU (1.2 equiv), DIPEA (3.0 equiv) and (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride (1.0 equiv). The solution was stirred at 25 °C for 12 h. The reaction mixture was purified by standard methods to provide 2-(2,6-dioxo-3-piperidinyl)-1-oxo-N-[(R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]isoindoline-5-carboxamide (59.1% yield). 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),9.72(d,J=9.2Hz,1H),8.11(s,1H),8.05-8.01(m,1H),7.87-7.85(m,1H),7.81-7.77(m,2H),7.32-7.28 (m,2H),6.19-6.12(m,1H),5.18-5.13(m,1H),4.57-4.40(m,2H),2.97 -2.92(m,1H),2.64-2.55(m,1H),2.44-2.41(m,1H),2.05-2.03(m,1H). LCMS(ESI)m / z:464.2[M+H] + . Example 9: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)isoindoline-5-carboxamide.

[0149] A. (S,E)-2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfenamide. To a solution of pyridinecarboxaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfenamide (1.0 eq.) in DCM (0.6 M) was added CsCO (2.0 eq.). The mixture was stirred at ambient temperature for 12 h. The mixture was filtered and concentrated under reduced pressure to provide (S,E)-2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfenamide (quantitative yield). 1 H NMR (400MHz, CDCl3) δ (d, J = 4.4Hz, 1H), 8.69 (s, 1H), 8.01 (d, J = 8.0Hz, 1H), 7.81 (t, J = 7.6Hz, 1H), 7.42-7.35 (m, 1H), 1.27 (s, 9H). LCMS(ESI)m / z 211.0[M+H]+.

[0150] B. (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)propane-2-sulfinamide. To a solution of (S,E)-2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfinamide (1.0 eq.) in THF (0.19 M) was added tetrabutylammonium difluorotriphenylsilicate (0.20 eq.) at -60 °C and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (2.0 eq.) was added dropwise and the mixture was stirred at -60 °C for 5 h. The mixture was then warmed to -10 °C and stirred for 12 h. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc in petroleum ether) to provide the crude product and then further purified by preparative HPLC (28 to 58% acetonitrile in water + 0.05% ammonium hydroxide over 10 min). The fractions containing the product were extracted with EtOAc. The organic layer was concentrated in vacuo to provide (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)propane-2-sulfenamide (49.5% yield). 1 H NMR(400MHz, DMSO-d6)δ8.64(d,J=4.8Hz,1H),7.96-7.89(m,1H),7.68(d,J=7.6H z,1H),7.51-7.44(m,1H),6.05(d,J=7.6Hz,1H),5.53-5.43(m,1H),1.18(s,9H). LCMS(ESI)m / z:281.1[M+H] + .

[0151] C. (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethan-1-amine hydrochloride. To a solution of (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)propane-2-sulfinamide (1.0 equiv) in DCM (0.33 M) was added a 4 M solution of hydrochloric acid in EtOAc (8.4 equiv) at 0°C. The mixture was stirred at 15°C for 1 h. The mixture was concentrated under reduced pressure to provide (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethan-1-amine hydrochloride (98.8% yield). LCMS (ESI) m / z: 176.0 [M+H] + .

[0152] D. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)isoindoline-5-carboxamide. To a solution of (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethan-1-amine hydrochloride (1.2 eq) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 eq) in DMF (0.33 M) was added DIPEA (3.0 eq) and HATU (1.2 eq). The mixture was stirred at 20° C. for 12 h. The reaction mixture was purified by standard methods to afford 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)isoindoline-5-carboxamide (43.4% yield). 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.65(d,J=9.2Hz,1H),8.65(d,J=4.4Hz,1H),8 .15(s,1H),8.04(d,J=7.6Hz,1H),7.97-7.91(m,1H),7.88-7.79(m,2H),7.52-7.45( m,1H),6.24-6.12(m,1H),5.15(dd,J=5.2,13.2Hz,1H),4.58-4.49(m,1H),4.46-4.3 7(m,1H),2.98-2.86(m,1H),2.65-2.58(m,1H),2.46-2.35(m,1H),2.07-1.99(m,1H). LCMS(ESI)m / z:447.0[M+H]+. Example 10: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)isoindoline-5-carboxamide

[0153] A. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (R)-2,2,2-trifluoro-1-(pyridin-3-yl)ethan-1-amine hydrochloride (1.2 equiv), DIPEA (5.0 equiv) and DMF (0.19 M) were combined and stirred for 5 min. HATU (1.2 equiv) was added and the resulting mixture was stirred at ambient temperature for 12 h. The reaction mixture was purified by standard methods to afford 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)isoindoline-5-carboxamide (29.0% yield). 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.85(dd,J=2.0Hz,9.6Hz,1H),9.07(d,J=2.0Hz,1H),8.79(dd,J= 1.2Hz,4.8Hz,1H),8.47(d,J=8.0Hz,1H),8.13(s,1H),8.04(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),7.77 (dd,J=5.2Hz,8.0Hz,1H),6.43-6.34(m,1H),5.15(dd,J=4.8Hz,13.2Hz,1H),4.54(dd,J=4.0Hz,17.6Hz, 1H), 4.42 (d, J = 17.2Hz, 1H), 2.97-2.88 (m, 1H), 2.64-2.59 (m, 1H), 2.45-2.37 (m, 1H), 2.06-2.01 (m, 1H). LCMS(ESI)m / z 447.1[M+H] + . Examples 11 and 12: 2-((R)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide and 2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide

[0154] A. 2-((R)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide and 2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide (preparation described herein) was separated by preparative chiral SFC chromatography to provide individual diastereomers, whose absolute stereochemistry was confirmed using vibrational circular dichroism.

[0155] 2-((R)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide was obtained in 42.0% yield after isolation. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.73(d,J=9.2Hz,1H),8.12(s,1H),8.03(d,J=7.6Hz,1H),7.86(d,J=8.0Hz,1H),7.72-7.71(m,2H),7.46-7 .43(m,3H),6.11-6.07(m,1H),5.18-5.13(m,1H),4.57-4.40(m,2H),2.9 6-2.90(m,1H),2.64-2.59(m,1H),2.49-2.42(m,1H),2.05-2.03(m,1H). LCMS(ESI)m / z446.3[M+H] + .

[0156] 2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide was obtained in 29.0% yield after isolation. 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.73(d,J=9.2Hz,1H),8.12(s,1H),8.03(d,J=8.0Hz,1H),7.86(d,J=8.0Hz,1H),7.73-7.71(m,2H),7.47-7 .43(m,3H),6.11-6.07(m,1H),5.18-5.14(m,1H),4.56-4.40(m,2H),2.9 7-2.93(m,1H),2.64-2.51(m,1H),2.45-2.41(m,1H),2.08-2.04(m,1H). LCMS(ESI)m / z446.1[M+H] + . Example 13: 2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide.

[0157] A. 3-(5-bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione. To a solution of methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (1.0 equiv) in acetonitrile (0.13 M) was added 3-aminopiperidine-2,6-dione hydrochloride (1.0 equiv) and DIPEA (2.5 equiv). The solution was stirred at 80 °C for 12 h. The solution was concentrated, triturated with EtOAc, filtered and washed with EtOAc to provide 3-(5-bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (quantitative yield). 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.70-8.68 (m, 1H), 7.81 (dd, J = 0.8, 8.0Hz, 1H), 7.36 (dd, J = 4.4, 8.4Hz, 1H), 1.30 (s, 9H). LCMS(ESI)m / z 340.9[M+H]+.

[0158] B. 2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-carboxylic acid. To a solution of 3-(5-bromo-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione (1.0 eq) in DMF (0.15 M) was added palladium acetate (0.5 eq), 1,3-bis(diphenylphosphino)propane (0.5 eq), DIPEA (1.0 eq) and water (10.0 eq). The mixture was stirred at 80 °C under a carbon monoxide atmosphere (50 psi) for 48 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-carboxylic acid (6.3% yield). 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.09(d,J=6.0Hz,1H),7.62(d,J=9.2Hz,1H),5.16-5.11(m,1 H),4.52-4.36(m,1H),2.95-2.85(m,1H),2.68-2.55(m,1H),2.45-2.30(m,1H),2.10-1.98(m,1H). LCMS(ESI)m / z:307.1[M+H] + .

[0159] C. 2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (R)-2,2,2-trifluoro-1-phenylethylamine (1.0 equiv), DIPEA (3.0 equiv) and DMF (0.16 M) were combined and stirred for 5 min. HATU (1.1 equiv) was added and the resulting mixture was stirred at ambient temperature for 3 h. The reaction mixture was purified by standard methods to afford 2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide (61.8% yield). 1H NMR (400MHz, DMSO-d6) δ10.93-11.07(m,1H),9.83-9.93(m,1H),7.74-7.81(m,1H),7.59-7.71(m,3H),7.35-7.52(m,3H),5.97-6.10(m,1 H),5.09-5.20(m,1H),4.44-4.52(m,1H),4.31-4.40(m,1H),2.86-2.98(m,1H),2.56-2.65(m,1H),2.34-2.46(m,1H),1.98-2.08(m,1H). LCMS(ESI)m / z 464.0[M+H] + . Example 14: 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide

[0160] A. 3-((3,6-dibromo-2-fluorobenzyl)amino)piperidine-2,6-dione. To a solution of 3,6-dibromo-2-fluorobenzaldehyde (1.0 eq.) in acetonitrile (0.21 M) was added 3-aminopiperidine-2,6-dione hydrochloride (1.5 eq.) and sodium acetate (1.5 eq.). 2-Methylpyridine borane complex (2.0 eq.) was added and the solution was stirred at ambient temperature for 12 h. The solution was concentrated, dissolved in EtOAc, washed with water and the organic layer was concentrated. The residue was purified by standard methods to provide 3-((3,6-dibromo-2-fluorobenzyl)amino)piperidine-2,6-dione (71.5% yield). 1 H NMR(400MHz, CDCl3)δ8.03-7.89(m,1H),7.42-7.38(m,1H),7.32-7.30(m,1H),4.17-4.10(m,2H) ,3.36-3.32(m,1H),2.98-2.83(m,1H),2.63-2.59(m,1H),2.41-2.40(m,1H),2.07-1.96(m,1H). LCMS(ESI)m / z 394.8[M+H]+.

