CN117157286A - Pyridyl-substituted oxo-isoindoline compounds - Google Patents
Pyridyl-substituted oxo-isoindoline compounds Download PDFInfo
- Publication number
- CN117157286A CN117157286A CN202280026530.6A CN202280026530A CN117157286A CN 117157286 A CN117157286 A CN 117157286A CN 202280026530 A CN202280026530 A CN 202280026530A CN 117157286 A CN117157286 A CN 117157286A
- Authority
- CN
- China
- Prior art keywords
- oxoisoindolin
- methyl
- amino
- fluoro
- ser
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000001875 compounds Chemical class 0.000 claims abstract description 291
- 238000000034 method Methods 0.000 claims abstract description 151
- 150000003839 salts Chemical class 0.000 claims abstract description 132
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- -1 2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-methyl-1-oxoisoindolin-5-yl Chemical group 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 230000000694 effects Effects 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 230000014509 gene expression Effects 0.000 claims description 19
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Abstract
The present application discloses a compound of formula (I) or a salt thereof, wherein R 1 、R 2 、R 4 、R 6 M and n are defined in the present application. Methods of using these compounds to inhibit Helios proteins are also disclosed, as are pharmaceutical compositions comprising these compounds. These compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.
Description
Cross reference
The application claims the benefits of indian provisional application serial number 202111016193 filed on month 4 of 2021 and indian provisional application serial number 202111022098 filed on month 5 of 2021, each of which is incorporated herein in its entirety.
Technical Field
The present application relates generally to pyridyl-substituted oxoisoindoline compounds that inhibit Helios proteins. Provided herein are pyridyl-substituted oxo-isoindoline compounds, compositions comprising these compounds, and methods of use thereof. The application further relates to pharmaceutical compositions comprising at least one compound according to the application, which are useful for the treatment of proliferative disorders (e.g. cancer) and viral infections.
Background
Regulatory T cells (tregs) play a necessary role in controlling self-tolerance and immune homeostasis by maintaining inhibitory activity and disability in the face of powerful immune and inflammatory responses. Tregs attenuate excessive immune responses and prevent or ameliorate autoimmunity by preserving stable, disabling and suppressive phenotypes. Many reports have described the presence of tregs in human tumor tissue. Studies have demonstrated a clear negative correlation between the number of tregs and T cell infiltration to tumor and survival (Curiel et al, 2004, nat. Med.10:942-949; vigbier et al, 2004,J Immuno.1173:1444-1453; beyer et al, 2006,Blood 108:804-811; zou et al, 2006, nat. Rev. Immunol. 6:295-307), suggesting a potential key role for tregs in preventing the development of effective anti-tumor immunity. Accumulated evidence suggests that foxp3+cd25+cd4+ tregs predominantly infiltrate into tumors and apparently block immune responses to tumor cells in rodents and humans. Once activated by specific antigen, tregs suppress responsive T cells in vitro in an antigen-non-specific and bystander fashion (Takahashi et al 1998,Int Immunol.10:1969-80; thornton et al 1998,J Exp.Med.188:287-96). Foxp3+cd25+cd4+ tregs are clearly able to suppress a wide range of anti-tumor immune responses involving cd4+ helper T cells, cd8+ T cells, natural killer cells and natural killer T cells (Tanaka et al, 2017,Cell Research 27:109-118). Intratumoral depletion of cd25+cd4+ tregs induces regression of established tumors as the cytokine environment at the tumor site changes (Yu et al 2005,J Exp Med.201:779-91). Furthermore, the transfer of Treg-depleted cd4+ T cells significantly enhanced the anti-tumor immune response compared to T-cell transfer containing tregs (antonny et al 2005,J Immunol 174:2591-601). Tumor-infiltrating tregs activated by tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific anti-tumor immune responses. Modulation of the activity of key factors in controlling Treg differentiation may represent a potential therapeutic strategy for the treatment of certain diseases, including cancer and viral infections.
Foxp3+cd4 tregs were significantly stable. Research has evolved to understand the genetic mechanisms that ensure their phenotypic stability during inflammation, infection or autoimmunity after amplification. Transcription Factors (TF) responsible for maintaining the stable immunosuppressive phenotype of tregs can contribute to this process. The Helios (IKZF 2) gene (a member of the Ikaros family of TF) differs from other Ikaros family members by its selective expression by thymocytes undergoing negative selection and by the regulatory profile of CD4 and CD 8T cells. Helios expressed by two regulatory T-cell profiles, foxP3+CD4+ and Ly49+CD8+ Treg, which were necessary for maintenance of self tolerance (Kim et al 2015,Science 350:334-339; sebastin et al 2016,J Immunol 196:144-155). Interestingly, recent studies have shown that although Helios is largely tolerant to Treg activity in steady state, genetic programming of foxp3+cd4 tregs in inflammatory settings is necessary to maintain a stable phenotype and to enhance inhibition by control of Helios (Thornton et al 2010,J Immunol.184:3433-3441; kim et al 2015). Helios is demonstrated by Treg expression to be critical in its ability to maintain an inhibitory and non-energy phenotype in the face of a strong inflammatory response. Activation of the IL-2rα -STAT5 pathway has been demonstrated as a key contributor to ensuring Treg survival and stability (Kim et al, 2015). Helios play an indispensable role in maintaining the foxp3+cd4 Treg phenotype by exerting an intrinsic suppression of dominant lymphocytes to prevent autoimmune diseases in the presence of highly activated autoreactive T cells from dander mice, which do not have foxp3 fork domains. Marrow (BM) chimeras reconstituted with Helios-/-/dandruff BM but not Helios +/+/dandruff BM cells rapidly developed autoimmunity (Kim et al 2015). These observations indicate an important contribution of Helios to autoreactive T cell selection, differentiation, and function. Immunosuppression exerted by tregs can block anti-tumor immune responses. The selective lack of Helios in foxp3+cd4 tregs results in increased Treg instability and conversion of intratumoral CD4 tregs to effector T cells (Teff). Instability of tregs within tumors can increase the number of Teff cells within tumors, as a result of a combination of Treg transformation and reduced Treg inhibitory activity. Furthermore, a lack of IL-2 response was observed in Helios-deficient intratumoral tregs, which results in a reduced number of activated tregs, which may also contribute to an increase in intratumoral Teff activity. The interaction between tumor cells and infiltrating immune cells results in secretion of inflammatory mediators, including TNF- α, IL-6, IL-17, IL-1 and TGF- β, and formation of a local inflammatory environment (Kim et al, 2015).
The lineage instability of Helios-deficient tregs is also accompanied by reduced FoxP3 expression and results in acquisition of effector phenotypes by the production of pro-inflammatory cytokines. Effector cell transformation of Helios-deficient tregs in tumor-tissue microenvironment is associated with increased expression of genes controlling the Teff phenotype (Yates et al, 2018, pnas,2018, 115:2162-2167). Acquisition of the unstable phenotype by Helios deficiency occurs only in the Tumor Microenvironment (TME), but not in peripheral lymphoid organs (Nakagawa et al 2016, PNAS113:6248-6253). In chronic inflammatory TMEs, helios deficiency in tregs can dramatically alleviate the genetic program of inhibition associated with T-helper cell differentiation by up-regulating T-helper cell related TF and effector cytokines. These genetic changes in Helios-deficient tregs are most pronounced in Treg sub-populations with high autoantigen affinity, as shown by enhanced GITR/PD-1 expression and increased responsiveness to autoantigens. Their combined effects can promote the phenotypic conversion of tregs to Teff in TMEs, engagement with increased T-cell receptors (TCRs) and co-stimulatory receptor expression by tregs, suggesting that modification of gene expression, which is a major feature of Treg conversion, is immune environment dependent (Yates et al 2018).
Reduced Helios expression in foxp3+cd4 tregs may allow memory Treg cells to be transformed into Teff cells that express autoreactive T-cell receptors with specificity for tumor antigens. Altered Treg gene characteristics can be selectively induced in chronic inflammatory conditions of growing tumors. Helios-deficient tregs may show a high affinity TCR repertoire that is biased towards self peptides/MHC, which may promote robust activation in TMEs (Yates et al, 2018). Given the increased autoreactivity of TCRs in CD4 tregs as compared to conventional T cells, treg transformation can produce a highly potent effect on CD 4T cells, with reduced Treg-mediated suppression within TME. More efficient strategies may depend on methods of selectively transforming intratumoral tregs into Teff cells without affecting the systemic Treg population. As a key role in maintaining Treg size and functional stability to different immune perturbation responses, pharmacological intervention by Helios may be associated with strategies that potentiate current tumor immunotherapy. Because Treg conversion to Teff may be limited to the inflammatory intratumoral microenvironment, antibody or small molecule based approaches targeting Helios may result in improved Treg-dependent cancer immunotherapy. Importantly, helios-deficient Treg transformation occurs only within the local inflammatory environment of the tumor. This approach may not provoke autoimmune side effects associated with systemic reduction of tregs. Thus, strategies that exploit in particular the Helios-dependent control of the intratumoral Treg phenotype represent an important prospect for improving cancer immunotherapy. Furthermore, removal of Foxp3+ tregs to enhance vaccine-induced anti-tumor T-cell responses has also been reported (Nishikawa et al, 2010,Int.J.Cancer 127:759-767), suggesting that reducing Helios levels may be beneficial in enhancing the efficacy of cancer vaccines.
In addition to anti-tumor immunotherapy, treg cells can limit the immunopathology due to excessive inflammation during viral infection, as well as potentially inhibit potent antiviral T cell responses and promote viral persistence (Schmitz et al, 2013,PLOS Pathogens 9:e1003362). Chronic (but non-acute) infection of mice with lymphocytic choriomeningitis virus results in significant expansion of foxp3+ tregs, suggesting that certain infectious agents may escape the underlying mechanisms of host immune response by activating and expanding tregs (punkody et al 2011, pnas108:3677-3682). Therapeutic benefit may be achieved by reducing the level of Helios in activated tregs in the context associated with chronic viral infections.
There is a need for compounds that are useful as inhibitors of the Helios protein.
Disclosure of Invention
The present invention provides pyridyl-substituted oxoisoindoline compounds of formula (I) or salts thereof, useful for reducing the level of Helios protein, reducing the level of Helios activity and/or inhibiting the level of Helios expression in a cell.
The present invention also provides pharmaceutical compositions comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
The invention also provides a method of treating a disease or condition by reducing the activity of the Helios protein, which method comprises administering to a patient a compound of formula (I) and/or a pharmaceutically acceptable salt thereof.
The invention also provides methods and intermediates for preparing compounds of formula (I) and/or salts thereof.
The invention also provides a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, for use in therapy.
The invention also provides the use of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the level of Helios protein in a cell, reducing the level of Helios activity and/or inhibiting the level of Helios expression to control Treg differentiation, for the treatment of certain diseases, including cancer and viral infections.
The compounds of formula (I) and compositions comprising the compounds of formula (I) are useful in the treatment, prevention or cure of viral infections and various proliferative disorders, such as cancer. Pharmaceutical compositions comprising these compounds are useful in treating, preventing or slowing the progression of diseases or conditions in a variety of therapeutic areas, such as viral infections and cancers.
These and other features of the invention will be set forth in a more expanded form as the invention proceeds.
Detailed Description
Applicants have discovered substituted oxoisoindoline compounds that inhibit Helios proteins by promoting interactions between the Helios proteins and the corresponding E3 ubiquitin ligase complex (Cullin 4-Cereblon, CUL 4-CRBN). These compounds reduce the level of Helios protein in cells, reduce the level of Helios activity, and/or inhibit the level of Helios expression to control Treg differentiation. These compounds are useful in the treatment of certain diseases, including cancer and viral infections. The compounds are provided for use as pharmaceuticals having desirable stability, bioavailability, therapeutic index and toxicity values important to their patentability.
In a first aspect the present invention provides at least one compound of formula (I):
or a salt thereof, wherein:
R 1 is-NH 2 or-NH (CH) 3 );
Each R is 2 Is independently F, cl, -CN, C 1-4 Alkyl, -CH 2 F、-CHF 2 、-CF 3 、-OCH 3 Or cyclopropyl;
each R is 4 Is independently F, cl, -CH 3 、-CH 2 F、-CHF 2 、-CF 3 or-OCH 3 ;
R 6 Is hydrogen, C 1-2 Alkyl or C 1-2 A fluoroalkyl group;
m is 0, 1, 2 or 3; and is also provided with
n is 0, 1, 2 or 3;
with the proviso that when R 6 In the case of hydrogen, m is 1, 2 or 3.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 1 is-NH 2 。
One embodiment provides a formulation of formula (I)A compound or salt thereof, wherein R 1 is-NH (CH) 3 )。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently F, cl, -CN, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 F、-CHF 2 、-CF 3 、-OCH 3 Or cyclopropyl.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently F, cl, -CN, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 F、-CHF 2 or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently F, cl, -CN, -CH 3 、-CH 2 CH 3 、-CH 2 F、-CHF 2 or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently F, cl, -CN, -CH 3 or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently-CN, -CH 3 or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently F, -CN, -CH 3 or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently F, -CN or-CH 3 。
An embodiment provides a compound of formula (I) or a salt thereof, wherein n is 0, 1 or 2.
An embodiment provides a compound of formula (I) or a salt thereof, wherein n is 0 or 1.
An embodiment provides a compound of formula (I) or a salt thereof, wherein n is 1 or 2.
An embodiment provides a compound of formula (I) or a salt thereof, wherein n is 0.
An embodiment provides a compound of formula (I) or a salt thereof, wherein n is 1.
An embodiment provides a compound of formula (I) or a salt thereof, wherein n is 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently-CN, -CH 3 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And n is 0, 1 or 2. Included in this embodiment are compounds wherein n is 1 or 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently-CN, -CH 3 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And n is 0 or 1. Included in this embodiment are compounds wherein n is 1.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 Is independently-CN, -CH 3 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And n is 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 independently-CN or-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And n is 1 or 2. Included in this embodiment are compounds wherein n is 1. Also included in this embodiment are compounds wherein n is 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 2 independently-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And n is 1 or 2. Included in this embodiment are compounds wherein n is 1. Also included in this embodiment are compounds wherein n is 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 4 Is independently F, cl, -CH 3 、-CH 2 F、-CHF 2 or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 4 Is independently F, -CH 3 、-CH 2 F、-CHF 2 or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 4 Is independently F, -CH 3 、-CHF 2 or-CF 3 。
One or more ofEmbodiments provide compounds of formula (I) or a salt thereof, wherein each R 4 Independently F or-CH 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 4 F. Included in this embodiment are compounds wherein m is 1. Also included in this embodiment are compounds wherein m is 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein each R 4 is-CH 3 . Included in this embodiment are compounds wherein m is 1. Also included in this embodiment are compounds wherein m is 2.
An embodiment provides a compound of formula (I) or a salt thereof, wherein m is 0, 1 or 2.
An embodiment provides a compound of formula (I) or a salt thereof, wherein m is 0 or 1.
An embodiment provides a compound of formula (I) or a salt thereof, wherein m is 1 or 2.
An embodiment provides a compound of formula (I) or a salt thereof, wherein m is 1, 2 or 3.
An embodiment provides a compound of formula (I) or a salt thereof, wherein m is 1.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; and m is 1, 2 or 3.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; and m is 1 or 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; and m is 1.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; and m is 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; and m is 3.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; m is 1; and R is 4 Is F, cl, -CH 3 、-CH 2 F、-CHF 2 or-CF 3 . Included in this embodiment are those wherein R 4 Is F, -CH 3 、-CHF 2 or-CF 3 Is a compound of (a). Also included in this embodiment are those wherein R 4 Is F, -CH 3 or-CF 3 Is a compound of (a). In addition, included in this embodiment are those wherein R 4 Is F or-CH 3 Is a compound of (a).
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; m is 1; and R is 4 F.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; m is 1; and R is 4 is-CH 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is hydrogen; m is 1 or 2; and R is 4 Is F or-CH 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl or C 1-2 A fluoroalkyl group.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl, -CH 2 F、-CF 2 H、-CF 3 or-CH 2 CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl, -CH 2 F、-CF 2 H or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 An alkyl group.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 is-CH 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 is-CH 2 F、-CF 2 H、-CF 3 or-CH 2 CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 is-CH 2 F、-CF 2 H or-CF 3 。
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl or C 1-2 A fluoroalkyl group; and m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl, -CH 2 F、-CF 2 H、-CF 3 or-CH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl, -CH 2 F、-CF 2 H or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 Alkyl or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 Is C 1-2 An alkyl group; and m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 is-CH 2 F、-CF 2 H、-CF 3 or-CH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 6 is-CH 2 F、-CF 2 H or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And m is 0.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 1 is-NH 2 or-NH (CH) 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Each R is 2 Is independently-CN, -CH 3 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 4 Independently F or-CH 3 ;R 6 Is hydrogen or-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the m is 0 or 1; and n is 1 or 2; with the proviso that when R 6 When hydrogen, m is 1.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 1 is-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 2 Is independently-CN, -CH 3 or-CF 3 ;R 4 Is F or-CH 3 ;R 6 Is hydrogen or-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the m is 0 or 1; and n is 1 or 2; with the proviso that when R 6 When hydrogen, m is 1.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 1 is-NH (CH) 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Each R is 2 independently-CN or-CH 3 ;R 4 Is F or-CH 3 ;R 6 Is hydrogen or-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the m is 0 or 1; and n is 1 or 2; with the proviso that when R 6 When hydrogen, m is 1.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 1 is-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 2 Is independently-CN, -CH 3 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 4 Independently F or-CH 3 ;R 6 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the m is 1; and n is 1 or 2. Included in this embodiment are those wherein each R 2 is-CH 3 Is a compound of (a).
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 1 is-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 2 independently-CN or-CH 3 ;R 4 Is F or-CH 3 ;R 6 Is hydrogen; m is 1; and n is 1 or 2.
One embodiment provides a compound of formula (I) or a salt thereof, wherein R 1 is-NH 2 or-NH (CH) 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Each R is 2 independently-CH 3 ;R 4 F is the same as F; r is R 6 Is hydrogen or-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the m is 0 or 1; and n is 1 or 2; with the proviso that when R 6 When hydrogen, m is 1.
One embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
One embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, having the structure:
one embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is: 2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (1); 2-amino-6- (2, 6-dioxopiperidin-3-yl) -6-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (2); 2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (3); 3- (5- (6-amino-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (4); 3- (5- (6-amino-4- (trifluoroethyl) pyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (5); 3- (4-fluoro-5- (4-methyl-6- (methylamino) pyridin-2-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (6); 3- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (7); 3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (8); 3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (9); 2-amino-6- ((3S) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (10); 2-amino-6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (11); 3- ((S) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (12); 3- ((R) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (13); 6- ((3S) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile (14); 6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile (15); 3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (16); 3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (17); 3- (5- (6-amino-3-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (18); 3- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (19); 3- (5- (6-amino-3-fluoro-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (20); 3- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (21-22); 2-amino-6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (23); 3- ((R) -5- (6-amino-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (24); 3- ((R) -5- (6-amino-4- (trifluoromethyl) pyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (25); 3- ((R) -5- (6-amino-3-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (26); 3- ((R) -5- (6-aminopyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (27); (R) -3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (28); 3- ((R) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (29); or 3- ((S) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (30).
An embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is 3- ((R) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione.
An embodiment provides a compound of formula (I) or a salt thereof, wherein the compound is 3- ((S) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione.
The present application may be embodied in other specific forms without departing from its spirit or essential attributes. The present application includes all combinations of aspects and/or implementations of the application specified in the present application. It is to be understood that any and all embodiments of the application may be employed in conjunction with any other embodiment or embodiments to describe further embodiments. It should also be understood that each individual element of these embodiments is intended to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
The features and advantages of the present application will be more readily understood by those skilled in the art after reading the following embodiments. It is to be appreciated that certain features of the application, which are, for clarity, described above and below in the context of separate implementations, may also be combined to form a single implementation. Conversely, various features of the application, which are, for brevity, described in the context of a single embodiment, may also be combined to form sub-combinations thereof. The embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.
References in the singular may also include the plural unless specifically stated otherwise in this disclosure. For example, "a" or "an" may refer to one or more.
As used herein, the phrase "compound and/or salt thereof" refers to at least one compound, a salt of at least one compound, or a combination thereof. For example, the compounds of formula (I) and/or salts thereof comprise compounds of formula (I); two compounds of formula (I); salts of the compounds of formula (I); a compound of formula (I) and one or more salts of a compound of formula (I); and salts of two or more compounds of formula (I).
Unless otherwise specified, it is assumed that any atom having a valence that is not satisfied has a hydrogen atom sufficient to satisfy the valence.
The definitions set forth in this disclosure take precedence over the definitions set forth in any patent, patent application, and/or patent application publication that is incorporated by reference herein.
The definitions of the various terms used to describe the present application are set forth below. These definitions apply to these terms as they are used throughout this specification, individually or as part of a larger group (unless otherwise limited to a particular example).
Throughout this specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
According to the convention used in the art,bonds used in the formulae herein to describe the point of attachment of a moiety or substituent to a core or backbone structure.
As used herein, the terms "halo" and "halogen" refer to F, cl, br and I.
The term "cyano" refers to the group-CN.
The term "amino" refers to the group-NH 2 。
The term "oxo" refers to the group = O.
As used herein, the term "alkyl" refers to both branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (exampleSuch as n-butyl, isobutyl, sec-butyl and tert-butyl) and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl and 4-methylpentyl. When a number appears in the subscript following the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-4 Alkyl "means straight and branched alkyl groups having 1 to 4 carbon atoms.
As used in the present application, the term "fluoroalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 Fluoroalkyl is intended to include C substituted with one or more fluorine atoms 1 、C 2 、C 3 C (C) 4 An alkyl group. Representative examples of fluoroalkyl groups include, but are not limited to, -CF 3 -CH 2 CF 3 。
The compounds of the present application include all isotopes of atoms that are found in the compounds of the present application. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotope of carbon contains 13 C, C is a metal alloy 14 C. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the present application using a suitable isotopically-labeled reagent in place of the non-labeled reagent originally employed.
The phrase "pharmaceutically acceptable" is employed in the present application to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
The compounds of formula (I) may form salts which are also within the scope of the present application. Unless otherwise indicated, references to the compounds of the present application should be understood to include references to one or more salts thereof. The term "salt" means an acidic and/or basic salt formed with inorganic and/or organic acids and bases. Furthermore, the term "salt" may comprise zwitterionic (inner salts), for example, when the compounds of formula (I) contain basic moieties such as amine or pyridine or imidazole rings and acidic moieties such as carboxylic acids. Pharmaceutically acceptable (i.e., non-toxic physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts, wherein the cations do not significantly contribute to the toxicity or biological activity of the salt. However, other salts in the isolation or purification steps that may be employed during preparation, for example, may be useful and are, therefore, within the scope of the present application. Salts of the compounds of formula (I) may be formed, for example, by reacting a compound of formula (I) with an amount of an acid or base, such as an equivalent, in a medium such as one in which the salt precipitates or in an aqueous medium, followed by lyophilization.
Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphoric acid, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), hydroiodide, maleate (formed with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as those formed with sulfuric acid), sulfonate (such as those mentioned in the present application), tartrate, thiocyanate, tosylate, undecanoate, and the like.
Exemplary basic salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines (such as triethylamine), procaine (procaine), dibenzylamine, N-benzyl- β -phenethylamine, 1-dibenzenemethylolamine, N' -dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines, and salts with amino acids (such as arginine, lysine, etc.). Basic nitrogen-containing groups may be quaternized with agents such as: lower carbon alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
The compounds of formula (I) may be provided as amorphous solids or as crystalline solids. Lyophilization may be employed to provide the compound of formula (I) as a solid.
It is further understood that solvates (e.g., hydrates) of the compounds of formula (I) are also within the scope of the present application. The term "solvate" means a physical association of a compound of formula (I) with one or more solvent molecules (whether organic or inorganic). This physical association comprises hydrogen bonding. In certain examples, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to separate. "solvate" includes both solution phases and separable solvates. Exemplary solvates include hydrates, glycolates, methanolates, isopropanates, acetonitrile solvates and ethyl acetate solvates. Methods of solvation are known in the art.
Various forms of prodrugs are well known in the art and are described in Rautio, J. Et al, nature Review Drug Discovery,17,559-587 (2018).
Furthermore, after the preparation of the compound of formula (I), it may be isolated and purified to obtain a composition ("substantially pure") containing the compound of formula (I) in an amount equal to or greater than 99% by weight, which is then used or formulated as described in the present application. This "substantially pure" compound of formula (I) is also contemplated as part of the present application.
"stabilizing compound" and "stabilizing structure" are intended to indicate compounds that are sufficiently robust to survive isolation from a reaction mixture to a useful purity, and formulation into an effective therapeutic agent. The present application is intended to embody stable compounds.
The term "Helios inhibitor" refers to an agent that decreases the level of Helios protein in a cell, decreases the level of Helios activity, and/or inhibits the level of Helios expression to control Treg differentiation. The Helios inhibitor may be a reversible or irreversible inhibitor.
As used herein, "Helios" protein refers to a protein that is a member of the Ikaros family of zinc finger proteins. In humans, helios is encoded by the IKZF2 gene. Helios is also known as IKAROS family zinc finger 2, ANF1A2, ZNF1A2, ZNFN1A2, zinc finger subfamily 1A,2, and Ikaros family zinc finger protein 2. Members of this protein family include Ikaros, helios, aiolos, eos and Pegasus. As used in the present application, the Helios protein comprises various isoforms comprising isoforms 1 to 5 listed below.
Isoform 1 (UniProt Q9UKS 7-1)
Isoform 2 (UniProt Q9UKS 7-2)
Isoform 4 (UniProt Q9UKS 7-4)
Isotype 6 (UniProt Q9UKS 7-6)
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Isoform 7 (UniProt Q9UKS 7-7)
The "Helios" isoforms 1, 2, 4, 6 and 7 listed above comprise the down-resolution stator FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (bolded and underlined). The degradation stator is part of a protein that plays a role in regulating the rate of protein degradation.
As used in the present application, the "Eos" protein is encoded by the IKZF4 gene and is also known as IKAROS family zinc finger 4, ZNFN1A4, zinc finger subfamily 1A,4, ikaros family zinc finger protein 4 and KIAA1782. The "Eos" protein comprises isoforms encoded by the following two human isoforms 1 (Q9H 2S 9-1) and 2 (Q9H 2S 9-2):
isotype 1 (UniProt Q9H2S 9-1)
Isotype 2 (UniProt Q9H2S 9-2)
The "Eos" protein isoforms 1 and 2 listed above comprise degradation determinant FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (bolded and underlined) which is identical to the degradation determinant of the "Helios" protein.
As used in the present application, the "Ikaros" protein is encoded by the IKZF1 gene. Ikaros is also known as IKAROS family zinc finger 1, ZNFN1A1, zinc finger subfamily 1A,1, ikaros family zinc finger protein 1, IK1, lymphotranscription factor LyF-1, hs.54452, PPP1R92, protein phosphatase 1, regulatory subunit 92, PRO0758, CVID13, and CLL associated antigen KW-6. The Ikaros protein comprises isoforms encoded by the amino acid sequences Q13422-1, Q13422-2, Q13422-3, Q13422-4, Q13422-7 and Q13422-8. The Ikaros protein also comprises isoforms encoded by the amino acid sequences Q13422-5 and Q13422-6.
As used in the present application, the "Aiolos" protein is encoded by the IKZF3 gene. Aiolos proteins are also known as IKAROS family zinc finger protein 3, ZNFN1A3, zinc finger subfamily 1A,3, ikaros family zinc finger protein 3, and AIO. The Aiolos protein comprises isoforms encoded by the amino acid sequences Q9UKT9-1, Q9UKT9-3, Q9UKT9-4, Q9UKT9-6, Q9UKT9-7, Q9UKT9-8, Q9UKT9-9 and Q9UKT 9-14. The Aiolos protein also comprises isoforms encoded by the amino acid sequences Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12 and Q9UKT9-13, Q9UKT9-15 and Q9UKT 9-16.
As used herein, the "Pegasus" proteins are also referred to as IKAROS family zinc finger protein 5, ZNFN1A5, zinc finger subfamily 1A,5, and Ikaros family zinc finger protein 5.Pegasus is encoded by the IKZF5 gene.
As used herein, the term "contacting" refers to bringing together designated portions into an extracorporeal or an intracorporal system. For example, "contacting" a compound of formula (I) with a compound of formula (I) includes administering a compound of the application to an individual or patient (such as a human) having a compound of formula (I), and, for example, introducing the compound of formula (I) into a cell-containing sample or a purified preparation containing the compound of formula (I).
As used herein, the term "treatment" refers to any type of intervention or treatment performed on a subject, or administration of an active agent to a subject, with the goal of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical markers associated with a disease. In contrast, "prophylaxis" refers to administration to a subject not suffering from a disease to prevent the occurrence of the disease. "treatment" does not include prophylaxis (prophlaxis).
"therapeutically effective amount" is intended to encompass an amount of a compound of the application alone or in combination with a claimed compound or an amount of a compound of the application in combination with other active ingredients effective to reduce the level of Helios protein in a cell, reduce the level of Helios activity and/or inhibit the level of Helios expression or to treat or prevent viral infections and proliferative disorders such as cancer.
As used herein, the term "cell" is intended to refer to a cell in vitro, ex vivo, or in vivo. In some embodiments, the ex vivo cells may be part of a tissue sample excised from an organism (such as a mammal). In some embodiments, the cells in vitro may be cells in cell culture. In some embodiments, the in vivo cell is a cell that lives in an organism (such as a mammal).
The term "patient" includes humans and other mammalian subjects receiving therapeutic or prophylactic treatment.
The term "subject" encompasses any human or non-human animal. For example, the methods and compositions disclosed herein can be used to treat a subject suffering from cancer. Non-human animals include all vertebrates, e.g., mammals and non-mammals, including non-human primates, sheep, dogs, cows, chickens, amphibians, reptiles, and the like. In one embodiment, the subject is a human subject.
As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate, or stearic acid), or solvent encapsulation material that involves carrying or transporting the subject compound from one organ or portion of the body to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including (i.e., adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating, and dispersing agents, depending on the nature of the mode of administration and the dosage form; and is harmless to the patient.
The term "pharmaceutical composition" means a composition comprising a compound of the application in combination with at least one additional pharmaceutically acceptable carrier.
Practicality of use
The compounds of formula (I) are useful in the treatment of cancer.
In one embodiment, the present application provides a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and a combination of additional therapeutic agents for simultaneous, separate or sequential use in the treatment and/or prophylaxis of a variety of diseases or conditions associated with the activity of Helios protein. The combination formulation can be used to reduce the level of Helios protein, the level of Helios activity and/or the level of Helios expression in a cell to control Treg differentiation.
The compounds of formula (I) and pharmaceutical compositions comprising at least one compound of formula (I) are useful for treating or preventing any disease or condition associated with the activity of the Helios protein. These include viruses and other infections (e.g., skin infections, GI infections, urinary tract infections, genitourinary infections, systemic infections) and proliferative diseases (e.g., cancer). The compounds of formula (I) and pharmaceutical compositions comprising at least one compound of formula (I) may be administered to animals, preferably mammals (e.g., domestic animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration may be used to deliver the compound or pharmaceutical composition to a patient. In certain embodiments, the compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) is administered orally. In other embodiments, formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) is administered parenterally.
The compounds of formula (I) can selectively reduce the level of Helios protein, reduce the level of Helios activity, and/or inhibit the level of Helios expression in cells to control Treg differentiation. For example, the compounds of formula (I) may be used to selectively reduce the level of Helios activity and/or inhibit the level of Helios expression in a cell to control Treg differentiation in a cell or individual in need of reduction of the level of Helios protein, reduction of the level of Helios activity and/or inhibition of the level of Helios expression by administering an inhibitory amount of a compound of formula (I) or a salt thereof.
In one aspect, the compound(s) of formula (I) are administered sequentially prior to administration of the immunooncology agent. In another aspect, the compound of formula (I) is administered concurrently with the immunooncology agent. In yet another aspect, the compound of formula (I) is administered sequentially after administration of the immunooncology agent.
In another aspect, the compounds of formula (I) may be co-formulated with an immunooncology agent.
Immunooncology agents include, for example, small molecule drugs, antibodies, or other organisms or small molecules. Examples of biological immunooncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.
In one aspect, the immunooncology agent is either (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on a T cell, both of which result in an amplified antigen-specific T cell response (commonly referred to as an immune checkpoint modulator).
Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which comprises B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the cognate TNF receptor family, comprising CD40 and CD40L, OX-40, OX-40L, CD, CD27L, CD, CD30L, 4-1BBL, CD137 (4-1 BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT beta R, LIGHT, dcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha/TNF beta, TNFR2, TNFR, lymphotoxin alpha 1 beta 2, FAS, FASL, RELT, DR, TROY, NGFR.
In one aspect, the T cell response may be stimulated by a combination of a compound of formula (I) and one or more of the following: (i) Antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4, and (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD 137), 4-1BBL, ICOS, ICOS-L, OX, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
Other agents that may be used in combination with the compounds of formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds of formula (I) may be combined with an antagonist of KIR, such as Li Lushan anti (lirilumab).
Still other agents of combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155 (WO 11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO 13/132044) or FPA-008 (WO 11/140249, WO13169264, WO 14/036357).
In another aspect, the compounds of formula (I) may be used with one or more of the following: agonists that bind positive co-stimulatory receptors, blockers, antagonists and one or more agents that systematically increase the frequency of anti-tumor T cells through inhibitory receptors, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Treg (e.g., use of anti-CD 25 monoclonal antibodies (e.g., daclizumab) or deplete by ex vivo anti-CD 25 beads), inhibit metabolic enzymes (such as IDO) or reverse/prevent T cell failure or depletion), and agents that trigger innate immune activation and/or inflammation at the tumor site.
In one aspect, the immunooncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab (tremelimumab).
In another aspect, the immunooncology agent is a PD-1 antagonistAn agent, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO TM (na Wu Liyou mab (nivolumab)), KEYTRUDA TM (pambrizumab) or MEDI-0680 (AMP-514; wo 2012/145493). The immunooncology agent may also include Pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting PD-1 receptors is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1 (referred to as AMP-224).
In another aspect, the immunooncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG 7446; WO 2010/077634), dewaruzumab (durvalumab) (MEDI 4736), BMS-936559 (WO 207/005874) and MSB0010718C (WO 2013/79174).
In another aspect, the immunooncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO 10/19570, WO 14/08218), or IMP-731 or IMP-321 (WO 08/132601, WO 09/44273).
In another aspect, the immunooncology agent is a CD137 (4-1 BB) agonist, such as an agonistic CD137 antibody. Suitable antibodies to CD137 include, for example, wu Ruilu mab (urelumab) and PF-05082566 (WO 12/32433).
In another aspect, the immunooncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable antibodies to GITR include, for example, BMS-986153, BMS-986156, TRX-518 (WO 06/105021, WO 09/009116) and MK-4166 (WO 11/028683).
In another aspect, the immunooncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO 206/122150, WO07/75598, WO 08/36653, WO 08/36642), indoximod (indoximod), or NLG-919 (WO 09/73620, WO09/1156652, WO11/56652, WO 12/142237).
In another aspect, the immunooncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.
In another aspect, the immunooncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO 06/029879).
In another aspect, the immunooncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immunooncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, poncirumab (lucatumumab) or dactylotheca monoclonal antibody (daceatuzumab).
In another aspect, the immunooncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varluab (vardilumab).
In another aspect, the immunooncology agent is MGA271 (to B7H 3) (WO 11/109400).
Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents or at least two of these therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration may be achieved, for example, by administering a single dosage form of each therapeutic agent with a fixed ratio to the subject or in multiple single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of the therapeutic agents may be accomplished by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination may be administered by intravenous injection, while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy may also comprise administration of a therapeutic agent as described above in further combination with other bioactive ingredients and non-drug therapies (e.g., surgery or radiation therapy). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be performed at any suitable time, so long as the beneficial effect from the combined action of the therapeutic agent and the non-drug treatment is achieved. For example, where appropriate, the beneficial effect is still achieved when the non-drug treatment may be temporarily removed from the administered therapeutic agent for days or even weeks.
