TW202227082A - Combination therapies for use in treating cancer - Google Patents

Combination therapies for use in treating cancer Download PDF

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TW202227082A
TW202227082A TW110129858A TW110129858A TW202227082A TW 202227082 A TW202227082 A TW 202227082A TW 110129858 A TW110129858 A TW 110129858A TW 110129858 A TW110129858 A TW 110129858A TW 202227082 A TW202227082 A TW 202227082A
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inhibitor
pharmaceutically acceptable
acceptable salt
cancer
compound
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後補 後補
佩塔爾 卡萊夫
卡蒂亞 馬瓊
凱文 馬克斯
富 李
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美商施維雅製藥有限公司
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Abstract

The compound of Formula (I), or pharmaceutically acceptable salts thereof, is useful in, among other things, the treatment of cancer and provides a therapeutic advantage when used in combination with other agents as herein described compared to treatment with each agent when administered alone.

Description

用於治療癌症之組合療法Combination therapy for the treatment of cancer

本發明係關於式(I)化合物及其醫藥上可接受之鹽，其尤其適用於治療癌症，且與各劑單獨投與進行治療時，當與如本文描述之一或多種其他劑組合使用時提供治療優勢。The present invention pertains to compounds of formula (I) and pharmaceutically acceptable salts thereof, which are particularly useful in the treatment of cancer, and when administered alone with each agent for treatment, when used in combination with one or more other agents as described herein Provides a therapeutic advantage.

甲硫胺酸腺苷轉移酶(MAT) (亦稱為S-腺苷甲硫胺酸合成酶)係一種細胞酶，其催化自甲硫胺酸及ATP合成S-腺苷甲硫胺酸(SAM或AdoMet)；認為該催化係甲硫胺酸循環之速率限制步驟。SAM係多胺生物合成中之丙胺基供體，DNA甲基化之主要甲基供體，且參與基因轉錄及細胞增殖及次級代謝物之產生。Methionine adenosyltransferase (MAT) (also known as S-adenosylmethionine synthase) is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine ( SAM or AdoMet); the catalysis is believed to be the rate limiting step of the methionine cycle. SAM is a propylamine group donor in polyamine biosynthesis, the main methyl group donor for DNA methylation, and is involved in gene transcription, cell proliferation, and production of secondary metabolites.

命名為MAT1A及MAT2A之兩種基因分別編碼兩種不同之催化MAT同功型。第三種基因MAT2B編碼MAT2A調節次單元。MAT1A在成人肝中特異性表現，而MAT2A廣泛分佈。因為MAT同功型之催化動力學及調節性質不同，所以表現MAT1A之細胞具有比表現MAT2A之細胞高得多的SAM含量。已發現MAT2A啟動子之低甲基化及組蛋白乙醯化引起MAT2A表現之上調。The two genes, designated MAT1A and MAT2A, encode two different catalytic MAT isoforms, respectively. The third gene, MAT2B, encodes the MAT2A regulatory subunit. MAT1A is specifically expressed in the adult liver, whereas MAT2A is widely distributed. Because of the different catalytic kinetics and regulatory properties of the MAT isoforms, cells expressing MATlA have much higher SAM content than cells expressing MAT2A. Hypomethylation and histone acetylation of the MAT2A promoter have been found to cause upregulation of MAT2A expression.

在肝細胞癌(HCC)中，發生MAT1A之下調及MAT2A之上調，此稱為MAT1A:MAT2A開關。伴隨MAT2B上調之該開關導致SAM含量降低，此為肝細胞提供生長優勢。因為MAT2A在促進肝細胞生長中發揮重要作用，所以該MAT2A係抗腫瘤療法之標靶。最近研究已顯示藉由使用小干擾RNA沉默在肝細胞中大體上抑制生長並誘導細胞凋亡。參見例如T. Li等人，J. Cancer 7(10) (2016) 1317-1327。In hepatocellular carcinoma (HCC), downregulation of MAT1A and upregulation of MAT2A occurs, which is referred to as the MAT1A:MAT2A switch. This switch, accompanied by upregulation of MAT2B, results in a reduction in SAM content, which provides a growth advantage for hepatocytes. Because MAT2A plays an important role in promoting hepatocyte growth, this MAT2A is a target for anti-tumor therapy. Recent studies have shown that growth is largely inhibited and apoptosis is induced in hepatocytes by silencing using small interfering RNAs. See, eg, T. Li et al, J. Cancer 7(10) (2016) 1317-1327.

一些MTAP缺陷型癌細胞系對MAT2A抑制特別敏感。Marjon等人(Cell Reports 15(3) (2016) 574-587)。MTAP (甲硫腺苷磷酸化酶)係廣泛表現於正常組織中之酶，其催化將甲硫腺苷(MTA)轉化為腺嘌呤及5-甲基硫核糖-1-磷酸。補救腺嘌呤以產生單磷酸腺苷，並將該5-甲基硫核糖-1-磷酸轉化為甲硫胺酸及甲酸。因為此補救途徑，所以當(例如)用抗代謝藥(諸如L-亞硝基羥基丙胺酸(L-alanosine))阻斷從頭嘌呤合成時，MTA可充當替代嘌呤來源。Some MTAP-deficient cancer cell lines are particularly sensitive to MAT2A inhibition. Marjon et al. (Cell Reports 15(3) (2016) 574-587). MTAP (methylthioadenosine phosphorylase) is an enzyme widely expressed in normal tissues that catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Adenine is salvaged to produce adenosine monophosphate, and this 5-methylthioribose-1-phosphate is converted to methionine and formic acid. Because of this salvage pathway, MTA can serve as an alternative source of purines when de novo purine synthesis is blocked, for example, with antimetabolites such as L-alanosine.

MAT2A在缺乏MTAP缺失之另外癌症(包括肝細胞癌及白血病)中失調。J. Cai等人，Cancer Res. 58 (1998) 1444-1450；T. S. Jani等人，Cell. Res. 19 (2009) 358-369。MAT2A表現經由RNA干擾之沉默在數種癌症模型中導致抗增殖效應。H. Chen等人，Gastroenterology 133 (2007) 207-218；Q. Liu等人Hepatol. Res. 37 (2007) 376-388。MAT2A is dysregulated in additional cancers that lack MTAP deletion, including hepatocellular carcinoma and leukemia. J. Cai et al, Cancer Res. 58 (1998) 1444-1450; T. S. Jani et al, Cell. Res. 19 (2009) 358-369. Silencing of MAT2A expression via RNA interference leads to antiproliferative effects in several cancer models. H. Chen et al., Gastroenterology 133 (2007) 207-218; Q. Liu et al. Hepatol. Res. 37 (2007) 376-388.

許多人類及鼠惡性細胞缺乏MTAP活性。MTAP缺陷不僅存在於組織培養細胞中，且該缺陷亦存在於原發性白血病、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤(non-Hodgkin lymphoma)及間皮瘤中。編碼人類MTAP之基因定位至人類染色體9p上之區域9p21。此區域亦含有腫瘤抑制基因p16INK4A (亦稱為CDKN2A)及pl5INK4B。此等基因編碼p16及p15，其等分別係細胞週期蛋白D依賴性激酶cdk4及cdk6之抑制劑。Many human and murine malignant cells lack MTAP activity. MTAP deficiency is not only present in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, In head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma. The gene encoding human MTAP is mapped to region 9p21 on human chromosome 9p. This region also contains the tumor suppressor genes pl6INK4A (also known as CDKN2A) and pl5INK4B. These genes encode p16 and p15, which are inhibitors of the cyclin D-dependent kinases cdk4 and cdk6, respectively.

或者p16INK4A轉錄本可為剪接成編碼pl4ARF之轉錄本之選擇型閱讀框(alternative reading frame；ARF)。pl4ARF結合至MDM2並防止p53降解(Pomerantz等人(1998) Cell 92:713-723)。9p21染色體區域因為其經常在各種癌症(包括白血病、NSLC、胰臟癌、神經膠質瘤、黑色素瘤及間皮瘤)中純合缺失而受關注。該等缺失通常不活化超過一個基因。例如，Cairns等人((1995) Nat. Gen. 11:210-212)報導在研究超過500種原發性腫瘤後，此等腫瘤中鑑定之幾乎所有缺失均涉及含有MTAP、pl4ARF及P16INK4A之170 kb區域。Carson等人(WO 99/67634)報導腫瘤發展階段與編碼MTAP之基因及編碼p16之基因之純合性損失之間存在關聯。例如，據報導MTAP基因而非p16INK4A之缺失指示癌症處於早期發展階段，而據報導編碼p16及MTAP之基因之缺失指示癌症處於腫瘤發展之更晚期階段。在一些骨肉瘤病患中，MTAP基因在診斷時存在，但在稍後時間點缺失(Garcia-Castellano等人，Clin. Cancer Res. 8(3) 2002 782-787)。Alternatively, the pl6INK4A transcript may be an alternative reading frame (ARF) spliced into the transcript encoding pl4ARF. pl4ARF binds to MDM2 and prevents p53 degradation (Pomerantz et al. (1998) Cell 92:713-723). The 9p21 chromosomal region is of interest because of its frequent homozygous deletions in various cancers, including leukemia, NSLC, pancreatic cancer, glioma, melanoma, and mesothelioma. Such deletions generally do not activate more than one gene. For example, Cairns et al. ((1995) Nat. Gen. 11:210-212) reported that after studying more than 500 primary tumors, nearly all deletions identified in these tumors involved 170 containing MTAP, p14ARF, and P16INK4A kb area. Carson et al. (WO 99/67634) reported an association between stage of tumor development and loss of homozygosity for the gene encoding MTAP and the gene encoding p16. For example, deletion of the MTAP gene, but not p16INK4A, has been reported to indicate that the cancer is in an early stage of development, while deletion of the genes encoding p16 and MTAP has been reported to indicate that the cancer is in a more advanced stage of tumor development. In some patients with osteosarcoma, the MTAP gene is present at diagnosis but deleted at a later time point (Garcia-Castellano et al., Clin. Cancer Res. 8(3) 2002 782-787).

以WO 2018/045071公開之國際申請案第PCT/US2017/049439號描述新穎之MAT2A抑制劑，包括3-(環己-1-烯-1-基)-6-(4-甲氧基苯基)-2-苯基-5-(吡啶-3-基胺基)吡唑并[1,5-a]嘧啶-7(4H)-酮，如藉由生物化學及細胞分析證實。International Application No. PCT/US2017/049439 published in WO 2018/045071 describes novel MAT2A inhibitors, including 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl) )-2-phenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one, as confirmed by biochemical and cellular analysis.

在一些態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係PARP抑制劑、Chk1抑制劑、MDM2抑制劑、低甲基化劑、mTOR抑制劑、ATM抑制劑、CDK 4/6抑制劑、BCL-2抑制劑、PRMT5抑制劑或PRMT1抑制劑。在一些態樣中，該癌症係MTAP缺陷型。在其他態樣中，該癌症係MTAP野生型。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑(諸如化合物I)所致之S-腺苷甲硫胺酸(SAM)減少產生反應之癌症。In some aspects, the present invention relates to methods for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a PARP inhibitor, a Chk1 inhibitor, an MDM2 inhibitor, a hypomethylating agent, an mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a BCL -2 inhibitor, PRMT5 inhibitor or PRMT1 inhibitor. In some aspects, the cancer is MTAP deficient. In other aspects, the cancer is MTAP wild-type. In yet other embodiments, the cancer is one that responds to a decrease in S-adenosylmethionine (SAM) due to administration of a MAT2A inhibitor, such as Compound I.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括向該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係抗代謝藥、極光(Aurora)抑制劑、DNA交聯劑或微管穩定劑；其中該癌症係MTAP野生型。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is an antimetabolite, an Aurora inhibitor, a DNA cross-linking agent or a microtubule stabilizer; wherein the cancer is MTAP wild-type.

在又其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與治療有效量之式(I)化合物或其醫藥上可接受之鹽；其中該癌症係AML。In yet other aspects, the present invention relates to a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the cancer Department of AML.

在又其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與治療有效量之式(I)化合物或其醫藥上可接受之鹽；及治療有效量之BCL-2抑制劑，其中該癌症係AML。In yet other aspects, the present invention relates to a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and the therapeutically effective amount of a BCL-2 inhibitor, wherein the cancer is AML.

在又其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與(1)治療有效量之式(I)化合物或其醫藥上可接受之鹽；(2)治療有效量之BCL-2抑制劑；及(3)治療有效量之低甲基化劑；其中該癌症係AML。In yet other aspects, the present invention relates to a method for treating cancer in a patient comprising administering to the patient (1) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) a therapeutically effective amount of a BCL-2 inhibitor; and (3) a therapeutically effective amount of a hypomethylating agent; wherein the cancer is AML.

相關申請案之交叉參考Cross-references to related applications

本申請案主張2020年8月12日申請之美國臨時專利申請案第63/064,786號之權益，該案之全部內容係以引用之方式併入本文中。This application claims the benefit of US Provisional Patent Application No. 63/064,786, filed August 12, 2020, which is incorporated herein by reference in its entirety.

化合物3-(環己-1-烯-1-基)-6-(4-甲氧基苯基)-2-苯基-5-(吡啶-3-基胺基)吡唑并[1,5-a]嘧啶-7(4H)-酮在本文中可稱為式(I)化合物：

Figure 02_image002
式(I)。 為方便參考，該化合物亦可稱為化合物I。本發明亦包括式(I)化合物之醫藥上可接受之鹽。 Compound 3-(Cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-3-ylamino)pyrazolo[1, 5-a]pyrimidin-7(4H)-one may be referred to herein as a compound of formula (I):
Figure 02_image002
Formula (I). For ease of reference, this compound may also be referred to as Compound I. The present invention also includes the pharmaceutically acceptable salts of the compounds of formula (I).

如本文使用，術語「MTAP缺陷型癌症」係指缺乏代謝酶甲基硫腺苷磷酸化酶(MTAP)活性之癌症。因此，MTAP缺陷型癌症係與表現MTAP基因失敗相關聯之癌症，該失敗可歸因於MTAP基因之缺乏、MTAP蛋白表現之缺乏或MTAP受質MTA之積聚。在一些實施例中，術語「MTAP缺陷型」稱為「MTAP缺失」及/或「MTAP無效」且因此該等三種術語可互換使用。例如在一些實施例中，「MTAP缺失」或「MTAP無效」癌症係指MTAP基因之染色體丟失，導致MTAP DNA之全部或部分丟失，此阻止功能性全長MTAP蛋白之表現。在一些實施例中，MTAP缺陷型癌症係其中缺乏或缺失CDKN2A基因之基因座之癌症。在一些實施例中，MTAP缺陷型癌症係其中已缺失、丟失或另外去活化MTAP基因的癌症。在一些實施例中，MTAP缺陷型癌症係其中MTAP蛋白功能具有相較於野生型MTAP基因經減少的功能或經功能受損之癌症。因此，在本發明之一實施例中，提供一種用於治療個體之MTAP缺陷型癌症之方法，其中相較於其中MTAP基因及/或蛋白存在且充分發揮作用之相應癌症，或相較於具有野生型MTAP基因之相應癌症，該MTAP缺陷型癌症具有以下中之至少一者之特徵：(i) MTAP表現之減少或缺乏；(ii) MTAP基因之缺乏；及(iii) MTAP蛋白之功能減少。As used herein, the term "MTAP-deficient cancer" refers to a cancer that lacks the activity of the metabolic enzyme methylthioadenosine phosphorylase (MTAP). Thus, MTAP-deficient cancers are cancers that are associated with a failure to express the MTAP gene, which failure can be attributed to a lack of the MTAP gene, a lack of expression of the MTAP protein, or the accumulation of MTAP-receptor MTA. In some embodiments, the term "MTAP-deficient" is referred to as "MTAP-deficient" and/or "MTAP-null" and thus these three terms are used interchangeably. For example, in some embodiments, "MTAP-deficient" or "MTAP-null" cancers refer to chromosomal loss of the MTAP gene, resulting in total or partial loss of MTAP DNA, which prevents the expression of functional full-length MTAP protein. In some embodiments, the MTAP-deficient cancer is one in which the locus of the CDKN2A gene is absent or deleted. In some embodiments, the MTAP-deficient cancer is one in which the MTAP gene has been deleted, lost, or otherwise deactivated. In some embodiments, the MTAP-deficient cancer is a cancer in which MTAP protein function has reduced or impaired function compared to the wild-type MTAP gene. Accordingly, in one embodiment of the present invention, there is provided a method for treating an MTAP-deficient cancer in an individual in comparison to a corresponding cancer in which the MTAP gene and/or protein is present and fully functioning, or in comparison to having The corresponding cancer of the wild-type MTAP gene, the MTAP-deficient cancer is characterized by at least one of: (i) reduced or absent expression of MTAP; (ii) lack of the MTAP gene; and (iii) reduced function of the MTAP protein .

