1H-Pyrazolo[3,4-D]pyrimidine compounds useful for treating platinum-resistant cancers

Abstract

The present invention relates to compounds of formula (I) and related compounds and their use in the treatment of cancer, particularly platinum-resistant cancers. The present invention also provides treatments comprising the administration of a compound of formula (I) and a platinum-containing drug. [Formula 1] TIFF2023507188000042.tif76114

Description

[Technical Field]

[0001] The present invention relates to compounds of formula (I) for use in the treatment of cancer, particularly platinum-resistant cancers. The present invention also relates to treatments comprising the administration of a compound of formula (I) and a platinum-containing drug. The present invention also relates to compounds of formula (II) and their use in the treatment of cancer, particularly platinum-resistant cancers, and treatments comprising the administration of a compound of formula (II) and a platinum-containing drug. [Background technology]

[0002] It is estimated that there were more than 17 million new cases of cancer worldwide in 2018, and more than 9.6 million cancer deaths that same year (Cancer Research UK, "Worldwide Cancer," accessed December 2018). One of the most common treatments for cancer is chemotherapy using platinum-containing drugs such as cisplatin or carboplatin. Cisplatin and carboplatin have been used to treat a variety of cancers, including ovarian cancer, testicular cancer, head and neck cancer, non-small cell lung cancer, sarcoma, lymphoma, bladder cancer, cervical cancer, breast cancer, mesothelioma, and pancreatic cancer.

[0003] Most related cancers have high initial response rates to cisplatin or carboplatin. However, resistance to these drugs commonly develops after initial treatment. This is known as platinum resistance and is often defined as tumor progression during or within 6 months of completing prior therapy with a platinum-containing drug. Many cancers relapse as platinum-resistant, including lung, breast, and ovarian cancers.

[0004] Recent studies have shown that platinum-resistant tumor cells are present within platinum-sensitive primary tumors at the time of presentation (Non-Patent Document 1). Selection of resistant cells is thought to occur after initial chemotherapy treatment with cisplatin or carboplatin, resulting in platinum-resistant tumors.

[0005] Treatment of platinum-resistant tumors is more difficult than treatment of platinum-sensitive tumors, and the survival rate of platinum-resistant cancers is lower. In the case of ovarian cancer, several combination treatments, such as gemcitabine and cisplatin, and paclitaxel and carboplatin, have been used for patients with platinum-resistant cancer. However, the response rate to combination treatments is similar to that of monotherapy for platinum-resistant ovarian cancer, so no standardized treatment has been developed for these patients.

[0006] There remains a need for effective chemotherapy treatments for platinum-resistant cancers. There is also a need for improved chemotherapy treatments for cancers treated with platinum-containing drugs, including improved treatments that can reduce the likelihood of developing platinum-resistant cancers. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Schwarz RF,et al,PLoS Med(2015),Vol 12,e1001789, Cooke SL,et al,Oncogene(2010),Vol.29,pages 4905-4913 Summary of the Invention

[0008] The present invention provides a compound of formula (I) for use in the treatment of platinum-resistant cancer, [ka] During the ceremony, X is CH and Z is CR 4 or N, or X is N and Z is CR 4 or XZ is C=C, R 1 and R 2 are independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclyl, or R 1and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring, Each R 3 is independently selected from methyl, halogen, and CF3; m is 0, 1, 2, or 3; R 4 is H or OH, When Z is N or XZ is C=C, Y is selected from a bond, —C(O)—, and —SO2NH—; R 5 is selected from methyl, halogen, and CF3; or Y is selected from -SO2-, R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Z is CR 4 If Y is selected from a bond, —C(O)—, —SO2NH—, and —NHSO2—; R 5 is selected from methyl, halogen, and CF3; or Y is selected from -SO2-, R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Y is -NR 6 - and R 5 is selected from methyl, halogen, and CF3; or Y is -O- and R 5 is selected from methyl and halogen; Y is a bond, -SO2NH-, -O-, or -NR 6 - and -C(O)NR 6 - n is 1, 2, 3, or 4 when selected from when Y is selected from -NHSO2-, -SO2-, and -C(O)-, n is 0, 1, 2, 3, or 4; R 6 is H and C 1-4 a compound selected from alkyl, or a salt thereof.

[0009] The present invention is based on the surprising discovery by the inventors that compounds of formula (I) are particularly effective in restoring platinum sensitivity in platinum-resistant cancer cell lines in vitro.

[0010] The present invention also provides the compound of formula (I) and a platinum-containing drug for use in the combined treatment of cancer, by administering the compound of the present invention and a platinum-containing drug simultaneously or separately.Combined treatment is also particularly useful in treating cancer that is platinum-sensitive but at risk of developing platinum resistance.By using the combination, the appearance of platinum resistance can be delayed or eliminated.

[0011] Accordingly, the present invention further provides a compound of formula (I) and a platinum-containing drug for use in the treatment of cancer.

[0012] The present invention further provides a method for treating platinum-containing drug-resistant cancer, comprising administering to a subject in need thereof a compound of formula (I). The present invention further provides a method for treating cancer that is platinum-sensitive but at risk of developing platinum resistance, comprising administering to a subject in need thereof a compound of formula (I), and a method for treating cancer, comprising administering to a subject in need thereof a compound of formula (I) and a platinum-containing drug in combination therapy.

[0013] The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of platinum-resistant cancer. The present invention further provides the use of a compound of formula (I) in combination with a platinum-containing drug for the manufacture of a medicament for the treatment of cancer that is platinum-sensitive but at risk of developing platinum resistance. The present invention further provides the use of a compound of formula (I) in combination with a platinum-containing drug for the manufacture of a medicament for the treatment of cancer.

[0014] The present invention relates to compounds of formula (Ia): [ka] During the ceremony, X is CH and Z is CR 4 or N, or X is N and Z is CR 4 or XZ is C=C, R 1 and R 2 are independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclyl, or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring, Each R 3 is independently selected from methyl, halogen, and CF3; m is 0, 1, 2, or 3; R 4 is H or OH, When Z is N or XZ is C=C, Y is selected from a bond, —C(O)—, and —SO2NH—; R 5 is selected from methyl, halogen, and CF3; or Y is selected from -SO2-, R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Z is CR 4 If Y is selected from a bond, —C(O)—, —SO2NH—, and —NHSO2—; R 5 is selected from methyl, halogen, and CF3; or Y is selected from -SO2-, R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Y is -NR 6 - and R 5 is selected from methyl, halogen, and CF3; or Y is -O- and R 5 is selected from methyl and halogen; Y is a bond, -SO2NH-, -O-, or -NR 6 - and -C(O)NR 6 - n is 1, 2, 3, or 4 when selected from when Y is selected from -NHSO2-, -SO2-, and -C(O)-, n is 0, 1, 2, 3, or 4; R 6 H and C 1-4 alkyl, Further provided is a compound or a salt thereof, with the proviso that it is not one of the following compounds: 2-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 3-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylpropan-1-amine N'-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]-N,N-diethylethane-1,2-diamine 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]acetamide N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N',N'-diethylpropane-1,3-diamine N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N'-[2-(dimethylamino)ethyl]urea N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N',N'-diethylethane-1,2-diamine N-[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]-N',N'-diethyl-N-methylethane-1,2-diamine N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-N~3~,N~3~-diethyl-β-alaninamide 2-{[[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-fluorophenyl)methyl]oxy}-N,N-dimethylethanamine N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N-(4-chlorophenyl)-2-(diethylamino)ethanesulfonamide 2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine N-(4-bromo-3-fluorophenyl)-N-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-N'-[2-(dimethylamino)ethyl]urea 2-{[(S)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-dimethylethanamine 3-Bromo-4-(4-{(R)-(4-chlorophenyl)[(2-pyrrolidin-1-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 1-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-1-(4-chlorophenyl)-4-(dimethylamino)butan-1-ol 2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chloro-3-fluorophenyl)methyl]oxy}-N,N-dimethylethanamine 3-Bromo-4-(4-{(R)-(4-chlorophenyl)[(2-piperidin-1-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 4-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-4-(4-chlorophenyl)-N,N-dimethylbutan-1-amine 3-Bromo-4-(4-{(R)-(4-chlorophenyl)[(2-morpholin-4-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 3-Bromo-4-(4-{(R)-(4-chloro-3-fluorophenyl)[(2-pyrrolidin-1-ylethyl)oxy]methyl}piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine 2-{[(R)-[1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl](4-chlorophenyl)methyl]oxy}-N,N-diethylethanamine.

[0015] The present invention relates to a compound of formula (II), [ka] During the ceremony, X is CH and Z is CR 4 or N, or X is N and Z is CR 4 or XZ is C=C, R 1 and R 2 are independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclyl, or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring, Each R 3 is independently selected from methyl, halogen, and CF3; m is 0, 1, 2, or 3; R 4 is H or OH, When Z is N or XZ is C=C, Y is selected from a bond, —C(O)—, and —SO2NH—; R 5 is selected from methyl, halogen, and CF3; or Y is -SO2- and R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Z is CR 4 If Y is selected from a bond, —C(O)—, —SO2NH—, and —NHSO2—; R 5 is selected from methyl, halogen, and CF3; or Y is -SO2- and R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Y is -NR 6 - and R 5is selected from methyl, halogen, and CF3; or Y is -O- and R 5 is methyl, Y is -C(O)NR 6 - and -NR 6 - n is 1, 3, or 4 when selected from when Y is -SO2NH- or -O-, n is 1, 2, 3, or 4; Z is CR 4 or when XZ is C=C and Y is a bond, n is 1, 2 or 4; when Z is N and Y is a bond, n is 1 or 4; Z is CR 4 or when XZ is C=C and Y is selected from -NHSO2-, -SO2-, and -C(O)-, n is 0, 1, 2, 3, or 4; when Z is N and Y is selected from —SO— and —C(O)—, n is 0, 1, 3, or 4; R 6 H and C 1-4 a compound selected from alkyl, or a salt thereof. [Brief explanation of the drawings]

[0016] [Figure 1A-1]

[0049] Figure 1 shows isobologram analysis (Loewe's synergy and antagonism performed from the readout of a standard MTT cell viability assay) of a range of concentrations of Example 1 (i), LY3023414 (ii), or afuresertib (iii) (shown on the left side of each isobologram plot) in combination with a range of concentrations of cisplatin (above the isobologram plot) over 72 hours in the high-grade serous ovarian cancer isogenic-matched platinum-sensitive cell line PEO1. Data shown are for n=3. Decreasing negative numbers in each table indicate increasing levels of antagonism between cisplatin and the inhibitor compound, while increasing positive numbers indicate increasing levels of synergy between cisplatin and the inhibitor compound. [Figure 1A-2] Figure 1 shows isobologram analysis (Loewe's synergy and antagonism performed from standard MTT cell viability assay readouts) of a range of concentrations of uprosertib (iv), ipatasertib (v), or triciribine (vi) (shown on the left side of each isobologram plot) in combination with a range of concentrations of cisplatin (upper side of the isobologram plot) over 72 hours in the high-grade serous ovarian cancer isogenic-matched platinum-sensitive cell line PEO1. Data shown are for n=3. Decreasing negative numbers in each table indicate increasing levels of antagonism between cisplatin and the inhibitor compound, while increasing positive numbers indicate increasing levels of synergy between cisplatin and the inhibitor compound. [Figure 1A-3] Figure 1 shows an isobologram analysis (Loewe's synergy and antagonism performed from the readout of a standard MTT cell viability assay) of a range of NU7441(vii) concentrations (shown on the left side of each isobologram plot) in combination with a range of cisplatin concentrations (above the isobologram plot) over 72 hours in the high-grade serous ovarian cancer isogenic-matched platinum-sensitive cell line PEO1. Data shown are for n=3. Decreasing negative numbers in each table indicate increasing levels of antagonism between cisplatin and the inhibitor compound, while increasing positive numbers indicate increasing levels of synergy between cisplatin and the inhibitor compound. [Figure 1B-1]

[0049] Figure 1 shows isobologram analysis (Loewe's synergy and antagonism performed from the readout of a standard MTT cell viability assay) of a range of concentrations of Example 1 (i), LY3023414 (ii), or afuresertib (iii) (shown on the left side of each isobologram plot) in combination with a range of concentrations of cisplatin (above the isobologram plot) over 72 hours in the high-grade serous ovarian cancer isogenic-matched platinum-resistant cell line PEO4. Data shown are for n=3. A decrease in negative numbers within each table indicates an increasing level of antagonism between cisplatin and the inhibitor compound, and an increasing positive number indicates an increasing level of synergy between cisplatin and the inhibitor compound. [Figure 1B-2]Figure 1 shows an isobologram analysis (Loewe's synergy and antagonism performed from the readout of a standard MTT cell viability assay) of a range of concentrations of uprosertib (iv), ipatasertib (v), or triciribine (vi) (shown on the left side of each isobologram plot) in combination with a range of concentrations of cisplatin (above the isobologram plot) over 72 hours in the high-grade serous ovarian cancer isogenic-matched platinum-resistant cell line PEO4. Data shown are for n=3. Decreasing negative numbers within each table indicate increasing levels of antagonism between cisplatin and the inhibitor compound, while increasing positive numbers indicate increasing levels of synergy between cisplatin and the inhibitor compound. [Figure 1B-3] Figure 1 shows an isobologram analysis (Loewe's synergy and antagonism performed from the readout of a standard MTT cell viability assay) of a range of NU7441(vii) concentrations (shown on the left side of each isobologram plot) in combination with a range of cisplatin concentrations (above the isobologram plot) over 72 hours in the high-grade serous ovarian cancer isogenic-matched platinum-resistant cell line PEO4. Data shown are for n=3. Decreasing negative numbers in each table indicate increasing levels of antagonism between cisplatin and the inhibitor compound, while increasing positive numbers indicate increasing levels of synergy between cisplatin and the inhibitor compound. [Figure 1C-1]

[0039] Figure 1 shows isobologram analysis (Loewe's synergy and antagonism performed from the readout of a standard MTT cell viability assay) of a range of concentrations of Example 1 (i), LY3023414 (ii), or afuresertib (iii) (shown to the left of each isobologram plot) in combination with a range of concentrations of cisplatin (shown above each isobologram plot) over a 72-hour period in the platinum-resistant epithelial ovarian cancer cell line SKOV3. Data shown are for n=3. A decrease in negative numbers within each table indicates an increasing level of antagonism between cisplatin and the inhibitor compound, and an increase in positive numbers indicates an increasing level of synergy between cisplatin and the inhibitor compound. [Figure 1C-2]Figure 1 shows isobologram analysis (Loewe's synergy and antagonism performed from standard MTT cell viability assay readouts) of a range of concentrations of uprosertib (iv), ipatasertib (v), or triciribine (vi) (indicated to the left of each isobologram plot) in combination with a range of concentrations of cisplatin (indicated above each isobologram plot) over 72 hours in the platinum-resistant epithelial ovarian cancer cell line SKOV3. Data shown are for n=3. Decreasing negative numbers in each table indicate increasing levels of antagonism between cisplatin and the inhibitor compound, while increasing positive numbers indicate increasing levels of synergy between cisplatin and the inhibitor compound. [Figure 1C-3] Figure 1 shows isobologram analysis (Loewe's synergy and antagonism performed from standard MTT cell viability assay readouts) of a range of NU7441(vii) concentrations (shown to the left of each isobologram plot) in combination with a range of cisplatin concentrations (shown above each isobologram plot) over 72 hours in the platinum-resistant epithelial ovarian cancer cell line SKOV3. Data shown are for n=3. Decreasing negative numbers in each table indicate increasing levels of antagonism between cisplatin and the inhibitor compound, while increasing positive numbers indicate increasing levels of synergy between cisplatin and the inhibitor compound. [Figure 2A]