Types of cancers that may be treated with the compounds of formula (I) include, but are not limited to, brain, skin, bladder, ovary, breast, stomach, pancreas, prostate, colon, blood, lung and bone cancers. Examples of these types of cancer include neuroblastoma, intestinal cancer (such as rectal cancer, colon cancer, familiar adenomatous polyp cancer and hereditary non-polyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumor (such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroblastoma), hodgkin's (Hodgkin) lymphoma non-Hodgkin's lymphoma, burkitt's lymphoma, acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchi carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, ewing's sarcoma, and plasmacytoma.
One or more additional agents or methods of treatment, such as, for example, antiviral agents, chemotherapeutic agents or other anticancer agents, immunopotentiators, immunosuppressives, radiation, anti-tumor and antiviral vaccines, cytokine therapies (e.g., IL2 and GM-CSF) and/or tyrosine kinase inhibitors, may optionally be used in combination with the compound of formula (I) for the treatment of a Helios protein-related disease, disorder or condition. These agents may be combined with the compounds of the present invention in a single dosage form, or the agents may be administered simultaneously or sequentially in separate dosage forms.
Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to nitrogen mustard, ethyleneimine derivatives, and the like),Alkyl sulfonates, nitrosoureas, and triazenes), such as uratemustine (uracilmuttadine), nitrogen mustard (chlorrethane), cyclophosphamide (CYTOXAN) TM ) Ifosfamide, melphalan (melphalan), chlorambucil (chlorrambucil), pipobromine (pipobroman), triethylene-melamine, triethylenethiophosphamine (busulfan), carmustine (carmustine), robustamine (lomustine), streptozocin (streptozocin), dacarbazine (dacarbazine), temozolomide (temozolomide).
In treating melanoma, suitable agents for use in combination with the compounds of formula (I) include: dacarbazine (DTIC), optionally together with other chemotherapeutic agents, such as carmustine (BCNU) and cisplatin (cispratin); "Dartmouth protocol", which consists of DTIC, BCNU, cisplatin, tamoxifen (tamoxifen); cisplatin (vinblastine) and DTIC, temozolomide or YERVOY TM Is a combination of (a) and (b). The compounds of formula (I) may also be used in combination with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2 and Tumor Necrosis Factor (TNF), to treat melanoma.
The compounds of formula (I) may also be used in combination with vaccine therapies for the treatment of melanoma. Anti-melanoma vaccines are similar in some respects to antiviral vaccines, which are used to prevent diseases caused by viruses such as polio (polio), measles (measles), and mumps (mumps). Weakened melanoma cells, or portions of melanoma cells, called antigens, can be injected into a patient to stimulate the body's immune system to destroy the melanoma cells.
Melanoma localized to the arm or leg can also be treated with a combination of agents comprising one or more compounds of formula (I) using a hyperthermic isolated limb perfusion technique. This therapeutic protocol temporarily decouples the circulation involving the limb from the rest of the body and injects high doses of chemotherapeutic agents into the arteries that nourish the limb, thus providing high doses to the tumor area without exposing the internal organs to those doses that could otherwise cause serious side effects. The fluid is typically warmed to 38.9 ℃ to 40 ℃. Melphalan is the most common drug in this chemotherapy procedure. This may be provided by another agent known as Tumor Necrosis Factor (TNF).
Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including without limitation folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate (methotrerate), 5-fluorouracil, fluorouridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate (fludarabine), penstadine (pentastatine), and gemcitabine (gemcitabine).
Suitable chemotherapeutic or other anticancer agents further include, for example, certain natural products and derivatives thereof (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins), such as vinblastine (vinblastine), vincristine (vindesine), bleomycin (bleomycin), dactinomycin (dactinomycin), daunomycin (daunorubicin), doxorubicin (doxorubicin), epirubicin (epirubicin), idarubicin (idarubicin), ara-C, paclitaxel (paclitaxel) (Taxol), mithramycin (mithramycin), deoxyendo-formycin (mitomycin) -C, L-asparaginase, interferon (especially IFN-a), etoposide (etoposide) and teniposide (iposide).
Other cytotoxic agents include novelties (navlbene), CPT-11, anastrozole (anastrazole), letrozole (letrozole), capecitabine (capecitabine), raloxifene (reloxafine), and droloxifene (droloxifene).
Also suitable are cytotoxic agents such as epi-phyllotoxin (epothilone), antineoplastic enzyme, topoisomerase inhibitor, procarbazine (procarbazine), mitoxantrone (mitoxantrone), platinum complex compounds such as cisplatin and carboplatin, biological response modifiers, growth inhibitors, antihormonal therapeutic agents, leucovorin (leucovorin), tegafur (tegafur) and hematopoietic growth factors.
Other anticancer agents include antibody therapeutics, such as trastuzumab (trastuzumab)Antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-1O or TGF-beta).
Other anti-cancer agents also include those that block immune cell migration, such as antagonists of chemokine receptors (including CCR2 and CCR 4).
Other anticancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell transfer.
Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.
The pharmaceutical compositions of the invention may optionally comprise at least one Signal Transduction Inhibitor (STI). A "signaling inhibitor" is an agent that selectively inhibits one or more important steps in the signaling pathway in normal function of cancer cells, resulting in apoptosis. Suitable STI include (but are not limited to): (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC TM ) The method comprises the steps of carrying out a first treatment on the surface of the (ii) Epidermal Growth Factor (EGF) receptor inhibitors such as, for example, kinase Inhibitors (IRESSA) TM SSI-774) and antibodies (Imclone: c225[ Goldstein et al Clin. Cancer Res.,1:1311-1318 (1995)]And Abgenix: ABX-EGF); (iii) her-2/neu receptor inhibitors, such as Farnesyl Transferase Inhibitors (FTIs), such as, for example, L-744,832 (Kohl et al, nat. Med.,1 (8): 792-797 (1995)); (iv) Inhibitors of Akt family kinases or Akt pathways, such as, for example, rapamycin (see, e.g., sekulic et al, cancer res.,60:3504-3513 (200)); (v) Cell cycle kinase inhibitors such as, for example, fraapidol (flavopiridol) and UCN-O1 (see, for example, sausville, curr. Med. Chem. Anti-canc. Agents,3:47-56 (203)); and (vi) phosphatidylinositol kinase inhibitors such as, for example, LY294002 (see, e.g., vlahos et al, J.biol. Chem.,269:5241-5248 (1994)). Alternatively, at least one STI and at least one compound of formula (I) may be in separate pharmaceutical compositions. In certain embodiments of the invention, at least one compound of formula (I) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) may be administered first, at least one STI may be administered first, or at least one compound of formula (I) and at least one STI may be administered simultaneously. In addition, when more than one compound of formula (I) and/or STI is used, these compounds may be any cis-isomer And (5) sequential application.
The invention further provides a pharmaceutical composition for treating a chronic viral infection in a patient comprising at least one compound of formula (I), optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent in a pharmaceutically acceptable carrier.
Also provided is a method of treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.
In a particular embodiment of the invention, at least one compound of formula (I) and at least one chemotherapeutic agent are administered to the patient simultaneously or sequentially. In other words, at least one compound of formula (I) may be administered first, at least one chemotherapeutic agent may be administered first, or at least one compound of formula (I) and at least one STI may be administered simultaneously. In addition, when more than one compound of formula (I) and/or chemotherapeutic agent is used, the compounds may be administered in any order. Similarly, any antiviral agent or STI may be administered at any point as compared to the administration of the compound of formula (I).
Chronic viral infections that can be treated using the combination of the invention include, but are not limited to, diseases caused by: hepatitis C Virus (HCV), human Papilloma Virus (HPV), cytomegalovirus (CMV), herpes Simplex Virus (HSV), ai Ba (Epstein-Barr) virus (EBV), varicella zoster virus, coxsackie virus, and Human Immunodeficiency Virus (HIV).
Suitable antiviral agents contemplated for use in combination with the compounds of formula (I) may include nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI), non-nucleotide reverse transcriptase inhibitors (NNRTI), protease inhibitors and other antiviral agents.
Examples of suitable NRTI include zidovudine (AZT), didanosine (ddl), zalcitabine (zalcitabine) (ddC), stavudine (stavudine) (D4T), lamivudine (lamivudine) (3 TC), abacavir (abacavir) (1592U 89), adefovir (adefovir dipivoxil) [ bis (POM) -PMEA ], lobucavir (lobucavir) (BMS-180194), BCH-I0652, emtricitabine (emtricitabine) [ (-) -FTC ], beta-L-FD 4 (also known as beta-L-D4C, and beta-L-2 ',3' -dideoxy-5-fluoro-cytidine), DAPD (-) -beta-D-2, 6-diamino-purine dioxolane), and lopinosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587), delavirdine (BHAP, U-90152), efavirenz (efavirenz) (DMP-266), PNU-142721, AG-1549, MKC-442 (1- (ethoxy-methyl) -5- (1-methylethyl) -6- (phenylmethyl) - (2, 4 (1H, 3H) -pyrimidinedione), and (+) -calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ritonavir) (ABT-538), indinavir (indinavir) (AG-639), nelfinavir (nelfinavir) (AG-1343), amprenavir (amprenavir) (141W 94), lasinavir (234475), BMS (DMP-25), BMS, IL-2322623, IL-1542, and other antiviral agents including ABP-1548, IL-378.
Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents or at least two of these therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration may be achieved, for example, by administering a single dosage form of each therapeutic agent with a fixed ratio to the subject or in multiple single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of the therapeutic agents may be accomplished by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination may be administered by intravenous injection, while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy may also comprise administration of a therapeutic agent as described above in further combination with other bioactive ingredients and non-drug therapies (e.g., surgery or radiation therapy). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be performed at any suitable time, so long as the beneficial effect from the combined action of the therapeutic agent and the non-drug treatment is achieved. For example, where appropriate, the beneficial effect is still achieved when the non-drug treatment may be temporarily removed from administration of the therapeutic agent for days or even weeks.
Pharmaceutical composition
The application also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds of formula (I) formulated with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally, one or more additional therapeutic agents as described above.
The compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for this route, and in a dose which is effective for the intended treatment. The compounds and compositions of the compounds of formula (I) may be administered by any suitable means for any of the uses described herein, for example, orally, such as tablets, capsules (each of which comprises a sustained release or timed release formulation), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried suspensions), syrups and emulsions; sublingual delivery; is applied to the cheek; parenteral, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in sterile injectable aqueous or non-aqueous solutions or suspensions); transnasal, including administration to the nasal membrane, such as by inhalation spray; topical, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories. They may be administered alone, but are generally administered with a pharmaceutical carrier selected based on the route of administration selected and standard pharmaceutical practice.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided in a tablet or capsule comprising an active ingredient in an amount ranging from about 0.1 to 1000mg, preferably from about 0.25 to 250mg, and more preferably from about 0.5 to 100 mg. The appropriate daily dosage for a human or other mammal may vary widely depending on the condition of the patient and other factors, but may be determined using conventional methods.
Any pharmaceutical composition contemplated in the present application may be delivered orally, e.g., via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs. Pharmaceutical compositions intended for oral administration may be prepared according to any method known in the art for manufacturing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable preparation, the pharmaceutical composition according to the present application may contain at least one agent selected from the group consisting of sweetening agents, flavouring agents, colouring agents, demulcents, antioxidants and preserving agents.
Tablets may be prepared, for example, by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for use in the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid; binders such as, for example, starch, gelatin, polyvinylpyrrolidone and acacia; and lubricants such as, for example, magnesium stearate, stearic acid, and talc. In addition, the tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption of the active ingredient in the gastrointestinal tract and thereby allow the effect of the active ingredient to last longer. Exemplary water-soluble taste masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplary time delay materials include, but are not limited to, ethylcellulose and cellulose acetate butyrate.
Hard gelatine capsules may be prepared, for example, by mixing at least one compound of formula (I) and/or at least one salt thereof with at least one inert solid diluent such as, for example, calcium carbonate, calcium phosphate and kaolin.
Soft gelatine capsules may be prepared, for example, by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one water-soluble carrier such as, for example, polyethylene glycol, and at least one oily medium such as, for example, peanut oil, liquid paraffin and olive oil.
The aqueous suspension may be prepared, for example, by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for use in the manufacture of aqueous suspensions. Exemplary excipients suitable for use in making aqueous suspensions include, but are not limited to, suspending agents such as, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth and acacia; dispersing or wetting agents such as, for example, naturally occurring phospholipids, e.g., lecithin; condensation products of alkylene oxides with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain fatty alcohols such as, for example, heptadecaethylene-oxycetyl alcohol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative such as, for example, ethyl parahydroxybenzoate and n-propyl parahydroxybenzoate; at least one colorant; at least one flavoring agent; and/or at least one sweetener, including, but not limited to, for example, sucrose, saccharin, and aspartame.
Oily suspensions may be prepared, for example, by suspending at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof in a vegetable oil, such as, for example, arachis oil, olive oil, sesame oil and coconut oil, or in a mineral oil such as, for example, liquid paraffin. The oily suspensions may also contain at least one thickening agent, such as, for example, beeswax, hard paraffin or cetyl alcohol. To provide a palatable oily suspension, at least one of the sweeteners and/or at least one flavoring agent already described above may be added to the oily suspension. The oily suspension may further contain at least one preservative including, but not limited to, for example, antioxidants such as, for example, butylated hydroxyanisole and alpha-tocopherol.
Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one dispersing and/or wetting agent, at least one suspending agent, and/or at least one preservative. Suitable dispersing agents, wetting agents and suspending agents have been described above. Exemplary preservatives include, but are not limited to, for example, antioxidants, such as ascorbic acid. In addition, the dispersible powders and granules may also contain at least one excipient including, but not limited to, for example, sweeteners, flavoring agents, and coloring agents.
An emulsion of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof may be prepared, for example, as an oil-in-water emulsion. The oil phase of an emulsion comprising a compound of formula (I) may be constituted in a known manner from known ingredients. The oily phase may be provided by, for example, but not limited to, vegetable oils (such as, for example, olive oil and peanut oil), mineral oils (such as, for example, liquid paraffin), and mixtures thereof. While this phase may contain only emulsifiers, it may contain at least one emulsifier in combination with a fat or oil or with both a fat and an oil. Suitable emulsifiers include, but are not limited to, for example, naturally occurring phospholipids, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Also preferably comprises both oil and fat. Together, the emulsifier(s), with or without stabilizers, constitute a so-called emulsifying wax, and the wax together with oils and fats constitute a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. The emulsion may also contain sweeteners, flavoring agents, preservatives and/or antioxidants. Emulsifying agents and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or with waxes, or other materials well known in the art.
The compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof may also be delivered intravenously, subcutaneously and/or intramuscularly, e.g. via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions, sterile oil-in-water microemulsions, and aqueous or oily suspensions that include an acceptable vehicle and a solvent such as, for example, water, ringer's solutions, and isotonic sodium chloride solutions.
Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules, either as one or more of the carriers or diluents mentioned for the formulation for oral administration, or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth, and/or various buffers. Other adjuvants and modes of administration are well known and widely known in the pharmaceutical arts. The active ingredient may also be administered by injection in a composition with a suitable carrier, including saline, dextrose, or water, or with cyclodextrin (i.e., captisol), cosolvent solubilisation (i.e., propylene glycol), or micelle solubilisation (i.e., tween 80).
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed are water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids (such as oleic acid) find use in the preparation of injectables.
The sterile injectable oil-in-water microemulsion may be prepared, for example, by: 1) Dissolving at least one compound of formula (I) in an oil phase such as, for example, a mixture of soybean oil and lecithin; 2) Combining formula (I) containing an oil phase with water and a glycerol mixture; and 3) treating the combination to form a microemulsion.
Sterile aqueous or oily suspensions may be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions may be prepared using non-toxic parenterally acceptable diluents or solvents, such as, for example, 1, 3-butanediol; and sterile oily suspensions may be prepared using a sterile, non-toxic, acceptable solvent or suspending medium, such as, for example, a sterile, fixed oil, e.g., synthetic mono-or diglycerides, and a fatty acid, such as, for example, oleic acid.
Pharmaceutically acceptable carriers are formulated according to many factors within the purview of those skilled in the art. These include (without limitation): the type and nature of the active agent being formulated, the subject to whom the agent-containing composition is to be administered, the intended route of administration of the composition, and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and nonaqueous liquid media, as well as various solid and semi-solid dosage forms. These carriers can comprise many different ingredients and additives other than the active agent, which additional ingredients are included in the formulation for various reasons well known to those skilled in the art (e.g., stabilizing the active agent, binder, etc.). Descriptions of suitable pharmaceutically acceptable carriers and factors related to their selection are found in various readily available sources such as, for example, allen, l.v. jr et al, remington, the Science and Practice of Pharmacy (volume 2), 22 nd edition (2012), pharmaceutical Press.
Pharmaceutically acceptable carriers, adjuvants and vehicles useful in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-alpha-tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms, such as Tween, polyethoxylated castor oil, such as CREMOPHOR TM Surfactant (BASF)) or other similar polymer delivery matrix), serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicaMagnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. Cyclodextrins (such as alpha-, beta-and gamma-cyclodextrin) or chemically modified derivatives (such as hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl cyclodextrins) or other solubilizing derivatives may also be advantageously used to enhance delivery of the compounds of the formulas described herein.
The pharmaceutically active compounds of the present application can be processed according to conventional dosage methods to produce medicaments for administration to patients, including humans and other mammals. The pharmaceutical composition may be subjected to conventional pharmaceutical procedures (such as sterilization) and/or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like. Tablets and pills may be prepared with additional enteric coatings. These compositions may also contain adjuvants such as wetting agents, sweeteners, flavoring agents and perfuming agents.