如本文使用，術語「野生型MTAP癌症」或「MTAP野生型癌症」係指其中代謝酶甲基硫腺苷磷酸化酶(MTAP)之活性完整之癌症。因此，野生型MTAP癌症係表現MTAP基因及MTAP蛋白之癌症。As used herein, the term "wild-type MTAP cancer" or "MTAP wild-type cancer" refers to a cancer in which the activity of the metabolic enzyme methylthioadenosine phosphorylase (MTAP) is intact. Thus, wild-type MTAP cancers are cancers that express the MTAP gene and MTAP protein.

如本文使用，術語「對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症」係指當投與MAT2A抑制劑後降低S-腺苷甲硫胺酸(SAM)含量時，抑制生長之癌症As used herein, the term "cancer responsive to SAM reduction due to administration of a MAT2A inhibitor" refers to a cancer that inhibits growth when S-adenosylmethionine (SAM) levels are reduced following administration of a MAT2A inhibitor cancer

如本文使用，「醫藥上可接受之鹽」係本文描述之化合物之醫藥上可接受之有機或無機酸或鹼鹽。代表性醫藥上可接受之鹽包括(例如)鹼金屬鹽、鹼土鹽、銨鹽、水溶性及水不溶性鹽，諸如乙酸鹽、胺芪磺酸鹽(4,4-二胺基二苯乙烯-2,2-二磺酸鹽)、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、丁酸鹽、鈣鹽、依地酸鈣、樟腦磺酸鹽、碳酸鹽、氯化物、檸檬酸鹽、克拉維酸鹽(clavulariate)、二鹽酸鹽、依地酸鹽、乙二磺酸鹽、依託酸鹽、乙磺酸鹽、富馬酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、麩胺酸鹽、羥乙醯對胺基苯胂酸鹽、六氟磷酸鹽、己基間苯二酚鹽、海巴(hydrabamine)、氫溴酸鹽、鹽酸鹽、羥萘甲酸鹽、碘化物、異硫氰酸鹽、乳酸鹽、乳糖酸鹽、月桂酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、溴甲烷、硝酸甲酯、硫酸甲酯、黏液酸鹽(mucate)、萘磺酸鹽、硝酸鹽、N-甲基葡糖胺銨鹽、3-羥基-2-萘甲酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽(1,1-亞甲基-雙-2-羥基-3-萘甲酸鹽、依伯酸鹽(einbonate))、泛酸鹽、磷酸鹽/二磷酸鹽、苦味酸鹽、聚半乳醣醛酸鹽、丙酸鹽、對甲苯磺酸鹽、水楊酸鹽、硬脂酸鹽、次乙酸鹽、琥珀酸鹽、硫酸鹽、磺基水楊酸鹽、蘇拉酸鹽(suramate)、鞣酸鹽、酒石酸鹽、茶氯酸鹽(teoclate)、甲苯磺酸鹽、三乙基碘及戊酸鹽。醫藥上可接受之鹽可在其結構中具有多於一個帶電原子。在此情況下，該醫藥上可接受之鹽可具有多個相對離子。因此，醫藥上可接受之鹽可具有一或多個帶電原子及/或一或多個相對離子。As used herein, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, for example, alkali metal, alkaline earth, ammonium, water-soluble and water-insoluble salts such as acetate, amidostilbenesulfonate (4,4-diaminostilbene- 2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulphate, bitartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camphor sulfonate, carbonate, chloride, citrate, clavularianate, dihydrochloride, edetate, ethanedisulfonate, etorate, ethanesulfonate, fumarate acid salt, glucoheptonate, gluconate, glutamate, hydroxyacetate p-aminophenylarsonate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromic acid Salt, hydrochloride, xinafoate, iodide, isothiocyanate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, Methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, Oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / Diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, hypoacetate, succinate, sulfate, sulfo Salicylate, suramate, tannate, tartrate, teoclate, tosylate, triethyl iodide and valerate. A pharmaceutically acceptable salt may have more than one charged atom in its structure. In this case, the pharmaceutically acceptable salt may have multiple opposing ions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ions.

術語「治療(treat、treating及treatment)」係指疾病或與疾病相關聯之症狀之改善或根除。在某些實施例中，此等術語係指由對患有疾病之病患投與一或多種預防劑或治療劑而引起之最小化該疾病之傳播(例如，轉移)或最小化該疾病之惡化。The terms "treat, treating, and treatment" refer to amelioration or eradication of a disease or symptoms associated with a disease. In certain embodiments, these terms refer to minimizing the spread (eg, metastasis) of the disease or minimizing the effects of the disease caused by the administration of one or more prophylactic or therapeutic agents to a patient suffering from the disease. deterioration.

術語「預防(prevent、preventing及prevention)」係指由投與預防劑或治療劑而引起之預防或延遲病患疾病之發作、復發或傳播。The terms "prevent, preventing, and prevention" refer to the prevention or delay of the onset, recurrence, or spread of a disease in a patient caused by the administration of a prophylactic or therapeutic agent.

術語「有效量」係指式(I)化合物或其他活性成分足以提供治療或預防疾病之治療或預防益處或延遲或最小化與疾病相關聯之症狀之量。此外，關於式(I)化合物之治療有效量意謂治療劑單獨或與其他療法之組合提供治療或預防疾病之治療益處之量。該等術語可包含改善整體療法、減少或避免疾病之症狀或病因，或增強與另一治療劑之治療效用或協同效應之量。The term "effective amount" refers to an amount of a compound of formula (I) or other active ingredient sufficient to provide a therapeutic or prophylactic benefit for treating or preventing a disease or to delay or minimize symptoms associated with a disease. Furthermore, by reference to a therapeutically effective amount of a compound of formula (I) is meant that amount of the therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in treating or preventing the disease. These terms may encompass amounts that improve overall therapy, reduce or avoid symptoms or causes of disease, or enhance the therapeutic or synergistic effect of another therapeutic agent.

「病患」或「個體」包括動物，諸如人類、奶牛、馬、綿羊、羔羊、豬、小雞、火雞、鵪鶉、貓、狗、小鼠、大鼠、兔或豚鼠。根據一些實施例，該動物係哺乳動物諸如非靈長類動物及靈長類動物(例如，猴及人類)。在一個實施例中，病患係人類，諸如人類新生兒、嬰兒、兒童、青少年或成人。在一個實施例中，該病患係兒科病患，包括自出生至十八歲之病患。在一個實施例中，該病患係青少年病患，其中青少年係介於12歲至17歲之間的病患。在一個實施例中，該病患係成人病患。在又另一實施例中，根據適用之監管指南，諸如，舉例而言，由美國FDA規定之指南，使用指示病患年齡之術語，其中新生兒係出生至一月齡，嬰兒係一個月至兩歲；兒童係兩歲至十二歲；及青少年係十二歲至十六歲。A "patient" or "individual" includes animals such as humans, cows, horses, sheep, lambs, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs. According to some embodiments, the fauna is mammals such as non-primates and primates (eg, monkeys and humans). In one embodiment, the patient is a human, such as a human neonate, infant, child, adolescent or adult. In one embodiment, the patient is a pediatric patient, including patients from birth to eighteen years of age. In one embodiment, the patient is an adolescent patient, wherein the adolescent is a patient between the ages of 12 and 17 years. In one embodiment, the patient is an adult patient. In yet another embodiment, terms indicative of patient age are used in accordance with applicable regulatory guidelines, such as, for example, guidelines prescribed by the US FDA, where neonates are born to one month of age and infants are one month to one month of age. Two years old; children two to twelve years old; and adolescents twelve to sixteen years old.

「抑制劑」意謂阻止或減小給定蛋白質活性之化合物。"Inhibitor" means a compound that prevents or reduces the activity of a given protein.

投與之式(I)化合物或其醫藥上可接受之鹽之「治療有效量」可由考量(諸如發揮細胞毒性效應或抑制MAT2A活性或兩者必需之最小量)控制。此量可低於對正常細胞或病患(作為整體)有毒之量。一般而言，欲投與之式(I)化合物或其醫藥上可接受之鹽之初始治療有效量係在約0.01至約200 mg/kg或約0.1至約20 mg/kg病患體重/天之範圍內，及典型初始範圍係約0.3至約15 mg/kg/天。經口單位劑型(諸如錠劑及膠囊)可含有約1 mg至約1000 mg式(I)化合物或其醫藥上可接受之鹽。在另一實施例中，此等劑型可含有約20 mg至約800 mg式(I)化合物或其醫藥上可接受之鹽。在又另一實施例中，此等劑型可含有約20 mg、25 mg、50 mg、100 mg、150 mg、200 mg、250 mg、300 mg、350 mg、400 mg、450 mg、500 mg、550 mg、600 mg、650 mg、700 mg、750 mg或800 mg式(I)化合物或其醫藥上可接受之鹽。在又其他實施例中，此等劑型可含有介於約100 mg至約300 mg之間的式(I)化合物或其醫藥上可接受之鹽。在又其他實施例中，此等劑型可含有約100 mg、約125 mg、約150 mg、約175 mg、約200 mg、約225 mg、約250 mg、約275 mg或約300 mg。在其他實施例中，此等劑型可含有100 mg、125 mg、150 mg、175 mg、200 mg、225 mg、250 mg、275 mg或300 mg。在另一態樣中，將該劑量量測為對應於游離形式當量之式(I)化合物之量的量。如本文使用，「游離形式當量」係指無論以游離形式(或游離鹼形式)，或以鹽存在，均對應於給定量之式(I)游離形式化合物之式(I)化合物之數量。在另一態樣中，投與治療有效量之式(I)化合物或其醫藥上可接受之鹽包括其中於特定週期及持續時間內投與組合(即式(I)化合物或其藥用鹽及一或多種另外治療劑)之情況。在一些實施例中，包含式(I)化合物或其藥用鹽之劑型係每天一次給藥。在其他實施例中，該劑型係一天兩次給藥。如本文使用，術語「每日給藥」意謂於二十四週期內發生之式(I)化合物或其醫藥上可接受之鹽之特定給藥時間表。The "therapeutically effective amount" of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered can be governed by considerations such as the minimum amount necessary to exert a cytotoxic effect or inhibit MAT2A activity, or both. This amount can be lower than that which is toxic to normal cells or the patient (as a whole). In general, the initial therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to be administered will be from about 0.01 to about 200 mg/kg or from about 0.1 to about 20 mg/kg of patient body weight per day and a typical initial range is about 0.3 to about 15 mg/kg/day. Oral unit dosage forms such as lozenges and capsules may contain from about 1 mg to about 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, such dosage forms may contain from about 20 mg to about 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In yet another embodiment, such dosage forms may contain about 20 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In yet other embodiments, such dosage forms may contain between about 100 mg to about 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In yet other embodiments, such dosage forms may contain about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In other embodiments, such dosage forms may contain 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, or 300 mg. In another aspect, the dosage amount is measured as an amount corresponding to the amount of the compound of formula (I) equivalent in free form. As used herein, "free form equivalent" refers to the amount of a compound of formula (I) that corresponds to a given amount of a compound of formula (I) in free form, whether in free form (or free base form), or in the presence of a salt. In another aspect, administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, includes wherein the combination (ie, a compound of formula (I) or a pharmaceutically acceptable salt thereof) is administered for a specified period and duration and one or more additional therapeutic agents). In some embodiments, a dosage form comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered once daily. In other embodiments, the dosage form is administered twice a day. As used herein, the term "daily dosing" means a specific dosing schedule of a compound of formula (I) or a pharmaceutically acceptable salt thereof that occurs over a twenty-four week period.

在一些態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係PARP抑制劑、Chk1抑制劑、MDM2抑制劑、低甲基化劑、mTOR抑制劑、ATM抑制劑、CDK 4/6抑制劑、BCL-2抑制劑、PRMT5抑制劑或PRMT1抑制劑。將瞭解治療有效量之治療劑可由一或多種活性醫藥成分(例如，一或多種PARP抑制劑或PARP抑制劑及Chk1抑制劑)提供。In some aspects, the present invention relates to methods for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a PARP inhibitor, a Chk1 inhibitor, an MDM2 inhibitor, a hypomethylating agent, an mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a BCL -2 inhibitor, PRMT5 inhibitor or PRMT1 inhibitor. It will be appreciated that a therapeutically effective amount of a therapeutic agent can be provided by one or more active pharmaceutical ingredients (eg, one or more PARP inhibitors or a PARP inhibitor and a Chk1 inhibitor).

在一些態樣中，本發明係關於用於治療癌症之方法。在一些實施例中，該癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤或間皮瘤。In some aspects, the invention relates to methods for treating cancer. In some embodiments, the cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney carcinoma, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, or mesothelioma .

在一些實施例中，癌症係MTAP缺陷型癌症。在一些實施例中，該MTAP缺陷型癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤或間皮瘤。In some embodiments, the cancer is an MTAP-deficient cancer. In some embodiments, the MTAP-deficient cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma or mesothelioma.

在其他實施例中，MTAP缺陷型癌症係MTAP缺陷型肺癌、MTAP缺陷型胰臟癌、MTAP缺陷型食道癌、MTAP缺陷型結腸直腸癌、MTAP缺陷型腎癌或MTAP缺陷型白血病(諸如急性骨髓性白血病(AML))。In other embodiments, the MTAP-deficient cancer is MTAP-deficient lung cancer, MTAP-deficient pancreatic cancer, MTAP-deficient esophageal cancer, MTAP-deficient colorectal cancer, MTAP-deficient kidney cancer, or MTAP-deficient leukemia (such as acute myeloid leukemia (AML)).

在一些實施例中，MTAP缺陷型癌症係MTAP缺陷型肺癌，諸如NSCLC。In some embodiments, the MTAP-deficient cancer is an MTAP-deficient lung cancer, such as NSCLC.

在其他實施例中，MTAP缺陷型癌症係MTAP缺陷型胰臟癌，諸如PDAC。In other embodiments, the MTAP-deficient cancer is an MTAP-deficient pancreatic cancer, such as PDAC.

在其他實施例中，MTAP缺陷型癌症係MTAP缺陷型食道癌。In other embodiments, the MTAP-deficient cancer is an MTAP-deficient esophageal cancer.

在其他實施例中，MTAP缺陷型癌症係MTAP缺陷型結腸直腸癌。In other embodiments, the MTAP-deficient cancer is MTAP-deficient colorectal cancer.

在其他實施例中，MTAP缺陷型癌症係MTAP缺陷型腎癌。In other embodiments, the MTAP-deficient cancer is MTAP-deficient renal carcinoma.

在一些實施例中，MTAP缺陷型癌症係MTAP缺陷型白血病，諸如急性骨髓性白血病(AML)。In some embodiments, the MTAP-deficient cancer is an MTAP-deficient leukemia, such as acute myeloid leukemia (AML).

在其他實施例中，癌症係MTAP野生型癌症。在一些實施例中，該MTAP野生型癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤或間皮瘤。In other embodiments, the cancer is an MTAP wild-type cancer. In some embodiments, the MTAP wild-type cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma or mesothelioma.

在其他實施例中，MTAP野生型癌症係MTAP野生型肺癌、MTAP野生型胰臟癌、MTAP野生型食道癌、MTAP野生型結腸直腸癌、MTAP野生型腎癌或MTAP野生型白血病(諸如急性骨髓性白血病(AML))。In other embodiments, the MTAP wild-type cancer is MTAP wild-type lung cancer, MTAP wild-type pancreatic cancer, MTAP wild-type esophageal cancer, MTAP wild-type colorectal cancer, MTAP wild-type kidney cancer, or MTAP wild-type leukemia (such as acute myeloid leukemia (AML)).

在一些實施例中，MTAP野生型癌症係MTAP野生型肺癌，諸如NSCLC。In some embodiments, the MTAP wild-type cancer is an MTAP wild-type lung cancer, such as NSCLC.