[0039] Figure 1 shows the results of a phenotypic apoptosis assay (Caspase 3 / 7 assay (Caspase Glo® from Promega, normalized to the readout of a standard MTT viability assay)) in the platinum-resistant epithelial ovarian cancer cell line SKOV3 after 24 hours of incubation with Example 1 (2 μM), afuresertib (10 μM), uprosertib (10 μM), ipatasertib (20 μM), triciribine (20 μM), NU7441 (10 μM), or LY3023414 (10 μM), + / - cisplatin (cddp) 25 μM. Results are presented as the fold change in apoptosis compared to the vehicle DMSO control, and caspase 3 / 7 data were normalized to the cell viability data inferred from the corresponding MTT assay (compound concentration shown on the x-axis of the graph). Data shown are n=3±sem, **p<0.01, *p<0.05. [Figure 2B]

[0049] Figure 1 shows the results of a phenotypic apoptosis assay (Caspase 3 / 7 assay (Caspase Glo® from Promega, normalized to the readout of a standard MTT viability assay)) in the high-grade serous ovarian cancer isogenic-matched platinum-resistant cell line PEO4 after 24 hours of incubation with Example 1 (2 μM), afuresertib (10 μM), uprosertib (10 μM), ipatasertib (20 μM), triciribine (20 μM), NU7441 (10 μM), or LY3023414 (10 μM), + / - cisplatin (cddp) 25 μM. Results are presented as fold change in apoptosis compared to vehicle DMSO control, and caspase 3 / 7 data were normalized to the cell viability data inferred from the corresponding MTT assay (compound concentration shown on the x-axis of the graph). Data shown are n=3±sem, **p<0.01, *p<0.05. [Figure 3A]Figure 3B shows the results of proteomic analysis showing signaling changes in different response clusters (shown as response cluster 1 and response cluster 2 on the heat map) or due to temporal changes from reverse-phase protein array results performed on protein lysates collected after treatment of SKOV3 cells with a panel of inhibitor compounds (at 25 μM) (GSK-3g, Roche Compound 4, Example 1, Example 2, Example 12a, Example 12b) found to be either inactive or active at two different time points (2 h and 8 h) in the presence or absence of control (DMSO) or 6.67 μM cisplatin (increased phosphorylation of AKT at serine 473 and threonine 308 is observed upon treatment with active compounds). Figure 3A lists the compounds that were deemed active and inactive for the reverse-phase protein array proteomic analysis. [Figure 3B] FIG. 3B is a heat map showing the results of proteomic analysis of reverse-phase protein arrays. [Figure 3C] FIG. 3C lists proteins that decreased after treatment with active compounds (response cluster 1) and proteins that increased after treatment with active compounds (response cluster 2). [Figure 3D] FIG. 3D lists proteins that were altered by cisplatin treatment and the time effect. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention provides compounds of formula (I) for use in the treatment of platinum-resistant cancers.

[0018] Inhibition of various kinase pathways has been suggested as a potential treatment for cancer. The PI3K-AKT-mTOR pathway and opportunities for its disruption in cancer treatment have been discussed in several reviews (Janku F., et al., Nat Rev Clin Oncol., 2018, 15, 273-291; LoRusso PM, J Clin Oncol., 2016, 34, 3802-3815; Fruman DA and Rommel, C., Nature Rev Drug Disc., 2014, 10, 140-156). Triciribine (1,5-dihydro-5-methyl-1-β-D-ribofuranosyl-1,4,5,6,8-pentaazaacenaphthylene-3-amine) has been shown to resensitize clinically platinum-resistant ovarian cancer cell lines to cisplatin and induce apoptosis (Stronach, EA et al., Neoplasia, 2011, 13, 1069-80).The present inventors have found that not all compounds described as AKT inhibitors can resensitize clinically resistant ovarian cancer cells to cisplatin.

[0019] WO 2006 / 071819 (Exelixis, Inc.) discloses a family of [1H-pyrazolo[3,4-D]pyrimidin-4-yl]-piperidine or -piperazine compounds described as serine-threonine kinase modulators (P70S6k, Akt1, and Akt2) for use in kinase-dependent diseases and conditions (e.g., cancer, immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases).

[0020] The present inventors have discovered that compounds of formula (I) are surprisingly effective in treating cancer, particularly platinum-resistant cancers. They found that combining compounds of formula (I) of the present invention with platinum-containing drugs resulted in the restoration of platinum sensitivity in platinum-resistant cell lines in vitro. Compounds of formula (I) have been shown to be active as both AKT inhibitors and DNA-PK inhibitors, and thus can function as dual AKT / DNA-PK inhibitors. Furthermore, as shown in Figures 2A and 2B, the compounds of the present invention were found to be more effective at resensitizing platinum-resistant cell lines to cisplatin at concentrations 5-10 times lower than the known AKT inhibitors triciribine, afuresertib, uprosertib, and ipatasertib, the known DNA-PK inhibitor NU7441, and the known mTOR / DNA-PK inhibitor LY3023414 (samotricisib).

[0021] For example, when a compound of formula (I) and cisplatin were added to a clinically platinum-resistant (insensitive) ovarian cancer cell line, sensitivity to cisplatin was restored and apoptosis was increased compared to cisplatin alone.

[0022] Clinically, the addition of the compound of formula (I) of the present invention and cisplatin to platinum-sensitive cell lines can increase apoptosis in platinum-sensitive cells compared to cisplatin alone.

[0023] The present invention is particularly useful for treating platinum-resistant cancers, including cancers in which the majority of tumor cells are platinum-resistant, and cancers in which tumors contain both platinum-sensitive and platinum-resistant cells.Examples of platinum-resistant cancers include platinum-resistant ovarian cancer (e.g., platinum-resistant epithelial ovarian cancer), platinum-resistant pancreatic cancer, platinum-resistant non-small cell lung cancer, and platinum-resistant head and neck cancer.It will be useful in patients who are (completely or partially) resistant to treatment using platinum-containing drugs.

[0024] The present invention may also be useful in cancers that are platinum sensitive but prone to recurrence in platinum-resistant forms (eg, ovarian, breast, lung, mesothelioma, and pancreatic cancer).

[0025] Compounds for use in the present invention are compounds of formula (I) above (eg, compounds of formula (Ia), (Ib), or (II)).

[0026] The compounds of the invention may be used to treat cancer (e.g., ovarian cancer), and in particular, platinum-resistant cancer (e.g., platinum-resistant ovarian cancer), or cancer that is platinum-sensitive but at risk of developing platinum resistance (e.g., ovarian cancer that is platinum-sensitive but at risk of developing platinum resistance).

[0027] In a preferred embodiment, X is CH and Z is CR 4 or N, or X is N and Z is CR 4 is.

[0028] In a preferred embodiment, R 1 and R 2 independently, C 1-4 Alkyl and C 3-6 More preferably, R is selected from cycloalkyl. 1 and R 2 are respectively, C 1-4 alkyl, e.g., R 1 and R 2 are each the same C 1-4 Most preferably, R 1 and R 2 are each methyl.

[0029] In one embodiment, R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring. For example, R 1 and R 2together with the nitrogen to which they are attached form a 4-, 5-, 6-, or 7- (e.g., 5 or 7)-membered non-aromatic heterocyclyl ring containing one nitrogen and, optionally, one or two (e.g., one) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur (e.g., nitrogen or oxygen).

[0030] In a preferred embodiment, each R 3 is independently selected from methyl, halogen, and CF3, and m is 0, 1, or 2. More preferably, R 3 is selected from methyl, halogen, and CF3, and m is 0 or 1. More preferably, R 3 is a halogen, for example, R 3 is selected from fluoro, chloro, and bromo, and m is 1. Preferably, R 3 The group is in the para position. Most preferably, R 3 is chloro and m is 1, for example, m is 1 and R 3 is para-chloro.

[0031] In a preferred embodiment, R 4 is H.

[0032] In a preferred embodiment, R 5 is methyl, CF3, or halogen. More preferably, R 5 is a halogen, for example, R 5 is selected from fluoro, chloro, and bromo. Most preferably, R 5 is bromo. In an alternative preferred embodiment, R 5 is methyl.

[0033] In a preferred embodiment, Z is CR 4 and Y is a bond, —C(O)—, and —NR 6 - selected from R 5 is selected from methyl, halogen, and CF3, or Y is selected from -SO2- and -O-; R 5is selected from methyl and halogen. More preferably, Z is CR 4 and Y is a bond, —C(O)—, and —NR 6 - selected from R 5 is selected from methyl and halogen, or Y is selected from -SO2- and -O-, and R 5 is selected from methyl and halogen. In such embodiments, Y is a bond, —NR 6 When Y is -, -SO2-, or -O-, preferably n is 1, 2, 3, or 4, more preferably 1, 2, or 3, and most preferably 1 or 2. In such embodiments, when Y is -C(O)-, preferably n is 0, 1, or 2, and most preferably 0.

[0034] In a preferred embodiment, Z is N, Y is selected from a bond and —C(O)—, and R 5 is selected from methyl, halogen, and CF3, or Y is -C(O)NR 6 - and R 5 is halogen. More preferably, Z is N, Y is selected from a bond and —C(O)—, and R 5 is selected from methyl and halogen, or Y is —C(O)NR 6 - and R 5 is halogen. More preferably, Z is N, Y is a bond, and R 5 is selected from methyl and halogen, or Y is —C(O)NR 6 - and R 5 is halogen. In such embodiments, Y is a bond or —C(O)NR 6 When Y is -, n is preferably 1, 2, 3, or 4, more preferably 1, 2, or 3, and most preferably 1 or 2. In such embodiments, when Y is -C(O)-, preferably n is 0, 1, or 2, and most preferably 0.

[0035] In a preferred embodiment, Z is CR 4or N, Y is a bond, and R 5 is halogen (e.g., bromo), n is 1 or 2 (e.g., 1), or Y is selected from —SO— and —O—; R 5 is selected from methyl and halogen (e.g., methyl and bromo), n is 1 or 2 (e.g., 2), or Y is —C(O)NR 6 - and R 5 is halogen (e.g., bromo) and n is 1 or 2 (e.g., 2). In such embodiments, preferably, R 1 and R 2 are each methyl. In such embodiments, Y is —C(O)NR 6 - or a bond, preferably X is N and Z is CR 4 and R 4 is H, or when Y is -SO2-, preferably X is CH and Z is N, or when Y is -O-, preferably X is C and Z is CR 4 and R 4 is H. In such embodiments, when Y is —O—, preferably R 5 is methyl. In such embodiments, when Y is a bond, it is -SO2- or -C(O)NR 6 -, preferably R 5 is bromo.

[0036] In a more preferred embodiment, Z is CR 4 or N, Y is a bond, and R 5 is halogen (e.g., bromo) and n is 1 or 2 (e.g., 1). In such embodiments, preferably, R 1 and R 2 are each methyl. Alternatively, in such embodiments, preferably, R 1 and R 2 are each methyl, and / or preferably, X is N and Z is CR 4 and R 4 is H.

[0037] In a more preferred embodiment, Z is CR 4 or N, Y is selected from -SO2- and -O-, and R 5 is selected from methyl and halogen (e.g., methyl and bromo), and n is 1 or 2 (e.g., 2). In such embodiments, preferably, R 1 and R 2 are each methyl. In such embodiments, when Y is -SO2-, preferably X is CH and Z is N. In such embodiments, when Y is -SO2-, preferably R 5 In such embodiments, when Y is -O-, preferably X is C and Z is CR 4 and R 4 is H. In such embodiments, when Y is —O—, preferably R 5 is methyl.

[0038] In a more preferred embodiment, Z is CR 4 or N, and Y is —C(O)NR 6 - and R 5 is halogen (e.g., bromo) and n is 1 or 2 (e.g., 2). In such embodiments, preferably, R 1 and R 2 Additionally or alternatively, in such embodiments, preferably, X is N and Z is CR 4 and R 4 is H.

[0039] In a more preferred embodiment, Z is CR 4 or N, Y is -O-, and R 4 is H and R 5 is methyl, or Y is a bond, and R 4 is H and R 5 is halogen and n is 1 or 2 (e.g., 2). In such embodiments, preferably, X is N.

[0040] In a more preferred embodiment, Z is CR 4 or N, Y is -O-, and R 4 is H and R 5 is methyl and n is 1 or 2 (e.g., 2). In such embodiments, preferably, R 1 and R 2 and each is methyl. In such embodiments, preferably, X is N.

[0041] In another more preferred embodiment of the present invention, Z is CR 4 and Y is a bond, -C(O)-, -O-, or -C(O)NR 6 -, and -NR 6 -, or Z is N and Y is -SO2-. More preferably, Z is selected from CR 4 and Y is a bond, —C(O)—, —O—, and —C(O)NR 6 -. More preferably, Z is selected from CR 4 and Y is a bond.

[0042] In one highly preferred embodiment, Y is a bond and R 4 is H and R 5 is halogen (e.g., bromo) and n is 1 or 2 (e.g., 1). In such embodiments, preferably, R 1 and R 2 and each are methyl. In such embodiments, preferably X is N. In such embodiments, preferably R 3 is selected from methyl, halogen, and CF3, and m is 0 or 1 (e.g., R 3 is halogen and m is 1. Preferably, R 3 More preferably, the R 3 is chloro and m is 1 (e.g., m is 1 and R 3 is para-chloro).

[0043] In a preferred embodiment, Y is a bond, —O—, or —NR 6- and -C(O)NR 6 -, n is 1, 2, or 3, or when Y is selected from -SO2- and -C(O)-, n is 0, 1, 2, or 3. More preferably, Y is a bond, -O-, -NR 6 - and -C(O)NR 6 -, n is 1 or 2, or when Y is -SO2-, n is 1 or 2, or when Y is -C(O)-, n is 0.

[0044] For the avoidance of doubt, any embodiment or preferred aspect of any one feature of the compounds of the invention may be combined with any embodiment or preferred aspect of another feature of the compounds of the invention to create further embodiments.

[0045] Examples of compounds of formula (I) include: 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, 2-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylethan-1-amine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (-)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (+)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, N-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-N-(4-chlorophenyl)-2-(diethylamino)ethane-1-sulfonamide, and 2-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, N 1 -((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethan-1-amine, N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (+)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (-)-N 1-((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-5-(dimethylamino)pentan-1-ol, 4-(4-chlorophenyl)-N,N-dimethyl-4-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-ylidene)butan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-4-(dimethylamino)butan-1-ol, and 3-((1-(3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylpropan-1-amine.

[0046] Preferred compounds of formula (I) are: 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, 2-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylethan-1-amine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (-)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (+)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, N-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-N-(4-chlorophenyl)-2-(diethylamino)ethane-1-sulfonamide, and 2-(1-(3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine.

[0047] The present invention also provides a compound of formula (Ia) as the above set, and also provides the use of the compound of formula (Ia) in the treatment and method described herein.Specifically, the compound of formula (Ia) can be used to treat cancer (e.g., ovarian cancer), and in particular, platinum-resistant cancer (e.g., platinum-resistant ovarian cancer).In one embodiment, the ovarian cancer is high-grade serous ovarian cancer, for example, platinum-resistant high-grade serous ovarian cancer.Preferred embodiments of the compound of formula (I) are also applicable to the compound of formula (1a).

[0048] In certain embodiments, preferred compounds of formula (Ia) are as follows: 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N,N-dimethyl-ethanamine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, 2-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, (-)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (+)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, N 1 -((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethan-1-amine, N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (+)-N 1-((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (-)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-5-(dimethylamino)pentan-1-ol, and 4-(4-Chlorophenyl)-N,N-dimethyl-4-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-ylidene)butan-1-amine.

[0049] In certain embodiments, preferred compounds of formula (Ia) are as follows: 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, 2-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylethan-1-amine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, N-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-N-(4-chlorophenyl)-2-(diethylamino)ethane-1-sulfonamide, and 2-(1-(3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine.

[0050] The present invention also provides the compound of formula (II) above, and the use of the compound of formula (II) in the treatment and method described herein.Specifically, the compound of formula (II) can be used to treat cancer (e.g., ovarian cancer), and in particular, platinum-resistant cancer (e.g., platinum-resistant ovarian cancer).In one embodiment, the ovarian cancer is high-grade serous ovarian cancer, for example, platinum-resistant high-grade serous ovarian cancer.