For therapeutic purposes, the active compounds of the invention are generally combined with one or more adjuvants suitable for the intended route of administration. If administered orally, the compound may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol and then tableted or packaged for convenient administration. These capsules or tablets may contain a controlled release formulation, such as may be provided in a dispersion of the active compound in hydroxypropyl methylcellulose.
The amount of compound administered and the dosage regimen for treating a condition with the compounds and/or compositions of the invention will depend on a variety of factors including the age, weight, sex, medical condition, type of disease, severity of the disease, route and frequency of administration of the subject and the particular compound employed. Thus, dosage regimens may vary widely, but may be routinely determined using standard methods. Daily doses of about 0.001 to 100mg/kg body weight, preferably between about 0.0025 and about 50mg/kg body weight and most preferably about 0.005 to 10mg/kg body weight may be suitable. Daily doses may be administered in 1 to 4 doses per day. Other dosing schedules include one dose per week and one dose per two-day cycle.
The pharmaceutical compositions of the present application comprise at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof, and optionally further agents selected from any pharmaceutically acceptable carriers, adjuvants and vehicles. Alternative compositions of the application comprise a compound of formula (I) as described herein or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
The application also encompasses pharmaceutical kits useful, for example, in the treatment or prevention of Helios protein related diseases or disorders and other diseases mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I). If desired, these kits may further comprise one or more of a variety of conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as would be apparent to one of skill in the art. Instructions as an insert or label indicating the amount of the component to be administered, the instructions for administration, and/or the instructions for mixing the components may also be included in the kit.
The dosage regimen of the compounds of the application will of course vary depending on known factors such as: pharmacodynamic characteristics of the particular agent, and mode and route of administration thereof; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the variety of combined treatments; treatment frequency; the route of administration, the renal and hepatic function of the patient, and the desired effect.
The daily oral dosage of each active ingredient, when used for the indicated effect, ranges from about 0.001 to about 5000 mg/day, preferably from about 0.01 to about 1000 mg/day and most preferably from about 0.1 to about 250 mg/day, via general guidelines. The most preferred dosage range during constant rate infusion is about 0.01 to about 10 mg/kg/minute intravenously. The compound of formula (I) may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
These compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) which are suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs and syrups, and are consistent with conventional pharmaceutical practices.
Dosage forms suitable for administration (pharmaceutical compositions) may contain from about 1 mg to about 200 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is typically present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition.
Typical capsules for oral administration contain at least one of the compounds of formula (I) (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
Typical injectable formulations are prepared by aseptically placing at least one of the compounds of formula (I) (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial were mixed with 2mL of physiological saline to produce an injectable formulation.
The present invention includes within its scope pharmaceutical compositions containing an active ingredient, a therapeutically effective amount of at least one of the compounds of formula (I), alone or in combination with a pharmaceutically acceptable carrier. Optionally, the compounds of formula (I) may be used alone, in combination with other compounds of formula (I), or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).
Regardless of the route of administration selected, the compounds of formula (I) and/or the pharmaceutical compositions of the invention, which may be used in the form of suitable hydrates, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of active ingredient that is effective to achieve a therapeutic response to a particular patient, composition, and mode of administration that is non-toxic to the patient.
The selected dosage level will depend on a variety of factors including the activity of the particular compound of formula (I) or ester, salt or amide thereof employed, the route of administration, the time of administration, the rate or metabolism of excretion or absorption of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or substances used in combination with the particular compound being employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated and the like factors well known in the medical arts.
The physician or veterinarian of ordinary skill in the art can readily determine the effective amount of the pharmaceutical composition required and prescribe it. For example, the physician or veterinarian may begin the dosage of the compound of formula (I) employed in the pharmaceutical composition at the level necessary to achieve the therapeutic effect and gradually increase the dosage until the effect is achieved.
In general, a suitable daily dose of a compound of formula (I) will be the amount of the compound at the lowest dose effective to produce a therapeutic effect. The effective dose generally depends on the factors described above. Generally, the compounds of formula (I) are administered orally, intravenously, intraventricularly, and subcutaneously to a patient in a dosage range of about 0.01 to about 50mg/kg body weight/day.
If desired, an effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses, optionally in unit dosage forms, administered separately at suitable intervals throughout the day. In certain aspects of the invention, the administration is one administration per day.
Although the compounds of formula (I) may be administered alone, it is preferred to administer the compounds in a pharmaceutical formulation (composition).
When employed in combination with a compound of formula (I), the above additional therapeutic agents may be used, for example, in amounts indicated in the physics' Desk Reference (PDR) or as determined otherwise by those skilled in the art. In the methods of the invention, these other therapeutic agents may be administered prior to, concurrently with, or after administration of the compounds of the invention.
Preparation method
The compounds of the present application may be prepared by a number of methods well known to those skilled in the art. The compounds of the present application may be synthesized using the methods described below, in conjunction with synthetic methods known in the art of synthetic organic chemistry or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited in this application are incorporated by reference in their entirety.
The compounds of the application may be prepared using the reactions and techniques described in this section. The reaction is carried out in a solvent suitable for the reagents and materials employed and for the conversion being effected. Also, in the following description of the synthetic method, it should be understood that the choice of all suggested reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and treatment operation, are standard conditions for the reaction, which should be readily recognized by one skilled in the art. Those skilled in the art of organic synthesis will appreciate that the functional groups present on the various moieties of the molecule must be compatible with the proposed reagents and reactions. These limitations of substituents compatible with the reaction conditions will be apparent to those skilled in the art and alternative methods must then be used. This sometimes requires judgment to modify the order of synthesis steps or to select one particular process scheme over another to obtain the compounds of the application. It will also be appreciated that another major consideration in planning any synthetic pathway in the art is the judicious choice of protecting groups for protecting the reactive functional groups present in the compounds described in the present application. Authoritative reports describing many alternatives to trained practitioners are Greene and Wuts (Protective Groups In Organic Synthesis, 4 th edition, wiley and Sons, 207).
The compounds of formula (I) may be prepared by reference to the methods illustrated in the schemes below. As shown therein, the final product is a compound having the same structural formula as formula (I). It will be appreciated that any compound of formula (I) may be produced by scheme through appropriate selection of reagents and appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art. The starting materials are commercially available or readily prepared by a person skilled in the art. The composition of the compounds is as defined herein or elsewhere in this specification.
The general route for the compounds described in the present application is illustrated in schemes 1 to 2, wherein R 1 、R 2 、R 4 R is R 6 Previously defined in the text or as functional groups that can be converted to the final substituents. Substituent X is a leaving group such as a halide (preferably I, br)Or Cl) or triflate. The substituents M are suitable coupling partners, such as boric acid, boric acid esters or stannanes. The substituent R is a carboxylic acid protecting group such as t-butyl, methyl, ethyl or benzyl. As shown in scheme 1, the general procedure for preparing the compounds of the present application involves starting with an appropriately substituted aryl fluoride 1. When treated with a suitable nucleophile, such as intermediate 2 (where M may be MgBr or Li), substituted aryl halides, such as 3, may be produced. Halogenation, preferably bromination, can be accomplished by treating 3 with a reagent such as N-bromosuccinimide to give bromide 4. Treatment of 4 with amine 5 under basic conditions (such as potassium carbonate) will result in initial substitution of secondary bromide followed by cyclization to give lactam 6.
Scheme 1
When M is stannane, 6 may be coupled with a suitably substituted heterocycle 7 in a Stille (Stille) coupling reaction using a suitable catalytic system (e.g., pd (PPh) 3 ) 4 Or bis (triphenylphosphine) palladium (II) dichloride/CuI) to give 8. Alternatively, 6 may be converted to boric acid or borate 9 by conditions well known to those skilled in the art. The boric acid or borate 9 may be reacted with the suitably substituted heterocycle 10 in a Suzuki-Miyaura coupling reaction using a suitable palladium catalyst (e.g., pd (PPh) 3 ) 4 Or 1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride) in the presence of a suitable base (e.g., cesium carbonate, potassium phosphate, or sodium bicarbonate) to give 8.
Depending on the particular choice of acid protecting group R in intermediate 8, different conditions may be required to convert it to compound 11 (scheme 2). For example, in the case of r=methyl, ethyl or benzyl, base-induced cyclization of 8 using a suitable base (e.g. LiHMDS) in a suitable solvent (e.g. tetrahydrofuran) may be preferred for direct conversion of 8 to 11. In the case of r=tert-butyl, acid-induced cyclization of 12 using a suitable acid (e.g., benzenesulfonic acid) in a suitable solvent (e.g., acetonitrile) may be preferred for direct conversion of 8 to 11. In some cases, it may be preferable to use a two-step operation, with the free carboxylic acid corresponding to 8 being released first using conditions appropriate for the particular acid protecting group R. These methods are well known to those skilled in the art of organic synthesis. For example, in the case of r=tert-butyl, acidic hydrolysis using a suitable acid (e.g., trifluoroacetic acid or hydrochloric acid) may be preferred. In the case of r=methyl, ethyl or benzyl, basic hydrolysis using a suitable base (e.g., liOH) may be preferred. In other cases, in the case of r=benzyl, it may be advantageous to deprotect the protecting group by palladium-catalyzed hydrogenolysis. Once released, the carboxylic acid can be activated by the action of thionyl chloride/dimethylformamide or carbonyldiimidazole/dimethylaminopyridine towards intramolecular attack by a side chain primary amide to give 11.
Scheme 2
Examples
The following examples illustrate specific embodiments of the application and do not limit the scope of the application. Unless otherwise specified, chemical abbreviations and symbols as well as scientific abbreviations and symbols have their usual and customary meanings. The examples are defined above and additional abbreviations are used elsewhere in the present disclosure. Common intermediates can generally be used to make more than one embodiment. The compounds of the examples are identified by the examples and steps in which they were prepared (e.g., "1-a" for example 1, step a) or by the examples only (e.g., "1" for example 1) in the case where the compounds are the title compounds of the examples. In some examples, alternative methods of making intermediates or embodiments are described. Alternative methods of manufacture may be frequently designed by chemists of ordinary skill in the art based on one or more considerations such as shorter reaction times, less expensive starting materials, ease of handling or isolation, improved yields, compliance with catalysis, avoidance of toxic reagents, accessibility to specialized equipment, and reduced number of linear steps, among others, may be desired. The intent of describing alternative methods is to further enable the preparation of embodiments of the present application. In some examples, some of the functional groups outlined in the examples and claims may be replaced by well known bioisostere substitutions known in the art, for example, substitution of carboxylic acid groups with tetrazole or phosphate moieties.
Abbreviations
ACN acetonitrile
AIBN 2, 2-azobisisobutyronitrile
n-BuLi n-butyllithium
DCE dichloroethane
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMF dimethylformamide
DMSO dimethyl sulfoxide
dppf bis (diphenylphosphino) ferrocene
EtOH ethanol
EtOAc ethyl acetate
Hex hexane
H-Glu(OtBu)-NH 2 HCl (4S) -4, 5-diamino-5-oxopentanoic acid tert-butyl ester hydrochloride
HPLC high performance liquid chromatography
Henry's (Hunig's) base N, N-diisopropylethylamine
LiHMDS lithium bis (trimethylsilyl) amide
MeCN acetonitrile
min
mL of
NBS n-bromosuccinimide
Pd(dppf) 2 Cl 2 [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)
Pd(dtbpf)Cl 2 [1,1' -bis (di-t-butylphosphino) ferrocene]Palladium dichloride (II)
Pd(PPh 3 ) 4 Tetrakis (triphenylphosphine) palladium
PhSO 3 H-benzenesulfonic acid
PTSOH p-toluenesulfonic acid
TEA triethylamine
THF tetrahydrofuran
XPhos Pd G2 chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II)
Preparative HPLC method 1: XBIdge C18, 200mm x 19mm, 5-. Mu.m particles; mobile phase a:5:95 acetonitrile, water and 10-mM ammonium acetate; mobile phase B:95:5 acetonitrile, water and 10-mM ammonium acetate; gradient: holding at 15% b for 0 min, 15 to 50% b for 25 min, then at 100% b for 6 min; flow rate: 20mL/min; column temperature: 25 ℃. Fraction collection was triggered by MS signal.
Example 1
2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile
Preparation 1A: (S) -5-amino-4- (5-bromo-4-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester.
To a suspension of (S) -4, 5-diamino-5-oxopentanoic acid tert-butyl ester hydrochloride (2.162 g,6.06 mmol) in acetonitrile (30 ml) was added DIPEA (3.018 ml,17.28 mmol) at 0deg.C. After stirring for 20 min, the reaction mixture was treated with a solution of methyl 4-bromo-2- (bromomethyl) -3-methylbenzoate (2.650 g,8.22 mmol) in MeCN (10 mL). The reaction mixture was stirred at 0 ℃ for 5 minutes. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The reaction mixture was warmed to 60 ℃ and held at that temperature overnight. The reaction mixture was concentrated, dissolved in EtOAc, washed twice with water, then with 1.5. 1.5M K 2 HPO 4 Washed, and also washed with brine, and then over MgSO 4 Drying, filtering and concentrating. The material was purified using silica gel eluting with 30 to 100% etoac/Hex. The resulting material was triturated with 8mL of diethyl ether to give the title product in 33.7% yield. 1 H NMR (400 MHz, chloroform-d) delta 7.70 (d, j=8.1 hz, 1H), 7.56 (d, j=8.1 hz, 1H), 6.23 (br s, 1H), 5.31 (br s, 1H), 4.92 (dd, j=8.6, 6.4hz, 1H), 4.55-4.47 (m, 1H), 4.45-4.36 (m, 1H),2.41(s,3H),2.41-2.14(m,4H),1.45(s,9H)。
Preparation 1B: (S) -5-amino-4- (4-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan) -2-yl) -isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
Into a dry flask was placed (S) -5-amino-4- (5-bromo-4-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (300 mg,0.730 mmol), 4',4',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (274 mg,1.094 mmol) (214 mg,2.188 mmol) and flushing with nitrogen. (10 mL) and deaerated with a nitrogen stream for 5 minutes while stirring. The reaction mixture was taken up in Pd (dppf) Cl 2 (16.02 mg, 21.88. Mu. Mol). The flask was degassed for 5 minutes, sealed and heated to 60 ℃ under nitrogen for 18 hours. The reaction mixture was diluted with EtOAc, washed with brine, and over MgSO 4 And (5) drying. It was concentrated and purified by passing through a 40g silica gel column through ISCO eluting with 0 to 40% B/DCM (where b=15% etoh/etoac+0.1% tea) to give the product in 99% yield. MS (ES) m/z=459.3 [ M+H ]] + 。
Example 1:
into a 2mL microwave vial was placed 2-amino-6-bromo-4-methylpyridine-3-carbonitrile (12 mg,0.057 mmol), (S) -5-amino-4- (4-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (28.5 mg,0.062 mmol), pd (dtbpf) Cl 2 (1.106 mg, 1.698. Mu. Mol), dioxane (1.5 mL), and K 3 PO 4 Aqueous solution (0.075 mL,0.226 mmol). The vial was sealed and the air was replaced with nitrogen. The reaction mixture was microwaved at 120℃for 15 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated and concentrated. The residue obtained was dissolved in 1mL of PhSO in MeCN 3 H solution (1.44 g/40 mL) and microwaved at 120℃for 10 minutes. The material was concentrated to dryness and the residue was dissolved in 1.9mL DMSO and purified by preparative HPLC method 1 to give the title compound in 49% yield. MS (ES) m/z=390.3 [ M+H ]] + 。 1 H NMR(500MHz,DMSO-d 6 )δppm 11.03(s,1H)7.66(d,J=7.63Hz,1H)7.53(d,J=7.93Hz,1H)6.91(s,2H)6.78(s,1H)5.18(br dd,J=13.43,5.19Hz,1H)4.52(br d,J=17.09Hz,1H)4.35(br d,J=17.40Hz,1H)2.91-3.01(m,1H)2.65(br d,J=16.78Hz,1H)2.47(br dd,J=13.12,4.27Hz,1H)2.43(s,3H)2.33(s,3H)2.03-2.10(m,1H)。
Example 2
2-amino-6- (2, 6-dioxopiperidin-3-yl) -6-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile
Preparation 2A: 4-bromo-2- (bromomethyl) -5-methylbenzoic acid methyl ester.
SOCl was added to a solution of 4-bromo-2, 5-dimethylbenzoic acid (5.0 g,21.82 mmol) at room temperature 2 (31.66 mL,436 mmol) and stirred for 2 hours. LCMS was used to confirm the formation of acid chloride and then concentrated to dryness. Methanol (30 mL) was added at room temperature and stirred for 0.5 hours and then concentrated again to dryness. Adding CCl to the obtained methyl ester 4 (180 mL) followed by 1-bromopyrrolidine-2, 5-dione (4.08 g,22.92 mmol) and then AIBN (0.108 g, 0.254 mmol). The resulting mixture was heated to 80 ℃ while stirring overnight. After cooling to room temperature, the mixture was concentrated, dissolved in EtOAc, washed with brine, and dried over MgSO 4 And (5) drying. LCMS showed two major peaks. The obtained mixture of positional isomers (5.4 g) was used in the next step.
Preparation 2B: (S) -5-amino-4- (5-bromo-6-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
To a suspension of methyl 4-bromo-2- (bromomethyl) -5-methylbenzoate (5.4 g,16.76 mmol) in acetonitrile (100 mL) was added tert-butyl (S) -4, 5-diamino-5-oxopentanoate, HCl (4.00 g,16.76 mmol), followed by henry' S base (5.84 mL,33.52 mmol). After stirring at room temperature for 1 hour, the reaction mixture was placed in a 40 ℃ bath and stirred at that temperature for 6 days. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed with brine, over MgSO 4 Drying, filtering and concentrating. The residue was passed through an ISCO [120g column]Self-extraction with EtOAc/DCM0 to 100% to obtain 2.80g of the desired compound. In addition, two other byproducts ((S) -5- (((1-amino-5- (tert-butoxy) -1, 5-dioxolan-2-yl) amino) methyl) -4-bromo-2-methylbenzoic acid methyl ester and (S) -5-amino-4- (((2- ((R) -1-amino-5- (tert-butoxy) -1, 5-dioxolan-2-yl) -6-bromo-3-oxoisoindolin-5-yl) methyl) amino) -5-oxopentanoic acid tert-butyl ester) were isolated. MS (ES) m/z=411.0 [ M+H ] ] + 。 1 H NMR (400 MHz, chloroform-d) delta ppm 7.70 (d, j=6.44 hz, 2H) 6.31 (br s, 1H) 5.36 (br s, 1H) 4.90 (dd, j=8.68, 6.34hz, 1H) 4.51 (d, j=16.98 hz, 1H) 4.41 (d, j=16.98 hz, 1H) 2.51 (s, 3H) 2.21-2.43 (m, 3H) 2.12-2.19 (m, 1H) 1.44 (s, 9H).