在其他實施例中，MTAP野生型癌症係MTAP野生型胰臟癌，諸如PDAC。In other embodiments, the MTAP wild-type cancer is an MTAP wild-type pancreatic cancer, such as PDAC.

在其他實施例中，MTAP野生型癌症係MTAP野生型食道癌。In other embodiments, the MTAP wild-type cancer is an MTAP wild-type esophageal cancer.

在其他實施例中，MTAP野生型癌症係MTAP野生型結腸直腸癌。In other embodiments, the MTAP wild-type cancer is MTAP wild-type colorectal cancer.

在其他實施例中，MTAP野生型癌症係MTAP野生型腎癌。In other embodiments, the MTAP wild-type cancer is MTAP wild-type renal carcinoma.

在一些實施例中，MTAP野生型癌症係MTAP野生型白血病，諸如急性骨髓性白血病(AML)。In some embodiments, the MTAP wild-type cancer is an MTAP wild-type leukemia, such as acute myeloid leukemia (AML).

在其他實施例中，癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。在一些實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤或間皮瘤。In other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. In some embodiments, the cancer that responds to the reduction in SAM due to administration of the MAT2A inhibitor is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreas cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, Soft tissue sarcoma, non-Hodgkin's lymphoma, or mesothelioma.

在其他實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係肺癌、胰臟癌、食道癌、結腸直腸癌、腎癌或白血病(諸如急性骨髓性白血病(AML))。In other embodiments, the cancer that responds to the reduction in SAM due to administration of the MAT2A inhibitor is lung cancer, pancreatic cancer, esophageal cancer, colorectal cancer, kidney cancer, or leukemia (such as acute myeloid leukemia (AML)) .

在一些實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係肺癌，諸如NSCLC。In some embodiments, the cancer that responds to the reduction in SAM due to administration of the MAT2A inhibitor is lung cancer, such as NSCLC.

在其他實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係胰臟癌，諸如PDAC。In other embodiments, the cancer that responds to the reduction in SAM due to administration of the MAT2A inhibitor is pancreatic cancer, such as PDAC.

在其他實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係食道癌。In other embodiments, the cancer that responds to the reduction in SAM due to administration of the MAT2A inhibitor is esophageal cancer.

在其他實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係結腸直腸癌。In other embodiments, the cancer that responds to the reduction in SAM due to administration of the MAT2A inhibitor is colorectal cancer.

在其他實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係腎癌。In other embodiments, the cancer responsive to the reduction in SAM due to administration of the MAT2A inhibitor is renal cancer.

在一些實施例中，對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症係白血病，諸如急性骨髓性白血病(AML)。In some embodiments, the cancer line leukemia, such as acute myeloid leukemia (AML), responds to a reduction in SAM due to administration of a MAT2A inhibitor.

在一些態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係PARP抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「PARP抑制劑」係指抑制酶聚ADP核糖聚合酶(PARP)活性之化合物。In some aspects, the present invention relates to methods for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a PARP inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, a "PARP inhibitor" refers to a compound that inhibits the activity of the enzyme poly ADP ribose polymerase (PARP).

在本發明之一些方法中，PARP抑制劑係奧拉帕尼(Olaparib) (AZD2281；可以LYNPARZA®獲得)、維利帕利布(Veliparib) (ABT-888)、磷酸魯卡帕裡布(Rucaparib) (AG-014699)、樟腦磺酸魯卡帕裡布(Rucaparib)(可以RUBRACA®獲得)、他拉唑帕尼(Talazoparib) (BMN 673)、甲苯磺酸他拉唑帕尼(Talazoparib)(可以TALZENNA®獲得)、AG-14361、INO-1001 (3-胺基苯甲醯胺)、A-966492、PJ34 HCl、尼拉帕裡布(Niraparib) (MK-4827)、UPF 1069、ME0328、RK-287107、帕米帕利布(Pamiparib) (BGB-290)、NMS-P118、E7449、吡啶甲醯胺(Picolinamide)、苯甲醯胺、甲苯磺酸尼拉帕裡布(Niraparib) (MK-4827) (可以ZEJULA®獲得)、NU1025、尼帕利布(Iniparib) (BSI-201)、AZD2461、BGP-15 2HCl、XAV-939、4-羥基喹唑啉、NVP-TNKS656、MN 64、G007-LK、E7106或CEP 9722；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the PARP inhibitor is Olaparib (AZD2281; available as LYNPARZA®), Veliparib (ABT-888), Rucaparib phosphate ) (AG-014699), Rucaparib (available as RUBRACA®), Talazoparib (BMN 673), Talazoparib tosylate ( Available as TALZENNA®), AG-14361, INO-1001 (3-aminobenzamide), A-966492, PJ34 HCl, Niraparib (MK-4827), UPF 1069, ME0328, RK-287107, Pamiparib (BGB-290), NMS-P118, E7449, Picolinamide, Benzylamide, Niraparib Tosylate (MK -4827) (available as ZEJULA®), NU1025, Iniparib (BSI-201), AZD2461, BGP-15 2HCl, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656, MN 64, G007-LK, E7106 or CEP 9722; or a pharmaceutically acceptable salt of the enumerated compounds.

在一些實施例中，PARP抑制劑係奧拉帕尼或其醫藥上可接受之鹽。In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係維利帕利布或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is veliparib or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係魯卡帕裡布或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係磷酸鹽。在其他實施例中，該鹽係樟腦磺酸鹽。In other embodiments, the PARP inhibitor is lucaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is a phosphate. In other embodiments, the salt is camphorsulfonate.

在其他實施例中，PARP抑制劑係他拉唑帕尼(BMN 673)或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係甲苯磺酸鹽。In other embodiments, the PARP inhibitor is tarazopanib (BMN 673) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is tosylate.

在其他實施例中，PARP抑制劑係AG-14361或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is AG-14361 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係INO-1001 (3-胺基苯甲醯胺)或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is INO-1001 (3-aminobenzamide) or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係A-966492或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is A-966492 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係PJ34或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，PJ34 HCl。In other embodiments, the PARP inhibitor is PJ34 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, PJ34 HCl.

在其他實施例中，PARP抑制劑係尼拉帕裡布(MK-4827)或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係甲苯磺酸鹽。In other embodiments, the PARP inhibitor is niraparib (MK-4827) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is tosylate.

在其他實施例中，PARP抑制劑係UPF 1069。In other embodiments, the PARP inhibitor is UPF 1069.

在其他實施例中，PARP抑制劑係ME0328或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is ME0328 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係RK-28710或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is RK-28710 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係帕米帕利布(BGB-290)或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is pamiparib (BGB-290) or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係NMS-P118或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is NMS-P118 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係E7449或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is E7449 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係吡啶甲醯胺或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is picolinamide or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係苯甲醯胺。In other embodiments, the PARP inhibitor is benzamide.

在其他實施例中，PARP抑制劑係NU1025或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is NU1025 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係AZD2461或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is AZD2461 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係BGP-15或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係2HCl鹽，即，BGP-15 2HCl。In other embodiments, the PARP inhibitor is BGP-15 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the 2HCl salt, ie, BGP-15 2HCl.

在其他實施例中，PARP抑制劑係XAV-939或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is XAV-939 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係4-羥基喹唑啉或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is 4-hydroxyquinazoline or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係NVP-TNKS656或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is NVP-TNKS656 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係MN 64。In other embodiments, the PARP inhibitor is MN64.

在其他實施例中，PARP抑制劑係G007-LK或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is G007-LK or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係CEP 9722或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is CEP 9722 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係E7016或其醫藥上可接受之鹽。In other embodiments, the PARP inhibitor is E7016 or a pharmaceutically acceptable salt thereof.

在其他實施例中，PARP抑制劑係尼帕利布。In other embodiments, the PARP inhibitor is niparib.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係Chk1抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「Chk1抑制劑」係指抑制酶檢查點激酶1 (Chk1，一種在人類中由CHEK1基因編碼之絲胺酸/蘇胺酸特異性蛋白激酶)之活性之化合物。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a Chk1 inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, "Chk1 inhibitor" refers to a compound that inhibits the activity of the enzymatic checkpoint kinase 1 (Chk1, a serine/threonine specific protein kinase encoded by the CHEK1 gene in humans).

在本發明之一些方法中，Chk1抑制劑係AZD7762、拉布塞蒂布(Rabusertib) (LY2603618)、MK-8776 (SCH 900776)、CHIR-124、PF-477736、VX-803 (M4344)、GDC-0575 (ARRY-575)、SAR-020106、CCT245737、PD0166285或普雷沙替鹽酸鹽(Prexasertib HCl) (LY2606368)，或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the Chk1 inhibitor is AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC -0575 (ARRY-575), SAR-020106, CCT245737, PD0166285, or Prexasertib HCl (LY2606368), or a pharmaceutically acceptable salt of the enumerated compounds.

在其他實施例中，Chk1抑制劑係AZD7762或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is AZD7762 or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係拉布塞蒂布(LY2603618)或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is Labsetib (LY2603618) or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係MK-8776 (SCH 900776)或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is MK-8776 (SCH 900776) or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係CHIR-124或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is CHIR-124 or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係PF-477736或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is PF-477736 or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係VX-803 (M4344)或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is VX-803 (M4344) or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係GDC-0575 (ARRY-575)或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is GDC-0575 (ARRY-575) or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係SAR-020106或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is SAR-020106 or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係CCT245737或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is CCT245737 or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係PD0166285或其醫藥上可接受之鹽。In other embodiments, the Chk1 inhibitor is PD0166285 or a pharmaceutically acceptable salt thereof.

在其他實施例中，Chk1抑制劑係普雷沙替或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽。In other embodiments, the Chk1 inhibitor is presacitide or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is an HCl salt.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係MDM2抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「MDM2抑制劑」係指抑制酶鼠雙微粒體2 (MDM2)之活性之化合物，該抑制包括藉由結合至MDM2蛋白並防止其結合至腫瘤抑制蛋白p53。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is an MDM2 inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, an "MDM2 inhibitor" refers to a compound that inhibits the activity of the enzyme murine double microsome 2 (MDM2), including by binding to the MDM2 protein and preventing its binding to the tumor suppressor protein p53.

在本發明之一些方法中，MDM2抑制劑係努特林(Nutlin)-3、NSC 207895、努特林-3a、努特林-3b、MX69、NVP-CGM097、MI-773 (SAR405838)、伊達沙努特林(Idasanutlin) (RG-7388)、RG-7112、HDM201 (西雷馬德林(Siremadlin))、YH239-EE、(-)-小白菊內酯(Parthenolide)或色地美坦(Serdemetan) (JNJ-26854165)；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the MDM2 inhibitor is Nutlin-3, NSC 207895, Nutlin-3a, Nutlin-3b, MX69, NVP-CGM097, MI-773 (SAR405838), Ida Idasanutlin (RG-7388), RG-7112, HDM201 (Siremadlin), YH239-EE, (-)-Parthenolide or Serdemetan (JNJ-26854165); or pharmaceutically acceptable salts of the listed compounds.

在其他實施例中，MDM2抑制劑係努特林-3或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is Nutrin-3 or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係NSC 207895或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is NSC 207895 or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係努特林-3a或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is Nutrin-3a or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係努特林-3b或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is Nutrin-3b or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係MX69或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is MX69 or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係NVP-CGM097或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is NVP-CGM097 or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係MI-773 (SAR405838)或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is MI-773 (SAR405838) or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係伊達沙努特林(RG-7388)或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is Idasanutrine (RG-7388) or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係RG-7112或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is RG-7112 or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係HDM201 (西雷馬德林)或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is HDM201 (cremadelin) or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係YH239-EE或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is YH239-EE or a pharmaceutically acceptable salt thereof.

在其他實施例中，MDM2抑制劑係(-)-小白菊內酯。In other embodiments, the MDM2 inhibitor is (-)-parthenolide.

在其他實施例中，MDM2抑制劑係色地美坦(JNJ-26854165)或其醫藥上可接受之鹽。In other embodiments, the MDM2 inhibitor is cerdemestane (JNJ-26854165) or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之MTAP缺陷型癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係低甲基化劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「低甲基化劑」係指抑制DNA之甲基化之化合物。In other aspects, the invention relates to methods for treating MTAP-deficient cancer in a patient, comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable amount thereof and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a hypomethylating agent. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, a "hypomethylating agent" refers to a compound that inhibits the methylation of DNA.

在本發明之一些方法中，低甲基化劑係地西他濱(Decitabine) (可以DACOGEN®獲得)、阿紮胞苷(Azacitidine) (5-氮胞苷；可以VIDAZA®獲得)、瓜地西他濱(Guadecitabine) (SGI-110)、RG108、硫鳥嘌呤(Thioguanine)、西布拉林(Zebularine)、SGI-1027、CM272、2'-脫氧-5-氟胞苷、普魯卡因胺鹽酸鹽(Procainamide HCl)、Bobcat339鹽酸鹽、γ-米糠醇(Gamma-Oryzanol)、β-檜酚酮(β-thujaplicin)、CP-4200、納奈黴素A (Nanaomycin A)或(-)-表沒食子兒茶素沒食子酸酯(Epigallocatechin Gallate)；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the hypomethylating agent is Decitabine (available as DACOGEN®), Azacitidine (5-azacytidine; available as VIDAZA®), Guadecitabine (SGI-110), RG108, Thioguanine, Zebularine, SGI-1027, CM272, 2'-deoxy-5-fluorocytidine, procaine Amine hydrochloride (Procainamide HCl), Bobcat339 hydrochloride, Gamma-Oryzanol, β-thujaplicin, CP-4200, Nanaomycin A or ( -) - Epigallocatechin Gallate; or a pharmaceutically acceptable salt of the enumerated compounds.

在其他實施例中，低甲基化劑係地西他濱或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is decitabine or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係阿紮胞苷(5-氮胞苷)或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is azacitidine (5-azacytidine) or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係瓜地西他濱(SGI-110)或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is citradecitabine (SGI-110) or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係RG108或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is RG108 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係硫鳥嘌呤或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is thioguanine or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係西布拉林或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is sibraline or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係SGI-1027或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is SGI-1027 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係CM272或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is CM272 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係2'-脫氧-5-氟胞苷或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is 2'-deoxy-5-fluorocytidine or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係普魯卡因胺或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，普魯卡因胺鹽酸鹽。In other embodiments, the hypomethylating agent is procainamide or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, procainamide hydrochloride.

在其他實施例中，低甲基化劑係Bobcat339鹽酸鹽或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is Bobcat 339 hydrochloride or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係γ-米糠醇或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is gamma-ricefuryl alcohol or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係β-檜酚酮或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is β-cynophenol ketone or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係CP-4200或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is CP-4200 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係納奈黴素A或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is nanamycin A or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係(-)-表沒食子兒茶素沒食子酸酯或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係mTOR抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「mTOR抑制劑」係指抑制稱為雷帕黴素(rapamycin)之哺乳動物標靶(mTOR)之絲胺酸/蘇胺酸特異性蛋白激酶之活性之化合物。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is an mTOR inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, an "mTOR inhibitor" refers to a compound that inhibits the activity of the serine/threonine specific protein kinase known as the mammalian target of rapamycin (mTOR).