[0051] In a preferred embodiment, X is CH and Z is CR 4 or X is N and Z is CR 4 or XZ is C=C. More preferably, X is CH and Z is CR 4 or X is N and Z is CR 4 is.

[0052] In a preferred embodiment, R 1 and R 2 independently, C 1-4 Alkyl and C 3-6 More preferably, R is selected from cycloalkyl. 1 and R 2 are respectively, C 1-4alkyl, most preferably R 1 and R 2 are each methyl.

[0053] In one embodiment, R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring. For example, R 1 and R 2 together with the nitrogen to which they are attached form a 4-, 5-, 6-, or 7- (e.g., 5 or 7)-membered non-aromatic heterocyclyl ring containing one nitrogen and, optionally, one or two (e.g., one) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur (e.g., nitrogen or oxygen).

[0054] In a preferred embodiment, each R 3 is independently selected from methyl, halogen, and CF3, and m is 0, 1, or 2. More preferably, R 3 is selected from methyl, halogen, and CF3, and m is 0 or 1. More preferably, R 3 is a halogen, for example, R 3 is selected from fluoro, chloro, and bromo, and m is 1. Preferably, R 3 The group is in the para position. Most preferably, R 3 is chloro and m is 1, for example, m is 1 and R 3 is para-chloro.

[0055] In a preferred embodiment, R 4 is H.

[0056] In a preferred embodiment, R 5 is halogen or methyl. More preferably, R 5 is a halogen, for example, R 5 is selected from fluoro, chloro, and bromo. More preferably, R 5 is bromo. In an alternative more preferred embodiment, R 5is methyl.

[0057] In preferred embodiments, Y is a bond, —C(O)—, and —NR 6 - selected from R 5 is selected from halogen and CF, more preferably R 5 is halogen (e.g., bromo), or Y is —O—, and R 4 is H or OH, and R 5 In such embodiments, preferably, X is CH and Z is CR 4 or X is N and Z is CR 4 is.

[0058] In a preferred embodiment, Z is CR 4 wherein n is 1, 2, or 3 and Y is -O-, or n is 1 or 3 and Y is -NR 6 - and -C(O)NR 6 or n is 1 or 2 and Y is a bond, or n is 0, 1, 2, or 3 and Y is selected from -SO2- and -C(O)-. More preferably, n is 1 or 2 and Y is selected from a bond and -O-, or n is 1 and Y is -NR 6 - and -C(O)NR 6 -, or n is 0 or 1, and Y is -C(O)- or -SO2-. More preferably, when Y is selected from -SO2- and -C(O)-, n is 0. In such embodiments, preferably, X is CH and Z is CR 4 or X is N and Z is CR 4 is.

[0059] In a particularly preferred embodiment, n is 1 or 2 and Y is a bond (e.g., n is 1 and Y is a bond). In such an embodiment, preferably, X is CH and Z is CR 4 is.

[0060] In another preferred embodiment, Y is —NR 6 -, -SO2-, or -O-, R 5 is preferably selected from methyl, fluoro, chloro, and bromo, more preferably R 5 is methyl or bromo, most preferably R 5 In such embodiments, preferably, X is CH and Z is CR 4 or X is N and Z is CR 4 is.

[0061] In a preferred embodiment, Z is CR 4 and Y is a bond, —C(O)—, and —NR 6 - selected from R 4 is H and R 5 is selected from halogen and CF3, preferably R 5 is halogen (e.g., bromo), Y is —SO—, and R 4 is H and R 5 is selected from methyl and halogen, preferably R 5 is halogen (e.g., bromo), Y is —O—, and R 4 is H and R 5 is methyl or Y is —C(O)NR 6 - and R 4 is H and R 5 is halogen (e.g., bromo). In such embodiments, preferably when Y is selected from a bond and —O—, n is 1 or 2, or when Y is —NR 6 - and -C(O)NR 6 -, n is 1, or when Y is selected from -SO2- and -C(O)-, n is 0 or 1. More preferably, when Y is selected from -SO2- and -C(O)-, n is 0.

[0062] In one particularly preferred embodiment, n is 1 or 2, Y is a bond (e.g., n is 1 and Y is a bond), and R5 is halogen (e.g., bromo). In such embodiments, preferably, X is CH and Z is CR 4 is.

[0063] In a more preferred embodiment, Z is CR 4 and Y is selected from a bond and —C(O)—; and R 4 is H and R 5 is selected from halogen and CF3, preferably R 5 is halogen (e.g., bromo), or Y is —O—, and R 4 is H or OH, and R 5 is methyl. More preferably, Y is a bond and R 4 is H and R 5 is selected from halogen and CF3, preferably R 5 is halogen (e.g., bromo), Y is —O—, and R 4 is H or OH, and R 5 is methyl. Preferably, when Y is selected from a bond and -O-, n is 1 or 2, or when Y is -C(O)-, n is 0. In such embodiments, preferably, X is CH and Z is CR 4 or X is N and Z is CR 4 is.

[0064] In another more preferred embodiment, Z is CR 4 and Y is -O-, and R 4 is H and R 5 is methyl, or Y is a bond, and R 4 is H and R 5 is halogen and n is 1 or 2 (e.g., 2). In such embodiments, preferably, R 1 and R 2 are each methyl.

[0065] In another more preferred embodiment, Z is CR 4 and Y is -O-, and R5 is methyl and n is 1 or 2 (e.g., 2). In such embodiments, preferably, R 1 and R 2 and each X is methyl. In such embodiments, preferably, X is CH.

[0066] In one highly preferred embodiment, Z is CR 4 Y is a bond and R 4 is H and R 5 is halogen (e.g., bromo) and n is 1 or 2 (e.g., 1). In such embodiments, preferably, R 1 and R 2 and each is methyl. In such embodiments, preferably, X is N.

[0067] In another preferred embodiment, X is CH and Z is CR 4 or X is N and Z is CR 4 or XZ is C=C, R 1 and R 2 are independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclyl, or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring, more preferably R 1 and R 2 are respectively, C 1-4 alkyl, most preferably R 1 and R 2 are each methyl, m is 0, 1, 2, or 3; R 3 is independently selected from methyl, halogen, and CF; more preferably, m is 1 and R 3 is chloro, and most preferably m is 1 and R 3 is para-chloro.

[0068] R 4 is H or OH, more preferably R 4 is H, R 6 H and C 1-4 alkyl, more preferably R 6 is H, Y is a bond, -C(O)-, and -NR 6 - selected from R 5 is selected from methyl, halogen, and CF3; or Y is -SO2- and R 5 is selected from methyl and halogen; or Y is -O- and R 5 is methyl, or Y is -C(O)NR 6 - and R 5 is a halogen, More preferably, Y is a bond, —C(O)—, —O—, and —NR 6 -, most preferably Z is selected from CR 4 and Y is -O-, and R 5 is methyl, and / or Y is a bond, —C(O)—, and —NR 6 - selected from R 5 is bromo, When Y is -O-, n is 1, 2, 3, or 4, or Y is -C(O)NR 6 -or-NR 6 -, n is 1, 3, or 4; or when Y is a bond, n is 1, 2, or 4; or when Y is selected from -SO2- and -C(O)-, n is 0, 1, 2, 3, or 4; more preferably, when Y is -O-, n is 1, 2, or 3; or when Y is -C(O)NR 6 -or-NR 6 -, then n is 1 or 3; or when Y is a bond, n is 1 or 2; or when Y is selected from -SO2- and -C(O)-, n is 0, 1, or 2; Or its salt.

[0069] Examples of compounds of formula (II) include: 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N,N-dimethyl-ethanamine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, 2-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, (-)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (+)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, N 1 -((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethan-1-amine, N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N2 ,N 2 -dimethylethane-1,2-diamine, (+)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (-)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-5-(dimethylamino)pentan-1-ol, 4-(4-Chlorophenyl)-N,N-dimethyl-4-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-ylidene)butan-1-amine.

[0070] Preferred compounds of formula (II) are: 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N,N-dimethyl-ethanamine, N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (+)-N 1-((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, and (-)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine.

[0071] For the avoidance of doubt, any embodiment or preferred aspect of any one feature of compounds of formula (II) may be combined with any embodiment or preferred aspect of another feature of compounds of formula (II) to form further embodiments.

[0072] In certain applications, the compound is a compound of formula (Ib) [ka] During the ceremony, X is CH and Z is CR 4 or N, or X is N and Z is CR 4 or XZ is C=C, R 1 and R 2 are independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclyl, or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring, Each R 3 is independently selected from methyl, halogen, and CF3; m is 0, 1, 2, or 3; R 4 is H or OH, Z is CR 4or N, or when XZ is C=C, Y is a bond, -SO2NH-, -SO2-, -C(O)NR 6 -, and -C(O)-; Z is CR 4 When Y is -NHSO2-, -NR 6 -, and -O-; Y is a bond, -SO2NH-, -O-, or -NR 6 - and -C(O)NR 6 - n is 1, 2, 3, or 4 when selected from when Y is selected from -NHSO2-, -SO2-, and -C(O)-, n is 0, 1, 2, 3, or 4; R 5 is selected from methyl, halogen, and CF3; R 6 H and C 1-4 a compound selected from alkyl, or a salt thereof.

[0073] The preferred embodiments of the compounds of formula (I) are equally applicable to the compounds of formula (Ib).

[0074] The present inventors have also found that the combination of a compound of formula (III) with a platinum-containing drug leads to the restoration of platinum sensitivity in platinum-resistant cell lines in vitro. Thus, the present invention also provides the use of a compound of formula (III) in the treatments and methods described herein. Specifically, the compound of formula (III) can be used to treat cancer (e.g., ovarian cancer), and in particular, platinum-resistant cancer (e.g., platinum-resistant ovarian cancer). In one embodiment, the ovarian cancer is high-grade serous ovarian cancer, e.g., platinum-resistant high-grade serous ovarian cancer. The present invention also provides a compound of formula (III) in combination with a platinum-containing drug for use in the treatment of cancer, in particular, platinum-resistant cancer. The compound of formula (III) is an AKT inhibitor and also has activity as a DNK-PK inhibitor. The compound of formula (III) has the following structure: [ka]

[0075] In one preferred embodiment, the compound of formula (III) has the following structure: [ka]

[0076] Suitable salts of the compounds of the invention (e.g., compounds of Formula (I), (Ia), (Ib), (II), or (III)) or for use in the invention include those formed with organic or inorganic acids or bases. Specifically, suitable salts formed with acids in accordance with the invention include salts formed with mineral acids, strong organic carboxylic acids such as unsubstituted or substituted alkanecarboxylic acids of 1 to 4 carbon atoms (e.g., dicarboxylic acids that are unsubstituted or substituted (e.g., by halogen), e.g., hydroxycarboxylic acids (e.g., amino acids)), or organic sulfonic acids (e.g., (C1-C4) alkyl or aryl sulfonic acids that are unsubstituted or substituted (e.g., by halogen)). Pharmaceutically acceptable acid addition salts include those formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, isethionic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid, and glutamic acid, lysine, and arginic acid.

[0077] Particularly preferred pharmaceutically acceptable salts of the compounds of the present invention are the hydrochloride and trifluoroacetate salts.

[0078] Cancer treatment The present invention provides for the treatment of platinum-resistant cancer in a subject or patient, particularly the treatment of platinum-resistant cancer in a human subject or patient using a compound of the invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)).

[0079] Cancer typically refers to or describes a physiological condition characterized by uncontrolled cell proliferation.Cancer as described herein includes benign and malignant cancers, as well as dormant tumors and micrometastases.This includes tumors of epithelial cells (carcinomas), blood or bone marrow (leukemia, lymphoma), connective tissue (sarcoma), and other cell types of cancer (e.g., brain cancer, blastoma).

[0080] Examples of cancer include ovarian cancer (including epithelial ovarian cancer (e.g., high-grade serous ovarian cancer) and platinum-resistant ovarian cancer (e.g., platinum-resistant high-grade serous ovarian cancer)), breast cancer (including platinum-resistant breast cancer), squamous cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, and platinum-resistant lung cancer), peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer (including platinum-resistant pancreatic cancer), glioblastoma, cervical cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer These include, but are not limited to, breast cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma, and various types of head and neck cancer, as well as B-cell lymphomas (including low-grade / follicular non-Hodgkin's lymphoma (NHL)), small lymphocytic NHL, intermediate-grade / follicular NHL, intermediate-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, small non-cleaved cell NHL, bulky mass disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's macroglobulinemia), chronic lymphocytic leukemia, acute lymphoblastic leukemia, hairy cell leukemia, chronic myeloblastic leukemia, and post-transplant lymphoproliferative disorder, as well as abnormal blood vessel growth associated with phacomatosis, edema (such as that associated with brain tumors), and Meigs' syndrome.

[0081] The treatments of the present invention are particularly useful in the treatment of ovarian cancer, including epithelial ovarian cancer (eg, high-grade serous ovarian cancer) and platinum-resistant ovarian cancer (eg, platinum-resistant high-grade serous ovarian cancer).

[0082] The term platinum-resistant cancer is defined as a cancer that progresses during chemotherapy using a platinum-containing drug (i.e., the cancer is platinum-refractory), or a cancer that responds to chemotherapy using a platinum-containing drug but recurs within a relatively short period after the completion of the platinum-containing drug treatment (e.g., a cancer that recurs within 18 months, 12 months, 9 months, 6 months, 3 months, or 1 month, particularly within 6 months, of the completion of the platinum-containing drug treatment). For example, in the case of ovarian cancer (especially high-grade serous ovarian cancer, the most common subtype of epithelial ovarian cancer), recurrence within 12 months, particularly within 6 months, after the completion of initial platinum-based chemotherapy is considered platinum-resistant according to the present invention. The term platinum-resistant cancer also includes cancers whose tumors contain cells that are resistant to chemotherapy using a platinum-containing drug. Such cancers may be platinum-refractory (disease progression during therapy) or may recur after the completion of therapy.

[0083] The treatment of the present invention is useful for treating platinum-resistant cancer in any of the cancer types listed above.

[0084] The treatments of the invention are particularly useful in the treatment of platinum-resistant ovarian cancer (e.g., platinum-resistant epithelial ovarian cancer, and particularly high-grade platinum-resistant serous ovarian cancer), testicular cancer, head and neck cancer, lung cancer (e.g., non-small cell lung cancer), sarcoma, lymphoma, bladder cancer, cervical cancer, breast cancer, mesothelioma, and pancreatic cancer, and especially in the treatment of platinum-resistant ovarian cancer (e.g., platinum-resistant epithelial ovarian cancer, and particularly platinum-resistant high-grade serous ovarian cancer).

[0085] The treatments of the present invention are also particularly useful in treating platinum-resistant cancers in which the majority of tumor cells are platinum-resistant, and cancers in which the tumor contains both platinum-sensitive and platinum-resistant cells. These treatments are useful in patients who are resistant (completely or partially) to treatment with platinum-containing drugs.

[0086] The treatments of the invention are also useful in treating cancers that are platinum sensitive but prone to recurrence in platinum-resistant forms (eg, ovarian, breast, lung, mesothelioma, and pancreatic cancer).

[0087] The present invention also provides a method for the treatment of cancer (e.g., treatment of a cancer described above, e.g., treatment of a platinum-resistant cancer such as platinum-resistant ovarian cancer), comprising administering to a subject in need thereof a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)). The present invention also provides use of a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) for the manufacture of a medicament for the above treatment (e.g., treatment of a platinum-resistant cancer such as platinum-resistant ovarian cancer).

[0088] The present invention further provides the treatment of cancer (e.g., the cancers described above and / or platinum-resistant cancers) in a subject or patient, particularly the treatment of ovarian cancer (e.g., platinum-resistant ovarian cancer) in a human subject or patient, using a compound of the invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) in combination with a platinum-containing drug (e.g., cisplatin or carboplatin). Such treatments of the invention are useful for treating cancers that are platinum-sensitive but prone to recurrence in a platinum-resistant form (e.g., ovarian cancer, breast cancer, lung cancer, mesothelioma, and pancreatic cancer).