Preparation 2C: (S) -5-amino-4- (6-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
Into a 40mL pressure vial was placed (S) -5-amino-4- (5-bromo-6-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (600 mg,1.458 mmol), 4',4',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (554 mg,2.188 mmol) and potassium acetate (430 mg,4.376 mmol) were purged with nitrogen. The solid was suspended in dioxane (20 mL) and degassed with a nitrogen stream for 5 min while stirring. The reaction mixture was taken up in Pd (dppf) Cl 2 (32.02 mg,0.044 mmol) was treated and degassed for 5 min. The vial was sealed and heated to 95 ℃ under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and dried over MgSO 4 And (5) drying. The filtrate was concentrated and purified by passing through a 40g silica gel column through ISCO, eluting with (0% to 40% B/DCM, where b=15% etoh/etoac+0.1% tea) to give the title compound in 95% yield. MS (ES) m/z=459.3 [ M+H ] ] + 。
Example 2:
into a 2mL microwave vial was placed 2-amino-6-bromo-4-methylpyridine-3-carbonitrile (12 mg,0.057 mmol), (S) -5-amino-4- (6-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (28.5 mg,0.062 mmol), pd (dtbpf) Cl 2 (1.106 mg, 1.698. Mu. Mol), dioxane (1.5 mL), and K 3 PO 4 Aqueous solution(0.075 mL,0.226 mmol). The vial was sealed and the air was replaced with nitrogen. The reaction mixture was microwaved at 120℃for 15 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was separated and concentrated. The residue obtained was dissolved in 1mL of PhSO in MeCN 3 H solution (1.44 g/40 mL) and microwaved at 120℃for 10 minutes. The mixture was concentrated to dryness and the residue was dissolved in 1.7mL DMSO and purified by preparative HPLC method 1 to give the title compound in 35% yield. MS (ES) m/z=390.3 [ M+H ]] + 。 1 H NMR(500MHz,DMSO-d 6 )δppm 10.97-11.02(m,1H)7.65(s,1H)7.55(s,1H)6.76(s,1H)5.13(dd,J=13.31,5.18Hz,1H)4.39-4.51(m,1H)4.28-4.39(m,1H)2.87-2.98(m,1H)2.58-2.65(m,1H)2.51(d,J=1.74Hz,3H)2.42-2.46(m,1H)2.41(br s,3H)2.39-2.40(m,1H)1.99-2.06(m,1H)。
Example 3
2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile
Intermediate 3A: 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1 (3H) -one
To a stirred solution of 2, 6-tetramethylpiperidine (7.07 mL,41.6 mmol) in THF (150 mL) was added a 2.5M n-BuLi in hexane (16 mL,40.0 mmol) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 30 minutes. A solution of 4-bromo-3-fluorobenzoic acid (3.5 g,15.98 mmol) in anhydrous THF (100 mL) was added dropwise thereto at-50deg.C. The reaction mixture was stirred at the same temperature for 3 hours. Anhydrous DMF (2.48 ml,32.0 mmol) was added at-50 ℃ and the reaction mixture was allowed to come to room temperature and stirred for 16 hours. The reaction was quenched with 1.5N HCl (100 mL). The reaction mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Dried, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO 2 120g column, 0 to 50% EtOAc/petroleum ether) Purification was performed to give 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1 (3H) -one (1.0 g,23% yield) as a yellow solid. LCMS (method a): retention time 0.48min, [ M+H ]] + 245.1,247.1; 1 H NMR (400 MHz, acetonitrile-d) 3 )δ7.93(dd,J=8.0,5.5Hz,1H),7.59(d,J=8.0Hz,1H),6.74(br s,1H),5.94(br s,1H)。
Intermediate 3B: (S) -5-amino-4- (5-bromo-4-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
To a stirred solution of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1 (3H) -one (1.7 g,6.88 mmol) and tert-butyl (S) -4, 5-diamino-5-oxopentanoate HCl (1.67 g,8.26 mmol) in DMF (30 mL) was added sodium triacetoxyborohydride (3.65 g,17.21 mmol) at 0deg.C. The reaction mixture was allowed to reach room temperature and stirred for 48 hours. The reaction mixture was diluted with ice water (50 mL) and the resulting white solid was filtered and dried under reduced pressure to give (S) -5-amino-4- (5-bromo-4-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (1.6 g,50% yield) as a white solid. LCMS (method a): retention time 1.39min, [ M+H ]] + 413.9,415.3; 1 H NMR(400MHz,DMSO-d 6 )δ7.85(dd,J=8.0,6.0Hz,1H),7.59(br s,1H),7.51(d,J=8.0Hz,1H),7.23(br s,1H),4.77-4.59(m,3H),2.26-2.13(m,3H),2.08-1.96(m,1H),1.34(s,9H)。
Intermediate 3C: (S) -5-amino-4- (5- (6-amino-5-cyano-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
A stirred solution of 2-amino-6-chloro-4-methylpyridine-3-carbonitrile (50 mg,0.30 mmol) and hexamethyl-ditin (0.093 mL,0.45 mmol) in toluene (2 mL) was flushed with argon for 5min followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (9.72 mg,0.015 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude product. [ M+H ]] + 298.2. To a solution of the crude product in dioxane (2 mL) was added (S) -5-amino-4- (5-bromo-4-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (98 mg,0.24 mmol). The reaction mixture was purged with argon for 5 minutes and bis (triphenylphosphine) chloride was addedPalladium (II) (16.60 mg,0.024 mmol), and the reaction mixture was heated at 100deg.C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash chromatography (SiO 2 80g column, 0 to 100% B (B=15% EtOH/EtOAc,0.5% TEA)/chloroform) to give (S) -5-amino-4- (5- (6-amino-5-cyano-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (60 mg,40.7% yield). LCMS (method a): retention time 1.35min, [ M+H ] ] + 468.3。
Example 3:
to a stirred solution of intermediate 3C (60 mg,0.13 mmol) in acetic acid (2 mL) was added benzenesulfonic acid (20.30 mg,0.13 mmol). The reaction mixture was heated to 150 ℃ for 10 minutes under microwave irradiation. Volatiles were removed under reduced pressure and the resulting crude product was purified via preparative LC-MS (column: waters XBridge C18, 19x150mm,5 μm particles; mobile phase a:0.1% trifluoroacetic acid in water; mobile phase B: acetonitrile; gradient: 10 to 40% B for 20 min then 100% B for 5 min; flow rate: 15 mL/min). The desired fraction was lyophilized to give 2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (15 mg,29% yield). LCMS (method G): retention time 1.62min, [ M+H ]] + 394.2; 1 H NMR(400MHz,DMSO-d 6 )δ11.01(br s,1H),8.01(t,J=7.3Hz,1H),7.70(d,J=7.9Hz,1H),7.06(d,J=1.5Hz,1H),6.99(s,2H),5.14(dd,J=13.3,5.1Hz,1H),4.74-4.38(m,2H),3.05-2.85(m,1H),2.75-2.57(m,2H),2.46(s,3H),2.13-1.95(m,1H)。
General procedure 2: the stirred solution of intermediate 3B (1 eq.) and the arylstannane reagent (1 eq.) in dioxane (5 mL/mmol) was flushed with argon for 5 minutes. Bis (triphenylphosphine) palladium (II) chloride (0.1 eq.) was added and the reaction mixture was heated at 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad, and the filtrate was concentrated under reduced pressure. Transfer the crude material to a microwave vial and add PhSO 3 H (2 eq.) and acetic acid (5 mL/mmol) and the mixture was heated in a microwave reactor at 150℃for 10 minutes. Concentrating the mixture and passing the residue throughPurification by preparative HPLC.
Example 4
3- (5- (6-amino-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 4A: 4-methyl-6- (trimethylstannyl) pyridin-2-amine
A stirred solution of 6-bromo-4-methylpyridin-2-amine (75 mg,0.382 mmol) and hexamethylditin (0.119 mL,0.57 mmol) in toluene (5 mL) was flushed with argon for 5 min followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (12.4 mg,0.02 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give 4-methyl-6- (trimethylstannyl) pyridin-2-amine (130 mg,89% yield). LCMS (method a): retention time 1.62min, [ M+H ]] + 273.1。
Example 4:
the steller coupling and cyclization was achieved by following general procedure 2 using preparation 4A and preparation 3B. MS (ES) M/z= [ M+H ]] + 369.1; 1 H NMR(400MHz,DMSO-d 6 )δ=11.02(s,1H),8.02(t,J=7.2Hz,1H),7.65(d,J=7.8Hz,1H),6.84(s,1H),6.34(s,1H),6.03(s,2H),5.15(dd,J=5.0,13.3Hz,1H),4.66-4.57(m,1H),4.49-4.38(m,1H),3.02-2.85(m,1H),2.62(br d,J=17.4Hz,1H),2.49-2.40(m,1H),2.22(s,3H),2.07-1.98(m,1H)。
Example 5
3- (5- (6-amino-4- (trifluoroethyl) pyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 5A:
6-chloro-4- (trifluoromethyl) pyridin-2-amine (75 mg,0.382 mmol) and hexamethylditin in toluene (5 mL) with stirring A solution of (0.119 mL,0.57 mmol) was flushed with argon for 5 min, followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (12.4 mg,0.02 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give 4- (trifluoromethyl) -6- (trimethylstannyl) pyridin-2-amine (130 mg,89% yield). LCMS (method a): retention time 1.92min, [ M+H ]] + 327.1。
Example 5:
the steller coupling and cyclization is achieved by following general procedure 1 using intermediate 5A and intermediate 3B. MS (ES) M/z= [ M+H ]] + 423.3; 1 H NMR(400MHz,DMSO-d 6 )δ=11.02(s,1H),8.05(t,J=7.3Hz,1H),7.69(d,J=7.8Hz,1H),7.15(s,1H),6.78(d,J=11.8Hz,3H),5.15(dd,J=5.0,13.3Hz,1H),4.68-4.57(m,1H),4.52-4.39(m,1H),2.99-2.82(m,1H),2.67-2.58(m,1H),2.48-2.39(m,1H),2.12-1.93(m,1H)。
Example 6
3- (4-fluoro-5- (4-methyl-6- (methylamino) pyridin-2-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 6A: n, 4-dimethyl-6- (trimethylstannyl) pyridin-2-amine
A stirred solution of 6-chloro-N, 4-dimethylpyridin-2-amine (100 mg,0.64 mmol) and hexamethylditin (0.199mL, 0.96 mmol) in toluene (10 mL) was flushed with argon for 5 min followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (20.8 mg,0.032 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give N, 4-dimethyl-6- (trimethylstannyl) pyridin-2-amine (250 mg,55.0% yield). LCMS (method a): retention time 1.29min, [ M+H ] ] + 287.1。
Example 6:
the steller coupling and cyclization is achieved by following general procedure 2 using intermediate 6A and intermediate 3B. MS [ (MS)ES):m/z=[M+H] + 383.1; 1 H NMR(400MHz,DMSO-d 6 )δ11.03(s,1H),8.02(s,1H),7.72(d,J=7.5Hz,1H),6.93(s,1H),6.58(br s,1H),5.16(dd,J=13.1,5.0Hz,1H),4.82-4.40(m,3H),2.89(s,3H),2.75-2.63(m,1H),2.64-2.57(m,1H),2.46-2.41(m,1H),2.36-2.28(m,3H),2.06-2.00(m,1H)。19/19
Example 7
3- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 7A:3, 4-dimethyl-6- (trimethylstannyl) pyridin-2-amine
A stirred solution of 6-chloro-3, 4-dimethylpyridin-2-amine (75 mg,0.48 mmol) and hexamethylditin (0.149 mL,0.72 mmol) in toluene (3 mL) was flushed with argon for 5 min followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (15.6 mg,0.024 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give 3, 4-dimethyl-6- (trimethylstannyl) pyridin-2-amine (150 mg,55.0% yield). LCMS (method a): retention time 1.16min, [ M+H ]] + 287.2。
Example 7:
the steller coupling and cyclization is achieved by following general procedure 1 using intermediate 7A and intermediate 3B. MS (ES) M/z= [ M+H ]] + 383.0; 1 H NMR(400MHz,DMSO-d 6 )δ11.01(br s,1H),8.05(t,J=7.3Hz,1H),7.65(d,J=7.9Hz,1H),6.93(d,J=1.5Hz,1H),5.81(s,2H),5.14(dd,J=13.3,5.1Hz,1H),4.71-4.34(m,2H),3.01-2.88(m,1H),2.67-2.58(m,2H),2.46-2.41(m,1H),2.23(s,3H),2.04(s,3H)。
Examples 8 and 9
3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione and 3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 8A: 4-bromo-2-ethylbenzoic acid
To a solution of 4-bromo-2-fluorobenzoic acid (5 g,22.83 mmol) in anhydrous THF (100 mL) at-78deg.C was added a 1M solution of ethyl magnesium bromide in THF (22.83 mL,68.5 mmol) over 15 min. The reaction mixture was slowly warmed to room temperature and stirred under nitrogen for 12 hours. The reaction mixture was cooled to 0 ℃. The reaction was quenched with dropwise addition of MeOH (15 mL). The reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and 2M aqueous HCl. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure to give the crude product. The crude product was purified by flash chromatography (SiO 2 80g column, 0 to 30% EtOAc/petroleum ether) to give 4-bromo-2-ethylbenzoic acid (4 g,76% yield). LCMS (method D): retention time 2.49min, [ M+H ]] + 228.8,230.0; 1 H NMR(400MHz,DMSO-d 6 )δ13.04(br s,1H),7.71(d,J=8.5Hz,1H),7.55(d,J=2.0Hz,1H),7.49(dd,J=8.0,2.0Hz,1H),2.92(q,J=7.2Hz,2H),1.15(t,J=7.5Hz,3H)。
Intermediate 8B: 4-bromo-2-ethylbenzoic acid methyl ester
To stirred 4-bromo-2-ethylbenzoic acid (4.0 g,17.46 mmol) in DMF (40 mL) and Cs 2 CO 3 To a mixture of (11.38 g,34.9 mmol) was added methyl iodide (2.18 mL,34.9 mmol). The reaction mixture was stirred at room temperature for 14 hours, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 80g column, 0 to 50% EtOAc/petroleum ether) to give methyl 4-bromo-2-ethylbenzoate (3.3 g,78% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) delta 7.76 (d, j=8.5 hz, 1H), 7.46 (d, j=1.5 hz, 1H), 7.40 (dd, j=8.5, 2.0hz, 1H), 3.91 (s, 3H), 2.99 (q, j=7.5 hz, 2H), 1.26 (t, j=7.5 hz, 3H).
Intermediate 8C: 4-bromo-2- (1-bromoethyl) benzoic acid methyl ester
To a stirred solution of methyl 4-bromo-2-ethylbenzoate (3.0 g,12.34 mmol) in benzene (40 mL) was added NBS (3.29 g,18.51 mmol) followed by AIBN (0.405 g,2.47 mmol). The reaction mixture was heated at 85 ℃ for 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated 10% sodium thiosulfate solution and brine solution. The organic layer was treated with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The residue was purified by flash chromatography (SiO 2 40g column, 0 to 30% EtOAc/petroleum ether) to afford methyl 4-bromo-2- (1-bromoethyl) benzoate (2.1 g,53% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) delta 7.96 (d, j=2.0 hz, 1H), 7.73 (s, 1H), 7.49 (dd, j=8.5, 2.0hz, 1H), 6.28 (q, j=7.0 hz, 1H), 3.95 (s, 3H).