在本發明之一些方法中，mTOR抑制劑係達克利司(Dactolisib) (BEZ235)、雷帕黴素(Rapamycin) (西羅莫司(Sirolimus)；可以RAPAMUNE®獲得)、依維莫司(Everolimus) (RAD001)、AZD8055、替西羅莫司(Temsirolimus) (CCI-779)、PI-103、KU-0063794、托基尼布(Torkinib) (PP242)、利達福莫司(Ridaforolimus) (地福莫司(Deforolimus)、MK-8669)、沙帕舍替(Sapanisertib) (MLN0128)、沃他利司(Voxtalisib) (XL765)類似物、通潤1 (Torin 1)、奧帕利司(Omipalisib) (GSK2126458)、OSI-027、PF-04691502、阿托利司(Apitolisib) (GDC-0980)、GSK1059615、吉托利司(Gedatolisib) (PKI-587)、WYE-354、維妥色替(Vistusertib) (AZD2014)、通潤2、WYE-125132 (WYE-132)、PP121、WYE-687、WAY-600、ETP-46464、GDC-0349、XL388、GNE-477、比米利司(Bimiralisib) (PQR309)、SF2523、CZ415、派克利塞(Paxalisib) (GDC-0084)、CC-115、奧納塔塞爾蒂布(Onatasertib) (CC 223)、沃他利司 (XL765)、佐他莫司(Zotarolimus) (ABT-578)、他克莫司(Tacrolimus) (FK506)、馬來酸BGT226 (馬來酸NVP-BGT226)、帕羅米德529 (Palomid 529) (P529)、LY3023414 (沙托利塞(Samotolisib))或大黃酸(Chrysophanic Acid)；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the mTOR inhibitor is Dactolisib (BEZ235), Rapamycin (Sirolimus; available as RAPAMUNE®), Everolimus ) (RAD001), AZD8055, Temsirolimus (CCI-779), PI-103, KU-0063794, Torkinib (PP242), Ridaforolimus (Deformol) Deforolimus, MK-8669), Sapanisertib (MLN0128), Voxtalisib (XL765) analogs, Torin 1, Omipalisib ( GSK2126458), OSI-027, PF-04691502, Apitolisib (GDC-0980), GSK1059615, Gedatolisib (PKI-587), WYE-354, Vistusertib (AZD2014), Tongrun 2, WYE-125132 (WYE-132), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, Bimiralisib (PQR309) , SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Voltaris (XL765), Zotarolimus ) (ABT-578), Tacrolimus (FK506), BGT226 maleate (NVP-BGT226 maleate), Palomid 529 (Palomid 529) (P529), LY3023414 (Satolix) (Samotolisib)) or rhein (Chrysophanic Acid); or a pharmaceutically acceptable salt of the enumerated compounds.

在一些實施例中，mTOR抑制劑係依維莫司。In some embodiments, the mTOR inhibitor is everolimus.

在其他實施例中，mTOR抑制劑係達克利司(BEZ235)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is daclix (BEZ235) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係雷帕黴素(西羅莫司)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is rapamycin (sirolimus) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係AZD8055或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is AZD8055 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係替西羅莫司(CCI-779)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is temsirolimus (CCI-779) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係PI-103或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is PI-103 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係KU-0063794或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is KU-0063794 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係托基尼布(PP242)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is tokinib (PP242) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係利達福莫司(地福莫司、MK-8669)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is Ridafolimus (Deformolimus, MK-8669) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係沙帕舍替(MLN0128)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is sapassatide (MLN0128) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係沃他利司(XL765)類似物或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is a Votalis (XL765) analog or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係通潤1或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is Tongrun 1 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係奧帕利司(GSK2126458)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is Opallix (GSK2126458) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係OSI-027或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is OSI-027 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係PF-04691502或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is PF-04691502 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係阿托利司(GDC-0980)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is atolix (GDC-0980) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係GSK1059615或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is GSK1059615 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係吉托利司(PKI-587)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is gitolix (PKI-587) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係WYE-354或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is WYE-354 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係維妥色替(AZD2014)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is vertoxetir (AZD2014) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係通潤2或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is Tongrun 2 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係WYE-125132 (WYE-132)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is WYE-125132 (WYE-132) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係PP121或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is PP121 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係WYE-687或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is WYE-687 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係WAY-600或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is WAY-600 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係ETP-46464或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is ETP-46464 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係GDC-0349或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is GDC-0349 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係XL388或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is XL388 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係GNE-477或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is GNE-477 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係比米利司(PQR309)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is bimirex (PQR309) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係SF2523或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is SF2523 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係CZ415或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is CZ415 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係派克利塞(GDC-0084)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is Paclitaxel (GDC-0084) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係CC-115或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is CC-115 or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係奧納塔塞爾蒂布(CC 223)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is Onatasertib (CC 223) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係沃他利司(XL765)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is Votalis (XL765) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係佐他莫司(ABT-578)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is zotarolimus (ABT-578) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係他克莫司(FK506)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is tacrolimus (FK506) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係馬來酸BGT226 (馬來酸NVP-BGT226)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is BGT226 maleate (NVP-BGT226 maleate) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係帕羅米德529 (P529)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is paromide 529 (P529) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係LY3023414 (沙托利塞)或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is LY3023414 (Satolix) or a pharmaceutically acceptable salt thereof.

在其他實施例中，mTOR抑制劑係大黃酸或其醫藥上可接受之鹽。In other embodiments, the mTOR inhibitor is rhein or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係ATM抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「ATM抑制劑」係指抑制稱為共濟失調毛細血管擴張突變(ATM)激酶之絲胺酸/蘇胺酸蛋白激酶之活性之化合物。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is an ATM inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, an "ATM inhibitor" refers to a compound that inhibits the activity of a serine/threonine protein kinase known as ataxia telangiectasia mutant (ATM) kinase.

在本發明之一些方法中，ATM抑制劑係KU-55933、KU-60019、渥曼青黴素(Wortmannin)、通潤2、CP-466722、ETP-46464、CGK 733、AZ32、AZD1390、AZ31或AZD0156；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the ATM inhibitor is KU-55933, KU-60019, Wortmannin, Tongrun 2, CP-466722, ETP-46464, CGK 733, AZ32, AZD1390, AZ31 or AZD0156; or a pharmaceutically acceptable salt of the enumerated compounds.

在一些實施例中，ATM抑制劑係KU-55933或其醫藥上可接受之鹽。In some embodiments, the ATM inhibitor is KU-55933 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係KU-60019或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is KU-60019 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係渥曼青黴素或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is wortmannin or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係通潤2或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is Tongrun 2 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係CP-466722或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is CP-466722 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係ETP-46464或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is ETP-46464 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係CGK 733或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is CGK 733 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係AZ32或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is AZ32 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係AZD1390或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is AZD1390 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係AZ31或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is AZ31 or a pharmaceutically acceptable salt thereof.

在其他實施例中，ATM抑制劑係AZD0156或其醫藥上可接受之鹽。In other embodiments, the ATM inhibitor is AZD0156 or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係CDK 4/6抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「CDK 4/6抑制劑」係指抑制細胞週期蛋白依賴性激酶4及/或6 (CDK4/6)之活性之化合物。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a CDK 4/6 inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, a "CDK 4/6 inhibitor" refers to a compound that inhibits the activity of cyclin-dependent kinases 4 and/or 6 (CDK4/6).

在本發明之一些方法中，CDK 4/6抑制劑係帕博西尼(Palbociclib) (PD-0332991；可以IBRANCE®獲得)、帕博西尼鹽酸鹽(PD-0332991)、氟哌啶醇(Flavopiridol) (夫拉平度(Alvocidib))、AT7519、氟哌啶醇鹽酸鹽、JNJ-7706621、PHA-793887、羥乙基磺酸帕博西尼(PD0332991)、甲磺酸阿貝西利(abemaciclib mesylate) (LY2835219)、BMS-265246、米爾西利(Milciclib) (PHA-848125)、R547、利維昔布鹽酸鹽(Riviciclib hydrochloride) (P276-00)、MC180295、G1T38、阿貝西利(可以VERZENIO®獲得)、ON123300、AT7519 HCl、嘌呤醇A (Purvalanol A)、SU9516、瑞波西尼(Ribociclib) (LEE011)或BSJ-03-123；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the CDK 4/6 inhibitor is Palbociclib (PD-0332991; available as IBRANCE®), Palbociclib hydrochloride (PD-0332991), haloperidol (Flavopiridol) (Alvocidib), AT7519, Haloperidol hydrochloride, JNJ-7706621, PHA-793887, Palbociclib isethionate (PD0332991), Abescilli mesylate ( abemaciclib mesylate) (LY2835219), BMS-265246, Milciclib (PHA-848125), R547, Riviciclib hydrochloride (P276-00), MC180295, G1T38, abemaciclib (can VERZENIO®), ON123300, AT7519 HCl, Purvalanol A, SU9516, Ribociclib (LEE011) or BSJ-03-123; or a pharmaceutically acceptable salt of the enumerated compounds.

在其他實施例中，CDK 4/6抑制劑係帕博西尼(PD-0332991)或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，帕博西尼鹽酸鹽。在其他實施例中，該醫藥上可接受之鹽係羥乙基磺酸鹽，即，羥乙基磺酸帕博西尼。In other embodiments, the CDK 4/6 inhibitor is palbociclib (PD-0332991) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, palbociclib hydrochloride. In other embodiments, the pharmaceutically acceptable salt is the isethionate salt, ie, palbociclib isethionate.

在其他實施例中，CDK 4/6抑制劑係氟哌啶醇(夫拉平度)或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，氟哌啶醇鹽酸鹽。In other embodiments, the CDK 4/6 inhibitor is haloperidol (flapin) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, haloperidol hydrochloride.

在其他實施例中，CDK 4/6抑制劑係AT7519或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，AT7519 HCl。In other embodiments, the CDK 4/6 inhibitor is AT7519 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, AT7519 HCl.

在其他實施例中，CDK 4/6抑制劑係JNJ-7706621或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is JNJ-7706621 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係PHA-793887或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is PHA-793887 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係阿貝西利或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係甲磺酸鹽，即，甲磺酸阿貝西利(LY2835219)。In other embodiments, the CDK 4/6 inhibitor is abeccillin or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the mesylate salt, ie, abeccillin mesylate (LY2835219).

在其他實施例中，CDK 4/6抑制劑係BMS-265246或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is BMS-265246 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係米爾西利(PHA-848125)或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is Mircili (PHA-848125) or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係R547或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is R547 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係利維昔布或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，利維昔布鹽酸鹽(P276-00)。In other embodiments, the CDK 4/6 inhibitor is rivecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, rivecoxib hydrochloride (P276-00).

在其他實施例中，CDK 4/6抑制劑係MC180295或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is MC180295 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係G1T38或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is G1T38 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係ON123300或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is ON123300 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係嘌呤醇A或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is Purinol A or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係SU9516或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is SU9516 or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係瑞波西尼(LEE011)或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is ribociclib (LEE011) or a pharmaceutically acceptable salt thereof.

在其他實施例中，CDK 4/6抑制劑係BSJ-03-123或其醫藥上可接受之鹽。In other embodiments, the CDK 4/6 inhibitor is BSJ-03-123 or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係BCL-2抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，術語「BCL-2」係指由BCL2基因編碼之調節蛋白。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a BCL-2 inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, the term "BCL-2" refers to the regulatory protein encoded by the BCL2 gene.

在一些實施例中，BCL-2抑制劑係ABT-737、納維托克(Navitoclax) (ABT-263)、甲磺酸奧巴克拉(Obatoclax Mesylate) (GX15-070)、TW-37、維奈托克(Venetoclax) (ABT-199；可以VENCLEXTA®獲得)、AT101、HA14-1、沙布托克(Sabutoclax)、S55746或藤黃酸(Gambogic Acid)；或所列舉化合物之醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW-37, vitamin Venetoclax (ABT-199; available as VENCLEXTA®), AT101, HA14-1, Sabutoclax, S55746, or Gambogic Acid; or a pharmaceutically acceptable compound of the enumerated compounds of salt.

在一些實施例中，BCL-2抑制劑係ABT-737或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is ABT-737 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係納維托克(ABT-263)或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is Navitas (ABT-263) or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係甲磺酸奧巴克拉(GX15-070)或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is obaclava mesylate (GX15-070) or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係TW-37或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is TW-37 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係維奈托克(ABT-199)或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is venetoclax (ABT-199) or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係AT101或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is AT101 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係HA14-1或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is HA14-1 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係沙布托克或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is sabutok, or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係S55746或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is S55746 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係藤黃酸或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is gambogic acid or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係PRMT5抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「PRMT5抑制劑」係指抑制酶蛋白精胺酸甲基轉移酶5之活性之化合物。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a PRMT5 inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, a "PRMT5 inhibitor" refers to a compound that inhibits the activity of the enzyme protein arginine methyltransferase 5.

在本發明之一些方法中，PRMT5抑制劑係JNJ-64619178 (AGI-931)、HLCL-61、GSK591、EPZ015666(GSK3235025)、GSK3326595 (EPZ015938；AGI-219)；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the PRMT5 inhibitor is JNJ-64619178 (AGI-931), HLCL-61, GSK591, EPZ015666 (GSK3235025), GSK3326595 (EPZ015938; AGI-219); or a pharmaceutically acceptable compound of the enumeration of salt.

在一些實施例中，PRMT5抑制劑係JNJ-64619178或其醫藥上可接受之鹽。In some embodiments, the PRMT5 inhibitor is JNJ-64619178 or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT5抑制劑係HLCL-61或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，HLCL-61 HCL。In some embodiments, the PRMT5 inhibitor is HLCL-61 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, HLCL-61 HCL.

在一些實施例中，PRMT5抑制劑係GSK591或其醫藥上可接受之鹽。In some embodiments, the PRMT5 inhibitor is GSK591 or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT5抑制劑係EPZ015666(GSK3235025)或其醫藥上可接受之鹽。In some embodiments, the PRMT5 inhibitor is EPZ015666 (GSK3235025) or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT5抑制劑係GSK3326595 (EPZ015938)或其醫藥上可接受之鹽。In some embodiments, the PRMT5 inhibitor is GSK3326595 (EPZ015938) or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT5抑制劑係AGI-219或其醫藥上可接受之鹽。In some embodiments, the PRMT5 inhibitor is AGI-219 or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT5抑制劑係AGI-931或其醫藥上可接受之鹽。In some embodiments, the PRMT5 inhibitor is AGI-931 or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係PRMT1抑制劑。在一些實施例中，該癌症係MTAP缺陷型癌症。在其他實施例中，該癌症係MTAP野生型癌症。在又其他實施例中，該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。如本文使用，「PRMT1抑制劑」係指抑制酶蛋白精胺酸甲基轉移酶1之活性之化合物。In other aspects, the invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a PRMT1 inhibitor. In some embodiments, the cancer is an MTAP-deficient cancer. In other embodiments, the cancer is an MTAP wild-type cancer. In yet other embodiments, the cancer is one that responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, "PRMT1 inhibitor" refers to a compound that inhibits the activity of the enzyme protein arginine methyltransferase 1.

在本發明之一些方法中，PRMT1抑制劑係GSK3368715 (EPZ019997)、C7280948、EPZ020411 2HCl、MS023或AMI-1；或所列舉化合物之醫藥上可接受之鹽。In some methods of the invention, the PRMT1 inhibitor is GSK3368715 (EPZ019997), C7280948, EPZ020411 2HCl, MS023 or AMI-1; or a pharmaceutically acceptable salt of the enumerated compounds.

在一些實施例中，PRMT1抑制劑係GSK3368715 (EPZ019997)或其醫藥上可接受之鹽。In some embodiments, the PRMT1 inhibitor is GSK3368715 (EPZ019997) or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT1抑制劑係C7280948或其醫藥上可接受之鹽。In some embodiments, the PRMT1 inhibitor is C7280948 or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT1抑制劑係EPZ020411或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，EPZ020411 2HCl。In some embodiments, the PRMT1 inhibitor is EPZ020411 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, EPZ020411 2HCl.

在一些實施例中，PRMT1抑制劑係MS023或其醫藥上可接受之鹽。In some embodiments, the PRMT1 inhibitor is MS023 or a pharmaceutically acceptable salt thereof.

在一些實施例中，PRMT1抑制劑係AMI-1或其醫藥上可接受之鹽。In some embodiments, the PRMT1 inhibitor is AMI-1 or a pharmaceutically acceptable salt thereof.

在其他態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；及(b)治療有效量之治療劑，其中該治療劑係抗代謝藥、極光抑制劑、DNA交聯劑或微管穩定劑；其中該癌症係MTAP野生型。In other aspects, the present invention relates to a method for treating cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is an antimetabolite, an aurora inhibitor, a DNA cross-linking agent, or a microtubule stabilizer; wherein the cancer is MTAP wild-type.

在一些實施例中，MTAP野生型癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤或間皮瘤。In some embodiments, the MTAP wild-type cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer , kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma or skin tumor.

在一些實施例中，治療劑係抗代謝藥。如本文使用，術語「抗代謝藥」係指抑制DNA合成之化合物。In some embodiments, the therapeutic agent is an antimetabolite. As used herein, the term "antimetabolite" refers to a compound that inhibits DNA synthesis.