[0161] B. 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-carboxylic acid. To a solution of 3-((3,6-dibromo-2-fluorobenzyl)amino)piperidine-2,6-dione (1.0 eq.) in DMF (0.19 M) was added 1,3-bis(diphenylphosphino)propane (0.1 eq.), palladium acetate (0.1 eq.), DIPEA (5.0 eq.) and water (3.0 eq.). The solution was stirred at 80° C. under a carbon monoxide atmosphere (50 psi) for 12 h. The solution was filtered, washed with DMF and concentrated under reduced pressure to provide a residue. The residue was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-carboxylic acid (60.8% yield). 1 HNMR(400MHz,DMSO-d6)δ11.04(s,1H),8.04-8.00(m,1H),7.68-7.66(m,1H),5.17-5.13(m,1H) ,4.65-4.44(m,1H),2.95-2.92(m,1H),2.63-2.53(m,1H),2.48-2.44(m,1H),2.05-2.03(m,1H). LCMS(ESI)m / z:329.1[M+H] + .

[0162] C. 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (R)-2,2,2-trifluoro-1-phenylethylamine (1.0 equiv), DIPEA (3.0 equiv) and DMF (0.16 M) were combined and stirred for 5 min. HATU (1.1 equiv) was added and the resulting mixture was stirred at ambient temperature for 3 h. The reaction mixture was purified by standard methods to afford 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)isoindoline-5-carboxamide (49.8% yield). 1H NMR(400MHz,DMSO-d6)δppm 10.99-11.06(m,1H),9.83-9.92(m,1H),7.61-7.72(m,4H),7.40-7.50(m,3H),5.97-6.09(m,1H),5.10-5.20(m,1H) ,4.58-4.65(m,1H),4.41-4.49(m,1H),2.87-2.98(m,1H),2.57-2.65(m,1H),2.39-2.48(m,1H),1.99-2.09(m,1H). LCMS(ESI)m / z 464.2[M+H] + . Examples 15 and 16: 2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide and 2-((R)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide

[0163] A. 2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide and 2-((R)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide (preparation described herein) was separated by chiral preparative SFC chromatography to provide individual diastereomers, whose absolute stereochemistry was confirmed using vibrational circular dichroism.

[0164] 2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide was obtained in 44.0% yield after isolation. 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.70(d,J=9.6Hz,1H),8.10(s,1H),8.02(d,J=8.0Hz,1H),7.87-7.77(m,3H),7.32-7.28(m,2H),6.16 -6.11(m,1H),5.15(dd,J=5.2,13.2Hz,1H),4.55-4.39(m,2H),2.97-2.87(m,1H),2.64-2.58(m,1H),2.45-2.41(m,1H),2.07-2.02(m,1H). LCMS(ESI)m / z 464.3[M+H] + .

[0165] 2-((R)-2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide was obtained in 43.0% yield after isolation. 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.70(d,J=9.6Hz,1H),8.11(s,1H),8.01(d,J=8.0Hz,1H),7.87-7.77(m,3H),7.32-7.28(m,2H),6.16 -6.11(m,1H),5.15(dd,J=5.2,13.2Hz,1H),4.56-4.39(m,2H),2.96-2.88(m,1H),2.63-2.59(m,1H),2.45-2.41(m,1H),2.07-2.03(m,1H). LCMS(ESI)m / z 464.4[M+H] + . Example 17: N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0166] AN-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. To a solution of (R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (preparation described herein, 1.1 eq) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 eq) in DMF (0.28 M) was added DIPEA (3.0 eq) and HATU (1.2 eq). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to afford N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (52.2% yield). 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.68(d,J=8.8Hz,1H),8.67(dd,J=0.8,4.8Hz,1 H),8.14(s,1H),8.10(dd,J=1.6,8.4Hz,1H),8.04-8.00(m,1H),7.81(d,J=8.0Hz,1H), 7.57(dd,J=4.4,8.0Hz,1H),6.57-6.53(m,1H),5.14(dd,J=4.8,13.2Hz,1H),4.54-4. 37(m,2H),2.93-2.87(m,1H),2.63-2.58(m,1H),2.44-2.37(m,1H),2.07-1.96(m,1H). LCMS(ESI)m / z:481.0[M+H] + . Example 18: N-((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0167] A. (S,E)-N-((5-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 5-chloropicolinaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (1.0 eq.) in DCM (0.35 M) was added CsCO (2.0 eq.). The mixture was stirred at 40 °C for 12 h. The mixture was filtered and concentrated under reduced pressure to provide (S,E)-N-((5-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (quantitative yield). LCMS (ESI) m / z 245.0 [M+H]+.

[0168] B. (S)-N-((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-((5-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 eq.) in THF (0.33 M) was added tetrabutylammonium difluorotriphenylsilicate (0.20 eq.) at -60 °C and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (2.0 eq.) was added dropwise and the mixture was stirred at -60 °C for 2.5 h. The mixture was then warmed to -20 °C and stirred for 2.5 h. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (40 to 58% acetonitrile + 0.2% formic acid in water over 25 min) and the fractions containing the product were concentrated under reduced pressure to afford (S)-N-((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (58.3% yield). 1 H NMR (400MHz, CDCl3) δ8.59 (d, J = 2.4 Hz, 1H), 7.76-7.73 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 5.61 (d, J = 6.4 Hz, 1H), 4.96-4.89 (m, 1H), 1.33 (s, 9H). LCMS(ESI)m / z:315.1[M+H] + .

[0169] C. (R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (1.0 equiv) in DCM (0.18 M) was added a 4 M solution of hydrochloric acid in EtOAc (19.5 equiv) at 0°C. The mixture was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure and the residue was triturated with petroleum ether (60 mL), filtered and dried under reduced pressure to provide (R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (quantitative yield). LCMS (ESI) m / z: 211.0 [M+H] + .

[0170] D-N-((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. To a solution of (R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (1.1 eq) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 eq) in DMF (0.30 M) was added DIPEA (3.0 eq) and HATU (1.2 eq). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to afford N-((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (33.5% yield). 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),9.72(d,J=9.2Hz,1H),8.72(d,J=2.4Hz,1H),8.14-8.11(m,2H),8.10-8.05(m,1H),7.87-7.84(m,2 H),6.25-6.20(m,1H),5.17-5.13(m,1H),4.56-4.39(m,2H),2.93-2.92(m,1H),2.63-2.52(m,1H),2.45-2.42(m,1H),2.07-2.04(m,1H). LCMS(ESI)m / z:481.2[M+H] + . Example 19: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethyl)isoindoline-5-carboxamide

[0171] A. (S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 3-fluoropicolinaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (1.2 eq.) in DCM (0.53 M) was added CuSO4 (2.0 eq.). The mixture was stirred at ambient temperature for 3 h. The mixture was filtered and concentrated under reduced pressure to provide (S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (quantitative yield). 1H NMR (400MHz, DMSO-d6) δ8.63 (d, J = 4.4Hz, 1H), 8.59 (s, 1H), 7.96-7.91 (m, 1H), 7.73-7.69 (m, 1H), 1.19 (s, 9H). LCMS(ESI)m / z 229.0[M+H]+.

[0172] B. (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethyl)propane-2-sulfinamide. To a solution of (S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 eq.) in THF (0.22 M) was added tetrabutylammonium difluorotriphenylsilicate (0.20 eq.) at -60 °C and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (2.0 eq.) was added dropwise and the mixture was stirred at -60 °C for 2.5 h. The mixture was then warmed to -20 °C and stirred for 11.5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (38 to 68% acetonitrile + 0.05% ammonium hydroxide in water over 10 min) and the fractions containing the product were concentrated under reduced pressure to afford (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethyl)propane-2-sulfenamide (18.4% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.57-8.55 (m, 1H), 7.94-7.89 (m, 1H), 7.66-7.61 (m, 1H), 6.07 (d, J = 8.4Hz, 1H), 5.59 (t, J = 7.6Hz, 1H), 1.16 (s, 9H). LCMS(ESI)m / z:299.1[M+H] + .

[0173] C. (R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-amine hydrochloride. To a solution of (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethyl)propane-2-sulfinamide (1.0 equiv) in DCM (0.13 M) was added a 4 M solution of hydrochloric acid in EtOAc (30.0 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to provide (R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-amine hydrochloride (97.0% yield). LCMS (ESI) m / z: 195.0 [M+H] + .