Intermediate 8D: (4S) -5-amino-4- (5-bromo-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
To stirred methyl 4-bromo-2- (1-bromoethyl) benzoate (1.0 g,3.11 mmol) and H-Glu (OtBu) -NH in acetonitrile (30 mL) 2 To a solution of HCl (0.754 g,3.73 mmol) was added DIPEA (2.71 mL,15.53 mmol). The resulting reaction mixture was heated at 85 ℃ for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 40g column, 0 to 10% MeOH/DCM) to give (4S) -5-amino-4- (5-bromo-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester as a semi-solid (650 mg,51% yield). LCMS (method a): retention time 1.45min, [ M+H ]] + 411.3,413.3。
Intermediate 8E: 5-amino-4- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
A stirred solution of 6-chloro-3, 4-dimethylpyridin-2-amine (200 mg,1.28 mmol) and hexamethylditin (544 mg,1.66 mmol) in toluene (6 mL) was flushed with argon for 5min followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (83 mg,0.13 mmol). The reaction mixture was stirred at 100deg.C for 2 hours and cooled toAnd (5) filtering at room temperature. The filtrate was concentrated under reduced pressure to give a crude product. [ M+H ] ] + 287.0. To a solution of this crude product in dioxane (4 mL) was added 5-amino-4- (5-bromo-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (0.289 g,0.70 mmol). The reaction mixture was purged with argon for 5 minutes. Bis (1, 2-bis (diphenylphosphino) ethane) palladium (0) (0.063 g,0.07 mmol) was added and the reaction mixture was heated at 100℃for 16 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash chromatography (SiO 2 80g column, 0 to 100% B (b=15% etoh/etoac+0.5% tea)/chloroform) to give 5-amino-4- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (110 mg,34.6% yield). LCMS (method a): retention time 1.40min, [ M+H ]] + 453.3。
Intermediate 8F:3- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
To a stirred solution of tert-butyl 5-amino-4- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoate (110 mg,0.243mmol,34.6% yield) in acetonitrile (5 mL) was added p-toluenesulfonic acid (84 mg,0.442 mmol). The reaction mixture was heated to 120 ℃ for 30 minutes under microwave irradiation. Volatiles were removed under reduced pressure and the crude product was purified by preparative HPLC (column: hypersil gold c18 (19X 250 mM), 5 μm, mobile phase A-10mM ammonium acetate/water, mobile phase B: ACN, flow rate: 20mL T/B%:0/20, 18/80, 19/100, 21/100, 22/20, 24/20). The desired fractions were lyophilized to give 3- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione. LCMS (method D): retention time 2.15min, [ M+H ] ] + 379.0。
Examples 8 and 9:
3- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (100 mg) was subjected to SFC separation (column Welk-01 (R, R) (250X 4.6) mm,5 μm;% CO) 2 :45%; cosolvent%: containing 5mM acetic acidMethanol and acetonitrile (1:1) of ammonium; flow rate: 4g/min; temperature: 30 ℃; UV:237 nm), the first peak fraction eluting at 2.64min retention time was concentrated to dryness and lyophilized to give 3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (12 mg,15% yield). LCMS (method D): retention time 2.112min, [ M+H ]] + 379.0; 1 H NMR(400MHz,DMSO-d 6 ) δ11.10-10.71 (s, 1H), 8.19 (s, 1H), 8.12 (d, j=7.9 hz, 1H), 7.69 (d, j=8.0 hz, 1H), 7.14 (s, 1H), 5.73 (s, 2H), 4.93-4.67 (m, 2H), 2.85-2.71 (m, 2H), 2.25 (s, 3H), 2.04 (s, 3H), 1.51 (d, j=6.6 hz, 3H), and concentrating the second peak fraction eluted at 4.03min retention time to dryness and lyophilization gave 3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (8 mg,10% yield). LCMS (method D): retention time 2.162min, [ M+H ]] + 379.0; 1 H NMR(400MHz,DMSO-d 6 )δ11.00-10.89(s,1H),8.18(s,1H),8.13(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.13(s,1H),5.73(s,2H),4.84-4.68(m,2H),2.91-2.65(m,3H),2.25(s,3H),2.04(s,3H),1.51-1.46(m,3H)。
Examples 10 and 11
2-amino-6- ((3S) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile and 2-amino-6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile
Intermediate 10A and 11A:
a stirred solution of 2-amino-6-chloro-4-methylpyridine-3-carbonitrile (300 mg, 1.79mmol) and 1, 2-hexamethyldisiloxane (762 mg,2.327 mmol) in toluene (10 mL) was flushed with argon for 5 min followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (117 mg, 0.178 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a crude product. [ M+H ]] + 298.0。The crude material was dissolved in dioxane and intermediate 8D (0.695 g,1.689 mmol) was added. The reaction mixture was purged with argon for 5 minutes and bis (diphenylphosphino) ethane) palladium (0) (0.153 g,0.169 mmol) was added. The reaction mixture was heated to 100 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash chromatography (SiO 2 80g column, 0 to 100% B (b=15% etoh/EtOAc,0.5% tea)/chloroform) to give 5-amino-4- (5- (6-amino-5-cyano-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (200 mg,0.431mmol,25.5% yield). LCMS (method a): retention time 1.47min, [ M+H ] ] + 464.3。
Examples 10 and 11:
to a stirred solution of tert-butyl 5-amino-4- (5- (6-amino-5-cyano-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoate (200 mg,0.431 mmol) in acetonitrile (10 mL) was added p-toluenesulfonic acid (164 mg,0.863 mmol). The reaction mixture was heated to 120 ℃ for 30 minutes under microwave irradiation. Volatiles were removed under reduced pressure and the resulting crude product was purified by preparative HPLC (column: hypersil gold c18 (19X 250 mM), 5 μm, mobile phase A-water containing 10mM ammonium acetate; mobile phase B: ACN, flow rate: 20mL T/B%:0/20, 18/80, 19/100, 21/100, 22/20, 24/20). The desired fractions were lyophilized to give 2-amino-6- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile LCMS (method D) as a mixture of diastereomers: retention time 1.66min, [ M+H ]] + 390.2. These diastereomers were passed through SFC (column Welk-01 (R, R) (250X 4.6) mm,5 μm;%CO 2 :45%; cosolvent%: methanol and acetonitrile (1:1) containing 5mM ammonium acetate; flow rate: 4g/min; temperature: 30 ℃; UV:237 nm), and the first eluted isomer fraction at 2.28min retention time was concentrated to dryness and lyophilized to give 2-amino-6- ((3S) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (20 mg,12% yield). LCMS (method D): retention time 1.64min, [ M+H ] ] + 390.0; 1 H NMR(400MHz,DMSO-d 6 ) δ11.01-10.72 (s, 1H), 8.28 (s, 1H), 8.19 (dd, j=8.0, 1.3hz, 1H), 7.76 (d, j=8.0 hz, 1H), 7.35 (s, 1H), 6.92 (s, 2H), 4.94-4.68 (m, 2H), 2.65-2.58 (m, 2H), 2.44 (s, 3H), 2.14-1.91 (m, 2H), 1.51 (d, j=6.6 hz, 3H); and concentrating the second eluted isomer fraction at 3.25min retention time to dryness and lyophilizing to give 2-amino-6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (20 mg,12% yield). LCMS (method D): retention time 1.66min, [ M+H ]] + 390.0; 1 H NMR(400MHz,DMSO-d 6 )δ11.01-10.72(s,1H),8.27(s,1H),8.20(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,1H),7.34(s,1H),6.90(s,2H),4.84-4.70(m,2H),2.84-2.67(m,2H),2.44(s,3H),2.14-1.91(m,2H),1.49(br d,J=6.6Hz,3H)。
Examples 12 and 13
3- ((S) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione and 3- ((R) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 12A and 13A:
to a solution of intermediate 8D (350 mg,0.764 mmol) in dioxane (8 mL) was added 6-chloro-N, 3, 4-trimethylpyridin-2-amine (130 mg,0.764 mmol), followed by 3M aqueous dipotassium hydrogen phosphate (0.764 mL, 2.2910 mmol). The reaction mixture was purged with nitrogen at room temperature for 15 minutes. PdCl was added under nitrogen 2 (dppf)-CH 2 Cl 2 Adduct (62.4 mg,0.076 mmol) and the reaction mixture was heated at 100℃for 12 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 Purification on a 24g column, 0 to 10% MeOH/DCM) to give (4S) -5-amino-4- (5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (230 mg, 0.4) as an off-white solid93mmol,64.6% yield). LCMS (method a): retention time 1.81min, [ M+H ]] + 467.4。
Examples 12 and 13:
to a stirred solution of tert-butyl 5-amino-4- (5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoate (200 mg,0.429 mmol) in acetic acid (1 mL) was added benzenesulfonic acid (67.8 mg,0.429 mmol). The reaction mixture was heated to 120 ℃ for 30 minutes under microwave irradiation. Volatiles were removed under reduced pressure and the resulting crude product was purified by preparative HPLC (column: X Select CSH C18 (250X 20 mM), 5 μm, mobile phase: A:10mM ammonium acetate, B: ACN T/B:0/20, 18/85, 20/100, 21/20, 23/20, flow rate: 20 mL/min). The desired fractions were lyophilized to give 3- (5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione LCMS (method a) as a mixture of diastereomers: retention time 1.47min, [ M+H ] ] + 393.4. These diastereomers were passed through SFC (column, chiralpak IC (250X 4.6) mm,5 μm;% CO 2 :45%; % co-solvent: methanol and acetonitrile (1:1) containing 5mM ammonium acetate; flow rate: 4g/min; temperature: 30 ℃; UV:237 nm) to give 3- ((S) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (3 mg,2% yield), LCMS (method D): retention time 1.743min, [ M+H ]] + 393.4; 1 H NMR(400MHz,DMSO-d 6 ) δ11.07-10.81 (m, 1H), 8.35-8.12 (m, 2H), 7.71 (D, j=8.0 hz, 1H), 7.14 (s, 1H), 6.03 (br D, j=4.0 hz, 1H), 4.88-4.69 (m, 2H), 2.96 (D, j=4.5 hz, 3H), 2.78-2.63 (m, 3H), 2.26 (s, 3H), 2.03 (s, 4H), 1.49 (D, j=6.5 hz, 3H) and concentrating the second peak eluate eluted at 11.18min retention time to dryness and lyophilization to give 3- ((R) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (3 mg,2% yield) s (method D): retention time 1.669min, [ M+H ]] + 393.4; 1 H NMR(400MHz,DMSO-d 6 )δ11.07-10.81(m,1H),8.35-8.12(m,2H),7.71(d,J=8.0Hz,1H),7.14(s,1H),6.03(br d,J=4.0Hz,1H),4.88-4.69(m,2H),2.96(d,J=4.5Hz,3H),2.78-2.63(m,3H),2.26(s,3H),2.03(s,4H),1.49(d,J=6.5Hz,3H)。
Examples 14 and 15
6- ((3S) -2- (2, 6-Dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile and 6- ((3R) -2- (2, 6-Dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile
Intermediate 14A and 15A:
to a solution of intermediate 8D (200 mg,0.436 mmol) in dioxane (8 mL) was added 6-chloro-4-methyl-2- (methylamino) pyridine-3-carbonitrile (79 mg,0.436 mmol), followed by K 3 PO 4 (0.291mL,0.873mmol 3M aqueous solution). The reaction mixture was purged with nitrogen at room temperature for 15 minutes. Xphos Pd G4 (37.6 mg,0.044 mmol) was added under nitrogen and the reaction mixture was heated at 80℃for 12 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 24g column, 0 to 10% MeOH/DCM) to give (4S) -5-amino-4- (5- (5-cyano-4-methyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (75 mg,0.157mmol,36.0% yield) as an off-white solid. LCMS (method a): retention time 1.59min, [ M+H ]] + 478.2。
Examples 14 and 15:
to a solution of tert-butyl (4S) -5-amino-4- (5- (5-cyano-4-methyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoate (60 mg,0.126 mmol) in acetonitrile (3 mL) was added benzenesulfonic acid (19.87 mg,0.126 mmol) at room temperature. The reaction mixture was heated to 120 ℃ in a microwave reactor for 45 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography Method (SiO) 2 24g column, 0 to 10% meoh/DCM) to give 6- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile as a mixture of diastereomers as an off-white solid. LCMS (method a): retention time 1.22min, [ M+H ]] + 404.1. These diastereomers were passed through SFC (column Welk-01 (R, R) (250X 4.6) mm,5 μm;%CO 2 :45%; cosolvent%: methanol and acetonitrile (1:1) containing 5mM ammonium acetate; flow rate: 4g/min; temperature: 30 ℃; UV:237 nm), the first eluted isomer fraction at 2.91min retention time was concentrated to dryness and lyophilized to give 6- ((3S) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile (6 mg,12% yield), LCMS (method D): retention time 2.071min, [ M+H ]] + 404.2; 1 H NMR(400MHz,DMSO-d 6 ) δ11.27-10.74 (m, 1H), 8.35 (s, 1H), 8.28 (d, j=8.0 hz, 1H), 7.77 (d, j=8.5 hz, 1H), 7.37 (s, 1H), 7.12 (br d, j=4.5 hz, 1H), 4.87 (q, j=6.2 hz, 1H), 4.81-4.71 (m, 1H), 3.00 (d, j=4.5 hz, 3H), 2.68 (s, 1H), 2.44 (s, 3H), 1.72 (s, 3H), 1.52 (d, j=7.0 hz, 3H) and the second peak fraction eluted at the retention time of 4.74min was concentrated to dryness and lyophilized to give 6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoindol-5-yl) -4-methyl-2- (methylamino-2- (8 mg) pyridine-carbonitrile (16 mg). LCMS (method D): retention time 2.063min, [ M+H ] ] + 404.2;1H NMR(400MHz,DMSO-d 6 )δ11.08-10.87(m,1H),8.34(s,1H),8.28(d,J=8.3Hz,1H),7.77(d,J=8.0Hz,1H),7.36(s,1H),7.19-7.05(m,1H),4.91-4.71(m,2H),2.99(d,J=4.5Hz,3H),2.76-2.57(m,3H),2.44(s,3H),1.71(s,1H),1.49(d,J=6.8Hz,3H)。
Examples 16 and 17
3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione and 3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 16A: 4-bromo-2-ethyl-3-fluorobenzoic acid
A solution of 4-bromo-2, 3-difluorobenzoic acid (2.0 g,8.44 mmol) in tetrahydrofuran (40 mL) was cooled to-78deg.C and a 1M solution of ethylmagnesium bromide in THF (8.44 mL,25.3 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and stirred under nitrogen for 12 hours. The reaction was quenched by dropwise addition of MeOH (15 mL) at 0 ℃. The volatiles were removed under reduced pressure and the residue partitioned between EtOAc and 2M aqueous HCl. The layers were separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure to give the crude product. The crude product was purified by flash chromatography (SiO 2 40g column, 0 to 80% EtOAc/petroleum ether) to give 4-bromo-2-ethyl-3-fluorobenzoic acid (1 g,48% yield). LCMS (method a): retention time 0.69min, [ M-H ]] + 245.1,247.1; 1 H NMR(300MHz,DMSO-d 6 )δ13.36(s,1H),7.68-7.53(m,2H),2.95(qd,J=7.4,2.6Hz,2H),1.24-1.06(m,3H)。
Intermediate 16B: 4-bromo-2-ethyl-3-fluorobenzoic acid methyl ester
To stirred 4-bromo-2-ethyl-3-fluorobenzoic acid (0.7 g,2.83 mmol) in acetone (15 mL) and K at room temperature 2 CO 3 To a mixture of (0.783 g,5.67 mmol) was added dimethyl sulfate (0.541 mL,5.67 mmol) dropwise. The reaction mixture was stirred at 50 ℃ for 14 hours and filtered through a pad of celite. The filtrate was concentrated in vacuo and purified by flash chromatography (SiO 2 24g column, 0 to 50% EtOAc/petroleum ether) to give methyl 4-bromo-2-ethyl-3-fluorobenzoate (0.51 g,69% yield) as a colorless oil. 1 H NMR (300 MHz, chloroform-d) delta 7.58-7.51 (m, 1H), 7.49-7.37 (m, 1H), 3.90 (s, 3H), 3.01 (qd, j=7.4, 2.6hz, 2H), 1.23 (t, j=7.4 hz, 3H).
Intermediate 16C: 4-bromo-2- (1-bromoethyl) -3-fluorobenzoic acid methyl ester
To a stirred solution of methyl 4-bromo-2-ethyl-3-fluorobenzoate (0.515 g,1.972 mmol) in DCE (10 mL) was added NBS (0.3836 g,2.170 mmol), followed by AIBN (0.065 g,0.394 mmol). The reaction mixture was heated at 85 ℃ for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated 10% sodium thiosulfate solution and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO 2 24g column, 0 to 30% EtOAc/petroleum ether) to afford methyl 4-bromo-2- (1-bromoethyl) -3-fluorobenzoate (0.6 g,89% yield) as a white solid. 1 H NMR (300 MHz, chloroform-d) delta 7.70-7.53 (m, 1H), 7.52-7.44 (m, 1H), 6.16-5.87 (m, 1H), 3.93 (s, 3H), 1.95 (dd, J=7.0, 1.3Hz, 3H).
Intermediate 16D: (4S) -5-amino-4- (5-bromo-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
To stirred methyl 4-bromo-2- (1-bromoethyl) -3-fluorobenzoate (0.86 g,2.53 mmol) and H-Glu (OtBu) -NH in acetonitrile (15 mL) 2 To a solution of HCl (0.845 g,3.54 mmol) was added DIPEA (1.325 mL,7.59 mmol). The reaction mixture was heated at 85 ℃ for 15 hours. Volatiles were removed under reduced pressure and purified by flash chromatography (SiO 2 40g column, 0 to 10% MeOH/DCM) to give (4S) -5-amino-4- (5-bromo-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (0.23 g,21% yield) as a pale yellow solid. LCMS (method a): retention time 1.19min, [ m+23h ]] + 451.3,453.4。
Intermediate 16E: (4S) -5-amino-4- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
To a stirred solution of (4S) -5-amino-4- (5-bromo-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (350 mg,0.815 mmol) in 1, 4-dioxane (20 mL) was added 3, 4-dimethyl-6- (trimethylstannane) pyridin-2-amine (232 mg,0.815 mmol). The mixture was purged with argon for 5 minutes and bis (triphenylphosphine) palladium (II) chloride (57.2 mg,0.082 mmol) was added. The reaction mixture was heated at 100 ℃ for 16 hours, cooled to room temperature and diluted with ethyl acetate. The mixture was washed with brine solution and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. The crude compound was purified by flash chromatography (SiO 2 24g column, 0 to 5% MeOH/DCM) and the combined product fractions were concentrated under reduced pressure to give (4S) -5-amino-4- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (270 mg,70.4% yield) as a light brown solid. LCMS (method a): retention time 1.64min, [ M+H ]] + 471.2 1 H NMR(400MHz,DMSO-d 6 )δ7.99(t,J=6.9Hz,1H),7.59(s,1H),7.47(br s,1H),7.30-7.13(m,2H),6.90(s,1H),5.74(br d,J=5.3Hz,2H),4.89(q,J=6.1Hz,1H),4.50-4.37(m,1H),2.31-2.19(m,6H),2.04(s,3H),1.55-1.45(m,3H),1.37(d,J=2.9Hz,9H)。
Examples 16 and 17:
to a stirred solution of (4S) -5-amino-4- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (270 mg, 0.514 mmol) in acetonitrile (10 mL) was added PTSOH (218 mg,1.148 mmol). The reaction mixture was heated at 120 ℃ under microwave irradiation for 30 minutes. Volatile substances were removed under reduced pressure and the crude product obtained was purified by preparative HPLC using a polar organic method (CELLLOSE-2 [250X4.6 mm)]MeOH with 10mM ammonium acetate, flow rate: 23mL/min (isocratic)), and the first eluted isomer fraction at 9.73min retention time was concentrated to dryness and lyophilized to give 3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (60 mg,27% yield). LCMS (method G): retention time 1.83min, [ M+H ] ] + 397.1; 1 H NMR(400MHz,DMSO-d 6 ) δ11.10-10.87 (m, 1H), 8.01 (t, j=7.3 hz, 1H), 7.57 (d, j=8.0 hz, 1H), 6.92 (d, j=2.0 hz, 1H), 5.78 (s, 2H), 5.01 (q, j=6.5 hz, 1H), 4.73 (brdd, j=12.3, 4.8hz, 1H), 2.82-2.67 (m, 1H), 2.64-2.55 (m, 2H), 2.23 (s, 3H), 2.04 (s, 3H), 1.54 (d, j=7.0 hz, 3H). The second peak fraction eluted at 13.96min retention time was concentrated to dryness and lyophilized to give 3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (70 mg,31% yield). LCMS (method G): retention time 1.84min, [ M+H ]] + 397.1; 1 H NMR(400MHz,DMSO-d 6 )δ11.07-10.89(m,1H),8.01(t,J=7.1Hz,1H),7.58(d,J=8.0Hz,1H),6.91(s,1H),5.79(s,2H),4.89(q,J=6.5Hz,1H),4.80(dd,J=12.6,5.1Hz,1H),2.94-2.78(m,1H),2.73-2.59(m,2H),2.22(s,3H),2.03(s,3H),1.51(d,J=6.8Hz,3H)。
Method A: ACQUITYBEH C18 (3.0X105 mm) 1.7 μm; mobile phase a:95:5 water acetonitrile with 2.5mM NH 4 OAc; mobile phase B:5:95 water acetonitrile with 2.5mM NH 4 OAc; temperature: 40 ℃; gradient: 20% b to 100% b for 2 minutes; flow rate: 0.7mL/min; and (3) detection: MS and UV (220 nm).