在一些實施例中，抗代謝藥係5-氟尿嘧啶(5-FU)、6-巰嘌呤(6-MP)、卡培他濱(Capecitabine) (Xeloda®)、阿糖胞苷(Cytarabine) (Ara-C®)、氟尿苷(Floxuridine)、氟達拉濱(Fludarabine)、吉西他濱(Gemzar®)、羥基脲(Hydroxycarbamide)、胺甲喋呤(Methotrexate)、培美曲塞(Alimta®)或光胺喋呤(Phototrexate)，或所列舉化合物之醫藥上可接受之鹽。In some embodiments, the antimetabolite is 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), Capecitabine (Xeloda®), Cytarabine (Ara -C®), Floxuridine, Fludarabine (Fludarabine), Gemcitabine (Gemzar®), Hydroxycarbamide (Hydroxycarbamide), Methotrexate (Methotrexate), Pemetrexed (Alimta®) or Light Amopterin (Phototrexate), or a pharmaceutically acceptable salt of the enumerated compounds.

在一些實施例中，抗代謝藥係培美曲塞或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係二鈉鹽。培美曲塞係(2S)-2-[[4-[2-(2-胺基-4-氧負離子基-7H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲醯基]胺基]戊二酸，其具有以下結構：

Figure 02_image004
。 In some embodiments, the antimetabolite is pemetrexed or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the disodium salt. Pemetrexed is (2S)-2-[[4-[2-(2-amino-4-oxanionyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] Benzyl]amino]glutaric acid, which has the following structure:
Figure 02_image004
.

如本文使用，術語「培美曲塞」亦包括其醫藥上可接受之鹽，諸如可以ALIMTA®獲得之培美曲塞二鈉。As used herein, the term "pemetrexed" also includes pharmaceutically acceptable salts thereof, such as pemetrexed disodium, available as ALIMTA®.

在一些實施例中，抗代謝藥係胺甲喋呤或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係二鈉鹽。In some embodiments, the antimetabolite is methotrexate or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the disodium salt.

在一些實施例中，抗代謝藥係光胺喋呤或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is photoaminopterin or a pharmaceutically acceptable salt thereof.

在一些實施例中，抗代謝藥係6-巰嘌呤(6-MP)或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is 6-mercaptopurine (6-MP) or a pharmaceutically acceptable salt thereof.

在一些實施例中，抗代謝藥係5-氟尿嘧啶或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is 5-fluorouracil or a pharmaceutically acceptable salt thereof.

在一些實施例中，抗代謝藥係卡培他濱或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is capecitabine or a pharmaceutically acceptable salt thereof.

在一些實施例中，抗代謝藥係吉西他濱或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽。In some embodiments, the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is an HCl salt.

在一些實施例中，抗代謝藥係氟達拉濱或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is fludarabine or a pharmaceutically acceptable salt thereof.

在一些實施例中，抗代謝藥係氟尿苷或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is floxuridine or a pharmaceutically acceptable salt thereof.

在一些實施例中，抗代謝藥係羥基脲或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is hydroxyurea or a pharmaceutically acceptable salt thereof.

在一些實施例中，抗代謝藥係阿糖胞苷或其醫藥上可接受之鹽。In some embodiments, the antimetabolite is cytarabine or a pharmaceutically acceptable salt thereof.

在其他實施例中，治療劑係極光抑制劑。如本文使用，術語「極光抑制劑」係指抑制酶極光激酶之化合物。In other embodiments, the therapeutic agent is an aurora inhibitor. As used herein, the term "Aurora inhibitor" refers to a compound that inhibits the enzyme Aurora kinase.

在一些實施例中，極光抑制劑係阿立塞替(Alisertib) (MLN8237)、托紮舍替(Tozasertib) (VX-680、MK-0457)、巴拉塞替(Barasertib) (AZD1152-HQPA)、ZM 447439、MLN8054、達魯舍替(Danusertib) (PHA-739358)、AT9283、JNJ-7706621、赫斯帕汀(Hesperadin)、極光A抑制劑I (TC-S 7010)、KW-2449、SNS-314、ENMD-2076、PHA-680632、MK-5108 (VX-689)、CYC116、AMG-900、PF-03814735、CCT129202、GSK1070916、TAK-901、CCT137690、MK-8745、ENMD-2076 L-(+)-酒石酸、極光激酶抑制劑III、甲磺酸SNS-314、BI-847325、逆轉素(Reversine)或ABT-348，或所列舉化合物之醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is Alisertib (MLN8237), Tozasertib (VX-680, MK-0457), Barasertib (AZD1152-HQPA) , ZM 447439, MLN8054, Danusertib (PHA-739358), AT9283, JNJ-7706621, Hesperadin, Aurora A inhibitor I (TC-S 7010), KW-2449, SNS -314, ENMD-2076, PHA-680632, MK-5108 (VX-689), CYC116, AMG-900, PF-03814735, CCT129202, GSK1070916, TAK-901, CCT137690, MK-8745, ENMD-2076 L-( +)-tartaric acid, Aurora kinase inhibitor III, methanesulfonic acid SNS-314, BI-847325, Reversine or ABT-348, or a pharmaceutically acceptable salt of the enumerated compounds.

在一些實施例中，極光抑制劑係阿立塞替(MLN8237)或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is ariceptir (MLN8237) or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係托紮舍替(VX-680, MK-0457)或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is tozasertib (VX-680, MK-0457) or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係巴拉塞替(AZD1152-HQPA)或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is balacetib (AZD1152-HQPA) or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係ZM 447439或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is ZM 447439 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係MLN8054或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is MLN8054 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係達魯舍替(PHA-739358)或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is darusetib (PHA-739358) or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係AT9283或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is AT9283 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係JNJ-7706621或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is JNJ-7706621 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係赫斯帕汀或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is Hespatin or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係極光A抑制劑I (TC-S 7010)或其醫藥上可接受之鹽。In some embodiments, the Aurora inhibitor is Aurora A inhibitor I (TC-S 7010) or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係KW-2449或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is KW-2449 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係SNS-314或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is SNS-314 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係ENMD-2076或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is ENMD-2076 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係PHA-680632或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is PHA-680632 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係MK-5108 (VX-689)或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is MK-5108 (VX-689) or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係CYC116或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is CYC116 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係AMG-900或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is AMG-900 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係PF-03814735或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is PF-03814735 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係CCT129202或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is CCT129202 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係GSK1070916或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is GSK1070916 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係TAK-901或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is TAK-901 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係CCT137690或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is CCT137690 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係MK-8745或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is MK-8745 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係ENMD-2076 L-(+)-酒石酸或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is ENMD-2076 L-(+)-tartaric acid or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係極光激酶抑制劑III或其醫藥上可接受之鹽。In some embodiments, the Aurora inhibitor is Aurora Kinase Inhibitor III or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係甲磺酸SNS-314或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is SNS-314 mesylate or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係BI-847325或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is BI-847325 or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係逆轉素或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is reversin or a pharmaceutically acceptable salt thereof.

在一些實施例中，極光抑制劑係ABT-348或其醫藥上可接受之鹽。In some embodiments, the aurora inhibitor is ABT-348 or a pharmaceutically acceptable salt thereof.

在其他實施例中，治療劑係微管穩定劑。如本文使用，術語「微管穩定劑」係指促進微管蛋白聚合、穩定微管蛋白及/或防止微管蛋白解聚之化合物。In other embodiments, the therapeutic agent is a microtubule stabilizer. As used herein, the term "microtubule stabilizer" refers to a compound that promotes tubulin polymerization, stabilizes tubulin, and/or prevents tubulin depolymerization.

在一些實施例中，微管穩定劑係紫杉醇(paclitaxel)、白蛋白結合型紫杉醇(nab-paclitaxel)、多西他賽(docetaxel)、埃坡黴素A (Epothilone A)或埃坡黴素B。In some embodiments, the microtubule stabilizer is paclitaxel, nab-paclitaxel, docetaxel, Epothilone A, or Epothilone B .

在一些實施例中，微管穩定劑係紫杉醇。In some embodiments, the microtubule stabilizer is paclitaxel.

在其他實施例中，微管穩定劑係白蛋白結合型紫杉醇。In other embodiments, the microtubule stabilizer is nab-paclitaxel.

在一些實施例中，微管穩定劑係多西他賽。In some embodiments, the microtubule stabilizer is docetaxel.

在一些實施例中，微管穩定劑係埃坡黴素A。In some embodiments, the microtubule stabilizer is epothilone A.

在一些實施例中，微管穩定劑係埃坡黴素B。In some embodiments, the microtubule stabilizer is epothilone B.

在其他實施例中，治療劑係DNA交聯劑。如本文使用，術語「DNA交聯劑」係指交聯DNA股之化合物。In other embodiments, the therapeutic agent is a DNA cross-linking agent. As used herein, the term "DNA cross-linking agent" refers to a compound that cross-links DNA strands.

在一些實施例中，DNA交聯劑係順鉑(cisplatin)。In some embodiments, the DNA cross-linking agent is cisplatin.

在一些實施例中，DNA交聯劑係卡鉑(carboplatin)。In some embodiments, the DNA cross-linking agent is carboplatin.

在其他實施例中，DNA交聯劑係奧沙利鉑(oxaliplatin)。In other embodiments, the DNA cross-linking agent is oxaliplatin.

在本發明之一些方法中，MTAP野生型癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤或間皮瘤。In some methods of the invention, the MTAP wild-type cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), Bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma or mesothelioma.

在一些實施例中，MTAP野生型癌症係肺癌、胰臟癌、食道癌、結腸直腸癌、腎癌、白血病或骨髓性白血病(AML)。In some embodiments, the MTAP wild-type cancer is lung cancer, pancreatic cancer, esophageal cancer, colorectal cancer, kidney cancer, leukemia, or myeloid leukemia (AML).

在一些態樣中，本發明係關於用於治療病患之癌症之方法，其包括對該病患投與治療有效量之式(I)化合物或其醫藥上可接受之鹽；其中該癌症係急性骨髓性白血病(AML)。在一些實施例中，該AML係MTAP缺陷型。在其他實施例中，該AML係MTAP野生型。在又其他實施例中，該AML對由於投與MAT2A抑制劑所致之SAM減少產生反應。In some aspects, the present invention relates to methods for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; wherein the cancer is Acute myeloid leukemia (AML). In some embodiments, the AML is MTAP deficient. In other embodiments, the AML is MTAP wild-type. In yet other embodiments, the AML responds to a reduction in SAM due to administration of a MAT2A inhibitor.

在一些實施例中，治療病患之癌症之方法包括藉由投與治療有效量之式(I)化合物或其醫藥上可接受之鹽治療急性骨髓性白血病(AML)，且進一步包括向該病患投與BCL-2抑制劑。在一些實施例中，該AML係MTAP缺陷型。在其他實施例中，該AML係MTAP野生型。在又其他實施例中，該AML對由於投與MAT2A抑制劑所致之SAM減少產生反應。如本文使用，術語「BCL-2」係指由BCL2基因編碼之調節蛋白。In some embodiments, the method of treating cancer in a patient comprises treating acute myeloid leukemia (AML) by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and further comprising treating the disease Patients were administered a BCL-2 inhibitor. In some embodiments, the AML is MTAP deficient. In other embodiments, the AML is MTAP wild-type. In yet other embodiments, the AML responds to a reduction in SAM due to administration of a MAT2A inhibitor. As used herein, the term "BCL-2" refers to the regulatory protein encoded by the BCL2 gene.

在一些實施例中，BCL-2抑制劑係ABT-737、納維托克(ABT-263)、甲磺酸奧巴克拉(GX15-070)、TW-37、維奈托克(ABT-199；可以VENCLEXTA®獲得)、AT101、HA14-1、沙布托克、S55746或藤黃酸；或所列舉化合物之醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is ABT-737, Navitas (ABT-263), Obacela mesylate (GX15-070), TW-37, Venetoclax (ABT-199) ; available as VENCLEXTA®), AT101, HA14-1, Sabutok, S55746, or gambogic acid; or a pharmaceutically acceptable salt of the enumerated compounds.

在一些實施例中，BCL-2抑制劑係ABT-737或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is ABT-737 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係納維托克(ABT-263)或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is Navitas (ABT-263) or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係甲磺酸奧巴克拉(GX15-070)或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is obaclava mesylate (GX15-070) or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係TW-37或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is TW-37 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係維奈托克(ABT-199)或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is venetoclax (ABT-199) or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係AT101或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is AT101 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係HA14-1或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is HA14-1 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係沙布托克或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is sabutok, or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係S55746或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is S55746 or a pharmaceutically acceptable salt thereof.

在一些實施例中，BCL-2抑制劑係藤黃酸或其醫藥上可接受之鹽。In some embodiments, the BCL-2 inhibitor is gambogic acid or a pharmaceutically acceptable salt thereof.

在一些實施例中，治療急性骨髓性白血病(AML)之方法包括對該病患投與治療有效量：(1)式(I)化合物或其醫藥上可接受之鹽，(2)治療有效量之BCL-2抑制劑，及(3)低甲基化劑。在一些實施例中，該AML係MTAP缺陷型。在其他實施例中，該AML係MTAP野生型。在又其他實施例中，該AML對由於投與MAT2A抑制劑所致之SAM減少產生反應。In some embodiments, a method of treating acute myeloid leukemia (AML) comprises administering to the patient a therapeutically effective amount of: (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (2) a therapeutically effective amount BCL-2 inhibitors, and (3) hypomethylating agents. In some embodiments, the AML is MTAP deficient. In other embodiments, the AML is MTAP wild-type. In yet other embodiments, the AML responds to a reduction in SAM due to administration of a MAT2A inhibitor.

在此等方法之一些實施例中，低甲基化劑係地西他濱、阿紮胞苷(5-氮胞苷)、瓜地西他濱(SGI-110)、RG108、硫鳥嘌呤、西布拉林、SGI-1027、CM272、2'-脫氧-5-氟胞苷、普魯卡因胺鹽酸鹽、Bobcat339鹽酸鹽、γ-米糠醇、β-檜酚酮、CP-4200、納奈黴素A或(-)-表沒食子兒茶素沒食子酸酯；或所列舉化合物之醫藥上可接受之鹽。In some embodiments of these methods, the hypomethylating agent is decitabine, azacitidine (5-azacytidine), citrucitabine (SGI-110), RG108, thioguanine, Sibraline, SGI-1027, CM272, 2'-deoxy-5-fluorocytidine, procainamide hydrochloride, Bobcat339 hydrochloride, γ-ricefuryl alcohol, β-cypress ketone, CP-4200 , nanamycin A, or (-)-epigallocatechin gallate; or a pharmaceutically acceptable salt of the enumerated compounds.

在其他實施例中，低甲基化劑係地西他濱或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is decitabine or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係阿紮胞苷(5-氮胞苷)或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is azacitidine (5-azacytidine) or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係瓜地西他濱(SGI-110)或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is citradecitabine (SGI-110) or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係RG108或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is RG108 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係硫鳥嘌呤或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is thioguanine or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係西布拉林或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is sibraline or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係SGI-1027或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is SGI-1027 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係CM272或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is CM272 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係2'-脫氧-5-氟胞苷或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is 2'-deoxy-5-fluorocytidine or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係普魯卡因胺或其醫藥上可接受之鹽。在一些實施例中，該醫藥上可接受之鹽係HCl鹽，即，普魯卡因胺鹽酸鹽。In other embodiments, the hypomethylating agent is procainamide or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HCl salt, ie, procainamide hydrochloride.

在其他實施例中，低甲基化劑係Bobcat339鹽酸鹽或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is Bobcat 339 hydrochloride or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係γ-米糠醇或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is gamma-ricefuryl alcohol or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係β-檜酚酮或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is β-cynophenol ketone or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係CP-4200或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is CP-4200 or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係納奈黴素A或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is nanamycin A or a pharmaceutically acceptable salt thereof.

在其他實施例中，低甲基化劑係(-)-表沒食子兒茶素沒食子酸酯或其醫藥上可接受之鹽。In other embodiments, the hypomethylating agent is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt thereof.