[0174] D. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethyl)isoindoline-5-carboxamide. To a solution of (R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-amine hydrochloride (1.0 eq) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.2 eq) in DMF (0.13 M) was added DIPEA (3.0 eq) and HATU (1.2 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was purified by standard methods to afford 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethyl)isoindoline-5-carboxamide (31.4% yield). 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.76(d,J=8.8Hz,1H),8.56(d,J=4.4Hz,1H) ,8.15(s,1H),8.05(dd,J=4.0,7.6Hz,1H),7.92-7.87(m,1H),7.83(d,J=8.0Hz,1H ),7.64-7.61(m,1H),6.45-6.37(m,1H),5.16(dd,J=5.2,13.2Hz,1H),4.54-4.37( m,2H),2.96-2.86(m,1H),2.62-2.58(m,1H),2.44-2.38(m,1H),2.04-2.00(m,1H). LCMS(ESI)m / z:465.2[M+H] + . Example 20: N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0175] A. (S,E)-N-((5-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 5-chloro-3-fluoropicolinaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (1.2 eq.) in DCM (0.5 M) was added CuSO4 (1.5 eq.). The mixture was stirred at ambient temperature for 3 h. The mixture was filtered and concentrated under reduced pressure to provide (S,E)-N-((5-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (98.7% yield). LCMS (ESI) m / z 262.0 [M+H]+.

[0176] B. (S)-N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-((5-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 eq.) in THF (0.38 M) was added tetrabutylammonium difluorotriphenylsilicate (0.20 eq.) at -78°C and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (3.0 eq.) was added dropwise and the mixture was stirred at -10°C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (48 to 78% acetonitrile + 0.05% ammonium hydroxide in water over 10 min) and the fractions containing the product were concentrated under reduced pressure to afford (S)—N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (22.1% yield). 1 H NMR (400MHz, DMSO-d6) δ8.66 (d, J = 2.0 Hz, 1H), 8.30 (dd, J = 2.0, 9.6 Hz, 1H), 6.14 (d, J = 8.8 Hz, 1H), 5.61-5.58 (m, 1H), 1.13 (s, 9H). LCMS(ESI)m / z:333.1[M+H] + .

[0177] C. (R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (1.0 equiv) in DCM (0.28 M) was added a 4 M solution of hydrochloric acid in EtOAc (14.3 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to provide (R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (98.6% yield). LCMS (ESI) m / z: 229.0 [M+H] + .

[0178] D-N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. To a solution of (R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (1.0 eq.) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.2 eq.) in DMF (0.11 M) was added DIPEA (3.0 eq.) and HATU (1.2 eq.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to afford N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (63.1% yield). 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.82(d,J=8.8Hz,1H),8.67(s,1H),8.29(d d,J=2.0,9.6Hz,1H),8.14(s,1H),8.04-8.01(m,1H),7.83(d,J=8.0Hz,1H),6.41 (t,J=8.0Hz,1H),5.15(dd,J=5.2,13.2Hz,1H),4.55-4.50(m,1H),4.42-4.38(m, 1H),2.95-2.92(m,1H),2.63-2.59(m,1H),2.45-2.41(m,1H),2.06-2.01(m,1H). LCMS (ESI) m / z: 499.0 [M+H] + . Example 21: N-((R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0179] A. (S,E)-N-((3,5-difluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 3,5-difluoropicolinaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (1.2 eq.) in DCM (0.63 M) was added CuSO4 (1.5 eq.). The mixture was stirred at ambient temperature for 23 h. The mixture was filtered and concentrated under reduced pressure to provide (S,E)-N-((3,5-difluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (quantitative yield). 1H NMR (400MHz, CDCl3) δ8.85(s,1H),8.53(s,1H),7.37-7.27(m,1H),1.31(s,9H). LCMS(ESI)m / z247.0[M+H]+.

[0180] B. (S)-N-((R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-((3,5-difluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 eq.) in THF (0.29 M) at -70 °C was added tetrabutylammonium difluorotriphenylsilicate (0.20 eq.) and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (3.0 eq.) was added dropwise and the mixture was stirred at -70 °C for 4 h. The mixture was warmed to -10 °C and stirred for 12 h, then quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography on silica gel (9% to 33% EtOAc in petroleum ether). The residue was purified by preparative HPLC (38 to 68% acetonitrile + 0.225% formic acid in water over 10 min) and the fractions containing the product were concentrated under reduced pressure to provide (S)-N-((R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (6.8% yield). 1 HNMR (400MHz, CDCl3) δ8.39 (d, J = 2.0Hz, 1H), 7.33-7.29 (m, 1H), 5.34-5.31 (m, 1H), 5.23 (t, J = 6.4Hz, 1H), 1.32 (s, 9H). LCMS(ESI)m / z:316.9[M+H] + .

[0181] C. (R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (1.0 equiv) in DCM (0.14 M) was added a 4 M solution of hydrochloric acid in EtOAc (30.0 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to provide (R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (quantitative yield). LCMS (ESI) m / z: 212.9 [M+H] + .

[0182] D-N-((R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. To a solution of (R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (1.0 eq) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 eq) in DMF (0.35 M) was added DIPEA (3.0 eq) and HATU (1.5 eq). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to afford N-((R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (64.9% yield). 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.79(d,J=8.8Hz,1H),8.66(d,J=2.0Hz,1H),8.16-8.11(m,2H),8.05-8.01(m,1H),7.82(d,J=8.0Hz,1H),6 .40(t,J=8.4Hz,1H),5.14(dd,J=5.2,13.6Hz,1H),4.55-4.38(m,2H),2. 92-2.89(m,1H),2.63-2.59(m,1H),2.45-2.37(m,1H),2.06-1.97(m,1H). LCMS(ESI)m / z:483.2[M+H] + . Example 22: 4-Chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide

[0183] A. 3-((3,6-dibromo-2-chlorobenzyl)amino)piperidine-2,6-dione. To a solution of 1,4-dibromo-2-(bromomethyl)-3-chlorobenzene (1.0 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (3.0 equiv) in acetonitrile (0.28 M) was added DIPEA (5.0 equiv). The mixture was stirred at 60 °C for 12 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (9% to 33% EtOAc in petroleum ether) to provide 3-((3,6-dibromo-2-chlorobenzyl)amino)piperidine-2,6-dione (69.5% yield). 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.65-7.55(m,2H),4.20-4.07(m,2H),3.38 (dd,J=3.6,11.2Hz,1H),2.58-2.50(m,2H),2.23-2.19(m,1H),1.82-1.72(m,1H). LCMS(ESI)m / z 410.7[M+H]+.

[0184] B. 4-Chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid. To a solution of 3-((3,6-dibromo-2-chlorobenzyl)amino)piperidine-2,6-dione (1.0 eq) in DMF (0.22 M) was added palladium acetate (0.1 eq), 1,3-bis(diphenylphosphino)propane (0.1 eq), DIPEA (5.0 eq) and water (3.0 eq). The mixture was stirred at 80 °C under a carbon monoxide atmosphere (50 psi) for 60 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (1 to 30% acetonitrile + 0.2% formic acid in water over 30 min) to provide 4-chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (35.7% yield). 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),7.94(d,J=8.0Hz,1H),7.79-7.77(m,1H),5.15(dd,J=4.8,13.2Hz, 1H), 4.56-4.35 (m, 2H), 2.96-2.87 (m, 1H), 2.61 (d, J = 17.2Hz, 1H), 2.46-2.45 (m, 1H), 2.07-2.02 (m, 1H). LCMS(ESI)m / z:322.8[M+H] + .

[0185] C. 4-Chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide. 4-Chloro-2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindoline-5-carboxylic acid (1.0 equiv), (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethylamine hydrochloride (1.0 equiv) and DIPEA (4.0 equiv) were combined in DMF (0.16 M). To this solution was added HATU (1.1 equiv) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was purified by standard methods to afford 4-chloro-2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isoindoline-5-carboxamide (53.6% yield). 1 H NMR(400MHz,DMSO-d6)δ10.98-11.06(m,1H),9.88-9.97(m,1H),7.77-7. 84(m,1H),7.66-7.76(m,2H),7.55-7.62(m,1H),7.25-7.37(m,2H),6.03- 6.16(m,1H),5.12-5.22(m,1H),4.50 to 4.59(m,1H),4.32-4.43(m,1H),2. 86-2.98(m,1H),2.55-2.65(m,1H),2.39-2.48(m,1H),1.99-2.10(m,1H). LCMS (ESI) m / z: 498.0 [M+H] + . Example 23: 2-(2,6-dioxopiperidin-3-yl)-N-((S)-2-methyl-1-phenylpropyl)-1-oxoisoindoline-5-carboxamide

[0186] A. 2-(2,6-dioxopiperidin-3-yl)-N-((S)-2-methyl-1-phenylpropyl)-1-oxoisoindoline-5-carboxamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv), (S)-2-methyl-1-phenyl-propan-1-amine hydrochloride (1.0 equiv), and DIPEA (4.0 equiv) were combined in DMF (0.17 M). To this solution was added HATU (1.1 equiv) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was purified by standard methods to provide 2-(2,6-dioxopiperidin-3-yl)-N-((S)-2-methyl-1-phenylpropyl)-1-oxoisoindoline-5-carboxamide (52.8% yield).1 H NMR (400MHz, DMSO-d6) δ10.98-11.03(m,1H),8.88-8.95(m,1H),8.02-8.06(m,1H),7.94-7.99( m,1H),7.79-7.84(m,1H),7.38-7.47(m,2H),7.32(s,2H),7.18-7.26(m,1H),5.09-5.17(m,1H) ,4.65-4.72(m,1H),4.48-4.55(m,1H),4.35-4.43(m,1H),2.86-2.98(m,1H),2.57-2.65(m,1H) ,2.35-2.45(m,1H),2.09-2.20(m,1H),1.97-2.06(m,1H),0.99-1.05(m,3H),0.69-0.76(m,3H). LCMS(ESI)m / z:420.2[M+H] + . Example 24: N-((R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0187] A. 2-Cyclopropyloxybenzaldehyde. To a solution of 2-hydroxybenzaldehyde (1.0 eq.) and bromocyclopropane (10.0 eq.) in DMA (0.82 M) was added CsCO (2.0 eq.) and potassium iodide (0.3 eq.). The mixture was stirred at 150 °C for 12 h. The reaction mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by standard methods to provide 2-cyclopropyloxybenzaldehyde (25.1% yield). 1 H NMR (400MHz, CDCl3) δ10.41(s,1H),7.83-7.81(m,1H),7.58-7.56(m,1H),7. 37(d,J=8.0Hz,1H),7.05-7.03(m,1H),3.88-3.83(m,1H),0.88-0.86(m,4H).