[0089] The present invention further provides methods for treating cancer (e.g., treating the cancers described above, such as those that are platinum-sensitive but at risk of developing platinum resistance), comprising administering to a subject in need thereof a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) and a platinum-containing drug; and methods for treating cancer (e.g., treating the cancers described above), comprising administering to a subject in need thereof a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) and a platinum-containing drug in combination therapy.

[0090] The present invention further provides the use of a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) in combination with a platinum-containing drug for the manufacture of a medicament for the above-described treatments (e.g., treatment of cancers that are platinum-sensitive but at risk of developing platinum resistance).The present invention further provides the use of a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) in combination with a platinum-containing drug for the manufacture of a medicament for the above-described treatments (e.g., treatment of cancers such as ovarian cancer).

[0091] definition The following definitions apply to terms used throughout this specification unless otherwise limited in specific instances.

[0092] As used herein, the term "alkyl" refers to both straight-chain and branched saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, and hexyl groups. Among unbranched alkyl groups, methyl, ethyl, n-propyl, and n-butyl groups are preferred. Among branched alkyl groups, isopropyl, t-butyl, i-butyl, 1-ethylpropyl, and 1-ethylbutyl groups can be mentioned.

[0093] As used herein, the term "cycloalkyl" refers to a saturated group of a ring system. Cycloalkyl groups can be monocyclic or bicyclic. Bicyclic groups can be, for example, fused or bridged. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl, and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclo[2.2.1]hept-2-yl. Preferably, the cycloalkyl group is monocyclic.

[0094] As used herein, the term "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine. Unless otherwise specified, fluorine, chlorine, and bromine are particularly preferred.

[0095] As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic cyclic group of carbon atoms in which 1 to 3 of the carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. A heterocyclyl (or heterocyclic) group may be, for example, monocyclic or bicyclic. In a bicyclic heterocyclyl (or heterocyclic) group, there may be one or more heteroatoms in each ring, or only one of the rings. The heteroatom may be S, O, or N, and is preferably O or N. Heterocyclyl groups containing suitable nitrogen atoms include the corresponding N-oxides.

[0096] Examples of monocyclic non-aromatic heterocyclyls include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and azepanyl.

[0097] Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzazepanyl.

[0098] Examples of monocyclic aromatic heterocyclyl groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, tetrazolyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

[0099] Examples of bicyclic aromatic heterocyclyl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl, isoquinolinyl, and benzodroxazole. Further examples of bicyclic aromatic heterocyclyl groups include those in which one ring is aromatic and the other is non-aromatic, such as dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, and benzazepanyl.

[0100] The compounds of the present invention may contain chiral (asymmetric) centers, or the entire molecule may be chiral. For example, Z may be CR 4 The compounds of formula (I), (Ia), (Ib), or (II) above, wherein: have a chiral center at the Z atom. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures thereof are within the scope of the present invention.

[0101] Composition and Dosage The amount of a compound of the invention required to achieve a therapeutic effect will vary depending on the particular compound, the route of administration, the subject being treated (including the type, species, age, weight, sex, and medical condition of the subject, as well as the subject's renal and hepatic function), and the particular disorder or disease being treated, and its severity. An ordinarily skilled physician can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition for which the compound of the invention is administered, e.g., for the treatment of cancer.

[0102] A pharmaceutical product typically contains from about 0.01 mg to about 500 mg of the active ingredient (ie, a compound of the invention), for example, from about 0.1 mg to about 100 mg of the active ingredient, or from 1 mg to about 100 mg of the active ingredient.

[0103] The oral dosage of the compound of the present invention, when used for the indicated disease, is in the range of about 0.001 mg / kg body weight (mg / kg / day) to about 10 mg / kg / day, e.g., 0.01 to 5 mg / kg / day, 0.1 to 5 mg / kg / day, or 0.5 to 3.0 mg / kg / day for adult humans. Therefore, the daily oral dosage of the compound of the present invention is in the range of 0.05 mg to about 700 mg, e.g., 0.5 mg to 350 mg, 5 mg to 350 mg, or 25 to 250 mg for adult humans, e.g., 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, or 250 mg.

[0104] The compounds of the present invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses two, three, or four times daily. For oral administration, the compositions are preferably provided in tablets or other presentation forms provided in discrete units containing about 0.01 mg to about 500 mg of the compounds of the present invention, e.g., about 0.1 mg to about 100 mg, about 1 mg to about 100 mg, e.g., 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, or 500 milligrams of active ingredient.

[0105] Intravenously, the most preferred doses are in the range of about 0.001 to about 10 mg / kg / minute during a constant rate infusion, e.g., 0.01 to 5 mg / kg / day, 0.1 to 5 mg / kg / day, or 0.5 to 3.0 mg / kg / day during a constant rate infusion.

[0106] Although the active ingredient can be administered alone, it is preferable that it is present in a pharmaceutical formulation or composition.Therefore, the present invention provides a pharmaceutical formulation or composition comprising a compound according to the present invention and a pharmaceutically acceptable diluent, excipient, or carrier (collectively referred to herein as "carrier" material).The pharmaceutical composition of the present invention can take the form of a pharmaceutical formulation as described below.

[0107] Pharmaceutical formulations of the compounds of the invention include those suitable for oral, parenteral (subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), intraperitoneal, and intraarticular), inhalation (including fine particle dusts or mists that may be generated by various types of metered dose pressurized aerosols), nebulizer or insufflator, rectal, and topical (cutaneous, buccal, sublingual, and ocular) administration.

[0108] The formulations of the compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0109] Formulations of the compounds of the invention suitable for oral administration can each be presented as discrete units (e.g., capsules, cachets, pills, or tablets containing a predetermined amount of the active ingredient), as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, such as an elixir, tincture, suspension, or syrup, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary, or paste.

[0110] Formulations for parenteral administration, particularly intravenous and intraperitoneal administration, include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes (to render the formulation isotonic with the blood of the intended recipient), as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier (e.g., saline or water for injection) immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind described above. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may include a suitable non-toxic parenterally-acceptable diluent or solvent (e.g., mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution) or other suitable dispersing or wetting agents and suspending agents (including synthetic mono- or diglycerides), and fatty acids (including oleic acid or Cremaphor).

[0111] Exemplary compositions for nasal, aerosol, or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other solubilizing or dispersing agents (e.g., those known in the art).

[0112] Formulations for rectal administration may be presented as a suppository with conventional carriers (e.g., cocoa butter, synthetic glyceride esters, or polyethylene glycols). Such carriers are typically solid at ordinary temperatures but liquefy and / or melt in the rectal cavity to release the drug.

[0113] Formulations for topical administration in the mouth (e.g., buccal or sublingual administration) include lozenges (active ingredient in a flavored base such as sucrose and acacia or tragacanth) and pastilles (active ingredient in a base such as gelatin and glycerin or sucrose and acacia). Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0114] Preferred unit dosage formulations of the compounds of the invention are those containing an effective dose, as herein above recited, or an appropriate fraction thereof.

[0115] It will be understood that in addition to the ingredients particularly mentioned above, formulations for use in the present invention may include other agents conventional in the art having regard to the type of formulation in question (e.g., those suitable for oral administration may include flavoring agents).

[0116] Although the compounds of the present invention can be used as the sole active ingredient in a pharmaceutical preparation, the compounds can also be used in combination with one or more additional therapeutic agents. Thus, the present invention also provides compounds according to the present invention together with additional therapeutic agents for simultaneous, sequential, or separate administration.

[0117] Platinum-containing drugs The compounds and treatments of the present invention may be used in combination with platinum-containing drugs.

[0118] The present invention further provides compositions (e.g., pharmaceutical compositions) comprising a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)), a platinum-containing drug, and, optionally, a pharmaceutically suitable carrier.

[0119] The present invention further provides a kit, comprising a compound of the present invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) and a platinum-containing drug.

[0120] Various platinum-containing compounds are known that can be used as anticancer agents for the treatment of ovarian cancer, testicular cancer, head and neck cancer, lung cancer, sarcoma, lymphoma, bladder cancer, cervical cancer, breast cancer, mesothelioma, and pancreatic cancer, among others.

[0121] Platinum-containing drugs (also known as platinum-containing anticancer drugs or platinum-based antitumor drugs) comprise organic compounds that contain platinum as an integral part of the molecule. Platinum-containing drugs include cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, tetraplatin, ormaplatin, phosphaplatin, and lipoplatin (liposomal version of cisplatin). Preferably, the platinum-containing drug is carboplatin or cisplatin.

[0122] In embodiments in which the treatment comprises administering a compound of the present invention and a platinum-containing drug, the platinum-containing drug may be selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, tetraplatin, ormaplatin, phosphaplatin, and lipoplatin. Preferably, the platinum-containing drug is cisplatin or carboplatin. The choice of platinum-containing drug may depend on factors including the type of cancer and the health of the patient. For example, in the case of treating ovarian cancer, the treatment of the present invention may comprise a compound of the present invention and a platinum-containing drug, preferably, the platinum-containing drug is carboplatin or cisplatin.

[0123] Pharmaceutical formulations of platinum-containing drugs for use in the present invention are preferably formulations for intravenous administration (e.g., in the case of cisplatin, carboplatin, and oxaliplatin) or oral administration (e.g., in the case of satraplatin).

[0124] The optimal dose of platinum-containing drug depends on the dosage schedule, the efficacy of the specific drug selected, the age, size, sex, and condition of the patient, the nature and severity of the disease, and other related medical and physical factors.Therefore, the pharmaceutically effective amount can be easily determined by caregivers or clinicians.The platinum-containing drug can be used in the amount shown in, for example, Physicians' Desk Reference (PDR), or in the amount determined by those skilled in the art.

[0125] Generally, an appropriate amount of platinum-containing drug is selected to achieve a chemotherapeutic effect. For intravenous doses of platinum-containing drugs, typical infusion rates range from about 0.005 to about 0.05 mg / kg / min. An effective intravenous dose of platinum-containing drug is typically about 0.1 to about 50 mg / kg body weight, preferably about 1 to about 5 mg / kg body weight. For example, in embodiments where the platinum-containing drug is cisplatin, the intravenous dose of cisplatin is typically about 10 mg / m 2 ~about 400mg / m 2 of active ingredient, preferably about 50 mg / m 2 ~about 200mg / m 2 of active ingredient, e.g., 75 mg / m 2 ~100mg / m 2 (corresponding to a dosage of about 125-185 mg per day). For example, in embodiments where the platinum-containing drug is carboplatin, the intravenous dose of carboplatin is typically about 100 mg / m 2 ~about 600mg / m 2 of active ingredient, preferably about 200 mg / m 2 ~about 400mg / m 2 of active ingredient, e.g., 300 mg / m 2 ~360mg / m 2 (corresponding to a daily dosage of approximately 500-600 mg).

[0126] The compounds of the invention and the platinum-containing drug for use in the present invention may be administered simultaneously, sequentially, or separately. The platinum-containing drug is typically present in a therapeutically effective amount.

[0127] The platinum-containing drug is typically administered on day 1 of a cycle (preferably a cycle lasting 20 to 30 days, e.g., a 21-day or 28-day cycle). On days of the cycle after day 1, the platinum-containing drug is typically not administered. The compound of the present invention may be administered simultaneously, sequentially, or separately with the platinum-containing drug on day 1 of the cycle. The compound of the present invention may be administered on one or more additional days of the cycle, e.g., every 7 days of the cycle, every 2 days of the cycle, or every day of the cycle. The cycle may be repeated two or more times, e.g., four, six, or eight times.

[0128] The active agents in the present invention (eg, a compound of the present invention and / or a platinum-containing drug and / or any additional therapeutic agent) can be administered by the same or different routes of administration.

[0129] Further treatments In addition to or instead of the platinum-containing drug, the treatment of the present invention can include the administration of one or more additional therapeutic agents.The therapeutic agent is a chemical compound useful for treating disease.The additional therapeutic agent can be, for example, a chemotherapeutic agent, a radiotherapeutic agent, another compound of the present invention, an AKT inhibitor, or a dual AKT / DNA-PK inhibitor.The treatment of the present invention can be used in combination with surgery for the treatment of cancer.

[0130] The compound of the invention and the additional therapeutic agent may be administered simultaneously, sequentially, or separately. The additional therapeutic agent will typically be present in a therapeutically effective amount.

[0131] The present invention further provides compositions (e.g., pharmaceutical compositions) comprising a compound of the invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)), an additional therapeutic agent, and, optionally, a pharmaceutically suitable carrier.

[0132] The present invention further provides kits, comprising a compound of the invention (e.g., a compound of Formula (I), (Ia), (Ib), (II), or (III)) and an additional therapeutic agent.

[0133] A chemotherapeutic agent is a chemical compound useful in the treatment of cancer. A chemotherapeutic agent according to the present invention can be an alkylating agent, an anthracycline, a cytoskeletal disrupting agent (taxane), an epothilone, a histone deacetylase inhibitor, a kinase inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a mitotic inhibitor, a monoclonal antibody, a nucleotide analog or precursor, a peptide antibiotic, a retinoid, a vinca alkaloid or derivative, or an immuno-oncology agent.