在一些實施例中，本發明係關於藉由投與以下治療急性骨髓性白血病(AML)之方法：(a)治療有效量之式(I)化合物或其醫藥上可接受之鹽；(b)治療有效量之維奈托克或其醫藥上可接受之鹽；及(c)治療有效量之阿紮胞苷或其醫藥上可接受之鹽。在一些實施例中，該AML係MTAP缺陷型。在其他實施例中，該AML係MTAP野生型。在又其他實施例中，該AML對由於投與MAT2A抑制劑所致之SAM減少產生反應。In some embodiments, the present invention relates to methods of treating acute myeloid leukemia (AML) by administering: (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) A therapeutically effective amount of venetoclax or a pharmaceutically acceptable salt thereof; and (c) a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt thereof. In some embodiments, the AML is MTAP deficient. In other embodiments, the AML is MTAP wild-type. In yet other embodiments, the AML responds to a reduction in SAM due to administration of a MAT2A inhibitor.

在上文描述之治療方法之任一者中，式(I)化合物或其醫藥上可接受之鹽可與上文描述之一或多種治療劑同時或循序投與。在前述治療方法之任一者之一些實施例中，對病患同時投與(a)式(I)化合物或其醫藥上可接受之鹽，及(b)一或多種治療劑。在其他實施例中，該式(I)化合物或其醫藥上可接受之鹽及一或多種治療劑可循序投與。在又其他實施例中，該式(I)化合物或其醫藥上可接受之鹽係與一或多種治療劑同時或循序投與。In any of the methods of treatment described above, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered simultaneously or sequentially with one or more of the therapeutic agents described above. In some embodiments of any of the foregoing methods of treatment, (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) one or more therapeutic agents are administered concurrently to a patient. In other embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents may be administered sequentially. In yet other embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently or sequentially with one or more therapeutic agents.

在前述治療方法之任一者之又其他實施例中，式(I)化合物或其醫藥上可接受之鹽係經口投與。在前述治療方法之任一者之其他實施例中，該式(I)化合物或其醫藥上可接受之鹽係每天一次或兩次投與。In yet other embodiments of any of the foregoing methods of treatment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. In other embodiments of any of the foregoing methods of treatment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

癌症之積極治療效應可以許多方式量測。投與治療有效量之本文描述之組合係比個別組分化合物更治療有利。如本文使用之「治療有利」之組合係彼等相較於個別投與治療有效量之組分化合物時，提供以下經改善性質中之至少一者之組合：i)比單獨使用活性最大之單一劑更大之抗癌效應；ii)協同抗癌效應；或iii)附加活性。The positive therapeutic effect of cancer can be measured in many ways. Administration of a therapeutically effective amount of the combinations described herein is more therapeutically beneficial than the individual component compounds. A "therapeutically advantageous" combination as used herein is a combination that provides at least one of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) the single most active single greater anticancer effect of the agent; ii) synergistic anticancer effect; or iii) additional activity.

在對病患投與治療有效量之式(I)化合物或其醫藥上可接受之鹽與治療有效量治療劑之組合之本發明實施例中，該組合係治療有利。In embodiments of the present invention wherein a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a therapeutic agent is administered to a patient, the combination is therapeutically beneficial.

在一些實施例中，使用本文描述模型中之至少一者確定協同效應。組合效應可藉由比較各資料點與來源於單一劑曲線之組合參考模型之資料點表徵。一般使用三種模型：(1)最高單一劑，其係簡單之參考模型，在該參考模型中，預期組合效應係相應濃度下單一劑反應之最大值；(2)布利斯獨立模型(Bliss Independence model)，其表示獨立競爭抑制劑之統計期望；(3)勒韋可加性模型(Loewe Additivity model)，在該模型中，若兩種劑實際上為相同化合物，則表示預期反應；(4)周-塔拉萊模型(Chou-Talalay model)，其自單一及組合治療之劑量效應資料推估且表示為組合指數(CI)評分；或一或多種模型之組合。In some embodiments, synergistic effects are determined using at least one of the models described herein. The combined effect can be characterized by comparing each data point to a data point derived from the combined reference model of the single agent curve. Three models are generally used: (1) the highest single agent, which is a simple reference model in which the expected combined effect is the maximum of the single agent response at the corresponding concentration; (2) the Bliss independence model model), which represents the statistical expectation of independent competing inhibitors; (3) the Loewe Additivity model, in which the expected response is represented if two agents are actually the same compound; (4) ) Chou-Talalay model, estimated from dose-response data for single and combination treatments and expressed as a combination index (CI) score; or a combination of one or more models.

勒韋可加性模型係協同效應之最普遍接受之參考，且因此使用該勒韋可加性模型，並自該模型推導度量，其在本文中表徵為「勒韋協同效應評分」。 勒韋可加性模型 The LeVert Additivity Model is the most commonly accepted reference for synergy, and the LeVert Additivity Model is therefore used and a metric is derived from the model, which is characterized herein as the "LeVert Synergy Score." LeVert Additivity Model

勒韋可加性模型係基於劑量且僅適用於由單一劑達成之活性程度。使用勒韋體積以評估超過該勒韋可加性模型之組合相互作用之整體量值。勒韋體積在區分表現型活性(正勒韋體積)相比於協同拮抗作用(負勒韋體積)之協同增加時特別有用。當觀測到拮抗作用時，應評估該勒韋體積以檢查拮抗作用與特定藥物靶標活性或細胞基因型之間是否存在任何關聯。此模型將可加性定義為非協同組合相互作用，其中組合劑量矩陣表面應無法與其自身交叉之藥物區分。勒韋可加性之計算為： 滿足(X/X I) + (Y/Y I) = 1之I Loewe其中X I及Y I係觀測到之組合效應I之單一劑有效濃度。例如，若由1 µM藥物A或1 µM藥物B分別達成50%抑制，則0.5 µM A及0.5 µM B之組合亦應抑制50%。 The LeVert additivity model is dose-based and applies only to the degree of activity achieved by a single dose. The Lewy volume was used to assess the overall magnitude of the combined interactions beyond the Lewy additivity model. The LeVert volume is particularly useful in distinguishing synergistic increases in phenotypic activity (positive LeVert volume) versus synergistic antagonism (negative LeVert volume). When antagonism is observed, this Leweis volume should be assessed to check for any association between antagonism and specific drug target activity or cellular genotype. This model defines additivity as a non-synergistic combination interaction, where the combination dose matrix surface should be indistinguishable from the drugs it crosses itself. Loewe additivity is calculated as: I Loewe satisfying (X/X I ) + (Y/Y I ) = 1 where X I and Y I are the single-dose effective concentrations of the observed combined effect I. For example, if 50% inhibition is achieved by 1 µM Drug A or 1 µM Drug B, respectively, the combination of 0.5 µM A and 0.5 µM B should also inhibit 50%.

觀測到超過勒韋可加性之活性定義潛在協同相互作用。針對本分析，將經驗推導之組合矩陣與其等由實驗收集之單一劑劑量反應曲線構建之各別勒韋可加性模型進行比較。整個劑量反應矩陣中此過度可加性之總和稱為勒韋體積。正勒韋體積表明潛在協同效應，而負勒韋體積表明潛在拮抗作用。 勒韋協同效應評分 Activity beyond LeVert additivity was observed to define potential synergistic interactions. For this analysis, the empirically derived combination matrices were compared with their respective Belavi additivity models constructed from experimentally collected single-dose dose-response curves. The sum of this excess additivity across the entire dose-response matrix is called the Levay volume. A positive LeVert volume indicates a potential synergistic effect, while a negative LeVert volume indicates a potential antagonistic effect. Levy synergy score

為量測超過勒韋可加性之組合效應，設計標量量度以表徵協同相互作用之強度，本文中將其稱為「勒韋協同效應評分」。該勒韋協同效應評分計算為： 勒韋協同效應評分= log f Xlog f YΣ max(0, I data) (I data- I Loewe) To measure combinatorial effects that exceed LeVert additivity, a scalar measure was designed to characterize the strength of synergistic interactions, which is referred to herein as the "LeVert Synergy Score". The Loewe synergy score is calculated as: Lewey synergy score = log f X log f Y Σ max(0, I data ) (I data - I Loewe )

相對於所有未處理/經媒介物處理之對照孔之中值，計算出矩陣中各組分劑及組合點之抑制分數。勒韋協同效應評分方程將該矩陣中超過使用勒韋可加性模型自組分劑之活性數值推導之模型表面之各點處的實驗觀測之活性體積積分。勒韋協同效應評分方程(上文)中之另外術語用以標準化用於個別劑之各種稀釋因子且容許在整個實驗中比較協同效應評分。包含正抑制閘控或I data乘數消除零效應程度附近之雜訊，且導致高活性程度下發生之協同相互作用產生偏差。具有較高最大生長抑制(Growth Inhibition；GI)效應之組合或彼等在低濃度下協同作用者具有較高勒韋協同效應評分。 Fractions of inhibition for each component agent and combination point in the matrix were calculated relative to the median of all untreated/vehicle-treated control wells. The Leverty synergy scoring equation integrates the experimentally observed activity volume at each point in the matrix over the model surface derived numerically from the activities of the component agents using the Levertir additivity model. An additional term in the Lewey synergy scoring equation (above) was used to normalize the various dilution factors for individual agents and to allow comparison of synergy scores across experiments. The inclusion of positive inhibitory gating or I data multipliers eliminates noise near the zero effect level and leads to biases in the synergistic interactions that occur at high activity levels. Combinations with higher maximal Growth Inhibition (GI) effects, or those that act synergistically at low concentrations, have higher Leweiler synergy scores.

如下文實例中將顯示，進行經進一步修飾之組合統計分析以確定式(I)化合物在與抗有絲***劑或DNA合成抑制劑組合時是否產生抗腫瘤組合益處。協同效應評分可稱為「活體內協同效應評分」。As will be shown in the Examples below, a further modified combinatorial statistical analysis was performed to determine whether a compound of formula (I) produced an anti-tumor combination benefit when combined with an anti-mitotic agent or a DNA synthesis inhibitor. The synergy score may be referred to as an "in vivo synergy score".

更詳細地，此組合分析之活體內方法如下：輸入資料由來自各動物於連續時間點之腫瘤體積構成。針對各腫瘤體積，加1並取以10為底之對數。針對各動物，自各時間點之對數(腫瘤體積+ 1)減最早時間點之對數(腫瘤體積+ 1)。使用所得差值相比於時間資料以針對各動物使用梯形規則計算曲線下面積(AUC)值。針對各組計算平均AUC。活體內協同效應評分= 100 x (平均AUCAB -平均AUCA -平均AUCB +平均AUCV) /平均AUCV，其中平均AUCAB、平均AUCA、平均AUCB及平均AUCV分別係組合組、A單一劑組、B單一劑組及媒介物/對照組之平均AUC值。使用個別動物之AUC值，針對活體內協同效應評分是否不為零進行ANOVA統計檢定，獲得p值。針對認為具有協同作用之組合，該活體內協同效應評分必須＜0；0之活體內協同效應評分係精確之可加性。隨著活體內協同效應評分增加至高於0，該評分自可加性轉向拮抗作用。若p值高於0.05，則認為該組合具有可加性。若該p值低於0.05且該活體內協同效應評分小於零，則認為該組合具有協同作用。若該p值低於0.05，該活體內協同效應評分大於零且該組合之平均AUC低於單一劑之最低平均AUC，則認為該組合具有次可加性。若該p值低於0.05，該活體內協同效應評分大於零且該組合之平均AUC大於單一劑中之至少一者之平均AUC，則認為該組合具有拮抗作用。 周 - 塔拉萊模型 In more detail, the in vivo approach to this combined analysis is as follows: The input data consists of tumor volumes from each animal at consecutive time points. For each tumor volume, add 1 and take the base 10 logarithm. For each animal, the log of the earliest time point (tumor volume + 1) was subtracted from the log of each time point (tumor volume + 1). The resulting differences were used compared to time data to calculate area under the curve (AUC) values for each animal using the trapezoidal rule. The mean AUC was calculated for each group. In vivo synergy score = 100 x (mean AUCAB - mean AUCA - mean AUCB + mean AUCV) / mean AUCV, where mean AUCAB, mean AUCA, mean AUCB, and mean AUCV are the combination group, the A single-dose group, and the B single-dose group, respectively Mean AUC values for group and vehicle/control group. Using the AUC values for individual animals, ANOVA statistical tests were performed for whether the in vivo synergy score was non-zero, and p values were obtained. For a combination to be considered synergistic, the in vivo synergy score must be <0; an in vivo synergy score of 0 is accurate additivity. As the in vivo synergy score increases above 0, the score shifts from additive to antagonistic. The combination was considered additive if the p-value was above 0.05. The combination was considered synergistic if the p-value was less than 0.05 and the in vivo synergy score was less than zero. The combination was considered subadditive if the p-value was below 0.05, the in vivo synergy score was greater than zero and the mean AUC of the combination was lower than the lowest mean AUC of a single agent. A combination is considered antagonistic if the p-value is less than 0.05, the in vivo synergy score is greater than zero, and the mean AUC of the combination is greater than the mean AUC of at least one of the single agents. Zhou - Talalay Model

協同效應之替代模型係使用周-塔拉萊模型評估藥物相互作用，該模型於1983年引入且容許在組合研究中估計兩種藥物之間的相互作用，本文中稱為「組合指數(CI)評分」。根據此模型，自單一及組合治療之劑量效應資料估計該等相互作用且表示為組合指數(CI)評分。將該CI定義為(D1/EDx1) + (D2/EDx2)，其中EDx1 (或EDx2)係產生所選效應x (諸如50%生長抑制)之單一劑藥物1 (或藥物2)之劑量，且D1及D2係當以組合給予時亦產生該效應x之藥物1及2之劑量。針對給定之化合物對，探究多種劑量組合(在矩陣設計中)以鑑定產生最低CI之D1/D2對。

Figure 02_image006
An alternative model of synergy is the assessment of drug interactions using the Zhou-Talalay model, which was introduced in 1983 and allows the estimation of interactions between two drugs in combination studies, referred to herein as the "combination index (CI)"score". According to this model, these interactions were estimated from dose-response data for single and combination treatments and expressed as combination index (CI) scores. The CI is defined as (D1/EDx1) + (D2/EDx2), where EDx1 (or EDx2) is the dose of a single dose of Drug 1 (or Drug 2) that produces a selected effect x (such as 50% growth inhibition), and D1 and D2 are the doses of drugs 1 and 2 that also produce this effect x when given in combination. For a given compound pair, various dose combinations were explored (in a matrix design) to identify the D1/D2 pair that yielded the lowest CI.
Figure 02_image006

若CI ＜ 1，則兩種藥物具有協同效應，且若CI ＞ 1，則該等藥物具有拮抗效應。最後，CI = 1表明該等藥物具有可加性效應。參考Chou, T. C.及Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27-55 (1984)。 醫藥組合物 If CI < 1, the two drugs have a synergistic effect, and if CI > 1, the drugs have an antagonistic effect. Finally, CI = 1 indicates that the drugs have additive effects. See Chou, T. C. and Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27-55 (1984). pharmaceutical composition

本發明亦提供包含治療有效量之式(I)化合物或其醫藥上可接受之鹽與醫藥上可接受之載劑混合之醫藥組合物。在一些實施例中，根據醫藥調配可接受之實務，該組合物進一步含有一或多種另外治療劑、醫藥上可接受之賦形劑、稀釋劑、佐劑、穩定劑、乳化劑、防腐劑、著色劑、緩衝劑、風味賦予劑。The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier. In some embodiments, in accordance with acceptable practice in pharmaceutical formulation, the composition further contains one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, Colorants, buffers, flavor imparting agents.

以符合良好醫學實踐之方式調配、給藥及投與式(I)化合物或其醫藥上可接受之鹽之醫藥組合物。此情境下之考量因素包括治療中之特定疾患、治療中之特定病患、病患之臨床病症、疾患之病因、遞送劑之位點、投與方法、投與時間表及開業醫師已知的其他因素。Pharmaceutical compositions of a compound of formula (I) or a pharmaceutically acceptable salt thereof are formulated, administered and administered in a manner consistent with good medical practice. Considerations in this context include the specific condition being treated, the specific patient being treated, the clinical condition of the patient, the etiology of the condition, the site of the delivery agent, the method of administration, the schedule of administration, and what is known to the medical practitioner. other factors.

醫藥組合物可經口、局部、非經腸、藉由吸入或噴霧，或經直腸以劑型單元調配物投與。如本文使用之術語非經腸包括皮下注射、靜脈內、肌內或胸骨內注射，或輸注技術。Pharmaceutical compositions can be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular or intrasternal injection, or infusion techniques.