[0188] B. (S,E)-N-(2-cyclopropyloxybenzylidene)-2-methylpropane-2-sulfenamide. To a solution of 2-cyclopropyloxybenzaldehyde (1.0 equiv), (S)-2-methylpropane-2-sulfenamide (1.0 equiv) in THF (0.28 M) was added tetraethoxytitanium (2.0 equiv), and the mixture was stirred at 20° C. for 0.5 h. The mixture was then stirred at 60° C. for 11.5 h. Water was added to the mixture, the mixture was filtered and the filter cake was washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by standard methods to provide (S,E)-N-(2-cyclopropyloxybenzylidene)-2-methylpropane-2-sulfenamide (81.5% yield). 1 HNMR(400MHz, CDCl3)δ8.98(s,1H),7.99-7.97(m,1H),7.50-7.46(m,1H),7.36-7 .33(m,1H),7.05-7.01(m,1H),3.82-3.77(m,1H),1.26(s,9H),0.87-0.82(m,4H). LCMS(ESI)m / z:266.1[M+H] + .

[0189] C. (S)-N-((R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-(2-cyclopropyloxybenzylidene)-2-methylpropane-2-sulfinamide (1.0 equiv.) in THF (50 mL) was added tetrabutylammonium difluorotriphenylsilicate (0.5 equiv.) at -60 °C. The mixture was stirred at -60 °C for 30 min and (trifluoromethyl)trimethylsilane (3.0 equiv.) was added. The mixture was stirred at -60 °C for 11.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by standard methods to provide (S)-N-((R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (47.47% yield). LCMS (ESI) m / z: 336.0 [M+H] + .

[0190] D. (R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (1.0 equiv) in DCM (0.3 M) was added a 4 M solution of hydrochloric acid in EtOAc (13.4 equiv). The solution was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added water and then the mixture was concentrated under reduced pressure to provide (R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethanamine hydrochloride (62.65% yield). 1 H NMR(400MHz,DMSO-d6)δ9.23(s,3H),7.60(m,1H),7.58-7.51(m,1H),7.46-7.43(m ,1H),7.15-7.10(m,1H),5.45-5.28(m,1H),4.01-3.97(m,1H),0.84-0.69(m,4H). LCMS(ESI)m / z:232.0[M+H] + .

[0191] EN-((R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. To a solution of (R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethylamine hydrochloride (1.0 eq.) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.2 eq.) in DMF (0.11 M) was added DIPEA (3.0 eq.) and HATU (1.2 eq.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to provide N-((R)-1-(2-cyclopropyloxyphenyl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (63.1% yield). 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.53(d,J=9.2Hz,1H),8.08(s,1H),7.99(d,J=7.6Hz,1H), 7.84(d,J=8.0Hz,1H),7.78(d,J=7.6Hz,1H),7.43-7.37(m,2H),7.07(t,J=7.2Hz,1H),6.43-6.36 (m,1H),5.16-5.12(m,1H),4.55-4.51(m,1H),4.43-4.39(m,1H),4.00(d,J=2.0Hz,1H),2.95-2. 88(m,1H),2.63(s,1H),2.42-2.41(m,1H),2.05-2.02(m,1H),0.82(d,J=3.1Hz,2H),0.66(s,2H). LCMS(ESI)m / z:502.2[M+H] + . Examples 25 and 26: N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide and N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((R)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0192] N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide and N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((R)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (preparation described herein) was separated by chiral preparative SFC chromatography to provide individual diastereomers, whose absolute stereochemistry was confirmed using vibrational circular dichroism.

[0193] N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide was obtained in 19.2% yield after isolation. 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.68(d,J=8.8Hz,1H),8.67(dd,J=1.2,4.4Hz,1H ),8.14(s,1H),8.10(dd,J=1.2,8.4Hz,1H),8.04-8.02(m,1H),7.81(d,J=8.0Hz,1H),7 .57(dd,J=4.4,8.0Hz,1H),6.55(t,J=8.4Hz,1H),5.14(dd,J=5.2,13.2Hz,1H),4.54-4 .37(m,2H),2.96-2.87(m,1H),2.63-2.58(m,1H),2.44-2.40(m,1H),2.07-2.00(m,1H). LCMS(ESI)m / z 481.1[M+H] + .

[0194] N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((R)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide was obtained in 14.9% yield after isolation. 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.67(d,J=8.8Hz,1H),8.67(dd,J=1.2,4.4Hz,1H),8. 14(s,1H),8.10(dd,J=1.2,8.0Hz,1H),8.02(d,J=7.6Hz,1H),7.81(d,J=7.6Hz,1H),7.57(d d,J=4.4,8.0Hz,1H),6.59-6.51(m,1H),5.14(dd,J=5.2,13.2Hz,1H),4.54-4.50(m,1H),4. 42-4.37(m,1H),2.96-2.87(m,1H),2.63-2.59(m,1H),2.38-2.37(m,1H),2.07-2.00(m,1H). LCMS(ESI)m / z 481.1[M+H] + . Example 27: Alternative Synthesis of N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0195] A. (S,E)-N-((3-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 3-chloropicolinaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (1.0 eq.) in DCM (0.6 M) was added CsCO (1.2 eq.). The mixture was stirred at ambient temperature for 12 h. The mixture was filtered and concentrated under reduced pressure to provide (S,E)-N-((3-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (quantitative yield). 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.70-8.68 (m, 1H), 7.81 (dd, J = 0.8, 8.0Hz, 1H), 7.36 (dd, J = 4.4, 8.4Hz, 1H), 1.30 (s, 9H). LCMS(ESI)m / z 245.0[M+H]+.

[0196] B. (S)-N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-((3-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 equiv) in THF (0.4 M) was added tetrabutylammonium difluorotriphenylsilicate (0.20 equiv) at -70°C and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (2.0 equiv) was added dropwise and the mixture was stirred at -70°C for 2 h. The mixture was then warmed to -10°C and stirred for 2 h. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (40 to 58% acetonitrile + 0.2% formic acid in water over 25 min) and the fractions containing the product were concentrated under reduced pressure to afford (S)-N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (58.2% yield). 1 HNMR(400MHz,DMSO-d6)δ8.67(d,J=4.8Hz,1H),8.12(d,J=8.0Hz,1H),7.57( dd,J=4.8,8.4Hz,1H),6.08(d,J=8.8Hz,1H),5.58-5.54(m,1H),1.13(s,9H). LCMS(ESI)m / z:315.1[M+H] + .

[0197] C. (R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (1.0 equiv) in DCM (0.2 M) was added a 4 M solution of hydrochloric acid in EtOAc (12.6 equiv) at 0°C. The mixture was stirred at 25°C for 2 h. The mixture was concentrated under reduced pressure and the residue was triturated with petroleum ether, filtered and dried under reduced pressure to provide (R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (quantitative yield). 1 HNMR (400MHz, DMSO-d6) δ10.00-9.17(m,3H),8.72-8.71(m,1H),8.18(dd,J=1.2,8.4Hz,1H),7.66(dd,J=4.4,8.0Hz,1H),5.84-5.75(m,1H). LCMS(ESI)m / z:211.0[M+H] + .

[0198] D. (S)-2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindoline-5-carboxylic acid. To a solution of 5-amino-4-[(2S)-5-bromo-1-oxo-isoindolin-2-yl]-5-oxo-pentanoic acid tert-butyl ester (1.0 equiv) and dicyclohexyl(3-dicyclohexylphosphonopropyl)phosphonium bistetrafluoroborate (1.0 equiv) in DMF (0.5 M) was added water (2.0 equiv), palladium acetate (0.1 equiv) and K2CO3 (1.5 equiv). The suspension was degassed under vacuum and flushed several times with carbon monoxide. The mixture was stirred at 80°C for 16 h under a carbon monoxide atmosphere (50 psi), then cooled to ambient temperature and filtered. To the filtrate was added water, and the aqueous layer was washed with EtOAc. The aqueous layer was then acidified to pH 2 with 12N aqueous hydrochloric acid and extracted with EtOAc and the combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was triturated with methyl tert-butyl ether and filtered to provide (2S)-2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-1-oxo-isoindoline-5-carboxylic acid (44.2% yield). LCMS (ESI) m / z: 385.1 [M+Na] + .

[0199] E. (S)-tert-butyl 5-amino-4-(5-(((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. To a solution of (S)-2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-carboxylic acid (1.0 equiv) and (R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (1.0 equiv) in DMF (0.28 M) were added HATU (1.2 equiv) and DIPEA (3.0 equiv). The mixture was stirred at 25° C. for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (40 to 70% acetonitrile + 0.2% formic acid in water over 13 min) and the fractions containing the product were concentrated under reduced pressure to afford (S)-tert-butyl 5-amino-4-(5-(((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (52.0% yield). 1 H NMR(400MHz,DMSO-d6)δ9.62(d,J=8.8Hz,1H),8.67(dd,J=1.2,4.4Hz,1H),8.13(s ,1H),8.10(dd,J=1.6,8.4Hz,1H),8.01(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,1H),7.5 8-7.55(m,2H),7.20(s,1H),6.59-6.51(m,1H),4.75(dd,J=3.6,10.0Hz,1H),4.67- 4.63(m,1H),4.54-4.49(m,1H),2.19-2.15(m,3H),2.07-1.95(m,1H),1.32(s,9H). LCMS(ESI)m / z:555.2[M+H] + .