[0134] Examples of chemotherapy agents include: Avitrexate (methotrexate injection), osteosarcoma, Abraxane (paclitaxel injection), Adcetris (brentuximab vedotin injection), Adriamycin (doxorubicin), Adrucil injection (5-FU (fluorouracil)), Afinitor (everolimus), Afinitor dispersible tablets (everolimus), Alimta (pemetrexed tablets), Rexed, Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Bexxar (Tositumomab), BiCNU (Carmustine), Blenox ane (bleomycin), Bosulif (bosutinib), Busulfex Injection (busulfan injection), Camppath (alemtuzumab), Camptosar (irinotecan), Caprelsa (vandetanib), Casodex (bicalutamide), CeeNU (lomustine), CeeNU Dose Pack (lomustine), Cerubidine (daunorubicin), Clolar (clofarabine injection), Cometriq (cabozantinib), Cosmegen (dactinomycin), CytosarU (cytarabine), Cytoxan, Cytoxan for injection (cyclophosphamide for injection), Dacogen (decitabine), DaunoXome (daunorubicin lipid complex for injection), Decadron (dexamethasone), DepoCyt (cytarabine lipid complex for injection), Dexamethasone Intensol (dexamethasone), Dexpak Taperpak (dexamethasone), Docefrez (docetaxel), Doxil (doxorubicin lipid complex injection), Droxia (hydroxyurea), DTIC (decarbazine), Eligard (leuprolide), Ellence (epirubicin), Elspar (asparaginase), Emcyt (estramustine), Erbitux (cetuximab), Erivedge (vismodegib), Erwinaze (asparaginase)Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Injection), Eulexin (Flutamide), Fareston (Toremifene), Faslodex (Fulvestrant), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fludarabine), Folex (Methotrexate Injection), Folotyn (Pralatrexate Injection), FUDR (Floxuridine), Ga zyva (obinutuzumab injection), Gemzar (gemcitabine), Gilotrif (afatinib), Gleevec (imatinib mesylate), Gliadel wafers (carmustine wafers), Halaven (eribulin injection), Herceptin (trastuzumab), Hexalen (altretamine), Hycamtin (topotecan), Hydrea (hydroxyurea), Iclusig (ponatinib), Idamycin PFS (idarubicin), Ifex (ifosfamide), Imbruvica (ibrutinib), Imfinzi (durvalumab), Inlyta (axitinib), Intron A alfab (interferon alfa-2a), Iressa (gefitinib), Istodax (romidepsin injection), Ixempra (ixabepilone injection), Jakafi (ruxolitinib), Jevtana (cabazitaxel injection), Kadcyla (adotrastuzumab)emtansine), Keytruda (pembrolizumab), Kyprolis (carfilzomib), Leukeran (chlorambucil), Leukine (sargramostim), Leustatin (cladribine), Lupron (leuprolide), Lupron Depot (leuprolide), Lupron Depot PED (leuprolide), Lynparza (olaparib), Lysodren (mitotane), Marqibo Kit (vincristine) (Methotrexate lipid complex injection), Matulane (procarbazine), Megace (megestrol), Mekinist (trametinib), Mesnex (mesna), Mesnex (mesna injection), Metastron (strontium-89 chloride), Mexate (methotrexate injection), Mastergen (mechlorethamine), Mutamycin (mitomycin), Myleran (busulfan), Mylotarg (gemtuzumab) Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (Filgrastim), Neulasta (PEG-Filgrastim), Neupogen (Filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (Nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), Onxol (Paclitaxel Injection), Opdivo (Nivolumab), Panretin (Alitretinoin), Perjeta (Pertuzumab Injection), Pomalyst (Pomalidomide), Prednisone Intensol (prednisone), Proleukin (aldesleukin), Purinethol (mercaptopurine), Reclast (zoledronic acid), Revlimid (lenalidomide), Rheumatrex (methotrexate), Rituxan (rituximab), RoferonAαa (interferon α-2a), Rubex (doxorubicin), Rubraca (rucaparib), Sandostatin (octreotide), SandostatinLAR Depot (octreotide), Soltamox (tamoxifen), Sprycel (dasatinib), Sterapred (prednisone), Sterapred DS (prednisone), Stivarga (regorafenib), Supprelin LA (Histrelin Implant), Sutent (Sunitinib), Sylatron (PEG-interferon alpha-2b injection (Sylatron)), Synribo (Omacetaxine injection), Tabloid (Thioguanine), Taflinar (Dabrafenib), Tarceva (Erlotinib), Targretin Capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel injection), Taxotere (Docetaxel), Temodar (Temozolomide), Temodar (Temozolomide injection), Tepadina (Thiotepa), Thalomid (Thalidomide), TheraCysBCG (BCG), Thioplex (Thiotepa), TICE BCG (BCG), Toposar (etoposide injection), Torisel (temsirolimus), Treanda (bendamustine hydrochloride), Trelstar (triptorelin injection), Trexall (methotrexate), Trisenox (diarsenic trioxide), Tykerb (lapatinib), Valstar (valrubicin injection), Vantas (histrelin implant), Vectibix (panitumumab), Velban (vinblastine), Velcade (bortezomib), Vepesid (etoposide), Vepesid (etoposide injection), Vesanoid (tretinoin), Vidaza (azacitidine), Vincasar PFS (vincristine), Vincrex (vincristine), Votrient (pazopanib), Vumon (teniposide), Wellcovorin IV (leucovorin injection), Xalkori (crizotinib), Xeloda (capecitabine), Xtandi (enzalutamide), Yervoy (ipilimumab injection), Zaltrap (Ziv-aflibercept injection), Zanosar (streptozocin), Zejula (niraparib), Zelboraf (vemurafenib), Zevalin (ibritumomab)tiuxetan), Zoladex (goserelin), Zolinza (vorinostat), Zometa (zoledronic acid), Zortress (everolimus), Zytiga (abiraterone), and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0135] Examples of immuno-oncology agents include checkpoint inhibitors, such as agents or antibodies that inhibit one or more of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, VISTA, and KIR. In particular, checkpoint inhibitors can be agents or antibodies that inhibit PD-1 or PD-L1, such as PD-1 inhibitors (including anti-PD antibodies) and PD-L1 inhibitors (including anti-PD-L1 antibodies). Examples of PD-1 inhibitors include cemiplimab, nivolumab, and pembrolizumab. Examples of PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab.

[0136] The treatment of the present invention may include a compound of the present invention and one additional therapeutic agent. The treatment of the present invention may include a compound of the present invention and two additional therapeutic agents. For example, the treatment of the present invention may include a compound of the present invention and two additional therapeutic agents, where one additional therapeutic agent is a platinum-containing drug and the other additional therapeutic agent is a second chemotherapeutic agent (e.g., a drug selected from the list in the previous section), a second compound of the present invention, an AKT inhibitor, or a dual AKT / DNA-PK inhibitor. For the treatment of ovarian cancer, the treatment of the present invention may include a compound of the present invention and one or more additional therapeutic agents (e.g., a platinum-containing drug), preferably, the platinum-containing drug is carboplatin or cisplatin, and / or an antimitotic drug, preferably, the antimitotic drug is paclitaxel.

[0137] The other therapeutic agents described above may be used, for example, in amounts indicated in the Pharmaceutical Description (PDR) or as otherwise determined by one of skill in the art.

[0138] AKT and DNA-PK inhibitors The compounds of the present invention (e.g., compounds of formula (I), (Ia), (Ib), (II), or (III)) have activity as inhibitors of the enzyme AKT. AKT inhibitors are compounds that can bind to the AKT enzyme site and block the action of the AKT enzyme. The compounds of the present invention (e.g., compounds of formula (I), (Ia), (Ib), (II), or (III)) also have activity as inhibitors of the enzyme DNA-PK. DNA-PK inhibitors are compounds that can bind to the DNA-PK enzyme site and block the action of DNA-PK.

[0139] Compounds had a pIC of 6.0 or higher. 50 inhibits the AKT enzyme with a pIC of 6.0 or higher 50 The compounds of the present invention are dual AKT / DNA-PK inhibitors because they have activity as inhibitors of the enzyme AKT and can bind to the enzymatic site of DNA-dependent protein kinase (DNA-PK) and block the action of the DNA-PK enzyme.

[0140] Compounds had a pIC of 6.0 or higher. 50 In certain embodiments, preferred compounds of the invention have a pIC of 7.0 or greater, 7.5 or greater, 8.0 or greater, 8.5 or greater, or 9.0 or greater against the AKT enzyme. 50 In a preferred embodiment, preferred compounds of the invention have a pIC of 8.0 or greater, 8.5 or greater, or 9.0 or greater against the AKT enzyme. 50 At the time of writing, three members of the AKT family have been identified: AKT1, AKT2, and AKT3. 50 A compound of the present invention is considered to be an inhibitor of AKT if it inhibits at least one AKT enzyme at a pIC of 6.0 or greater against AKT1 and / or AKT2 and / or AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 7.0 or greater against AKT1 and / or AKT2 and / or AKT3.50 In certain preferred embodiments, compounds of the invention have a pIC of 8.0 or greater against AKT1 and / or AKT2 and / or AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 8.5 or greater for AKT1 and / or AKT2 and / or AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 9.0 or greater against AKT1 and / or AKT2 and / or AKT3. 50 It has.

[0141] Certain preferred compounds of the present invention have the described pIC 50 Thus, preferred compounds of the present invention have a pIC of 6.0 or greater against at least two of AKT1, AKT2, and AKT3. 50 Thus, in certain preferred embodiments, compounds of the invention have a pIC of 7.0 or greater against at least two of AKT1, AKT2, and AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 8.0 or greater against at least two of AKT1, AKT2, and AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 8.5 or greater against at least two of AKT1, AKT2, and AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 9.0 or greater against at least two of AKT1, AKT2, and AKT3. 50 It has.

[0142] Certain preferred compounds are 50 Thus, preferred compounds of the present invention have a pIC of 6.0 or greater against AKT1. 50 and a pIC of 6.0 or higher for AKT2 50 and a pIC of 6.0 or higher for AKT3 50Thus, in certain preferred embodiments, compounds of the invention have a pIC of 7.0 or greater against AKT1, AKT2, and AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 8.0 or greater against AKT1, AKT2, and AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 8.5 or greater against AKT1, AKT2, and AKT3. 50 In certain preferred embodiments, compounds of the invention have a pIC of 9.0 or greater against AKT1, AKT2, and AKT3. 50 It has.

[0143] The compounds of the present invention can also bind to the enzyme site of DNA-dependent protein kinase (DNA-PK) and block the action of the DNA-PK enzyme. 50 A compound of the present invention is considered an inhibitor of DNA-PK if it inhibits the DNA-PK enzyme with a pIC of 6.0 or greater. Therefore, a compound of the present invention has a pIC of 6.0 or greater against DNA-PK. 50 In certain preferred embodiments, compounds of the invention have a pIC of 7.0 or greater with respect to DNA-PK. 50 In certain preferred embodiments, compounds of the invention have a pIC of 8.0 or greater with respect to DNA-PK. 50 In certain preferred embodiments, compounds of the invention have a pIC of 8.5 or greater against DNA-PK. 50 In certain preferred embodiments, compounds of the invention have a pIC of 9.0 or greater with respect to DNA-PK. 50 It has.

[0144] In certain preferred embodiments, compounds of the invention have a pIC of 7.5 or greater. 50 inhibits the AKT enzyme with a pIC of 7.5 or higher 50 In certain preferred embodiments, compounds of the present invention are dual AKT / DNA-PK inhibitors that inhibit the DNA-PK enzyme with a pIC of 8.0 or greater. 50 inhibits the AKT enzyme with a pIC of 7.5 or higher 50In certain preferred embodiments, compounds of the present invention are dual AKT / DNA-PK inhibitors that inhibit the DNA-PK enzyme with a pIC of 8.0 or greater. 50 inhibits the AKT enzyme with a pIC of 8.0 or higher 50 In certain preferred embodiments, compounds of the present invention are dual AKT / DNA-PK inhibitors that inhibit the DNA-PK enzyme with a pIC of 8.5 or greater. 50 inhibits the AKT enzyme with a pIC of 8.5 or higher 50 In certain preferred embodiments, compounds of the present invention are dual AKT / DNA-PK inhibitors that inhibit the DNA-PK enzyme with a pIC of 9.0 or greater. 50 inhibits the AKT enzyme with a pIC of 9.0 or higher 50 It is a dual AKT / DNA-PK inhibitor that inhibits the DNA-PK enzyme.

[0145] As mentioned above, the compounds of the present invention have the activity of both AKT and DNA-PK inhibitors.The compounds of the present invention can be competitive inhibitors or partial competitive inhibitors of one or more AKT enzymes.The compounds of the present invention can be competitive inhibitors or partial competitive inhibitors of DNA-PK enzymes. [Example]

[0146] 1. Synthesis of Exemplary Compounds Chemical Materials and Methods Numerous synthetic routes to the compounds of the present invention can be devised by one skilled in the art, and the exemplary synthetic routes described below are not intended to limit the present invention. Some possible synthetic routes are illustrated below. Where applicable, any compound initially produced according to the present invention can be converted into another compound according to the present invention by known methods.

[0147] Unless otherwise stated, commercially available compounds were purchased from Sigma Aldrich. Commercially available compounds were used without further purification.

[0148] LC-MS Compounds were purified and analyzed on an LC-MS system (Agilent 6310 Ion Trap LC / MS or Shimadzu LCMS-2010EV (single quadrupole)) as described in Table 1. Compounds were separated with a gradient of methanol in water (5-98% over 12 min, then 98% methanol for 3 min), both containing 0.1% formic acid, or starting from 20 or 50% methanol for the same time, or as indicated in the experimental section below.

[0149] NMR 1 H NMR spectra were recorded at room temperature on either a Varian Unity Inova 400 (400 MHz) or a Varian Unity Inova 500 (500 MHz) machine, as detailed in the following experimental procedure and in Table 1 below. Data are presented as follows: chemical shift in ppm, integral, multiplicity (br = broad, app = apparent, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet), and coupling constants in Hz.

[0150] HPLC Where indicated, compounds were separated by high performance liquid chromatography using a Shimadzu HPLC model LC20AD / SPD-M20A (Softa 400ELSD).

[0151] optical rotation Where indicated, optical rotations of compounds were measured using a Jasco P-2000 polarimeter (serial number: A087561232, Faraday cell: flint glass).

[0152] General Method I: Formation of 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N,N-dimethyl-ethanamine (Example 1) Intermediate 1: 2-Bromo-2-(4-chlorophenyl)acetate methyl [ka] To a stirred solution of methyl 2-(4-chlorophenyl)acetate (5 g, 27.08 mmol) in EDC (50 mL) under a N atmosphere, NBS (5.01 g, 28.17 mmol) was added followed by AIBN (0.44 g, 2.70 mmol) at room temperature (RT). The resulting reaction mixture was stirred at reflux temperature for 3 hours, and the progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with DCM, and washed with saturated NaHCO solution. The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give Intermediate 1 (5 g, crude) as a thick orange syrup. The crude Intermediate 1 was used for the preparation of Intermediate 2 without further purification. 1 H NMR (500MHz, CDCl3): δ 7.48(d,2H),7.32(d,2H),5.35(s,1H),3.79(s,3H).

[0153] Intermediate 2: tert-butyl 4-[1-(4-chlorophenyl)-2-methoxy-2-oxo-ethyl]piperazine-1-carboxylate [ka] To a stirred solution of intermediate 1 (0.5 g, 1.89 mmol; crude) in dry THF (5 mL) under a N atmosphere, tert-butyl piperazine-1-carboxylate (0.35 g, 1.89 mmol) and EtN (0.818 mL, 5.88 mmol) were added at room temperature, and the reaction mixture was stirred for 2 hours. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography eluting with 6% MeOH / CHCl and then repurified by silica gel column chromatography eluting with 40% EtOAc / hexane to give intermediate 2 (0.8 g, 85%) as a pale yellow thick syrup. TLC: 10% EtOAc / hexane (R f :0.45) 1 HNMR (400MHz, CDCl3): δ 7.38-7.32(m,4H),4.02(s,1H),3.69(s,3H),3.46-3.39(m,4H),2.43-2.38(m,4H),1.49(s,9H). LC-MS: m / z 269.2[M-Boc]4.09RT (purity 98.18%) (Column: X-select C-18 (50 x 3.0 mm x 3.5 μ); 5mM NH4OAc:ACN; 0.8ml / min)

[0154] Intermediate 3: 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(4-chlorophenyl)acetic acid [ka] To a stirred solution of intermediate 2 (0.8 g, 2.18 mmol) in MeOH:HO (8 mL, 1:1) was added NaOH (0.168 g, 4.20 mmol) at 0 °C under an inert atmosphere. The resulting reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. The reaction mixture was then neutralized to pH 7 using acetic acid and extracted with EtOAc. The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give intermediate 3 (0.6 g, crude) as a white solid. Intermediate 3 was used directly in the synthesis of intermediate 4. TLC: 40% EtOAc / hexane (R f :0.4) 1 HNMR(400MHz,DMSO-d6):δ 12.47(bs,1H),7.42-7.39(m,4H),4.02(s,1H),3.36-3.32(m,4H),2.39-2.35(m,4H),1.34(s,9H) LC-MS: m / z 355.3[M+2] + 2.56RT (purity 97.64%) (Column: X-select C-18 (50 × 3.0 mm × 3.5 μm); 5 mM NH4OAc:ACN; 0.8 ml / min)

[0155] Intermediate 4: tert-butyl 4-(1-(4-chlorophenyl)-2-(dimethylamino)-2-oxoethyl)piperazine-1-carboxylate [ka] A stirred solution of intermediate 3 (0.7 g, 1.98 mmol) in dry CHCl (35 mL) was cooled to 0 °C under a N atmosphere, and EDCI.HCl (1.13 g, 5.95 mmol), HOBt.HO (805 mg, 5.95 mmol), followed by NMM (1.3 mL, 11.91 mmol) and N,N-dimethylamine hydrochloride (0.64 mL, 7.94 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored by TLC), the reaction was diluted with CHCl and washed with water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography eluting with 4% MeOH / CHCl to give intermediate 4 (0.45 g, 60%) as a pale yellow syrup. TLC: 10% MeOH / CH2Cl2 (R f :0.7) 1 HNMR(500MHz,CDCl3):δ 7.39-7.29(m,4H),4.28(s,1H),3.43-3.41(m,4H),2.98(s,3H),2.96(s,3H),2.51-2.42(m,4H),1.42(s,9H) LC-MS: m / z 382[M+2] + 4.10RT (purity 94.65%) (Column: X-bridge C-18 (50 × 3.0 mm × 3.5 μm); 5 mM NH4OAc:ACN; 0.8 ml / min)

[0156] Intermediate 5: tert-butyl 4-(1-(4-chlorophenyl)-2-(dimethylamino)ethyl)piperazine-1-carboxylate: [ka] To a stirred solution of intermediate 4 (0.85 g, 2.64 mmol) in dry THF (8.5 mL) was added BH3.DMS (6.37 mL, 5 M in Et2O) under an inert atmosphere at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was then cooled to 0 °C, and HO:THF (8.5 mL 1:1), 2 N NaOH (8.5 mL), and 30% HO2 (8.5 mL) were added. Stirring was continued at room temperature for an additional 15 min. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 40% EtOAc / hexane to give intermediate 5 (0.5 g, 61%) as an off-white solid. TLC: 10% MeOH / DCM (R f :0.25)

[0157] Intermediate 6: 2-(4-chlorophenyl)-N,N-dimethyl-2-(piperazin-1-yl)ethanamine hydrochloride [ka] To a stirred solution of intermediate 5 (400 mg, 1.05 mmol) in MeOH (3.2 mL) was added 4N HCl in 1,4-dioxane (3.2 mL) at 0° C. under an inert atmosphere. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure to give intermediate 6 (335 mg, crude) as an off-white solid. Intermediate 6 was used directly in the synthesis of Example 1 without further purification.