根據本發明之合適之經口組合物包括(但不限於)錠劑、片劑、***錠、水性或油性懸浮液、可分散粉末或顆粒、乳液、硬質或軟質膠囊、糖漿或酏劑。Suitable oral compositions according to the present invention include, but are not limited to, lozenges, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

醫藥組合物可適用於包含式(I)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑之單一單位劑量。The pharmaceutical composition may be suitable for use in a single unit dose comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

可根據此項技術已知用於製造醫藥組合物之任何方法製備適用於經口使用之醫藥組合物。例如，液體調配物可含有選自由以下組成之群之一或多種劑：甜味劑、矯味劑、著色劑及防腐劑以提供醫藥上合適及/或可口之製劑。Pharmaceutical compositions suitable for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. For example, liquid formulations may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide a pharmaceutically suitable and/or palatable preparation.

對於錠劑組合物，可將式(I)化合物或其醫藥上可接受之鹽與無毒醫藥上可接受之賦形劑混合調配以用於製造錠劑。此等賦形劑之實例包括(但不限於)惰性稀釋劑(諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉)；造粒劑及崩解劑(例如，玉米澱粉或海藻酸)；黏合劑(例如澱粉、明膠或***樹膠)及潤滑劑(例如硬脂酸鎂、硬脂酸或滑石)。該等錠劑可未經包覆或其等可藉由已知包衣技術包覆以延遲在胃腸道中之分解及吸收並藉此於所需時間期內提供持續治療作用。例如，可採用延時材料(諸如單硬脂酸甘油酯或二硬脂酸甘油酯)。For lozenge compositions, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be formulated for use in the manufacture of lozenges in admixture with non-toxic pharmaceutically acceptable excipients. Examples of such excipients include, but are not limited to, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating and disintegrating agents (eg, corn starch or alginic acid); Binders (eg starch, gelatin or acacia) and lubricants (eg magnesium stearate, stearic acid or talc). These lozenges may be uncoated or the like may be coated by known coating techniques to delay breakdown and absorption in the gastrointestinal tract and thereby provide a sustained therapeutic effect for a desired period of time. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be employed.

經口使用之調配物亦可呈現為硬質明膠膠囊，其中活性成分與惰性固體稀釋劑(例如，碳酸鈣、磷酸鈣或高嶺土)混合，或呈現為軟質明膠膠囊，其中活性成分與水或油介質(例如花生油、液體石蠟或橄欖油)混合。Formulations for oral use can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (eg peanut oil, liquid paraffin or olive oil).

對於水性懸浮液，式(I)化合物或其醫藥上可接受之鹽可與適用於維持穩定懸浮液之賦形劑混合。此等賦形劑之實例包括(但不限於)羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍樹膠及***樹膠。For aqueous suspensions, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be mixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and acacia.

經口懸浮液亦可含有分散劑或潤濕劑，諸如天然生成之磷脂(例如，卵磷脂)，或環氧烷與脂肪酸之縮合產物(例如聚氧乙烯硬脂酸酯)，或環氧乙烷與長鏈脂肪醇之縮合產物(例如，十七乙烯氧基十六醇)，或環氧乙烷與衍生自脂肪酸及己糖醇之偏酯之縮合產物(諸如聚氧乙烯山梨糖醇單油酸酯)，或環氧乙烷與衍生自脂肪酸及己糖醇酐之偏酯之縮合產物(例如聚乙烯脫水山梨糖醇單油酸酯)。該等水性懸浮液亦可含有一或多種防腐劑(例如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯)、一或多種著色劑、一或多種矯味劑及一或多種甜味劑(諸如蔗糖或糖精)。Oral suspensions may also contain dispersing or wetting agents, such as naturally occurring phospholipids (for example, lecithin), or condensation products of alkylene oxides with fatty acids (for example, polyoxyethylene stearate), or ethylene oxide Condensation products of alkanes with long-chain fatty alcohols (for example, heptaethyleneoxyhexadecanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (such as polyoxyethylene sorbitol mono oleate), or the condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (eg polyethylene sorbitan monooleate). These aqueous suspensions may also contain one or more preservatives (for example, ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents ( such as sucrose or saccharin).

油性懸浮液可藉由將本發明之化合物懸浮於植物油(例如花生油、橄欖油、芝麻油或椰子油)或懸浮於礦物油(諸如液體石蠟)中加以調配。該等油性懸浮液可含有增稠劑(例如蜂蠟、硬質石蠟或鯨蠟醇)。Oily suspensions can be formulated by suspending the compounds of the invention in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil or in mineral oils such as liquid paraffin. These oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.

可添加甜味劑(諸如彼等上文列舉者)及矯味劑以提供可口之經口製劑。可藉由添加抗氧化劑(諸如抗壞血酸)保存此等組合物。Sweetening agents such as those listed above and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

適用於藉由添加水製備水性懸浮液之可分散粉末及顆粒提供與分散劑或潤濕劑、懸浮劑及一或多種防腐劑混合之本發明之化合物。由彼等上文已提及者例示合適之分散劑或潤濕劑及懸浮劑。亦可存在另外賦形劑(例如甜味劑、矯味劑及著色劑)。Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds of this invention in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present.

本發明之醫藥組合物亦可呈水包油乳液之形式。油相可為植物油(例如橄欖油或花生油)或礦物油(例如液體石蠟)或此等之混合物。合適之乳化劑可為天然生成之樹膠(例如***樹膠或黃蓍樹膠)、天然生成之磷脂(例如大豆卵磷脂)及衍生自脂肪酸及己糖醇酐之酯或偏酯(例如山梨糖醇酐單油酸酯)及該等偏酯與環氧乙烷之縮合反應產物(例如聚氧乙烯山梨糖醇酐單油酸酯)。該等乳液亦可含有甜味劑及矯味劑。The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil (eg olive or peanut oil) or mineral oil (eg liquid paraffin) or a mixture of these. Suitable emulsifiers can be naturally occurring gums such as acacia or tragacanth, naturally occurring phospholipids such as soy lecithin, and esters or partial esters derived from fatty acids and hexitols such as sorbitan. monooleate) and the condensation reaction products of these partial esters with ethylene oxide (eg polyoxyethylene sorbitan monooleate). These emulsions may also contain sweetening and flavoring agents.

糖漿及酏劑可與甜味劑(例如甘油、丙二醇、山梨糖醇或蔗糖)一起調配。此等調配物亦可含有緩和劑、防腐劑或矯味劑及著色劑。醫藥組合物可呈無菌可注射水性懸浮液或油質懸浮液之形式。此懸浮液可根據已知技術使用上文已提及之彼等合適之分散劑或潤濕劑及懸浮劑調配。該無菌可注射製劑亦可為於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液，例如呈於1,3-丁二醇中之溶液。在可接受之媒介物及溶劑中，可採用水、林格氏溶液及等滲氯化鈉溶液。另外，可使用無菌固定油作為溶劑或懸浮介質。出於此目的，可採用任何溫和固定油，包括合成甘油單酯或甘油二酯。另外，脂肪酸(諸如油酸)可發現用以製備可注射劑。Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. These formulations may also contain a demulcent, preservative or flavoring and coloring agents. Pharmaceutical compositions may take the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

式(I)化合物或其醫藥上可接受之鹽亦可呈用於直腸投與藥物之栓劑形式投與。此等組合物可藉由將藥物與在常溫下為固體但在直腸溫度下為液體且因此將在直腸中融化以釋放該藥物之合適之無刺激性賦形劑混合製備。此等材料係可可脂及聚乙二醇。The compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols.

用於非經腸投與之組合物在無菌介質中投與。取決於使用之媒介物及調配物中藥物之濃度，非經腸調配物可為含有溶解藥物之懸浮液或溶液。亦可將佐劑(諸如局部麻醉劑、防腐劑及緩衝劑)添加至非經腸組合物。 固體分散液 For parenteral administration compositions are administered in sterile media. Parenteral formulations can be either suspensions or solutions containing dissolved drug, depending on the vehicle used and the concentration of drug in the formulation. Adjuvants such as local anesthetics, preservatives and buffers can also be added to parenteral compositions. solid dispersion

下文描述之固體分散液亦描述於(例如)美國臨時專利申請案第63/064,866號中，出於所有目的將該案之揭示內容明確併入本文中。The solid dispersions described below are also described, for example, in US Provisional Patent Application No. 63/064,866, the disclosure of which is expressly incorporated herein for all purposes.

術語「分散液」係指其中一種物質(分散相)以離散單元分佈於整個第二種物質(連續相或媒介物)中之分散系統。該分散相之尺寸可顯著變化(例如，奈米尺寸之膠體顆粒，尺寸可達數微米)。一般而言，該等分散相可為固體、液體或氣體。在固體分散液之情況下，該等分散相及連續相均為固體。在醫藥應用中，固體分散液可包括於非晶型聚合物(連續相)中之結晶治療活性化合物(分散相)，或者，於非晶型聚合物(連續相)中之非晶型治療活性化合物(分散相)。The term "dispersion" refers to a dispersed system in which one substance (dispersed phase) is distributed in discrete units throughout a second substance (continuous phase or vehicle). The size of the dispersed phase can vary significantly (eg, nano-sized colloidal particles, up to several microns in size). In general, these dispersed phases can be solid, liquid or gaseous. In the case of solid dispersions, both the dispersed and continuous phases are solids. In pharmaceutical applications, solid dispersions may comprise a crystalline therapeutically active compound in an amorphous polymer (continuous phase) (dispersed phase) or, alternatively, an amorphous therapeutically active compound in an amorphous polymer (continuous phase) Compound (dispersed phase).

術語「非晶型固體分散液」一般係指具有兩種或更多種組分，通常治療活性化合物及聚合物(或複數種聚合物)，但可能含有其他組分(諸如表面活性劑或其他醫藥賦形劑)之固體分散液，其中該治療活性化合物係呈非晶型相，且該非晶型治療活性化合物之物理穩定性及/或溶解度及/或溶解性由其他組分增強。在一些實施例中，非晶型固體分散液包括構成分散相之聚合物(且視需要表面活性劑)，及該治療活性化合物構成連續相。在一些實施例中，非晶型固體分散液包括構成連續相之聚合物(且視需要表面活性劑)，及該治療活性化合物構成分散相。The term "amorphous solid dispersion" generally refers to having two or more components, usually a therapeutically active compound and a polymer (or polymers), but may contain other components such as surfactants or other pharmaceutical excipient), wherein the therapeutically active compound is in an amorphous phase, and the physical stability and/or solubility and/or solubility of the amorphous therapeutically active compound is enhanced by other components. In some embodiments, the amorphous solid dispersion includes a polymer (and optionally a surfactant) that constitutes the dispersed phase, and the therapeutically active compound constitutes the continuous phase. In some embodiments, the amorphous solid dispersion includes a polymer (and optionally a surfactant) that constitutes the continuous phase, and the therapeutically active compound constitutes the dispersed phase.

例示性固體分散液係特定治療活性化合物與一或多種聚合物之共沈澱物或共熔體。在將治療活性化合物及一或多種聚合物溶解於溶劑或溶劑混合物中，接著移除溶劑或溶劑混合物後產生「共沈澱物」。有時，可將該一或多種聚合物懸浮於溶劑或溶劑混合物中。該溶劑或溶劑混合物包括有機溶劑及超臨界流體。該溶劑或溶劑混合物亦可含有非揮發性溶劑。在視需要在溶劑或溶劑混合物之存在下，將治療活性化合物及一或多種聚合物加熱至熔化，接著混合，視需要移除至少一部分溶劑，並以選定速率冷卻至室溫後產生「共熔體」。在某些情況下，藉由添加治療活性化合物及固體聚合物之溶液，接著混合並移除溶劑或溶劑混合物製備固體分散液。為移除該溶劑或溶劑混合物，可施用真空乾燥、噴霧乾燥、盤式乾燥、凍乾及其他乾燥程序。根據本發明，施用使用適當處理參數之此等方法中之任一者將提供在最終固體分散液產物中呈非晶型狀態之特定治療活性化合物。 用於製備固體分散液之方法 Exemplary solid dispersions are co-precipitates or co-melts of specific therapeutically active compounds and one or more polymers. A "coprecipitate" results after dissolving the therapeutically active compound and one or more polymers in a solvent or solvent mixture, followed by removal of the solvent or solvent mixture. In some cases, the one or more polymers can be suspended in a solvent or solvent mixture. The solvent or solvent mixture includes organic solvents and supercritical fluids. The solvent or solvent mixture may also contain non-volatile solvents. The therapeutically active compound and one or more polymers are heated to melt in the presence of a solvent or solvent mixture, if desired, followed by mixing, optionally removing at least a portion of the solvent, and cooling to room temperature at a selected rate to produce a "eutectic" body". In some cases, solid dispersions are prepared by adding a solution of the therapeutically active compound and solid polymer, followed by mixing and removing the solvent or solvent mixture. To remove the solvent or solvent mixture, vacuum drying, spray drying, tray drying, freeze drying and other drying procedures can be applied. In accordance with the present invention, administration of any of these methods using appropriate processing parameters will provide the particular therapeutically active compound in an amorphous state in the final solid dispersion product. Process for preparing solid dispersions

在一些實施例中，固體分散液可根據本文描述之方法製備。在一些實施例中，如本文描述之固態形式可在製備該固體分散液之方法中用作起始材料。在一些實施例中，在製備該固體分散液之方法中用作起始材料之固態形式係本文描述之結晶形式中之一者。在一些實施例中，其中該固態形式係鹼性鹽，製備該固態分散液之方法包括可選脫鹽步驟，藉由該脫鹽步驟可在製備該分散液之前將該鹼性鹽轉化為游離鹼或中性形式。In some embodiments, solid dispersions can be prepared according to the methods described herein. In some embodiments, solid state forms as described herein can be used as starting materials in methods of preparing the solid dispersions. In some embodiments, the solid state form used as the starting material in the method of preparing the solid dispersion is one of the crystalline forms described herein. In some embodiments, wherein the solid form is an alkaline salt, the method of preparing the solid dispersion includes an optional desalting step by which the alkaline salt can be converted to the free base prior to preparing the dispersion or neutral form.

一般而言，可使用之方法包括彼等涉及自混合物快速移除溶劑或溶劑混合物或冷卻熔化樣品者。參見例如國際專利公開案第WO-2019/090059及WO-2015/138837號，其等係以引用之方式併入本文中。此等方法包括(但不限於)旋轉蒸發、冷凍乾燥(即，凍乾)、真空乾燥、熔化凝固及熔體擠出法。本發明之一個實施例涉及藉由噴霧乾燥獲得之固體分散液。在一個實施例中，乾燥藉由噴霧乾燥獲得之產物以移除溶劑或溶劑混合物。In general, methods that can be used include those that involve the rapid removal of solvent or solvent mixture from a mixture or cooling a melted sample. See, eg, International Patent Publication Nos. WO-2019/090059 and WO-2015/138837, which are incorporated herein by reference. Such methods include, but are not limited to, rotary evaporation, freeze drying (ie, lyophilization), vacuum drying, melt solidification, and melt extrusion. One embodiment of the present invention relates to a solid dispersion obtained by spray drying. In one embodiment, the product obtained by spray drying is dried to remove the solvent or solvent mixture.

可藉由噴霧乾燥包含化合物I或其醫藥上可接受之鹽、一或多種聚合物及適當之溶劑或溶劑混合物之混合物獲得本文揭示之製劑(例如，醫藥組合物)。噴霧乾燥涉及霧化含有(例如)固體及溶劑或溶劑混合物之液體混合物，並移除該溶劑或溶劑混合物。該溶劑或溶劑混合物亦可含有非揮發性溶劑。霧化可(例如)通過雙流體或壓力或電聲噴嘴或在旋轉盤上進行。The formulations disclosed herein (eg, pharmaceutical compositions) can be obtained by spray drying a mixture comprising Compound I, or a pharmaceutically acceptable salt thereof, one or more polymers, and a suitable solvent or solvent mixture. Spray drying involves atomizing a liquid mixture containing, for example, a solid and a solvent or solvent mixture, and removing the solvent or solvent mixture. The solvent or solvent mixture may also contain non-volatile solvents. Atomization can be carried out, for example, by two-fluid or pressure or electro-acoustic nozzles or on a rotating disc.