[0200] FN-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide. A mixture of (S)-tert-butyl 5-amino-4-(5-(((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 equiv), benzenesulfonic acid (2.5 equiv) in acetonitrile (0.18 M) was degassed and flushed with nitrogen three times and then the mixture was stirred at 60° C. under nitrogen atmosphere for 12 h. The mixture was concentrated and then diluted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by standard methods to afford N-((R)-1-(3-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (58.6% yield). 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.70(d,J=8.8Hz,1H),8.67(dd,J=1.2,4.4Hz,1 H),8.14(s,1H),8.10(dd,J=1.2,8.0Hz,1H),8.03(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1 H),7.57(dd,J=4.4,8.0Hz,1H),6.55(q,J=8.0Hz,1H),5.14(dd,J=5.2,13.2Hz,1H),4. 54-4.37(m,2H),2.96-2.87(m,1H),2.63(s,1H),2.41-2.38(m,1H),2.07-1.99(m,1H). LCMS(ESI)m / z:481.1[M+H] + . Example 28: N-((R)-1-(3,5-difluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0201] A. (S,E)-N-((3-chloro-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 3-chloro-5-fluoropicolinaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (1.5 eq.) in DCM (0.34 M) was added CuSO (2.0 eq.). The mixture was stirred at ambient temperature for 12 h. The mixture was filtered, concentrated under reduced pressure, and then purified by silica gel chromatography (0 to 8% EtOAc in petroleum ether) to provide (S,E)-N-((3-chloro-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (90.0% yield). 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 8.61 (d, J = 2.4Hz, 1H), 7.62 (dd, J = 2.4Hz, 7.6Hz, 1H), 1.33 (s, 9H). LCMS(ESI)m / z 262.9[M+H]+.

[0202] B. (S)-N-((R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-((3-chloro-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 eq.) in THF (0.26 M) at -60 °C was added tetrabutylammonium difluorotriphenylsilicate (0.2 eq.) and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (1.6 eq.) was added dropwise and the mixture was stirred at -60 °C for 3 h. The mixture was warmed to -10 °C, stirred for 12 h, then quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by standard methods to afford (S)-N-((R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (20.0% yield). 1 H NMR (400MHz, CDCl3) δ8.36 (d, J = 2.4Hz, 1H), 7.49 (dd, J = 2.4Hz, 7.6Hz, 1H), 5.36-5.29 (m, 1H), 5.13 (d, J = 8.8Hz, 1H), 1.22 (s, 9H). LCMS(ESI)m / z:332.9[M+H] + .

[0203] C. (R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (1.0 equiv) in DCM (0.09 M) was added a 4 M solution of hydrochloric acid in EtOAc (7.5 equiv). The mixture was stirred at 15 °C for 1 h. The mixture was concentrated under reduced pressure to provide (R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (96.6% yield). 1 H NMR (400MHz, CD3OD) δ 8.69 (d, J = 2.4Hz, 1H), 8.12 (dd, J = 2.4Hz, 8.0Hz, 1H), 5.93 (q, J = 6.4Hz, 1H). LCMS(ESI)m / z:228.9[M+H] + .

[0204] D-N-((R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. To a solution of (R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (1.0 eq) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 eq) in DMF (0.13 M) was added DIPEA (5.0 eq) and HATU (1.2 eq). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to afford N-((R)-1-(3-chloro-5-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (45.1% yield). 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.70(d,J=8.4Hz,1H),8.75(d,J=2.0Hz,1H),8.2 9(dd,J=2.4Hz,8.4Hz,1H),8.13(s,1H),8.02(t,J=3.2Hz,1H),7.82(d,J=8.0Hz,1H),6 .57-6.49(m,1H),5.14(dd,J=5.2Hz,13.2Hz,1H),4.52(d,J=17.6Hz,1H),4.40(d,J=17 .6Hz,1H),2.96-2.87(m,1H),2.63-2.59(m,1H),2.45-2.40(m,1H),2.04-2.03(m,1H). LCMS(ESI)m / z:499.0[M+H] + . Example 29: N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0205] A. (S,E)-N-((3,5-dichloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 3,5-dichloropyridinecarboxaldehyde (1.0 eq.) and (S)-2-methylpropane-2-sulfinamide (1.5 eq.) in DCM (0.61 M) was added CuSO4 (2.0 eq.). The mixture was stirred at ambient temperature for 12 h. The mixture was filtered, concentrated under reduced pressure, and then purified by silica gel chromatography (0 to 8% EtOAc in petroleum ether) to provide (S,E)-N-((3,5-dichloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (47.3% yield). 1 H NMR (400MHz, CDCl3) δ9.01 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 1.33 (s, 9H). LCMS(ESI)m / z278.9[M+H]+.

[0206] B. (S)-N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-((3,5-dichloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 eq.) in THF (0.24 M) at -60 °C was added tetrabutylammonium difluorotriphenylsilicate (0.2 eq.) and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (1.5 eq.) was added dropwise and the mixture was stirred at -60 °C for 3 h. The mixture was warmed to -10 °C and stirred for 12 h, then quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by standard methods to afford (S)-N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (29.9% yield). 1 H NMR (400MHz, CDCl3) δ8.52 (d, J = 2.4Hz, 1H), 7.82 (d, J = 2.0Hz, 1H), 5.44-5.37 (m, 1H), 5.23 (d, J = 8.8Hz, 1H), 1.32 (s, 9H). LCMS(ESI)m / z:349.1[M+H] + .

[0207] C. (R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (1.0 equiv) in DCM (0.3 M) was added a 4 M solution of hydrochloric acid in EtOAc (40.0 equiv). The mixture was stirred at 15 °C for 1 h. The mixture was concentrated under reduced pressure to provide (R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (quantitative yield). 1 H NMR (400MHz, DMSO-d6) δ9.17 (s, 2H), 8.84 (d, J = 2.0Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 5.82 (q, J = 6.8Hz, 1H). LCMS(ESI)m / z:244.9[M+H] + .

[0208] D-N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide. To a solution of (R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (1.0 eq) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 eq) in DMF (0.42 M) was added DIPEA (4.7 eq) and HATU (1.1 eq). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to afford N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (54.3% yield). 1 H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 9.73 (d, J = 8.4Hz, 1H), 8.77 (s, 1H), 8.43 (s, 1H),8.13(s,1H),8.02(dd,J=4.0Hz,7.2Hz,1H),7.82(d,J=8.0Hz,1H),6.55-6.47 (m,1H),5.15(dd,J=5.2Hz,13.2Hz,1H),4.52(d,J=17.6Hz,1H),4.40(d,J=17.6Hz ,1H),2.97-2.87(m,1H),2.63-2.59(m,1H),2.45-2.40(m,1H),2.04-2.01(m,1H). LCMS (ESI) m / z: 515.0 [M+H] + . Example 30: N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0209] A. (S)-tert-butyl 5-amino-4-(5-(((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. To a solution of (S)-2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-carboxylic acid (preparation described herein, 1.0 equiv) and (R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (preparation described herein, 1.0 equiv) in DMF (0.26 M) was added HATU (1.2 equiv) and DIPEA (3.0 equiv). The mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (45 to 75% acetonitrile + 0.2% formic acid in water over 15 min) and the fractions containing the product were concentrated under reduced pressure to afford tert-butyl (S)-5-amino-4-(5-(((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (59.5% yield). 1 HNMR (400MHz, DMSO-d6) δ9.78(d,J=8.8Hz,1H),8.67(d,J=1.6Hz,1H),8.29(dd,J=1.6,9.6Hz,1H),8.14(s,1H),8.01(d,J=8.4Hz,1H),7.79(d,J= 8.0Hz,1H),7.60(s,1H),7.22(s,1H),6.42-6.38(m,1H),4.77-4.50(m,1 H),4.67-4.63(m,3H),2.17-2.15(m,3H),2.02-2.01(m,1H),1.32(s,9H). LCMS(ESI)m / z:573.2[M+H] + .

[0210] BN-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide. A mixture of (S)-tert-butyl 5-amino-4-(5-(((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 equiv) and benzenesulfonic acid (2.5 equiv) in acetonitrile (0.18 M) was stirred at 60° C. under nitrogen atmosphere for 12 h. The mixture was concentrated, diluted with DCM, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by standard methods to afford N-((R)-1-(5-chloro-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (72.7% yield). 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.81(d,J=8.8Hz,1H),8.67(s,1H),8.31-8.30(m,1H),8.15(s,1H),8.04(d,J=8.0Hz,1H),7.82(d,J=8. 0Hz,1H),6.43-6.39(m,1H),5.18-5.11(m,1H),4.55-4.39(m,2H),2.97 -2.90(m,1H),2.63-2.58(m,1H),2.45-2.33(m,1H),2.05-2.04(m,1H). LCMS(ESI)m / z:499.2[M+H] + . Example 31: N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide hydrochloride

[0211] A. 3-chloro-5-((dimethylamino)methyl)picolinonitrile. To a solution of 3-chloro-5-(chloromethyl)picolinonitrile (1.0 eq.) in acetonitrile (0.4 M) was added dimethylamine hydrochloride (2.0 eq.) and KCO (3.0 eq.). The resulting mixture was stirred at 55 °C for 12 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 25% EtOAc in petroleum ether) to provide 3-chloro-5-((dimethylamino)methyl)picolinonitrile (84.0% yield). 1HNMR (400MHz, CDCl3) δ8.54(s,1H),7.90(s,1H),3.52(s,2H),2.29(s,6H). LCMS(ESI)m / z:195.9[M+H] + .