[0158] Intermediate 7: 1-(tert-butyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine [ka] Step 1: A stirred solution of ethyl 2-cyanoacetate (10 g, 0.088 mol) in dry DCM (100 mL) was cooled to 0 °C under a N atmosphere. To this was added trifluoroacetic anhydride (14.86 mL, 0.106 mol) followed by EtN (36.86 mL, 0.265 mol) and stirred at room temperature for 1 h. After the starting material was consumed (monitored by TLC), the reaction was diluted with CHCl and washed with saturated NaHCO. The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography eluting with 6% MeOH / CHCl to afford ethyl 2-cyano-4,4,4-trifluoro-3-oxobutanoate (18 g, 54%) as a thick orange syrup. TLC: 10% MeOH / CH2Cl2 (R f :0.25) 1 HNMR(400MHz,CDCl3):δ 4.18-4.07(m,1H),3.18-3.12(m,2H),1.28(t,3H) LC-MS: m / z 208.1[M-1]1.63RT (purity 95.70%)

[0159] Step 2: To a stirred solution of ethyl 2-cyano-4,4,4-trifluoro-3-oxobutanoate (1.8 g, 8.6 mmol) in dimethyl carbonate (16.3 mL) was added tert-butylhydrazine hydrochloride (1a) (1.93 g, 15.5 mmol), followed by trifluoroacetic acid (1.34 mL, 17.6 mmol), dried over molecular sieves (2.7 g). The resulting reaction mixture was heated to 80 °C and stirred for 18 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a Celite pad and the bed was washed with EtOAc. The resulting filtrate was washed with 5% NaHCO3, 5% NaOH, brine, and water. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with 15% EtOAc / hexane to give ethyl 5-amino-1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.25 g, 10.4%) as a pale yellow syrup. TLC: 5% MeOH / CH2Cl2 (R f :0.5) 1 HNMR(400MHz,CDCl3):δ 5.47(bs,2H),4.28(q,2H),1.64(s,9H),1.38(t,3H)

[0160] Step 3: To a stirred solution of ethyl 5-amino-1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.25 g, 0.89 mmol) in formamide (0.75 mL) was added ammonium carbonate (0.104 g, 10.8 mmol) under a N atmosphere. The reaction mixture was heated to 170 °C and stirred for 52 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 30% EtOAc / hexane to afford 1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.1 g, 43%) as an off-white solid. TLC: 20% EtOAc / hexane (R f :0.3) 1 HNMR(500MHz,CDCl3):δ 11.81(bs,1H),8.02(s,1H),1.84(s,9H) LC-MS: m / z 258.6[M-1]3.83RT (purity 84.09%)

[0161] Step 4: To a stirred solution of 1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.1 g, 0.35 mmol) in SOCl (1 mL) was added DMF (0.05 mL) at room temperature under a N atmosphere. The resulting reaction mixture was heated to 75 °C and stirred for 2 h. After the starting material was consumed (by TLC), the volatiles were removed under reduced pressure. The resulting residue was diluted with EtOAc and washed with saturated NaHCO solution. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. This was purified by silica gel column chromatography eluting with 6% EtOAc / hexane to give Intermediate 7 (0.05 g, 46%) as an off-white solid. TLC: 40% EtOAc / hexane (R f :0.8) 1 HNMR(400MHz,CDCl3):δ 8.81(s,1H),1.89(s,9H) LC-MS: m / z 278.9[M+1] + 4.33RT (purity 86.48%)

[0162] Intermediate 8: 4-Chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine [ka] Step 1: Under a N2 atmosphere, DMF was slowly added to a stirred solution of POCl3 (80 mL, 0.428 mol) at 0 °C and stirred at room temperature for 10 minutes. To this, pyrimidine-4,6-diol (20 g, 0.089 mol) was added portionwise at 0 °C and stirred at reflux for 3 hours. The resulting reaction mixture was cooled to room temperature and continued stirring at room temperature for an additional 16 hours. After the starting material was consumed (by TLC), crushed ice was added to the reaction and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4,6-dichloropyrimidine-5-carbaldehyde (20 g, crude) as a yellow solid. This material was used directly in the next step without further purification. TLC: 40% EtOAc / hexane (R f :0.75) 1 H NMR(500MHz,CD3OD):δ 8.22(s,2H),7.2-7.4(m,5H),5.99(d,1H),4.8(m,1H),4.6(s,2H),4.35(s,1H),4.2( s,1H),4.0(m,1H),3.95(d,1H),3.7(d,1H),2.25(m,1H),2.0(m,1H),1.9-1.6(m,4H). Mass (ESI):442.6(M + +1).

[0163] Step 2: To a stirred solution of 4,6-dichloropyrimidine-5-carbaldehyde (27 g, 0.015 mol) in dry ether (270 mL) at 0 °C under a N atmosphere, methylmagnesium bromide (1 M, 166.7 mL, 0.016 mol) was slowly added. The reaction mixture was stirred at room temperature for 3 h. After the starting material was consumed (by TLC), the reaction was quenched with saturated NH4Cl solution, and the aqueous layer was extracted with ether. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 15% EtOAc / hexane to afford 1-(4,6-dichloropyrimidin-5-yl)ethanol (20 g, 68%) as a yellow solid. TLC: 30% EtOAc / hexane (R f :0.2) 1 H NMR(500MHz,CDCl3):δ 8.4(s,1H),7.8(s,1H),7.4-7.2(m,5H),6.8(d,1H),5.85(m,1H),5.75(br s,1H),5.2(m,1H),5.15(m,1H),4.8-4.6(m,3H),4.55(s,1H),4.0-3.9(m,2H),3.8(t ,1H),2.35(m,1H),2.0-1.8(m,2H),1.79(m,2H),1.65(s,3H),1.6(m,1H),1.4(s,3H). HPLC (purity): 99.54%

[0164] Step 3: To a stirred solution of 1-(4,6-dichloropyrimidin-5-yl)ethanol (20 g, 0.1 mol) in acetone (320 mL) at 0 °C under a N atmosphere, CrO (20.6 g, 0.2 mol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After the starting material was consumed (by TLC), IPA (34 mL) was slowly added to the reaction and stirred for an additional 15 min. The reaction was diluted with CHCl and quenched with saturated NaHCO solution. The resulting product mass was filtered through a Celite pad, and the filtrate was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 15% EtOAc / hexane to afford 1-(4,6-dichloropyrimidin-5-yl)ethanone (15.1 g, 76.3%) as a yellow solid. TLC: 30% EtOAc / hexane (R f :0.7)

[0165] Step 4: To a stirred solution of 1-(4,6-dichloropyrimidin-5-yl)ethanone (15.1 g, 0.08 mol) in EtOH (156 mL) at 0 °C under a N atmosphere, EtN (10.7 mL, 0.076 mol) and hydrazine hydrate (4 mL, 0.08 mol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the starting material was consumed (monitored by TLC), volatiles were removed from the reaction under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting crude material was diluted with ether, stirred for an additional 10 minutes, filtered, and the filtrate was concentrated under reduced pressure to give 4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (12.6 g, 94%) as a yellow solid. TLC: 20% EtOAc / hexane (R f :0.2)

[0166] Example 1: 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N,N-dimethyl-ethanamine [ka] To a stirred solution of Intermediate 6 (335 mg, 1.05 mmol) in THF (10 mL) was added 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (293 mg, 1.05 mmol) followed by EtN (0.88 mL, 6.32 mmol) at 0 °C under a N atmosphere. The resulting reaction mixture was heated to 80 °C and stirred for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 4% MeOH / CHCl to give Example 1 (500 mg, 90%) as an off-white solid. TLC: 5% MeOH / DCM (R f :0.4) 1 H NMR(500MHz,CD3OD):δ 8.22(s,1H),7.37(d,J=8.5Hz,2H),7.29(d,J=8.0Hz,2H),3.90-3.85(m,5H),3.19- 3.15(m,1H),2.84-2.80(m,1H),2.67-2.62(m,2H),2.60-2.55(m,2H),2.41(s,6H). LC-MS: m / z 466[M+1] + 5.08RT (purity 95.54%) (Column: Ascentis (registered trademark) Express C18 (150 × 4.6 mm, 2.7 μ), λ = 218 nm HPLC purity: 97.07%

[0167] Exemplary compounds 3a, 3b, 4, 5, 7, 9, 11, 14, and 15 shown in Table 1 below can be made using commercially available starting materials, Intermediate 8, Intermediate 9, or Intermediate 10, following procedures similar to general method I. [Table 1-1] [Table 1-2]

[0168] Synthesis of Example Compounds 12a, 12b, and 13 Intermediate 9: (1-(1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methanone [ka] To a stirred solution of (4-chlorophenyl)(piperidin-4-yl)methanone (200 mg, 0.89 mmol) in THF (5 mL) was added Intermediate 7 (274 mg, 0.98 mmol) followed by EtN (0.747 mL, 5.38 mmol) under a N atmosphere at 0° C. The resulting reaction mixture was heated to 80° C. and stirred for 2 h. After the starting material was consumed (monitored by TLC), the reaction was diluted with EtOAc and washed with water. The separated organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 15% EtOAc / hexane to afford Intermediate 9 (390 mg, 94%) as a pale yellow solid. TLC: 20% EtOAc / hexane (R f :0.8) 1 HNMR(500MHz,CDCl3):δ 8.42(s,1H),7.94(d,2H),7.48(d,2H),4.36-4.32(m,2H),3.54-3.52(m,1H),3.31-3.27(m,2H),1.99-1.95(m,4H),1.82(s,9H) LC-MS: m / z 466.6[M+1] + 5.13RT (purity 83.02%)

[0169] Intermediate 10: (4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methanone [ka] Under a N2 atmosphere, methanesulfonic acid (4 mL) was added to intermediate 9 (400 mg, 0.85 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was poured into ice-cold water, basified with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 40% EtOAc / hexane to give intermediate 10 (300 mg, 85%) as a white solid. TLC: 40% EtOAc / hexane (R f :0.8) 1 HNMR(500MHz,DMSO-d6):δ 14.57(bs,1H),8.42(s,1H),8.03(d,2H),7.61(d,2H),4.24-4.21(m,4H),3.82-3.80(m,1H),1.94-1.92(m,2H),1.69-1.64(m,2H) LC-MS: m / z 410[M+1] + 3.94RT (purity 99.36%)

[0170] Examples 12a and 12b:N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -Dimethylethane-1,2-diamine (BCF3-E1(H)-NHC2NMe2 [ka] Intermediate 10 (125 mg, 0.30 mmol) was added to N 1 ,N 1-dimethylethane-1,2-diamine (0.06 mL, 0.61 mmol) and Ti(Oipr) (0.363 mL, 1.22 mmol) were added at 0 °C under an inert atmosphere. After stirring at room temperature for 12 hours, MeOH (1.25 mL), AcOH (0.412 mL), and NaBH (23 mg, 0.60 mmol) were added to the above solution at 0 °C, and stirring was continued at room temperature for another hour. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a Celite bed and washed with EtOAc. The resulting filtrate was washed with 5% NaOH, brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude material was purified by chiral preparative HPLC (described in more detail below) to give both Example 12a (110 mg, 46%) and Example 12b (110 mg, 46%) as white solids.

[0171] Example 12a is (+)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 Example 12b is (-)-N-dimethylethane-1,2-diamine. 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine.

[0172] The characterization data for Examples 12a and 12b are shown in Table 2 below.

[0173] Intermediate 11: 2-(4-chlorophenyl)-N,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride [ka] To a stirred solution of intermediate 4 (400 mg, 1.05 mmol) in MeOH (3.2 mL) was added 4N HCl in 1,4-dioxane (3.2 mL) at 0° C. under an inert atmosphere. The resulting reaction mixture was warmed to room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to give intermediate 11 (335 mg, crude) as an off-white solid. This material was used directly to make intermediate 12 without further purification. TLC: 5% MeOH / CH2Cl2 (R f :0.15) LC-MS: m / z 282[M+1] + 2.30RT (89.59% purity) (Column: X-bridge C-18 (50 x 3.0 mm x 3.5 μm); 5 mM NHOac:ACN in water; 0.8 ml / min)

[0174] Intermediate 12: 2-(4-(1-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide [ka] To a stirred solution of intermediate 11 (335 mg, 1.05 mmol) in THF (10 mL) was added intermediate 7 (293 mg, 1.05 mmol) followed by EtN (0.88 mL, 6.32 mmol) at 0 °C under a N atmosphere. The resulting reaction mixture was heated to 80 °C and stirred for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 4% MeOH / CHCl to afford intermediate 12 (500 mg, 90%) as an off-white solid. TLC: 10% EtOAc / hexane (R f :0.2) 1HNMR(400MHz,CDCl3):δ 8.38(s,1H),7.41-7.34(m,4H),4.31(s,1H),3.76-3.71(m,4H),2.98(s,3H),2.96(s,3H),2.63-2.59(m,4H),1.82(s,9H) LC-MS: m / z 524.2[M+1] + 5.04RT (purity 94.57%) (Column: X-bridge C-18 (50 × 3.0 mm × 3.5 μm); 5 mM NH4OAc:ACN; 0.8 ml / min)

[0175] Intermediate 13: 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl) [ka] Under a N2 atmosphere, methanesulfonic acid (5 mL) was added to intermediate 12 (500 mg, 0.95 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was poured into ice-cold water, basified with saturated NaHCO3, and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography eluting with 3% MeOH / CH2Cl2 to give intermediate 13 (350 mg, 78%) as an off-white solid. TLC: 10% MeOH / CH2Cl2 (R f :0.7) 1 HNMR(500MHz,CD3OD):δ 8.33(s,1H),7.47(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),4.48(s,1H),3.78-3.77(m,4H),3.03(s,3H),2.92(s,3H),2.61-2.53(m,4H) LC-MS: m / z 468[M+1] +3.38RT (purity 99.59%) (Column: X-bridge C-18 (150×4.6mm×3.5μ); 5mM NH4OAc:ACN; 0.8ml / min); λ=216nm

[0176] Example 13: 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethanamine [ka] To a stirred solution of Intermediate 13 (200 mg, 0.42 mmol) in dry THF (5 mL), LAH (0.17 mL, 0.34 mmol; 2 M in THF) was added at 0 °C and stirred under a N atmosphere for 1 hour. After the starting material was consumed (monitored by TLC), the reaction product was poured into saturated NH Cl and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give the crude material. This was purified by chiral preparative HPLC to give Example 13 (80 mg, 41%) as an off-white solid.

[0177] The characterization data for Example 13 is shown in Table 2 below.