Method B: column: xbridge BEH XP C18 (50x2.1) mm,2.5 μm; mobile phase a:95:5 water acetonitrile with 10mM NH 4 OAc; mobile phase B:5:95 water acetonitrile with 10mM NH 4 OAc; temperature: 50 ℃; gradient: 0% b to 100% b for 3 minutes; flow rate: 1.1mL/min; and (3) detection: MS and UV (220 nm).
Method D: column-kineex XB-C18 (75X 3mm-2.6 μm); mobile phase a: containing 5mM NH 4 COOH water; mobile phase B: acetonitrile; gradient: 10% b to 50% b for 3 minutes, flow rate: 1.0mL/min;50% B to 100% B up to 4.1min, flow rate: 1.0mL/min; maintaining for 4.5min;4.5min to 5.0min 90% b flow rate: 1.5mL/min; and (3) detection: MS and UV (220 nm).
Method G: column-kineex XB-C18 (75X 3mm-2.6 μm); mobile phase a: containing 5mM NH 4 CO 2 Water of H; mobile phase B: acetonitrile; gradient: 20% b to 100% b for 4 minutes, flow rate: 1.0mL/min; hold to 4.6min, flow rate: 1.5mL/min; maintaining for 4.7min;4.7min to 5.0min 20% b, flow rate: 1.0mL/min; and (3) detection: MS and UV (220 nm).
Example 18
3- (5- (6-amino-3-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Example 18 was synthesized from 6-chloropyridin-2-amine and intermediate 3B using general procedure 2. The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0min, 10 to 30% B for 20 min, then 100% B for 5min; flow rate: 20 mL/min). LCMS (method B): retention time 0.98min, [ M+H ] ] + 369.1; 1 H NMR(400MHz,DMSO-d 6 )δ11.04(s,1H),7.77(br d,J=7.6Hz,2H),7.74-7.68(m,1H),6.93-6.87(m,1H),5.17(dd,J=13.3,5.1Hz,1H),4.67(d,J=17.6Hz,1H),4.55-4.47(m,1H),3.01-2.89(m,2H),2.67-2.61(m,1H),2.47-2.39(m,1H),2.04(s,3H)。
General procedure 4:
a mixture of aryl halide (1 eq.), aryl pinacol borate (1.0 eq.), potassium carbonate (1.5 eq.), dioxane (4 mL/mmol) and water (0.4 mL/mmol) was purged with argon for 5 minutes at room temperature. Addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane complex (0.05 eq.) and the reaction mixture was heated at 110℃for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through a celite pad. The filtrate was washed with brine solution, dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The residue was purified by flash chromatography. Dissolving the separated product in acetonitrile, adding pTSA.H 2 O (2 eq.) and the mixture was heated in a microwave reactor at 120℃for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure and the crude product was purified by preparative HPLC to give the desired product.
Example 19
3- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 19A and 19B: 6-bromo-3-fluoro-4-methylpyridin-2-amine and 6-bromo-5-fluoro-4-methylpyridin-2-amine
To a solution of 6-bromo-4-methylpyridin-2-amine (2.6 g,13.90 mmol) in chloroform (100 mL) and water (100 mL) was added SelectFluor (2.460 g,6.95 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with DCM (200 mL), washed with brine solution, and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The residue obtained was purified by flash chromatography (SiO 2 80g column, 0 to 30% etoac/petroleum ether) to afford intermediate 19A: 6-bromo-3-fluoro-4-methylpyridin-2-amine (600 mg,19.6% yield); LCMS (method a): retention time 1.21min, [ M+H ]] + 207.1。 1 H NMR(300MHz,DMSO-d 6 ) Delta 6.60 (d, j=4.2 hz, 1H), 6.55 (s, 2H), 2.13 (d, j=1.9 hz, 3H); intermediate 19B: 6-bromo-5-fluoro-4-methylpyridin-2-amine (500 mg,4.4% yield); LCMS (method a): retention time 1.14, [ M+H ]] + 207.1; 1 H NMR (300 MHz, chloroform-d) delta 6.25 (d, j=4.2 hz, 1H), 4.52-4.22 (m, 2H), 2.23 (d, j=1.1 hz, 3H).
Example 19:
example 19 was synthesized by using general procedure 4 with 6-bromo-3-fluoro-4-methylpyridin-2-amine and (S) -5-amino-4- (4-fluoro-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2). The crude product was purified by preparative LCMS (column: YMC EXRS 250 mm. Times.21 mm, mobile phase A:5:95 acetonitrile: water and 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water and 0.1% trifluoroacetic acid; gradient: 10 to 30% B for 20 minutes at 10% B, then 5 minutes at 100% B; flow rate: 20 mL/min). LCMS (method D): retention time 1.56min, [ M+H ] ] + 387.15; 1 H NMR(400MHz,DMSO-d 6 )δ11.02(s,1H),8.09-7.92(m,1H),7.66(d,J=8.0Hz,1H),7.32-6.78(m,1H),5.14(dd,J=13.8,5.8Hz,1H),4.74-4.33(m,2H),2.98-2.86(m,1H),2.68-2.56(m,2H),2.24(s,3H),22.09-2.05(m,1H)。
Example 20
3- (5- (6-amino-3-fluoro-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Example 20 was synthesized by using general procedure 4 with 6-bromo-5-fluoro-4-methylpyridin-2-amine and (S) -5-amino-4- (4-fluoro-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2). The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0 min, 10 to 30% B for 20 min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.03min, [ M+H ]] + 387.1; 1 H NMR(400MHz,DMSO-d 6 )δ11.04(s,1H),7.74-7.57(m,2H),6.46(d,J=4.5Hz,1H),5.97(s,2H),5.16(dd,J=5.0,13.3Hz,1H),4.65(d,J=17.5Hz,1H),4.52-4.42(m,1H),3.03-2.86(m,1H),2.68-2.59(m,1H),2.49-2.41(m,1H),2.21(s,3H),2.12-1.99(m,1H)。
Examples 21 and 22
3- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Intermediate 21A: (4S) -5-amino-4- (3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
A mixture of intermediate 8D (1.0 g,2.43 mmol), potassium acetate (0.239 g,2.43 mmol) and Bispin (0.611 g,2.43 mmol) in anhydrous DME (15 mL) was flushed with argon for 10 min at room temperature. PdCl was added under argon atmosphere 2 (dppf)-CH 2 Cl 2 Adducts [ (]0.159g,0.195 mmol). The vial was sealed and the mixture was heated at 90 ℃ for 12 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give (4S) -5-amino-4- (3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (1.0 g,90% yield). LCMS (method a): retention time 1.70min, [ M+H ]] + 459.1。
Preparation 21B and 22B: (4S) -5-amino-4- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester
To a solution of (4S) -5-amino-4- (3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (0.241 g, 0.227 mmol) in dioxane (10 mL) was added 6-bromo-3-fluoro-4-methylpyridin-2-amine (0.09 g,0.44 mmol), followed by sodium bicarbonate (0.5M solution, 2.195mL,1.097 mmol). The reaction mixture was flushed with nitrogen for 15 minutes, bis (triphenylphosphine) palladium (II) chloride (0.031 g,0.044 mmol) was added under nitrogen and heated at 100 ℃ for 12 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 24g column, 50 to 100% EtOAc/DCM) to give (4S) -5-amino-4- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (150 mg) as a mixture of diastereomers. These diastereomers were passed through SFC (column Chiral Pak IG (250X 4.6) mm,5 μm;% CO 2 :45%; cosolvent%: methanol and acetonitrile (1:1) containing 5mM ammonium acetate; flow rate: 4g/min; temperature: 30 ℃; UV:237 nm), and the first eluted isomer fraction at 3.4min retention time was concentrated to dryness to give (4S) -5-amino-4- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (40 mg,20% yield). LCMS (method a): retention time 1.41, [ M+H ]] + 457.1 and the second peak to elute at a retention time of 4.6minThe fractions were concentrated to give (4S) -5-amino-4- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (50 mg,25% yield). LCMS (method a): retention time 1.40, [ M+H ]] + 457.4。
Example 21:
to a stirred solution of (4S) -5-amino-4- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (0.04 g,0.088 mmol) in acetonitrile (10 mL) was added benzenesulfonic acid (0.028 g,0.175 mmol). The reaction mixture was heated at 120℃for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by preparative LCMS (column: waters XBiridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water and 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water and 0.1% trifluoroacetic acid; gradient: 10 to 30% B for 20 minutes at 10% B, then 5 minutes at 100% B; flow rate: 20 mL/min). LCMS (method B): retention time 1.19min, [ M+H ] ] + 383.1; 1 H NMR(400MHz,DMSO-d 6 )δ10.95(s,1H),8.14(s,1H),8.07(dd,J=1.1,8.1Hz,1H),7.72(d,J=8.0Hz,1H),7.17(d,J=4.4Hz,1H),4.82-4.67(m,2H),2.93-2.79(m,1H),2.71-2.59(m,2H),2.26(s,3H),2.05-1.96(m,1H),1.48(d,J=6.6Hz,3H)。
Example 22:
to a stirred solution of (4S) -5-amino-4- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (0.04 g,0.088 mmol) in acetonitrile (10 mL) was added benzenesulfonic acid (0.028 g,0.175 mmol). The reaction mixture was heated at 120℃for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was purified by preparative LCMS (column: waters XB ridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0 min, 10 to 30% B for 20 min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.19min, [ M ]H] + 383.1; 1 H NMR(400MHz,DMSO-d 6 )δ10.92(s,1H),8.16(s,1H),8.07(dd,J=1.1,8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.17(d,J=4.3Hz,1H),6.26(br s,2H),4.83(q,J=6.6Hz,1H),4.74(br dd,J=4.3,11.3Hz,1H),2.83-2.71(m,1H),2.64-2.55(m,2H),2.25(d,J=1.5Hz,3H),2.09-1.96(m,1H),1.50(d,J=6.6Hz,3H)。
Example 23
2-amino-6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile
Example 23 was synthesized from 2-amino-6-chloro-4-methylpyridine-3-carbonitrile (S) -5-amino-4- ((R) -4-fluoro-3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2) using general procedure 4. The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0 min, 10 to 30% B for 20 min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.19min, [ M+H ] ] + 408.0; 1 H NMR(400MHz,DMSO-d 6 )δ11.00(s,1H),8.17-7.85(m,1H),7.73-7.52(m,1H),7.05(s,1H),6.99(s,2H),5.08-4.89(m,1H),4.86-4.72(m,1H),2.90-2.75(m,1H),2.74-2.58(m,2H),2.42(s,3H),2.12-2.00(m,1H),1.57-1.47(m,3H)。
Example 24
3- ((R) -5- (6-amino-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Example 24 was synthesized from 6-chloro-4-methylpyridin-2-amine (S) -5-amino-4- ((R) -4-fluoro-3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2) using general procedure 4. The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0min, 10 to 30% B for 20min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.20min, [ M+H ]] + 383.2; 1 H NMR(400MHz,DMSO-d 6 )δ11.00(d,J=0.8Hz,1H),8.01-7.84(m,1H),7.71(d,J=7.8Hz,1H),6.96(br d,J=1.0Hz,1H),6.71-6.54(m,1H),4.99-4.91(m,1H),4.87-4.78(m,1H),2.86(br dd,J=4.4,3.4Hz,1H),2.75-2.62(m,2H),2.47-2.44(m,1H),2.34(s,4H),1.94(d,J=16.0Hz,1H),1.53(d,J=6.8Hz,3H)。
Example 25
3- ((R) -5- (6-amino-4- (trifluoromethyl) pyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Example 25 was synthesized from 6-chloro-4- (trifluoromethyl) pyridin-2-amine and (S) -5-amino-4- ((R) -4-fluoro-3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2) using general procedure 4. The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0min, 10 to 30% B for 20min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.39min, [ M ] +H] + 438.1; 1 H NMR(400MHz,DMSO-d 6 )δ10.99(s,1H),8.13-7.95(m,1H),7.65(d,J=7.8Hz,1H),7.15(s,1H),6.79(s,2H),4.98-4.88(m,1H),4.86-4.77(m,1H),2.85(br s,1H),2.93-2.78(m,1H),2.72-2.59(m,2H),2.08-2.00(m,1H),1.52(d,J=6.8Hz,3H)。
Example 26
3- ((R) -5- (6-amino-3-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Example 26 was synthesized from 6-chloro-5-methylpyridin-2-amine and (S) -5-amino-4- ((R) -4-fluoro-3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2) using general procedure 4. The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0 min, 10 to 30% B for 20 min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.07min, [ m+h ]] + 383.1; 1 H NMR(400MHz,DMSO-d 6 )δ11.01(s,1H),7.90-7.77(m,1H),7.74-7.61(m,2H),6.86(br dd,J=5.5,3.9Hz,1H),4.96(q,J=6.5Hz,1H),4.84(dd,J=12.6,5.1Hz,1H),3.01-2.82(m,2H),2.71-2.60(m,2H),2.12-2.01(m,5H),1.51(d,J=6.6Hz,3H)。
Example 27
3- ((R) -5- (6-aminopyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Example 27 was from 6-chloropyridin-2-amine (S) -5-amino-4- ((R) -4-fluoro-3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2) was synthesized using general procedure 4. The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0 min, 10 to 30% B for 20 min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.01min, [ M+H ] ] + 369.1; 1 H NMR(400MHz,DMSO-d 6 )δ7.95(t,J=7.1Hz,1H),7.81-7.62(m,2H),7.22(s,1H),7.09(s,1H),7.04(br d,J=7.0Hz,1H),6.97(s,1H),6.78-6.72(m,1H),4.93(q,J=6.5Hz,1H),4.82(dd,J=12.4,5.3Hz,1H),2.91-2.83(m,1H),2.75-2.60(m,2H),2.36-2.32(m,1H),1.52(d,J=6.8Hz,3H)。
Example 28
(R) -3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
To a stirred solution of example 17 (250 mg,0.531 mmol) in acetonitrile (4 mL) was added TFA (1 mL,13.81 mmol). The reaction mixture was heated at 90℃for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude product was passed through preparative SFC (Chiral Pak IC (250X 50) mm,5 μm;% CO) 2 :50%; cosolvent%: 50% ACN: MEOH (50:50) with 5mM ammonium acetate; flow rate: 300.0g/min; temperature: 40 ℃; UV:240 nm), and the first eluted isomer fraction at 6.9min retention time was concentrated to dryness and lyophilized to give (R) -3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (15 mg,7% yield). LCMS (method D): retention time 1.28min, [ M+H ]] + 397.1; 1 H NMR(400MHz,DMSO-d 6 )δ10.97-10.89(m,1H),7.99(br d,J=6.8Hz,1H),7.57(d,J=8.0Hz,1H),6.91(s,1H),5.80(s,2H),5.00(q,J=6.7Hz,1H),4.76-4.67(m,1H),2.82-2.70(m,1H),2.67-2.55(m,2H),2.22(s,3H),2.03(s,4H),1.53(d,J=6.8Hz,3H)。
Example 29
3- ((R) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Example 29 was synthesized from 6-chloro-3-fluoro-4-methylpyridin-2-amine (S) -5-amino-4- ((R) -4-fluoro-3-methyl-1-oxo-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (synthesized starting with 4-bromo-3-fluoro-2-methylbenzoic acid by the procedure shown in example 2) using general procedure 4. The crude product was purified by preparative LCMS (column: waters XBridge C18, 150mm x 19mm, 5-. Mu.m particles; mobile phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B:95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient: 10% B for 0 min, 10 to 30% B for 20 min, then 100% B for 5 min; flow rate: 20 mL/min). LCMS (method B): retention time 1.18min, [ M+H ] ] + 401.3; 1 H NMR(400MHz,DMSO-d 6 )δ10.98(s,1H),7.95(t,J=7.1Hz,1H),7.60(d,J=7.8Hz,1H),6.93(d,J=3.3Hz,1H),4.90(q,J=6.6Hz,1H),4.80(dd,J=4.9,12.9Hz,1H),2.89-2.78(m,1H),2.70-2.60(m,2H),2.24(s,3H),2.07-1.97(m,1H),1.51(d,J=6.5Hz,3H)。
Example 30
3- ((S) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Preparation of 30A: 3-fluoro-4-methyl-6- (trimethylstannane) pyridin-2-amine
The mixture was stirred and added to toluene (3 mL)The solution of 6-bromo-3-fluoro-4-methylpyridin-2-amine (0.05 g,0.24 mmol) and hexamethylditin (0.076 mL,0.366 mmol) was flushed with argon for 5 min, followed by the addition of [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (0.016 g,0.024 mmol). The reaction mixture was stirred at 100 ℃ for 15 hours, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give 3-fluoro-4-methyl-6- (trimethylstannane) pyridin-2-amine (69 mg,82% yield). LCMS (method a): retention time 1.68, [ m+h ]] + 289.2。
Example 30:
the steller coupling and cyclization is achieved by following general procedure 2 using intermediate 30A and intermediate 16D. LCMS (method D): retention time 1.17min, [ M+H ]] + 401.3; 1 H NMR(400MHz,DMSO-d 6 )δ10.94(s,1H),7.94(t,J=7.3Hz,1H),7.58(d,J=8.0Hz,1H),6.93(d,J=3.3Hz,1H),6.31(br s,2H),5.01(q,J=6.6Hz,1H),4.72(dd,J=4.9,11.9Hz,1H),2.79-2.67(m,1H),2.64-2.55(m,2H),2.24(s,3H),2.07-1.98(m,1H),1.53(d,J=6.8Hz,3H)。
Biological analysis
The pharmacological properties of the compounds of the invention may be demonstrated by a number of biological assays. The following exemplary biological assays have been performed using the compounds of the present invention.