[0212] B. 3-chloro-5-((dimethylamino)methyl)picolinic acid hydrochloride. To a solution of 3-chloro-5-((dimethylamino)methyl)picolinonitrile (1.0 equiv.) in EtOH (0.8 M) was added an aqueous solution of sodium hydroxide (5.0 equiv.) in water (0.8 M). The resulting mixture was stirred at 90 °C for 12 h. The pH of the reaction mixture was adjusted to 1 with aqueous hydrochloric acid. The mixture was concentrated under reduced pressure. The residue was suspended in methanol, filtered and concentrated under reduced pressure to provide 3-chloro-5-((dimethylamino)methyl)picolinic acid hydrochloride as a white solid (quantitative yield). LCMS (ESI) m / z: 215.0 [M+H] + .

[0213] C. 3-Chloro-5-((dimethylamino)methyl)-N-methoxy-N-methylpicolinamide. To a mixture of 3-chloro-5-((dimethylamino)methyl)picolinamide hydrochloride (1.0 eq.) in DCM (0.22 M) was added N,O-dimethylhydroxylamine hydrochloride (1.6 eq.), 4-methylmorpholine (10.0 eq.), HOBt (1.0 eq.) and EDCI (1.7 eq.). The resulting mixture was stirred at 15 °C for 12 h. The mixture was diluted with DCM, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by standard methods to provide 3-chloro-5-((dimethylamino)methyl)-N-methoxy-N-methylpicolinamide (47.2% yield). 1 HNMR (400MHz, CDCl3) δ8.34(s,1H),7.69(s,1H),3.49(s,3H),3.38(s,2H),3.33(s,3H),2.19(s,6H). LCMS(ESI)m / z:258.0[M+H] + .

[0214] D. 3-chloro-5-((dimethylamino)methyl)picolinaldehyde. To a solution of 3-chloro-5-((dimethylamino)methyl)-N-methoxy-N-methylpicolinamide (1.0 equiv.) in THF (0.29 M) was added a 2.4 M solution (1.0 equiv.) of lithium aluminum hydride in THF at -70 °C under a nitrogen atmosphere. The resulting mixture was stirred for 4 h at -70 °C under a nitrogen atmosphere. The mixture was quenched with a saturated aqueous solution of ammonium chloride at -70 °C. The mixture was diluted with DCM and stirred at 10 °C for 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to produce 3-chloro-5-((dimethylamino)methyl)picolinaldehyde (47.2% yield). 1 H NMR (400MHz, CDCl3) δ10.33 (s, 1H), 8.65 (d, J = 1.6Hz, 1H), 7.87 (s, 1H), 2.74 (s, 2H), 2.30 (s, 6H). LCMS(ESI)m / z:198.9[M+H] + .

[0215] E. (S,E)-N-((3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 3-chloro-5-((dimethylamino)methyl)picolinaldehyde (1.0 equiv) and (S)-2-methylpropane-2-sulfinamide (1.0 equiv) in DCM (0.36 M) was added CsCO (2.0 equiv). The mixture was stirred at ambient temperature for 12 h. The mixture was filtered, concentrated under reduced pressure, and then purified by standard methods to provide (S,E)-N-((3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. 1 H NMR (400MHz, CDCl3) δ8.98 (s, 1H), 8.52 (s, 1H), 7.76 (d, J = 1.6Hz, 1H), 3.42 (s, 2H), 2.20 (s, 6H), 1.24 (s, 9H). LCMS(ESI)m / z 302.0[M+H]+.

[0216] F. (S)-N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-N-((3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 eq.) in THF (0.28 M) at -60 °C was added tetrabutylammonium difluorotriphenylsilicate (0.20 eq.) and the mixture was stirred for 10 min. (Trifluoromethyl)trimethylsilane (2.0 eq.) was added dropwise and the mixture was stirred at -60 °C for 2 h. The mixture was warmed to -20 °C and stirred for 12 h, then quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by standard methods to afford (S)-N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (43.2% yield). 1 H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 7.74 (s, 1H), 5.38-5.31 (m, 1H), 5.28 (d, J = 8.4Hz, 1H), 3.39 (s, 2H), 2.21 (s, 6H), 1.23 (s, 9H). LCMS(ESI)m / z:372.0[M+H] + .

[0217] G. (R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethan-1-amine dihydrochloride. To a solution of (S)-N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (1.0 equiv) in EtOAc (0.14 M) was added a 4 M solution of hydrochloric acid in EtOAc (16.8 equiv). The mixture was stirred at 15° C. for 1 h and the solids were filtered to provide (R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethan-1-amine dihydrochloride (88.2% yield). 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),9.18(s,2H),8.96(d,J=1.6Hz,1H),8.51(s,1H),5.85(q,J=6.8Hz,1H),2.43(s,2H),2.73(s,6H). LCMS(ESI)m / z:267.9[M+H] + .

[0218] H. N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide hydrochloride. To a solution of (R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethan-1-amine dihydrochloride (1.0 equiv) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 equiv) in DMF (0.14 M) was added DIPEA (5.0 equiv) and HATU (1.2 equiv). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to provide N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide hydrochloride (61.1% yield). 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),11.01(s,1H),9.73(d,J=8.8Hz,1H),8.86(s,1H),8.4 1(s,1H),8.15(s,1H),8.04(t,J=7.2Hz,1H),7.82(d,J=8.0Hz,1H),6.62-6.54(m,1H),5.15( dd,J=5.2Hz,13.6Hz,1H),4.53(d,J=17.6Hz,1H),4.42(s,2H),4.38(d,J=4.0Hz,1H),2.97- 2.88(m,1H),2.74(t,J=3.2Hz,6H),2.63-2.59(m,1H),2.45-2.38(m,1H),2.08-2.02(m,1H). LCMS(ESI)m / z:538.3.0[M+H] + . Example 32: 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(2-morpholinylphenyl)ethyl)isoindoline-5-carboxamide

[0219] A. (S,E)-2-methyl-N-(2-morpholinylbenzylidene)propane-2-sulfenamide. To a solution of (S,E)-2-methyl-N-(2-morpholinylbenzylidene)propane-2-sulfenamide (1.0 equiv) and (S)-2-methylpropane-2-sulfenamide (1.0 equiv) in DCM (0.36 M) was added tetraethoxytitanium (2.0 equiv). The mixture was stirred at 60 °C for 12 h. The mixture was filtered, concentrated under reduced pressure, and then purified by standard methods to provide (S,E)-2-methyl-N-(2-morpholinylbenzylidene)propane-2-sulfenamide. 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 7.97 (dd, J = 1.6, 7.6Hz, 1H), 7.50-7.46 (m ,1H),7.17-7.12(m,2H),3.92-3.89(m,4H),3.01-2.99(m,4H),1.27(s,9H). LCMS(ESI)m / z 295.0[M+H]+.

[0220] B. (S)-N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a solution of (S,E)-2-methyl-N-(2-morpholinobenzylidene)propane-2-sulfinamide (1.0 eq.) in THF (0.45 M) at -70 °C was added tetrabutylammonium difluorotriphenylsilicate (0.20 eq.) and the mixture was stirred for 0.5 h. (Trifluoromethyl)trimethylsilane (2.0 eq.) was added dropwise and the mixture was stirred at -70 °C for 0.5 h. The mixture was warmed to 0 °C, stirred for 2 h, then quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by standard methods to afford (S)-N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (4.1% yield). 1 H NMR (400MHz, CDCl3) δ7.42-7.36(m,3H),7.27-7.23(m,1H),5.64(t,J=8.4H z, 1H), 4.61 (d, J = 7.2Hz, 1H), 3.89 (s, 4H), 3.00-2.90 (m, 4H), 1.27 (s, 9H). LCMS(ESI)m / z:365.3.0[M+H] + .

[0221] C. (R)-2,2,2-trifluoro-1-(2-morpholinylphenyl)ethan-1-amine hydrochloride. To a solution of (S)-N-((R)-1-(3-chloro-5-((dimethylamino)methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (1.0 equiv) in DCM (0.18 M) was added a 4 M solution of hydrochloric acid in EtOAc (22.2 equiv). The mixture was stirred at 15 °C for 1 h and the solids were filtered to provide (R)-2,2,2-trifluoro-1-(2-morpholinylphenyl)ethan-1-amine hydrochloride (quantitative yield). LCMS (ESI) m / z: 261.3 [M+H] + .