[0178] The characterization data for Example compounds 3a, 3b, 4, 5, 7, 9, 11, 12a, 12b, 13, 14, and 15 are shown in Table 2 below. For Example compounds 3a and 3b and compounds 12a and 12b, an additional step of purifying the racemic mixture by chiral preparative HPLC was performed. The racemic mixture of compounds 3a and 3b was purified using a Chiralpak IC, 250 × 4.6 mm, 5 μm column (0.1% TEA in n-hexane:ethanol (50:50) as the mobile phase) to obtain fraction 1 (non-polar peak) and fraction 2 (polar peak). Fraction 1 was the dextrorotatory (+) isomer, compound 3b, and fraction 2 was the levorotatory (-) isomer, compound 3a. The racemic mixture of compounds 12a and 12b was purified using a Chiralpak IC, 250 × 4.6 mm, 5 μm column (mobile phase (A) 0.1% TEA in n-hexane, mobile phase (B) DCM:MeOH (80:20), (A:B 85:15, flow rate: 1.00 mL / min) to obtain fraction 1 (non-polar peak) and fraction 2 (polar peak). Fraction 1 was the dextrorotatory (+) isomer, compound 12a, and fraction 2 was the levorotatory (-) isomer, compound 12b. [Table 2-1] [Table 2-2]

[0179] Examples 2, 3, 6, 8, and 10 can be synthesized according to the procedures disclosed in US2008 / 0188482. [Table 3]

[0180] Enzyme inhibition assay Enzyme Inhibition Assay Description: AKT1, AKT2, AKT3 IC of compounds of the present invention against AKT1, AKT2, and AKT3 50Values ​​were measured using the HTRF (homogeneous time-resolved fluorescence) KinEASE assay (62ST3PEB-1000 test or 62ST3PEC-20,000 test) from cisbio.com.

[0181] DNA-PK Exemplary compounds of the present invention against DNA-PK IC 50 Values ​​were measured using the HTRF KinEASE assay as described above.

[0182] The reference compound used in the enzyme inhibition assays for AKT1, AKT2, AKT3, and DNA-PK was its phosphate form, triciribine (dihydrogenphosphate ((2R,3S,4R,5R)-5-(3-amino-5-methyl-1,4,5,6,8-pentaazaacenaphthylen-1(5H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl, Sigma-Aldrich, UK), a known AKT inhibitor. Triciribine is a PH domain inhibitor and does not bind to the AKT catalytic domain. Triciribine is inactive in AKT enzyme assays that do not include full-length protein.

[0183] The structure of triciribine phosphate is: [ka]

[0184] Roche Compound 4 (synthesized according to the procedure disclosed in Breitenlechner CB, Journal of Medicinal Chemistry, 2004, 47, issue 6, pages 1375-1390), a known AKT inhibitor, was also tested in this assay as a comparative example. Roche Compound 4 is N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl}-isonicotinamide. Example 4 is disclosed in Breitenlechner CB, Journal of Medicinal Chemistry, 2004, 47, issue 6, pages 1375-1390, and its structure is as follows: [ka]

[0185] A known AKT inhibitor, GSK-3g (GSK-690693, synthesized according to the procedure disclosed in Heerding, DA, et al., Journal of Medicinal Chemistry, 2008, Vol. 51, pages 5663-5679), was also tested in this assay as a comparative example. GSK-3g is 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol. Example 3g is disclosed in Heerding, DA, et al., Journal of Medicinal Chemistry, 2008, Vol. 51, pages 5663-5679, and its structure is as follows: [ka]

[0186] result The results of the AKT1, AKT2, AKT3, and DNA-PK enzyme inhibition assays are shown below in Table 4. As can be seen from the results in Table 4, all compounds of the present invention exhibited pIC activity against at least one of AKT1, AKT2, and / or AKT3. 50 is 6 or more, and pIC 50 are dual AKT and DNA-PK inhibitors, with pIC values ​​of 6 or higher. Furthermore, most of the compounds described have pIC values ​​of 5 or higher for each of AKT1, AKT2, and AKT3. 50 is 7.5 or more or 8.0 or more, and pIC 50 is 7.5 or greater or 8.0 or greater. Example 1 shows inhibitory potency against each isoform of AKT and DNA-PK against each enzyme target with a pIC50 of 9 or greater. [Table 4]

[0187] In vitro cell-based phenotypic assays Apoptosis was assessed using Caspase-Glo® 3 / 7 (Promega, US) according to the manufacturer's instructions. As outlined below, apoptotic caspase assays were used in different experiments / assays, but the basic protocol for assay readout remained the same for each different experiment.

[0188] Cell viability was assessed using the MTT assay, described in detail below, using a standard protocol. Although the MTT assay was used for different experiments / assays as outlined below, the basic protocol for assessing the MTT readout in each experiment following different experimental setups remained the same.

[0189] The cell lines used were the isogenic matched high-grade serous ovarian cancer platinum-sensitive PEO1 cell line (obtained from Dr. Simon Langdon, Edinburgh University), the isogenic matched high-grade serous ovarian cancer platinum-sensitive platinum-resistant PEO4 cell line (obtained from Dr. Simon Langdon, Edinburgh University), and the platinum-resistant epithelial ovarian cancer cell line SKOV3 (obtained from ATCC).

[0190] Comparative example compounds afuresertib, uprosertib, ipatasertib, triciribine, NU7441, and LY3023414 were obtained from Selleck Chem, UK.

[0191] Afuresertib is N-[(2S)-1-amino-3-(3-fluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)thiophene-2-carboxamide, a known AKT inhibitor, having the following structure: [ka]

[0192] Uprosertib is N-[(2S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)furan-2-carboxamide, a known AKT inhibitor, having the following structure: [ka]

[0193] Ipatasertib is (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(propan-2-ylamino)propan-1-one, a known AKT inhibitor, having the following structure: [ka]

[0194] NU7441 is 8-dibenzothiophen-4-yl-2-morpholin-4-ylchromen-4-one, a known DNA-PK inhibitor, having the following structure: [ka]

[0195] LY3023414 is 8-[5-(2-hydroxypropan-2-yl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methylimidazo[4,5-c]quinolin-2-one, a known mTOR / DNA-PK inhibitor, with the following structure: [ka]

[0196] protocol: MTT Assay Protocol: Cell viability was determined for different assays (as described in Figures 1 and 2 and Table 5) in optically clear 96-well plates using the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a colorimetric method for determining the number of metabolically active cells in cytotoxicity assays. MTT is bioreduced by mitochondrial dehydrogenase enzymes to a colored solid formazan product. MTT reagent (Sigma, UK) was first prepared by dissolving it in PBS at a concentration of 3 mg / ml. After different time points and relevant drug treatments in cell lines (described in the Results section and Figures 1 and 2), MTT reagent was added to each experimental well at a final concentration of 0.5 mg / ml. After incubation at 37 °C for 3 h in 5% CO2, an equal volume of stop solution (10% SDS in 0.01% HCl) was added, and the formed formazan crystals were dissolved overnight by shaking. The next day, optical density was read at 570 nm and analyzed according to each assay type.

[0197] Caspase assay protocol: Caspase-Glo® 3 / 7 activity was determined in cells after treatment with inhibitor compounds or vehicle (DMSO) using the Caspase-Glo® 3 / 7 Assay (Cat. No. G8093, Promega, US) according to the manufacturer's instructions. Briefly, 10,000 cells per well of the PEO1 and PEO4 cell lines or 5,000 cells per well of the SKOV3 cell line were grown in a 96-well plate in a final volume of 50 μl. After treating the cells with the relevant drug (exemplary compound ± cisplatin, comparative compound ± cisplatin, or vehicle ± cisplatin) for 24 hours, an equal volume of Caspase-Glo® Reagent containing luminescent substrates for caspase 3 and caspase 7 was added (i.e., if cells were cultured in 50 μl of medium, 50 μl of Caspase Reagent was added). After 1 h of incubation at room temperature in the dark, the luminescence of each sample was measured using a plate-reading luminometer (LUMIstar OPTIMA, BMG Labtech, Germany). Caspase 3 / 7 activity data were normalized to the corresponding viability data from MTT and analyzed according to each experimental setup.

[0198] Collection of protein lysates for reverse-phase protein array proteomics analysis. SKOV3 cells were seeded at 200,000 cells per well in 6-well plates. Cells were treated with 6.67 μM inhibitor compounds (listed in the Results section). After 1 hour, 25 μM cisplatin or media control was added, and the cells were incubated for two different time points (2 and 8 hours) before lysate collection. Protein lysates were collected according to the standard protocol for cell lysates at the RPPA Functional Proteomics Facility, MD Anderson. Protein concentration was adjusted to 1 mg / ml, and lysates were submitted to the facility for RPPA analysis.

[0199] result: Isobologram experiments to determine synergy or antagonism between example compounds, comparative compounds, and platinum chemotherapeutic drugs: First, IC 50 Experiments were performed to determine the optimal concentration range for synergy / antagonism assays of Example 1 and Comparative Examples (LY3023414, afuresertib, uprosertib, ipatasertib, triciribine, and NU7441, all obtained from Selleck Chem). All cell lines (PEO1, PEO4, and SKOV3) were seeded in triplicate in 96-well plates at 10,000 cells per well for each inhibitor compound 24 hours prior to treatment. Cells were treated with uniformly diluted concentrations (serial 1:2 dilutions) of each inhibitor against a medium control. After 72 hours of incubation, cell viability was assessed using an MTT assay (n=3). IC for each compound was calculated. 50 Values ​​were determined using GraphPad Prism software, non-linear regression of log(inhibitor) versus response (three parameters).

[0200] All isobologram assays used the standard MTT protocol as described above for assay readout. Cell lines were seeded into 96-well clear-bottom plates at 10,000 cells per well for PEO1 and PEO4 lines and 5,000 cells per well for SKOV3 line 24 hours prior to treatment. Cells were incubated at uniformly diluted concentrations (1:2 serial dilutions) of IC against medium control. 50Cells were treated with a range of concentrations of each compound (Example 1, LY3023414, afuresertib, uprosertib, ipatasertib, triciribine, or NU7441, Figure 1A-C) derived from the assay. After 1 hour of incubation, cells were treated with uniformly diluted concentrations of cisplatin (serial 1:2 dilutions starting from 50 μM cisplatin). Plates were incubated at 37°C and 5% CO2 for 72 hours. After 72 hours of incubation, cell viability was assessed using the MTT assay as described above. Analysis was performed using the Cambridge University Combenefit Analysis LOEWE program for synergy and antagonism (https: / / www.cruk.cam.ac.uk / research-groups / jodrell-group / combenefit). An increase in positive numbers in the isobologram analysis indicates increased synergy between the inhibitor compound and cisplatin. A decrease in negative numbers in the isobologram analysis indicates an increase in antagonism between the inhibitor compound and cisplatin.

[0201] Figures 1A, 1B, and 1C show isobologram analyses of PEO1, PEO4, and SKOV3 cell lines, respectively. As can be seen from Figures 1A-1C, Example 1, a dual AKT / DNAPK inhibitor of the present invention, demonstrates superior synergy in combination with cisplatin compared to the comparative compounds, which are a panel of currently marketed AKT inhibitors (afuresertib, uprosertib, ipatasertib, and triciribine), DNA-PK (NU7441), or mTOR / DNAPK inhibitors (LY3023414). In particular, for Example 1 compound, strong synergy (increasing positive counts) was observed in combination with cisplatin in both platinum-resistant cell lines (PEO4 and SKOV3) at several different concentrations of Example 1, including very low concentrations (see Figures 1B and 1C). Compared to Example 1, weak synergy or antagonism was observed in combinations of currently marketed AKT, DNA-PK, or mTOR / DNAPK inhibitors with cisplatin across all three cell line models.

[0202] Phenotypic apoptosis assay to demonstrate resensitization of platinum-resistant cells to cisplatin when treated with the AKT / DNAPK inhibitor compound of Example 1 A phenotypic apoptosis assay was performed to determine the level of caspase 3 / 7-dependent apoptosis induction by each inhibitor compound in the presence or absence of cisplatin (cddp). PEO4 and SKOV3 cells were seeded 24 hours before drug treatment. Cells were treated with different inhibitor concentrations: Example 1 (2 μM concentration) and five commercially available inhibitors (all obtained from Selleck Chem): an inhibitor inhibiting mTOR / DNAPK (10 μM LY3023414), an inhibitor inhibiting AKT (10 μM afuresertib, 10 μM uprosertib, 20 μM triciribine, 20 μM ipatasertib), or an inhibitor inhibiting DNA-PK (10 μM NU7441), or DMSO vehicle control, and incubated at 37°C, 5% CO2 for 1 hour. After incubation, 25 μM cisplatin or medium control was added to the cells and incubated for 24 hours. Duplicate plates were set up for each experiment for the caspase and MTT assays, which were performed according to the protocols described above.

[0203] The results of the caspase 3 / 7 assay were normalized to the results of the standard MTT viability assay for each corresponding well, and the results are shown in Figure 2A (Example 1 and various comparative compounds in SKOV3 cell line) and Figure 2B (Example 1 and various comparative compounds in PEO4 cell line). The results in Figures 2A and 2B are shown as fold change in apoptosis compared to the DMSO vehicle control. Data shown in Figures 2A and 2B are n=3±sem. Statistical significance was calculated using Student's t-test using GraphPad Prism software. **p<0.01, *p<0.05

[0204] As can be seen in Figures 2A and 2B, a statistically significant increase in apoptosis (resensitization) was observed with the dual AKT / DNAPK inhibitor Example 1 in combination with cisplatin (p<0.01) compared to cisplatin alone in both platinum-resistant cell lines tested. Comparative compounds tested in combination with cisplatin (afuresertib, uprosertib, ipatasertib, triciribine, NU7441, or LY3023414) also showed resensitization of platinum-resistant cells to cisplatin in both platinum-resistant cell lines, but at doses 5- or 10-fold higher than those of Example 1. Thus, Example 1, in combination with cisplatin, was able to resensitize platinum-resistant cells to cisplatin at 10% or 20% of the inhibitor concentrations required to elicit a similar apoptotic response to other AKT, DNAPK, or DNAPK / mTOR inhibitor compounds (afuresertib, uprosertib, ipatasertib, triciribine, NU7441, or LY3023414), demonstrating that the dual AKT / DNA-PK inhibitor compounds of the present invention are particularly effective in resensitizing platinum-resistant cells to cisplatin.

[0205] Relative resensitization ratio of apoptosis induction (caspase 3 / 7) of inhibitor compounds compared to triciribine phosphate. PEO4 cells, seeded 24 hours prior at 10,000 cells per well, were treated for 1 hour with the compounds of the present invention listed in Table 5 at concentrations of 1, 5, 10, and 20 μM, or with 25 μM triciribine. Cisplatin or a medium control was added at a final concentration of 25 μM, and the cells were incubated at 37°C and 5% CO2 for 24 hours. Apoptosis (caspase 3 / 7) and viability (MTT) assays were performed as described for each assay protocol and for the phenotypic apoptosis assays above. Relative apoptosis induction was estimated by normalizing the caspase 3 / 7 assay values ​​to the standard MTT viability assay values ​​for each corresponding well. For each compound, the relative resensitization ratio of each compound (at a 20 μM concentration) relative to the apoptosis induction of triciribine was calculated. The results in Table 5 show that the compounds of the present invention, when combined with cisplatin treatment, had resensitization ratios equivalent to or higher than those of triciribine. [Table 5]

[0206] Proteomic analysis of the inhibition of example compounds in SKOV3 cells Reverse-phase protein arrays were performed on protein lysates collected after treatment of SKOV3 cells with Examples 1, 2, 12a, or 12b of the present invention (active compounds), or one of the following comparative compounds: GSK-3g (GSK-690693) or Roche compound 4 (Breitenlechner CB, Journal of Medicinal Chemistry, 2004, 47, issue 6, pages 1375-1390), which were shown to be inactive in a phenotypic in vitro apoptotic platinum resensitization assay in SKOV3 cells at concentrations equivalent to the inhibitor at 6.67 μM and cisplatin at 25 μM (inactive compound); or DMSO (control) + / - cisplatin. RPPA assays were performed at the RPPA Functional Proteomics Facility, MD Anderson, USA, according to standard protocols (Tibes R. et al., Mol Cancer Ther (2006), Vol 5(10), Pages 2512-21, https: / / www.mdanderson.org / research / research-resources / core-facilities / functional-proteomics-rppa-core / technical-information.html).