Helios cell degradation assay
Jurkat cells were plated at 80,000 cells/well in 384 well cell culture plates in 40 μl rpmi+10% fbs, followed by the use of acoustic partitioning techniques to add the compound of interest. The cell culture was incubated at 37℃and 5% CO 2 Incubate for 72 hours. For ease of analysis, the cell cultures were spun down at 200rpm for 5 minutes and the supernatant discarded. After shaking the plate to remove the cell clusters, the cells were resuspended in 50 μl of fixation buffer (eBioScience FoxP3 buffer set 00-5523-00) at room temperature for 60 minutes. After centrifugation and discarding the supernatant, the cells were permeabilized with 50. Mu.L of permeabilization buffer (eBioscience FoxP3 buffer set 00-5523-00) for 10 min at room temperature. After permeation, cells were spun down and the supernatant was subjected to 20. Mu.L of fluorescently labeled anti Helios, ikaros and Aiolos in 1 Xpermeation bufferAntibodies or corresponding isotype controls (Ikaros-Alexa 488[ bioleged, cat. No. 368408, 1:50)]Helios-PE [ CST, catalog number 29360,1:50]Aiolos-Alexa647[ bioleged, catalog number 371106 bioleged, 1:25)]) Changing and culturing the dyeing reaction for 1 hour at room temperature; and (5) light shielding. Subsequently, 30 μl of 1x permeation buffer was added, after which the cells were centrifuged and the supernatant discarded. Stained cells were resuspended in 25 μl of flow cytometry staining buffer (pbs+0.2% bsa) and analyzed using a Intellicyt Ique Plus flow cytometer.
TABLE 4 Table 4
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SEQUENCE LISTING
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Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala Glu Ala Leu His Pro Leu
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Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser Glu Ser Ser His Asp Asp
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Leu Arg Thr His Ser Val Gly Lys Pro His Lys Cys Asn Tyr Cys Gly
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His Asn Tyr Leu Gln Asn Val Ser Met Glu Ala Ala Gly Gln Val Met
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Met Asp Asn Asn Ile Ser Leu Val Pro Phe Glu Arg Pro Ala Val Ile
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Glu Lys Leu Thr Gly Asn Met Gly Lys Arg Lys Ser Ser Thr Pro Gln
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Lys Phe Val Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp Ile His
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Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser
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His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala
290 295 300
Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile Ala Glu
305 310 315 320
Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His Pro Asn
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Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His Glu Asn
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Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln
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Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser
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Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro Ala Leu
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Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp Val Lys
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Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp Ile Tyr
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His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile His Met
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Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro
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Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
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Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val
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Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Glu Arg
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Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn
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Ser His His Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp Ile His
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Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser
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Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His Pro Asn
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Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His Glu Asn
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Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln
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Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser
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Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro Ala Leu
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Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp Val Lys
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Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro
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Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
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Val His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln
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Gly Lys Pro His Lys Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Arg
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Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu
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Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn
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Pro Phe Cys Ser Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His
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Pro Ile Met Asp Asn Asn Ile Ser Leu Val Pro Phe Glu Arg Pro Ala
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Val Ile Glu Lys Leu Thr Gly Asn Met Gly Lys Arg Lys Ser Ser Thr
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Pro Gln Lys Phe Val Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp
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Ile His Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met
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Gln Ser His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu
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Gly Ala Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile
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Ala Glu Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His
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Pro Asn Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His
290 295 300
Glu Asn Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg
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Pro Gln Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr
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Asp Ser Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro
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Ala Leu Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp
355 360 365
Val Lys Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp
370 375 380
Ile Tyr Lys Val Phe Asn Gly Glu Gly Glu Gln Ile Arg Ala Phe Lys
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Cys Glu His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile
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His Met Gly Cys His Gly Tyr Arg Asp Pro Leu Glu Cys Asn Ile Cys
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Gly Tyr Arg Ser Gln Asp Arg Tyr Glu Phe Ser Ser His Ile Val Arg
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Ser Asn His Phe Ile Met Glu Ser Leu Phe Cys Glu Ser Ser Gly Asp
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Ser Ser Leu Glu Lys Glu Phe Leu Gly Ala Pro Val Gly Pro Ser Val
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Ser Thr Pro Asn Ser Gln His Ser Ser Pro Ser Arg Ser Leu Ser Ala
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Asn Ser Ile Lys Val Glu Met Tyr Ser Asp Glu Glu Ser Ser Arg Leu
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Leu Gly Pro Asp Glu Arg Leu Leu Glu Lys Asp Asp Ser Val Ile Val
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Glu Asp Ser Leu Ser Glu Pro Leu Gly Tyr Cys Asp Gly Ser Gly Pro
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Glu Pro His Ser Pro Gly Gly Ile Arg Leu Pro Asn Gly Lys Leu Lys
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Cys Asp Val Cys Gly Met Val Cys Ile Gly Pro Asn Val Leu Met Val
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His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln Cys
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Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu Leu Arg His Ile Lys Leu
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His Ser Gly Glu Lys Pro Phe Lys Cys Pro Phe Cys Asn Tyr Ala Cys
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Arg Arg Arg Asp Ala Leu Thr Gly His Leu Arg Thr His Ser Val Ser
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Ser Pro Thr Val Gly Lys Pro Tyr Lys Cys Asn Tyr Cys Gly Arg Ser
245 250 255
Tyr Lys Gln Gln Ser Thr Leu Glu Glu His Lys Glu Arg Cys His Asn
260 265 270
Tyr Leu Gln Ser Leu Ser Thr Glu Ala Gln Ala Leu Ala Gly Gln Pro
275 280 285
Gly Asp Glu Ile Arg Asp Leu Glu Met Val Pro Asp Ser Met Leu His
290 295 300
Ser Ser Ser Glu Arg Pro Thr Phe Ile Asp Arg Leu Ala Asn Ser Leu
305 310 315 320
Thr Lys Arg Lys Arg Ser Thr Pro Gln Lys Phe Val Gly Glu Lys Gln
325 330 335
Met Arg Phe Ser Leu Ser Asp Leu Pro Tyr Asp Val Asn Ser Gly Gly
340 345 350
Tyr Glu Lys Asp Val Glu Leu Val Ala His His Ser Leu Glu Pro Gly
355 360 365
Phe Gly Ser Ser Leu Ala Phe Val Gly Ala Glu His Leu Arg Pro Leu
370 375 380
Arg Leu Pro Pro Thr Asn Cys Ile Ser Glu Leu Thr Pro Val Ile Ser
385 390 395 400
Ser Val Tyr Thr Gln Met Gln Pro Leu Pro Gly Arg Leu Glu Leu Pro
405 410 415
Gly Ser Arg Glu Ala Gly Glu Gly Pro Glu Asp Leu Ala Asp Gly Gly
420 425 430
Pro Leu Leu Tyr Arg Pro Arg Gly Pro Leu Thr Asp Pro Gly Ala Ser
435 440 445
Pro Ser Asn Gly Cys Gln Asp Ser Thr Asp Thr Glu Ser Asn His Glu
450 455 460
Asp Arg Val Ala Gly Val Val Ser Leu Pro Gln Gly Pro Pro Pro Gln
465 470 475 480
Pro Pro Pro Thr Ile Val Val Gly Arg His Ser Pro Ala Tyr Ala Lys
485 490 495
Glu Asp Pro Lys Pro Gln Glu Gly Leu Leu Arg Gly Thr Pro Gly Pro
500 505 510
Ser Lys Glu Val Leu Arg Val Val Gly Glu Ser Gly Glu Pro Val Lys
515 520 525
Ala Phe Lys Cys Glu His Cys Arg Ile Leu Phe Leu Asp His Val Met
530 535 540
Phe Thr Ile His Met Gly Cys His Gly Phe Arg Asp Pro Phe Glu Cys
545 550 555 560
Asn Ile Cys Gly Tyr His Ser Gln Asp Arg Tyr Glu Phe Ser Ser His
565 570 575
Ile Val Arg Gly Glu His Lys Val Gly
580 585
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Met Asp Ser Arg Tyr Leu Gln Leu Gln Leu Tyr Leu Pro Ser Cys Ser
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Leu Leu Gln Gly Ser Gly Asp Ser Ser Leu Glu Lys Glu Phe Leu Gly
20 25 30
Ala Pro Val Gly Pro Ser Val Ser Thr Pro Asn Ser Gln His Ser Ser
35 40 45
Pro Ser Arg Ser Leu Ser Ala Asn Ser Ile Lys Val Glu Met Tyr Ser
50 55 60
Asp Glu Glu Ser Ser Arg Leu Leu Gly Pro Asp Glu Arg Leu Leu Glu
65 70 75 80
Lys Asp Asp Ser Val Ile Val Glu Asp Ser Leu Ser Glu Pro Leu Gly
85 90 95
Tyr Cys Asp Gly Ser Gly Pro Glu Pro His Ser Pro Gly Gly Ile Arg
100 105 110
Leu Pro Asn Gly Lys Leu Lys Cys Asp Val Cys Gly Met Val Cys Ile
115 120 125
Gly Pro Asn Val Leu Met Val His Lys Arg Ser His Thr Gly Glu Arg
130 135 140
Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn
145 150 155 160
Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys
165 170 175
Pro Phe Cys Asn Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His
180 185 190
Leu Arg Thr His Ser Val Ser Ser Pro Thr Val Gly Lys Pro Tyr Lys
195 200 205
Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Gln Ser Thr Leu Glu Glu
210 215 220
His Lys Glu Arg Cys His Asn Tyr Leu Gln Ser Leu Ser Thr Glu Ala
225 230 235 240
Gln Ala Leu Ala Gly Gln Pro Gly Asp Glu Ile Arg Asp Leu Glu Met
245 250 255
Val Pro Asp Ser Met Leu His Ser Ser Ser Glu Arg Pro Thr Phe Ile
260 265 270
Asp Arg Leu Ala Asn Ser Leu Thr Lys Arg Lys Arg Ser Thr Pro Gln
275 280 285
Lys Phe Val Gly Glu Lys Gln Met Arg Phe Ser Leu Ser Asp Leu Pro
290 295 300
Tyr Asp Val Asn Ser Gly Gly Tyr Glu Lys Asp Val Glu Leu Val Ala
305 310 315 320
His His Ser Leu Glu Pro Gly Phe Gly Ser Ser Leu Ala Phe Val Gly
325 330 335
Ala Glu His Leu Arg Pro Leu Arg Leu Pro Pro Thr Asn Cys Ile Ser
340 345 350
Glu Leu Thr Pro Val Ile Ser Ser Val Tyr Thr Gln Met Gln Pro Leu
355 360 365
Pro Gly Arg Leu Glu Leu Pro Gly Ser Arg Glu Ala Gly Glu Gly Pro
370 375 380
Glu Asp Leu Ala Asp Gly Gly Pro Leu Leu Tyr Arg Pro Arg Gly Pro
385 390 395 400
Leu Thr Asp Pro Gly Ala Ser Pro Ser Asn Gly Cys Gln Asp Ser Thr
405 410 415
Asp Thr Glu Ser Asn His Glu Asp Arg Val Ala Gly Val Val Ser Leu
420 425 430
Pro Gln Gly Pro Pro Pro Gln Pro Pro Pro Thr Ile Val Val Gly Arg
435 440 445
His Ser Pro Ala Tyr Ala Lys Glu Asp Pro Lys Pro Gln Glu Gly Leu
450 455 460
Leu Arg Gly Thr Pro Gly Pro Ser Lys Glu Val Leu Arg Val Val Gly
465 470 475 480
Glu Ser Gly Glu Pro Val Lys Ala Phe Lys Cys Glu His Cys Arg Ile
485 490 495
Leu Phe Leu Asp His Val Met Phe Thr Ile His Met Gly Cys His Gly
500 505 510
Phe Arg Asp Pro Phe Glu Cys Asn Ile Cys Gly Tyr His Ser Gln Asp
515 520 525
Arg Tyr Glu Phe Ser Ser His Ile Val Arg Gly Glu His Lys Val Gly
530 535 540
Claims (20)
1. A compound of formula (I):
or a salt thereof, wherein:
R 1 is-NH 2 or-NH (CH) 3 );
Each R is 2 Is independently F, cl, -CN, C 1-4 Alkyl, -CH 2 F、-CHF 2 、-CF 3 、-OCH 3 Or cyclopropyl;
each R is 4 Is independently F, cl, -CH 3 、-CH 2 F、-CHF 2 、-CF 3 or-OCH 3 ;
R 6 Is hydrogen, C 1-2 Alkyl or C 1-2 A fluoroalkyl group;
m is 0, 1, 2 or 3; and is also provided with
n is 0, 1, 2 or 3;
with the proviso that when R 6 In the case of hydrogen, m is 1, 2 or 3.
2. The compound according to claim 1, or a salt thereof, wherein R 1 is-NH 2 。
3. The compound according to claim 1, or a salt thereof, wherein R 1 is-NH (CH) 3 )。
4. A compound according to any one of claims 1 to 3, wherein each R 2 Is independently F, -CN, -CH 3 or-CF 3 。
5. The compound according to any one of claims 1 to 5, or a salt thereof, wherein R 6 Is C 1-2 Alkyl, -CH 2 F、-CF 2 H、-CF 3 or-CH 2 CF 3 。
6. According to claimThe compound according to any one of claims 1 to 5, wherein R 6 is-CH 3 。
7. The compound according to any one of claims 1 to 5, or a salt thereof, wherein:
R 6 is C 1-2 Alkyl, -CH 2 F、-CF 2 H、-CF 3 or-CH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
m is 0.
8. The compound according to any one of claims 1 to 5, or a salt thereof, wherein:
R 6 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
m is 0.
9. The compound according to any one of claims 1 to 5, or a salt thereof, wherein each R 4 Is independently F, -CH 3 、-CHF 2 or-CF 3 。
10. The compound according to any one of claims 1 to 5, or a salt thereof, wherein:
each R is 4 Is F, -CH 3 、-CHF 2 or-CF 3 ;
R 6 Is hydrogen; and is also provided with
m is 1 or 2.
11. The compound according to any one of claims 1 to 5, or a salt thereof, wherein:
each R is 4 Is F or-CH 3 ;
R 6 Is hydrogen; and is also provided with
m is 1 or 2.
12. The compound according to any one of claims 1 to 5, or a salt thereof, wherein:
R 4 is F or-CH 3 ;
R 6 Is hydrogen; and is also provided with
m is 1.
13. The compound or salt thereof according to claim 1, wherein the compound is:
2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (1);
2-amino-6- (2, 6-dioxopiperidin-3-yl) -6-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (2);
2-amino-6- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (3);
3- (5- (6-amino-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (4);
3- (5- (6-amino-4- (trifluoroethyl) pyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (5);
3- (4-fluoro-5- (4-methyl-6- (methylamino) pyridin-2-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (6);
3- (5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (7);
3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (8);
3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (9);
2-amino-6- ((3S) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (10);
2-amino-6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (11);
3- ((S) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (12);
3- ((R) -5- (4, 5-dimethyl-6- (methylamino) pyridin-2-yl) -3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (13);
6- ((3S) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile (14);
6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -3-methyl-1-oxoisoindolin-5-yl) -4-methyl-2- (methylamino) pyridine-3-carbonitrile (15);
3- ((S) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (16);
3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (17);
3- (5- (6-amino-3-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (18);
3- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (19);
3- (5- (6-amino-3-fluoro-4-methylpyridin-2-yl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (20);
3- (5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (21-22);
2-amino-6- ((3R) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-3-methyl-1-oxoisoindolin-5-yl) -4-methylpyridine-3-carbonitrile (23);
3- ((R) -5- (6-amino-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (24);
3- ((R) -5- (6-amino-4- (trifluoromethyl) pyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (25);
3- ((R) -5- (6-amino-3-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (26);
3- ((R) -5- (6-aminopyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (27);
(R) -3- ((R) -5- (6-amino-4, 5-dimethylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (28);
3- ((R) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (29); or (b)
3- ((S) -5- (6-amino-5-fluoro-4-methylpyridin-2-yl) -4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (30).
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
15. Use of a compound according to any one of claims 1 to 11 for the treatment of cancer.
16. The use according to claim 13, wherein the cancer is selected from colon cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia and melanoma.
17. A method of reducing the level of Helios protein, the level of Helios activity or the level of Helios expression in a cell, said method comprising contacting the Helios protein with a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.
18. The method of claim 15, wherein the Helios protein is the amino acid sequence encoded by SEQ ID No. 1, 2, 3, 4 or 5.
19. A method of reducing the level of eosin, the level of eosin activity or the level of eosin expression in a cell, the method comprising contacting the eosin with a compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.
20. The method of claim 17, wherein the eosin is an amino acid sequence encoded by SEQ ID No. 7 or 8.
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IN202111016193 | 2021-04-06 | ||
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IN202111022098 | 2021-05-17 | ||
PCT/US2022/023387 WO2022216644A1 (en) | 2021-04-06 | 2022-04-05 | Pyridinyl substituted oxoisoindoline compounds |
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