[0222] D. 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(2-morpholinylphenyl)ethyl)isoindoline-5-carboxamide. To a solution of (R)-2,2,2-trifluoro-1-(2-morpholinylphenyl)ethan-1-amine hydrochloride (1.0 eq.) and 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid (1.0 eq.) in DMF (0.28 M) was added DIPEA (3.0 eq.) and HATU (1.2 eq.). The mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by standard methods to afford 2-(2,6-dioxopiperidin-3-yl)-1-oxo-N-((R)-2,2,2-trifluoro-1-(2-morpholinylphenyl)ethyl)isoindoline-5-carboxamide (38.5% yield). 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.57(d,J=9.6Hz,1H),8.09(s,1H),8.00(d,J=7.6H z,1H),7.86-7.82(m,2H),7.45-7.39(m,2H),7.31-7.29(m,1H),6.94(t,J=9.2Hz,1H),5. 14(dd,J=4.8,13.2Hz,1H),4.50-4.38(m,2H),3.85-3.81(m,2H),3.75-3.71(m,2H),2.98 -2.95(m,3H),2.70-2.67(m,2H),2.65-2.63(m,1H),2.50-2.40(m,1H),2.07-2.01(m,1H). LCMS(ESI)m / z:531.2[M+H] + . Example 33: N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide

[0223] A. (S)-tert-butyl 5-amino-4-(5-(((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate. To a solution of (S)-2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-carboxylic acid (preparation described herein, 1.0 equiv) and (R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (preparation described herein, 1.0 equiv) in DMF (0.20 M) was added HATU (1.2 equiv) and DIPEA (3.0 equiv). The mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (40 to 55% acetonitrile + 0.2% formic acid in water over 24 min) and the fractions containing the product were concentrated under reduced pressure to afford tert-butyl (S)-5-amino-4-(5-(((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (77.6% yield). 1 HNMR (400MHz, DMSO-d6) δ9.68(d,J=8.8Hz,1H),8.77(d,J=2.4Hz,1H),8.44(s,1H),8.13(d,J=6.0Hz,1H),8.02-7.99(m,1H),7.79(d,J=8.0H z,1H),7.60(s,1H),7.21(s,1H),6.55-6.47(m,1H),4.77-4.76(m,1H) ,4.75-4.50(m,2H),2.17-2.15(m,1H),2.08-2.01(m,1H),1.33(s,9H). LCMS(ESI)m / z:589.2[M+H]+.

[0224] BN-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-carboxamide. A mixture of (S)-tert-butyl 5-amino-4-(5-(((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamoyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 equiv) and benzenesulfonic acid (2.5 equiv) in acetonitrile (0.18 M) was stirred at 60° C. under nitrogen atmosphere for 12 h. The mixture was concentrated, diluted with DCM, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by standard methods to provide N-((R)-1-(3,5-dichloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (50.0% yield). 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.73(d,J=8.8Hz,1H),8.77(d,J=2.0Hz,1H),8.43(d,J=2.0Hz,1H),8.14(s,1H),8.03(d,J=8.0Hz,1H),7.82(d ,J=8.0Hz,1H),6.54-6.50(m,1H),5.17-5.13(m,1H),4.54-4.38(m,2H),2 .97-2.92(m,1H),2.64-2.59(m,1H),2.45-2.41(m,1H),2.05-2.03(m,1H). LCMS (ESI) m / z: 515.2 [M+H] + . analyze CK1α degradation analysis

[0225] CK1α ePL Assay. The following is an example of an assay that can be used to measure the CK1α degradation activity of isoindolinone carboxamide compounds in a cell line (eg, MDS-L cell line).

[0226] MDS-L cells stably expressing enhanced ProLabel (ePL) labeled CK1α were dispensed into 384-well plates (Catalog No. 3712, Corning) pre-spotted with compounds. Compounds were dispensed into 384 wells using an acoustic dispenser (ATS Acoustic Delivery System from EDC Biosystems) in a 10-point dose response curve starting at 10 μM and decreasing to 0.0005 μM in DMSO. Twenty-five microliters of culture medium (RPMI 1640 + 20% heat-inactivated FBS + 1X BME + 2 μg / mL puromycin + 200 μg / mL hygromycin) containing 5000 cells were dispensed into each well. The assay plates were incubated at 37°C with 5% CO2 for the specified time. At different time points, 25 μL InCELL Hunter TM Detection reagent working solution (Catalog No. 96-0002, DiscoverX, Fremont, CA) was added to each well and incubated at room temperature for 30 min, protected from light. After 30 min, luminescence was read on a PHERAstar luminometer (BMG LABTECH, Cary, NC). All percentages of control CK1α destruction curves were processed and evaluated using ActivityBase (IDBS, Alameda, CA) and then the results were combined and mapped using ActivityBase (IDBS).

[0227] The CK1α concentration in the compound-treated wells was normalized to that of the DMSO control and expressed as a percentage of the control (PoC) (y). A four-parameter logistic model (sigmoidal dose-response model) was used to determine the DCs of the compound. 50 and EC 50 , using the following equation: y=(A+((BA) / (1+((C / x)^D)))) A=Y Min (lowest CK1α concentration in response to compound treatment normalized to DMSO control as determined by curve fitting) B=Y Max (CK1α concentration in DMSO control) C=EC 50 D = Hill Slope x = compound concentration EC 50 =When y=(Y Max -Y Min ) / 2, the concentration of the compound DC 50= when y = 50% DMSO control (50% CK1α degradation), the concentration of the compound y = CK1α protein concentration normalized to DMSO control

[0228] The lowest measured CK1α concentration normalized to DMSO control in response to compound treatment (referred to as the Y value) was used to characterize the efficiency of CK1α degradation mediated by the compound.

[0229] Each of the isoindolinone carboxamide compounds in Table 1 was tested in the MDS-L CK1αePL degradation assay and found to be active therein. All compounds in Table 1 are shown to have a DC with DMSO control 50 <1μM and Y<50%. Cell-based assays

[0230] OCI-AML2 cell proliferation assay. The following is an example of an assay that can be used to determine the antiproliferative activity of CK1α-degrading isoindolinone carboxamide compounds in AML cell lines (e.g., OCI-AML2 cell line (DSMZ: catalog number ACC-99)) or MV-4-11 cell line (ATCC: catalog number CRL-9591) 120h after treatment. The seeding density (2000 cells per well) was optimized to ensure analytical linearity in a 384-well plate.

[0231] Increasing concentrations of test compounds (0 to 10 μM, semi-log intervals) were spotted into empty 384-well plates via an HP300 digital dispenser in a 10-point dilution pattern. The DMSO concentration was kept constant for the final assay concentration of 0.1% DMSO. Prior to testing, cells were grown in culture medium (MEM for OCI-AML2 cell line, IMDM for MV-4-11 cell line) with 10% FBS (HyClone) and expanded in culture flasks to provide sufficient starting material. The cells were then diluted to 2000 cells per well in a volume of 50 μL and added directly to the 384-well plate spotted with the compound. The cells were grown at 37°C for 120 h in 5% CO2. After the cells were exposed to the compound for 120 h, the cells were plated and plated with the compound. Luminescent cell viability assays were performed at a 1:2 volume ratio according to the manufacturer's instructions (Promega Corporation, Madison, WI) by quantifying the amount of luminescence generated by the presence of adenosine-5'-triphosphate (ATP) and reading the luminescence. All growth inhibition curves were processed and evaluated using an activity library (IDBS, Alameda, CA). Cell viability IC 50 Values ​​were calculated using a four-parameter logistic model (sigmoidal dose-response model): y=(A+((BA) / (1+((C / x)^D)))) in: A=Y Min B=Y Max C=EC 50 D = Hill slope IC 50 = When Y = 50% DMSO control, the concentration of the compound Y = cell viability measured as luminescence units, and x = concentration of compound.

[0232] Isoindolinone carboxamide compounds have been or will be tested in cell-based assays and have been or will be shown to be effective as inhibitors of AML cell growth. In vivo analysis

[0233] MV4-11 or OCI-AML2 AML xenograft models. MV4-11 (ATCC) or OCI AML2 (DSMZ) cell lines were cultured in culture medium according to the manufacturer's instructions. These cell lines were transduced with RediFect carrying a green-emitting Renilla luciferase transgene. TM Green Renilla-Puromycin lentiviral particles express luciferase under the control of a stable UbC promoter.

[0234] To establish an in vivo xenograft model of efficacy diffusion, female NSG mice (Jackson Laboratory) were injected intravenously with 5x10 6 cells / mouse. Bioluminescence was measured by IVIS Lumina Imaging System and animals were randomized into treatment groups on day 5 or day 14 for OCI-AML2 or MV4-11, respectively. Treatment started on the day of randomization and continued for up to 3 weeks. Animals were imaged once a week for disease progression using IVIS Lumina Imaging System and monitored for survival as study endpoints.

[0235] Tumor growth inhibition (TGI) was calculated using the following formula: TGI = bioluminescent photon value of the vehicle group at the final time point - bioluminescent photon value of the vehicle group at the starting time point = 100% growth. For each group, the starting bioluminescent photon value was subtracted from the final bioluminescent photon value and compared to 100% growth of the vehicle control.

[0236] CK1α degradation model. For PK-PD analysis, animals were inoculated with tumor cells subcutaneously in the hind flank. Four weeks after inoculation, tumor dimensions were measured in mm using an LCD digital caliper and tumor volumes (width 2x length / 2 in mm 3 (expressed as). If the tumor volume reaches approximately 500 mm 3 , the animals are randomly divided into treatment groups. The animals receive a single dose or 5 daily doses of vehicle (5% Tween 80 in 25 mM citrate buffer pH 3.0), test article, or positive control (Ara-c 50 mg / kg QD), and tumor and blood samples are taken at time points from 0.5 h to 48 h after the last dose for assessment of pharmacokinetic and pharmacodynamic endpoints. Pharmacodynamic endpoints include measurement of CK1α concentration to assess CK1α degradation and cleavage of caspase 3 by Western blot as a measure of apoptosis induction.

[0237] Cell lines that can be used in the xenograft assays described herein include AML cell lines such as MV4-11, OCI-AML2, MOLM-13, and HNT-34.