[0207] GSK-3g (GSK-690693) and Roche compound 4 are known AKT inhibitors as described above and were synthesized as described above.

[0208] In this assay, treatment with active compounds results in increased phosphorylation of AKT at serine 473 and threonine 308. Tested compounds were grouped as either inactive or active with or without cisplatin by the phenotypic in vitro apoptotic platinum resensitization assay (Figure 3A), and heat maps were generated showing signaling changes in different response clusters (1 and 2) or induced by cisplatin or over time (Figure 3B). Figure 3C lists proteins that were decreased upon treatment with an active inhibitor (response cluster 1—left panel) or increased after treatment with an active inhibitor (response cluster 2—right panel) in combination with cisplatin. Increased phosphorylation of AKT at serine 473 (AKT pS473) and threonine 308 (AKT pT308) in response cluster 2, and decreased phosphorylation of proteins downstream of AKT signaling (e.g., at pS235-S236, pS240-S244 of S6 observed in response cluster 1) demonstrate that the tested compounds of the present invention target the AKT pathway.

[0209] overview The results of the Examples herein demonstrate that the dual AKT / DNA-PK inhibitor compounds of the present invention act synergistically with cisplatin, particularly in the platinum-resistant cell lines tested, to restore apoptotic function and response to platinum at doses much lower than comparative compounds that are inhibitors of AKT, DNA-PK, or mTOR / DNA-PK. Proteomic analysis demonstrated increased phosphorylation of AKT at S473 and T308, and targeting of downstream molecules in the AKT pathway, by compounds of the present invention in combination with cisplatin treatment. Preferred embodiments of the present invention will be described below in detail. Embodiment 1 1. A compound of formula (I) for use in the treatment of platinum-resistant cancer, comprising: [ka] During the ceremony, X is CH and Z is CR 4 or N, or X is N and Z is CR4 or XZ is C=C, R 1 and R 2 are independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclyl, or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring, Each R 3 are independently methyl, halogen, and CF 3 is selected from m is 0, 1, 2, or 3; R 4 is H or OH, When Z is N or XZ is C=C, Y is a bond, -C(O)-, and -SO 2 NH-, R 5 is methyl, halogen, and CF 3 Selected from or Y is -SO 2 - selected from R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Z is CR 4 If Y is a bond, -C(O)-, or -SO 2 NH-, and -NHSO 2 - selected from R 5 is methyl, halogen, and CF 3 Selected from or Y is -SO 2 - selected from R 5 is selected from methyl and halogen; or Y is -C(O)NR 6 - and R 5 is a halogen, Y is -NR 6 - and R 5 is methyl, halogen, and CF 3 Selected from or Y is -O- and R 5 is selected from methyl and halogen; Y is a bond, -SO 2 NH-, -O-, -NR 6 - and -C(O)NR 6 - n is 1, 2, 3, or 4 when selected from Y is -NHSO 2 -, -SO 2 -, and -C(O)-, n is 0, 1, 2, 3, or 4; R 6 H and C 1-4 a compound selected from alkyl, Or its salt. Embodiment 2 Y is a bond, -C(O)-, -O-, and -NR 6 - The compound for use according to embodiment 1, selected from: Embodiment 3 R 1 and R 2 However, each 1-4 The compound for use according to embodiment 1 or 2, wherein each is alkyl, preferably methyl. Embodiment 4 m is 1 and R 3 is chloro, for example, m is 1, and R 3 The compound for use according to any one of embodiments 1 to 3, wherein is para-chloro. Embodiment 5 R 4 is H. Embodiment 6 R 5 The compound for use according to any one of embodiments 1 to 5, wherein is bromo. Embodiment 7 The compound for use according to any one of embodiments 1 to 5, wherein n is 1 (eg, n is 1 and Y is a bond). Embodiment 8 The compound for use according to embodiment 1, wherein the compound is selected from the following: 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, 2-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylethan-1-amine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (-)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (+)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, N-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-N-(4-chlorophenyl)-2-(diethylamino)ethane-1-sulfonamide, and 2-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, N 1 -((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethan-1-amine, N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (+)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, (-)-N 1 -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-5-(dimethylamino)pentan-1-ol, 4-(4-chlorophenyl)-N,N-dimethyl-4-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-ylidene)butan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-4-(dimethylamino)butan-1-ol, and 3-((1-(3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylpropan-1-amine. Embodiment 9 The compound for use according to any one of embodiments 1 to 8, wherein the cancer is ovarian cancer (e.g., high-grade serous ovarian cancer). Embodiment 10 The compound for use according to any one of embodiments 1 to 9, wherein the compound is administered in combination with a platinum-containing drug (e.g., cisplatin or carboplatin). Embodiment 11 The compound for use according to any one of embodiments 1 to 10, wherein the compound is administered in combination with a further therapeutic agent (e.g., a chemotherapeutic or immuno-oncology agent). Embodiment 12 The method for treating platinum-containing drug-resistant cancer, comprising administering to a subject in need thereof a compound of any one of embodiments 1-8. Embodiment 13 The compound and platinum-containing drug of any one of embodiments 1 to 8 for use in the combination treatment of cancer, wherein the compound and the platinum-containing drug are administered simultaneously or separately. Embodiment 14 The compound of any one of embodiments 1 to 8 and a platinum-containing drug for use in said treatment of cancer that is resistant to said platinum-containing drug. Embodiment 15 The compound and platinum-containing drug for use according to embodiment 13 or 14, wherein the cancer is ovarian cancer (e.g., high-grade serous ovarian cancer). Embodiment 16 The compound platinum-containing drug for use according to any one of embodiments 13 to 15, wherein the platinum-containing drug is cisplatin or carboplatin. Embodiment 17 The compound and platinum-containing drug for use according to any one of embodiments 13 to 16, wherein the compound and platinum-containing drug are administered in combination with an additional therapeutic agent (e.g., a chemotherapeutic or immuno-oncology agent). Embodiment 18 The compound for use according to any one of embodiments 1 to 11, or the compound for use and a platinum-containing drug according to any one of embodiments 13 to 17, wherein the platinum-resistant cancer is a cancer that progressed while undergoing chemotherapy treatment using a platinum-containing drug, or a cancer that recurred within 18 months (e.g., within 12 months or within 6 months) of completing treatment using a platinum-containing drug. Embodiment 19 A method for the treatment of cancer, comprising administering to a patient subject in need thereof a compound of any one of embodiments 1-8 and a platinum-containing drug in combination therapy. Embodiment 20 A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 8, a pharmaceutically suitable carrier, and a platinum-containing drug. Embodiment 21 A compound of formula (Ia):

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Claims

1. A pharmaceutical composition for treating platinum-resistant cancer, comprising a compound of formula (I) or a salt thereof as an active ingredient: 【Chemical 1】 During the ceremony, X is CH and Z is CR ４ or N, or X is N and Z is CR ４ or X-Z is C=C; R １ and R ２ are independently H, C １－４ Alkyl, C ３－６ cycloalkyl, and 5- to 6-membered heterocyclyl, or R １ and R ２ together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring; Each R ３ are independently methyl, halogen, and CF ３ is selected from m is 0, 1, 2, or 3; R ４ is H or OH, When Z is N or X-Z is C=C, Y is a bond, —C(O)—, or —SO ２ NH—, and R ５ is methyl, halogen, and CF ３ Selected from or Y is -SO ２ -, and R ５ is selected from methyl and halogen; or Y is —C(O)NR ６ - and R ５ is a halogen, Z is CR ４ If Y is a bond, —C(O)—, or —SO ２ NH- and -NHSO ２ -, and R ５ is methyl, halogen, and CF ３ Selected from or Y is -SO ２ -, and R ５ is selected from methyl and halogen; or Y is —C(O)NR ６ - and R ５ is a halogen, Y is -NR ６ - and R ５ is methyl, halogen, and CF ３ Selected from or Y is —O—, and R ５ is selected from methyl and halogen; Y is a bond, —SO ２ NH-, -O-, -NR ６ -, and -C(O)NR ６ -, n is 1, 2, 3, or 4; Y is -NHSO ２ -, -SO ２ -, and -C(O)-, n is 0, 1, 2, 3, or 4; R ６ is H and C １－４ alkyl.

2. Y is a bond, —C(O)—, —O—, or —NR ６ The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

3. R １ and R ２ However, each １－４ 3. The pharmaceutical composition of claim 1 or 2, wherein the aryl group is alkyl.

4. R １ and R ２ The pharmaceutical composition of claim 3, wherein each is methyl.

5. m is 1, and R ３ The pharmaceutical composition of any one of claims 1 to 4, wherein is chloro.

6. m is 1, and R ３ The pharmaceutical composition of claim 5, wherein is para-chloro.

7. R ４ The pharmaceutical composition of any one of claims 1 to 6, wherein is H.

8. R ５ The pharmaceutical composition of any one of claims 1 to 7, wherein is bromo.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein n is 1.

10. 10. The pharmaceutical composition of claim 9, wherein n is 1 and Y is a bond.

11. 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the following: 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, 2-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylethan-1-amine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (-)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (+)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, N-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-N-(4-chlorophenyl)-2-(diethylamino)ethane-1-sulfonamide, and 2-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, N １ -((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethan-1-amine, N １ -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, (+)-N １ -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, (-)-N １ -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-5-(dimethylamino)pentan-1-ol, 4-(4-chlorophenyl)-N,N-dimethyl-4-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-ylidene)butan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-4-(dimethylamino)butan-1-ol, and 3-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methoxy)-N,N-dimethylpropan-1-amine.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the platinum-resistant cancer is ovarian cancer.

13. The pharmaceutical composition of claim 12, wherein the ovarian cancer is high-grade serous ovarian cancer.

14. The pharmaceutical composition of any one of claims 1 to 13, administered in combination with a platinum-containing drug.

15. 15. The pharmaceutical composition of claim 14, wherein the platinum-containing drug is cisplatin or carboplatin.

16. 16. The pharmaceutical composition of claim 14 or 15, administered simultaneously or separately with the platinum-containing drug.

17. The pharmaceutical composition of any one of claims 1 to 15, administered in combination with a further therapeutic agent.

18. 18. The pharmaceutical composition of claim 17, wherein the additional therapeutic agent is a chemotherapeutic agent or an immuno-oncology agent.

19. The pharmaceutical composition of any one of claims 14 to 16, wherein the platinum-resistant cancer is resistant to the platinum-containing drug.

20. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein the platinum-resistant cancer is a cancer that has progressed while undergoing chemotherapy treatment using a platinum-containing drug, or a cancer that has recurred within 18 months of completing treatment using a platinum-containing drug.

21. 12. The pharmaceutical composition of any one of claims 1 to 11, comprising a pharmaceutically suitable carrier and a platinum-containing drug.

22. A compound of formula (II): 【Chemistry 2】 During the ceremony, X is CH and Z is CR ４ or N, or X is N and Z is CR ４ or X-Z is C=C; R １ and R ２ are independently H, C １－４ Alkyl, C ３－６ cycloalkyl, and 5- to 6-membered heterocyclyl, or R １ and R ２ together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclyl ring; Each R ３ are independently methyl, halogen, and CF ３ is selected from m is 0, 1, 2, or 3; R ４ is H or OH, When Z is N or X-Z is C=C, Y is a bond, —C(O)—, or —SO ２ NH—, and R ５ is methyl, halogen, and CF ３ Selected from or Y is -SO ２ - and R ５ is selected from methyl and halogen; or Y is —C(O)NR ６ - and R ５ is a halogen, Z is CR ４ If Y is a bond, —C(O)—, or —SO ２ NH- and -NHSO ２ -, and R ５ is methyl, halogen, and CF ３ Selected from or Y is -SO ２ - and R ５ is selected from methyl and halogen; or Y is —C(O)NR ６ - and R ５ is a halogen, Y is -NR ６ - and R ５ is methyl, halogen, and CF ３ Selected from or Y is —O—, and R ５ is methyl, Y is —C(O)NR ６ - and -NR ６ -, n is 1, 3, or 4; Y is -SO ２ When NH— or —O—, n is 1, 2, 3, or 4; Z is CR ４ or when X-Z is C=C and Y is a bond, n is 1, 2 or 4; when Z is N and Y is a bond, n is 1 or 4; Z is CR ４ or X-Z is C=C and Y is -NHSO ２ -, -SO ２ -, and -C(O)-, n is 0, 1, 2, 3, or 4; Z is N and Y is -SO ２ - and -C(O)-, n is 0, 1, 3, or 4; R ６ is H and C １－４ a compound selected from alkyl, or a salt thereof.

23. Z is CR ４ 23. The compound of claim 22, wherein:

24. Y is a bond, —C(O)—, —O—, or —NR ６ 24. The compound according to claim 22 or 23, selected from:

25. R １ and R ２ However, each １－４ The compound of any one of claims 22 to 24, which is alkyl.

26. R １ and R ２ 26. The compound of claim 25, wherein each is methyl.

27. m is 1, and R ３ The compound of any one of claims 22 to 26, wherein is chloro.

28. m is 1, and R ３ The compound of claim 27, wherein is para-chloro.

29. Z is CR ４ and Y is —O—, and R ５ The compound of any one of claims 22 to 28, wherein is methyl.

30. Y is a bond, —C(O)—, or —NR ６ -, and R ５ The compound of any one of claims 22 to 28, wherein is bromo.

31. X is CH and Z is CR ４ and Y is a bond.

32. The compound of any one of claims 22 to 31, wherein n is 1.

33. A compound selected from: 2-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-2-(4-chlorophenyl)-N,N-dimethyl-ethanamine, 2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N,N-dimethylacetamide, 2-((4-chlorophenyl)(1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methoxy)-N,N-dimethylethan-1-amine, 2-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-chlorophenyl)-N,N-dimethylethan-1-amine, (-)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, (+)-2-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)acetamide, N １ -((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)(4-chlorophenyl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethan-1-amine, N １ -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, (+)-N １ -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, (-)-N １ -((4-chlorophenyl)(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-N ２ , N ２ -dimethylethane-1,2-diamine, 2-(4-chlorophenyl)-N,N-dimethyl-2-(4-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-amine, 1-(1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)-1-(4-chlorophenyl)-5-(dimethylamino)pentan-1-ol, and 4-(4-chlorophenyl)-N,N-dimethyl-4-(1-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-ylidene)butan-1-amine.

34. A compound according to any one of claims 22 to 33 for use as a pharmaceutical.

35. A compound according to any one of claims 22 to 33 for the treatment of cancer.

36. 36. The compound of claim 35, wherein the cancer is a platinum-resistant cancer.

37. 37. The compound of claim 36, wherein the platinum-resistant cancer is ovarian cancer and / or the platinum-resistant cancer is a cancer that has progressed while undergoing chemotherapy treatment using a platinum-containing drug or a cancer that has recurred within 18 months of completing treatment using a platinum-containing drug.

38. 38. The compound of claim 37, wherein the ovarian cancer is high-grade serous ovarian cancer.

39. A pharmaceutical composition comprising a compound according to any one of claims 22 to 33 and a pharmaceutically suitable carrier.

40. 40. The pharmaceutical composition of claim 39, comprising an additional therapeutic agent.

41. 41. The pharmaceutical composition of claim 40, wherein the additional therapeutic agent is a platinum-containing drug.

42. A pharmaceutical composition according to any one of claims 39 to 41 for use as a medicament.

43. The pharmaceutical composition according to any one of claims 39 to 41 for the treatment of cancer.

44. 44. The pharmaceutical composition of claim 43, wherein the cancer is a platinum-resistant cancer.

45. 45. The pharmaceutical composition of claim 44, wherein the platinum-resistant cancer is ovarian cancer and / or the platinum-resistant cancer is a cancer that has progressed while undergoing chemotherapy treatment using a platinum-containing drug or a cancer that has recurred within 18 months of completing treatment using a platinum-containing drug.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the ovarian cancer is high-grade serous ovarian cancer.

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