[0238] Isoindolinone carboxamide compounds have been or will be tested in the AML xenograft models described herein and have shown or will show efficacy as a treatment for AML in such models. Activity table

[0239] Each of the isoindolinone carboxamide compounds in Table 1 was tested in one or more of the assays (e.g., ePL CK1α degradation assay) and was found to be active therein. All compounds in Table 1 are shown to have a DC 50 and a Y value < 50% of the DMSO control, and some compounds have a DC 50 indicated by C: DC 50 ≤ 0.10 μM, some have a DC 50 indicated by B: 0.10 μM < DC 50 ≤ 0.50 μM, and others have a DC 50 indicated by A: 0.50 μM < DC 50 ≤ 1.0 μM.

[0240] In addition, the compounds are shown to have a CK1α degradation efficacy Y value < 50% of the DMSO control, and some compounds have a Y value of 0 < Y ≤ 20% (shown as *), some compounds have a Y value of 20% < Y ≤ 35% (shown as **), and others have a Y value of 35% < Y < 50% (shown as ***).

[0241] Table 1:

[0242] A number of references have been cited herein, the disclosures of which are incorporated by reference in their entireties.

[0243] In summary, the present invention includes but is not limited to the following items: 1. A compound of formula (I): or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, in: R 1 It is C 1-3 Alkyl or C 1-3 Fluoroalkyl; R 2 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl; R 3 It is H; R 4 is a halogen; and n is 0 to 3. 2. The compound of item 1, wherein the compound is a compound of formula (II): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 3. The compound of item 1, wherein the compound is a compound of formula (III): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 4. The compound of item 1, wherein the compound is a compound of formula (IV): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 5. The compound of item 1, wherein the compound is a compound of formula (V): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 6. The compound of item 1, wherein the compound is a compound of formula (VI): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 7. The compound of item 1, wherein the compound is a compound of formula (VII): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 8. The compound of item 1, wherein the compound is a compound of formula (VIII): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 9. The compound of item 1, wherein the compound is a compound of formula (IX): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 10. The compound of item 1, wherein the compound is a compound of formula (X): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 11. The compound of item 1, wherein the compound is a compound of formula (XI): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof. 12. A compound according to any one of items 1 to 11, wherein R 1 It is methyl, ethyl, n-propyl, isopropyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CHFC H3, CF2CH3 or CF2CF3. 13. A compound according to any one of items 1 to 12, wherein R1 It is methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3 or CF2CH3. 14. A compound according to any one of items 1 to 13, wherein R 2 is substituted with one or more substituents selected from the group consisting of halogen, CN, OR', substituted or unsubstituted C 1-3 Alkyl and substituted or unsubstituted -(C 0-3 alkyl) (3 to 6 membered heterocyclic group); wherein each R' is independently selected from H, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl and phenyl. 15. A compound according to any one of items 1 to 14, wherein R 2 is substituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, OCH3, OCF3, OCH2CH3, O-n-propyl, O-isopropyl, O-n-butyl, O-sec-butyl, O-tert-butyl, O-cyclopropyl, O-cyclobutyl, O-phenyl, CH3, CH2CH3, CF3, CH2CF3, CH2NHCH3, CH2N(C H3)2, and -(C 0-3 alkyl)(3 to 6 membered heterocyclic group) selected from piperidinyl, piperazinyl, morpholinyl, CH2-aziridine, CH2-pyrrolidinyl, CH2-piperazinyl, CH2-piperidinyl, CH2-morpholinyl and CH2(2-oxa-6-azaspiro[3.3]heptyl), wherein the -(C 0-3 alkyl) (3 to 6 membered heterocyclyl) is optionally substituted by one or more F, Cl or CH3. 16. A compound according to any one of items 1 to 15, wherein R 2 is substituted with one or more substituents selected from the group consisting of F, Cl, CN, OH, OCH3, OCF3, O-isopropyl, O-cyclopropyl, O-phenyl, CH3, CF3, CH2CF3, CH2N(CH3)2, and -(C 0-3 alkyl)(3 to 6 membered heterocyclic group) selected from morpholinyl, piperazinyl, CH2-aziridine, CH2-pyrrolidinyl, CH2-piperazinyl, CH2-morpholinyl and CH2(2-oxa-6-azaspiro[3.3]heptyl), wherein the -(C 0-3 alkyl) (3 to 6 membered heterocyclyl) is optionally substituted with one or more F or CH3. 17. A compound according to any one of items 1 to 16, wherein R 2 It is C 1-6 Alkyl, which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CN and OR'; C 3-10Cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, OR' and substituted or unsubstituted C 1-3 alkyl; a 3- to 6-membered heterocyclic group which is unsubstituted or substituted with one or more substituted or unsubstituted C 1-3 Alkyl substituted; C 6-10 Aryl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, OR', substituted or unsubstituted C 1-3 Alkyl, and substituted or unsubstituted -(C 0-3 alkyl) (3 to 6 membered heterocyclyl); or 5 to 10 membered heteroaryl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, OR' and substituted or unsubstituted C 1-3 wherein each R' is independently selected from H, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, and phenyl. 18. A compound according to any one of items 1 to 13 and 17, wherein R 2 It is C 1-6 Alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, CN and OH. 19. The compound of item 18, wherein R 2 It is CH3, isopropyl, tert-butyl, C(CH3)2CH2OH, C(CH3)2CN or C(CH3)2CF3. 20. A compound according to any one of items 1 to 13, wherein R 2 It is C 3-10 Cycloalkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, OH, CH3, C(C H3)2OH and CF3. 21. The compound of item 20, wherein R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.5]nonyl, bicyclo[1.1.1]pentyl or spiro[2.5]octyl. 22. A compound according to any one of items 1 to 13, wherein R 2 is a 3- to 6-membered heterocyclyl group which is unsubstituted or substituted by one or more CH3 and CH2CF3. 23. The compound of item 22, wherein R 2 is oxetanyl, tetrahydropyranyl or piperidinyl. 24. A compound according to any one of items 1 to 13, wherein R 2 It is C 6-10Aryl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, Cl, CN, OH, OCH3, OCF3, O-isopropyl, O-cyclopropyl, O-phenyl, CH3, CF3, and CH2N(CH3)2; and -(C 0-3 alkyl)(3 to 6 membered heterocyclic group) selected from piperazinyl, morpholinyl, CH2-aziridine, CH2-pyrrolidinyl, CH2-piperazinyl, CH2-morpholinyl and CH2(2-oxa-6-azaspiro[3.3]heptyl), wherein the -(C 0-3 alkyl) (3 to 6 membered heterocyclyl) is optionally substituted with one or more F or CH3. 25. The compound of item 24, wherein R 2 It is phenyl. 26. A compound according to any one of items 1 to 13, wherein R 2 is a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of F, Cl, OCH3, CH3, CF3 and CH2N(CH3)2. 27. A compound according to any one of items 1 to 13 and 26, wherein R 2 is pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl. 28. A compound according to any one of items 1 to 27, wherein R 4 It is F or Cl. 29. A compound as described in any one of items 1 to 28, wherein n is 0, 1 or 2. 30. A compound from Table 1 or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof. 31. A pharmaceutical composition comprising an effective amount of a compound according to any one of items 1 to 30, or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle. 32. A method for treating or preventing acute myeloid leukemia, which comprises administering an effective amount of a compound according to any one of items 1 to 30 to a subject in need thereof. 33. A method for treating or preventing acute myeloid leukemia, which comprises administering an effective amount of the pharmaceutical composition of item 31 to an individual in need thereof. 34. The method of any one of items 32 to 33, wherein the acute myeloid leukemia is newly diagnosed acute myeloid leukemia. 35. The method of any one of items 32 to 33, wherein the acute myeloid leukemia is relapsed, refractory or resistant to conventional therapy. 36. A method for reducing CK1α protein concentration, the method comprising contacting a cell with an effective amount of a compound according to any one of items 1 to 30. 37. The method of claim 36, wherein the cell line is in an individual. 38. A compound according to any one of items 1 to 30 or a pharmaceutical composition according to item 31 for use as a medicament. 39. A compound according to any one of items 1 to 30, for use in a method for treating or preventing acute myeloid leukemia, the method comprising administering an effective amount of the compound to a subject in need thereof. 40. The pharmaceutical composition of claim 31, which is used in a method for treating or preventing acute myeloid leukemia, the method comprising administering an effective amount of the pharmaceutical composition to an individual in need thereof. 41. A compound for use in claim 39 or a pharmaceutical composition for use in claim 40, wherein the acute myeloid leukemia is newly diagnosed acute myeloid leukemia. 42. A compound for use in claim 39 or a pharmaceutical composition for use in claim 40, wherein the acute myeloid leukemia is relapsed, refractory or resistant to conventional therapy. 43. A method for reducing the concentration of CK1α protein in cells in vitro or in vitro, the method comprising contacting the cells with an effective amount of a compound according to any one of items 1 to 30.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, in: R 1 It is C 1-3 Alkyl or C 1-3 Fluoroalkyl; R 2 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl; R 3 It is H; R 4 is a halogen; and n is 0 to 3.

2. The compound of claim 1, wherein the compound is a compound of formula (II): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

3. The compound according to claim 1, wherein the compound is a compound of formula (III): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

4. The compound of claim 1, wherein the compound is a compound of formula (IV): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

5. The compound of claim 1, wherein the compound is a compound of formula (V): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

6. The compound of claim 1, wherein the compound is a compound of formula (VI): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

7. The compound of claim 1, wherein the compound is a compound of formula (VII): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

8. The compound of claim 1, wherein the compound is a compound of formula (VIII): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

9. The compound of claim 1, wherein the compound is a compound of formula (IX): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

10. The compound of claim 1, wherein the compound is a compound of formula (X): or a pharmaceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

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