噴霧乾燥將液體進料轉化為乾燥顆粒形式。噴霧乾燥一般涉及將液體進料溶液霧化為液滴噴霧並在乾燥室中使該等液滴與熱空氣或氣體接觸。該等噴霧一般由旋轉(輪)或噴嘴霧化器產生。自該等液滴蒸發水分及形成乾燥顆粒係在受控溫度及氣流條件下進行。Spray drying converts a liquid feed into dry granular form. Spray drying generally involves atomizing a liquid feed solution into a spray of droplets and contacting the droplets with hot air or gas in a drying chamber. These sprays are typically produced by rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles occurs under controlled temperature and airflow conditions.

視需要，可使用第二乾燥過程(諸如流化床乾燥或真空乾燥)以將殘餘溶劑(及其他添加劑，諸如冰乙酸)減少至醫藥上可接受程度。通常，噴霧乾燥涉及使高度分散之液體懸浮液或溶液(例如，霧化溶液)與足量體積之熱空氣或氣體(例如，氮，例如，純氮)接觸以產生液滴之蒸發及乾燥。欲噴霧乾燥之製劑可為可使用選定噴霧乾燥裝置霧化之任何溶液、粗懸浮液、漿液、膠體分散液或糊劑。在標準程序中，將該製劑噴入一股熱過濾空氣內(或噴入氣體，例如，氮內)，該熱過濾空氣蒸發溶劑並將乾燥產物運輸至收集器(例如，旋風器)。然後用過的空氣或氣體與溶劑(或包括任何添加劑(諸如冰乙酸)之溶劑混合物)一起排出，(例如，然後過濾)，或者將用過的空氣或氣體送至冷凝器以捕獲並潛在再循環該溶劑或溶劑混合物。例如，若使用氣體(例如，氮)，然後視需要再循環該氣體，再次加熱並返回至閉環系統中之單元。可使用市售類型之裝置以進行該噴霧乾燥。例如，商業噴霧乾燥器由Buchi Ltd.及Niro製造(例如，由Niro製造之噴霧乾燥器之PSD線)。Optionally, a second drying process (such as fluid bed drying or vacuum drying) can be used to reduce residual solvent (and other additives, such as glacial acetic acid) to pharmaceutically acceptable levels. Generally, spray drying involves contacting a highly dispersed liquid suspension or solution (eg, atomized solution) with a sufficient volume of hot air or gas (eg, nitrogen, eg, pure nitrogen) to produce evaporation and drying of droplets. The formulation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion or paste that can be atomized using the selected spray drying device. In a standard procedure, the formulation is sprayed into a stream of hot filtered air (or into a gas, eg, nitrogen), which evaporates the solvent and transports the dried product to a collector (eg, a cyclone). The used air or gas is then either vented with the solvent (or solvent mixture including any additives such as glacial acetic acid), (eg, then filtered), or sent to a condenser for capture and potential reuse The solvent or solvent mixture is recycled. For example, if a gas (eg, nitrogen) is used, the gas is then optionally recycled, reheated and returned to the unit in the closed loop system. Commercially available types of equipment can be used for this spray drying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (eg, the PSD line of spray dryers manufactured by Niro).

噴霧乾燥通常採用約1%至約30%或高達約50% (即，治療活性化合物加及賦形劑)，較佳至少約10%之材料之固體負載。在一些實施例中，小於10%之固體負載可導致產率差及無法接受之長運行時間。一般而言，由所得溶液之黏性(例如，泵送能力)及該溶液中組分之溶解性控制固體負載之上限。一般而言，該溶液之黏性可決定所得粉狀產物中顆粒之尺寸。Spray drying typically employs from about 1% to about 30% or up to about 50% (ie, the therapeutically active compound plus excipients), preferably at least about 10% solids loading of the material. In some embodiments, solids loadings of less than 10% can result in poor yields and unacceptably long run times. In general, the upper limit of solids loading is controlled by the viscosity (eg, pumpability) of the resulting solution and the solubility of the components in the solution. In general, the viscosity of the solution can determine the size of the particles in the resulting powdered product.

用於噴霧乾燥之技術及方法可參見Perry's Chemical Engineering Handbook，第6版，R. H. Perry、D. W. Green及J. O. Maloney編，McGraw-Hill Book Co. (1984)；及Marshall 「Atomization and Spray-Drying」 50, Chem. Eng. Prog. Monogr. Series 2 (1954)。一般而言，該噴霧乾燥以約40℃至約200℃，例如，約70℃至約150℃，較佳約40℃至約60℃、約50℃至約55℃、或約80℃至約110℃ (例如，約90℃)之入口溫度進行。該噴霧乾燥一般以約20℃至約100℃，例如約25℃至約30℃ (例如，約26℃)、約40℃至約50℃、約50℃至約65℃ (例如，約56℃至約58℃)之出口溫度進行。Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th Edition, edited by R. H. Perry, D. W. Green and J. O. Maloney, McGraw-Hill Book Co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). In general, the spray drying is carried out at about 40°C to about 200°C, eg, about 70°C to about 150°C, preferably about 40°C to about 60°C, about 50°C to about 55°C, or about 80°C to about 80°C An inlet temperature of 110°C (eg, about 90°C) was performed. The spray drying is generally carried out at about 20°C to about 100°C, eg, about 25°C to about 30°C (eg, about 26°C), about 40°C to about 50°C, about 50°C to about 65°C (eg, about 56°C) to an outlet temperature of about 58°C).

溶劑或溶劑混合物的移除可需後續乾燥步驟，諸如盤式乾燥、流化床乾燥(例如，約室溫至約100℃)、真空乾燥、微波乾燥、轉鼓乾燥或雙錐真空乾燥(例如，約室溫至約200℃)。Removal of the solvent or solvent mixture may require subsequent drying steps, such as tray drying, fluid bed drying (eg, from about room temperature to about 100°C), vacuum drying, microwave drying, drum drying, or double cone vacuum drying (eg, , about room temperature to about 200°C).

在一個實施例中，噴霧乾燥係流化噴霧乾燥(FSD)。FSD中之步驟可包括(例如)：製備液體進料溶液(例如，含有化合物I或其醫藥上可接受之鹽，及視需要聚合物及/或表面活性劑，溶解或懸浮於溶劑中)；一經遞送至噴霧乾燥器之乾燥室內即霧化(例如，用壓力噴嘴、旋轉霧化器或盤式雙流體噴嘴或其他霧化方法)該進料溶液，例如，以FSD模式操作；在該乾燥室中用熱空氣或熱氣體(例如，氮)乾燥該進料溶液以獲得產物，其中分離出(例如，脫落)較大之產物顆粒，而細粉由空氣或氣體流攜載至該乾燥室之頂部(例如，藉由自然對流)並攜載至旋風器，且將該等細粉重新引入(例如，於該乾燥室之頂部或軸向至該室中間)該乾燥室內，其中該等重新引入之細粉可與新形成之產物一起聚集以產生聚集產物，其中若該聚集產物足夠大，則將其分離出，若其不足以大至分離出，則藉由對流將該聚集產物攜載至該室頂部及攜載至旋風器並重新引入該室內。重複此過程直至形成足夠大至脫落之聚集產物。可經由進料管將該等細粉自該旋風器重新引入至該乾燥室。In one embodiment, the spray drying is fluidized spray drying (FSD). Steps in FSD can include, for example: preparing a liquid feed solution (eg, containing Compound I or a pharmaceutically acceptable salt thereof, and optionally a polymer and/or surfactant, dissolved or suspended in a solvent); The feed solution is atomized (eg, with pressure nozzles, rotary atomizers, or disc two-fluid nozzles or other atomization methods) upon delivery into the drying chamber of the spray dryer, eg, operating in FSD mode; The feed solution is dried with hot air or hot gas (eg, nitrogen) in a chamber to obtain the product, wherein larger product particles are separated (eg, shed) and fines are carried by the air or gas stream to the drying chamber the top of the drying chamber (eg, by natural convection) and carried to the cyclone, and the fines are reintroduced (eg, at the top of the drying chamber or axially to the middle of the chamber) within the drying chamber, where the The introduced fines can aggregate with the newly formed product to produce an aggregated product, which is separated if it is large enough to be separated, and carried by convection if it is not large enough to separate out to the top of the chamber and carried to the cyclone and reintroduced into the chamber. This process is repeated until an aggregated product large enough to fall off is formed. The fines can be reintroduced from the cyclone to the drying chamber via a feed pipe.

在一些實施例中，方法包括在製備液體進料溶液前，視需要進行將化合物I之醫藥上可接受之鹽脫鹽之步驟(以便於形成化合物I之游離鹼)。In some embodiments, the methods include the optional step of desalting a pharmaceutically acceptable salt of Compound 1 (to facilitate formation of the free base of Compound 1) prior to preparing the liquid feed solution.

在一些實施例中，不同於用熱空氣或熱氣體乾燥該進料溶液，可改用噴霧凝結進料溶液，例如，乾燥室處於室溫(例如，21 ± 4℃)或經冷卻，例如，針對該方法使用冷卻氣體(例如，氮)。In some embodiments, instead of drying the feed solution with hot air or hot gas, spray coagulation of the feed solution can be used instead, eg, the drying chamber is at room temperature (eg, 21 ± 4°C) or cooled, eg, A cooling gas (eg, nitrogen) is used for this method.

FSD可進一步包括在第一流化室中收集聚集產物；接著可將該聚集產物自該第一流化室排放至第二流化室，在該第二流化室中可發生後乾燥過程。The FSD can further include collecting the aggregated product in a first fluidization chamber; the aggregated product can then be discharged from the first fluidization chamber to a second fluidization chamber where a post-drying process can occur.

然後可將聚集產物(例如，在乾燥室中分離出)自第二流化室轉移至第三流化室，在該第三流化室中冷卻該聚集產物。然後可進一步處理該聚集產物(例如，非晶型化合物之固體分散液)。例如，可直接壓縮產物。該產物可視需要與表面活性劑、賦形劑或醫藥上可接受之載劑摻合，例如，在直接壓縮前。可視需要進一步處理該產物，例如，與熔化顆粒、表面活性劑、賦形劑及/或醫藥上可接受之載劑一起研磨、造粒、摻合及/或混合。The aggregated product (eg, separated in a drying chamber) can then be transferred from the second fluidization chamber to a third fluidization chamber where it is cooled. The aggregated product (eg, a solid dispersion of amorphous compound) can then be further processed. For example, the product can be compressed directly. The product may optionally be admixed with surfactants, excipients or pharmaceutically acceptable carriers, eg, prior to direct compression. The product may optionally be further processed, eg, milled, granulated, blended and/or mixed with molten granules, surfactants, excipients and/or pharmaceutically acceptable carriers.

FSD可在以流化噴霧乾燥器模式(FSD模式)操作之商業噴霧乾燥器中進行。FSD可以開環模式或閉環模式 (例如，再循環乾燥氣體，例如，氮)進行。適用於FSD中之噴霧乾燥器之實例包括來自Niro之乾燥器(例如，由Niro製造之噴霧乾燥器之PSD線：PHARMASD™；化學或SD線乾燥器)。FSD可基本上在經組態以容許將細粉重新引入乾燥室內之任何噴霧乾燥器中進行。FSD can be performed in commercial spray dryers operating in fluidized spray dryer mode (FSD mode). FSD can be performed in open-loop mode or closed-loop mode (eg, recirculating a drying gas, eg, nitrogen). Examples of spray dryers suitable for use in FSD include those from Niro (eg, PSD line of spray dryers manufactured by Niro: PHARMASD™; chemical or SD line dryers). FSD can be performed in essentially any spray dryer configured to allow reintroduction of fines into the drying chamber.

若需/適用於移除其他溶劑，則可進行另外後乾燥，例如，在真空或流化床乾燥器或雙錐形或雙錐後乾燥器或滾筒乾燥器中進行另外後乾燥。在一些實施例中，進行後乾燥步驟。Additional post-drying may be carried out if required/suitable for removal of other solvents, eg in a vacuum or fluid bed dryer or in a biconical or biconical post-dryer or in a drum dryer. In some embodiments, a post-drying step is performed.

為移除溶劑或溶劑混合物，可施用真空乾燥、噴霧乾燥、流化噴霧乾燥、盤式乾燥、凍乾、旋轉蒸發及其他乾燥程序。根據本發明，施用使用適當處理參數之此等方法中之任一者將提供在最終固體分散液產物中呈非晶型狀態之化合物I或其醫藥上可接受之鹽。倘若使用適當條件(例如，噴霧乾燥器中之低出口溫度、使用低沸點溶劑、使用熱氣體)，該等條件導致具有所需性質(例如，中值粒度(d 50)為40至200微米，例如，40至150微米)，粉末堆積密度＞0.2 g/ml (例如，0.2至0.5 g/ml)或＞ 0.25 g/ml、經改善之粉末流動性(例如，低內聚力、低顆粒間內摩擦)之分散液(例如，粉末)；及/或具有低OVI (有機揮發性雜質)之乾燥粉末，例如，低於ICH臨限值及/或用戶規格)，則可將該分散液直接壓縮成劑型。 To remove the solvent or solvent mixture, vacuum drying, spray drying, fluidized spray drying, tray drying, lyophilization, rotary evaporation and other drying procedures can be applied. In accordance with the present invention, administration of any of these methods using appropriate processing parameters will provide Compound I or a pharmaceutically acceptable salt thereof in an amorphous state in the final solid dispersion product. Provided appropriate conditions are used (e.g., low outlet temperature in spray dryer, use of low boiling point solvent, use of hot gas), such conditions result in desirable properties (e.g., median particle size ( d50 ) of 40 to 200 microns, For example, 40 to 150 microns), powder bulk density >0.2 g/ml (eg, 0.2 to 0.5 g/ml) or >0.25 g/ml, improved powder flow (eg, low cohesion, low interparticle friction) ) dispersions (e.g., powders); and/or dry powders with low OVI (organic volatile impurities), e.g., below ICH thresholds and/or user specifications), the dispersions can be compressed directly into dosage form.

在一些實施例中，入口溫度係約50℃至約200℃，例如，約60℃至約150℃、約70℃至約100℃、約60℃至約95℃、約65℃至約85℃、約70℃至約90℃、約85℃至約95℃、或約70℃至約85℃。In some embodiments, the inlet temperature is about 50°C to about 200°C, eg, about 60°C to about 150°C, about 70°C to about 100°C, about 60°C to about 95°C, about 65°C to about 85°C , about 70°C to about 90°C, about 85°C to about 95°C, or about 70°C to about 85°C.

在一些實施例中，出口溫度係約室溫(例如，USP室溫(例如，21 ± 4℃))至約80℃，例如，約25℃至約75℃、約30℃至約65℃、約35℃至約70℃、約40℃至約65℃、約45℃至約60℃、約35℃至約45℃、約35℃至約40℃、或約37℃至約40℃。In some embodiments, the outlet temperature is about room temperature (eg, USP room temperature (eg, 21 ± 4°C)) to about 80°C, eg, about 25°C to about 75°C, about 30°C to about 65°C, About 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 60°C, about 35°C to about 45°C, about 35°C to about 40°C, or about 37°C to about 40°C.

在一些實施例中，流化床之溫度設定點(各床之溫度獨立地選自針對另一床選擇之溫度)係約室溫(例如，USP室溫(例如，21±4℃))至約100℃，例如，約30℃至約95℃、約40℃至約90℃、約50℃至約80℃、約60℃至約85℃、約65℃至約95℃、或約80℃至約95℃。In some embodiments, the temperature set point for the fluidized bed (the temperature of each bed is independently selected from the temperature selected for the other bed) is from about room temperature (eg, USP room temperature (eg, 21±4°C)) to about 100°C, eg, about 30°C to about 95°C, about 40°C to about 90°C, about 50°C to about 80°C, about 60°C to about 85°C, about 65°C to about 95°C, or about 80°C to about 95°C.

可對含有受關注化合物(例如，治療活性化合物或API，諸如化合物I或其醫藥上可接受之鹽)之混合物進行FSD。例如，可對含有化合物I或其醫藥上可接受之鹽及一或多種聚合物，及視需要一或多種表面活性劑，及視需要一或多種另外賦形劑之混合物進行FSD以獲得可直接壓縮成經口劑型(例如，錠劑)之非晶型化合物I或其醫藥上可接受之鹽之固體分散液。或者，該分散液可在壓縮前與一或多種賦形劑摻合。FSD can be performed on a mixture containing a compound of interest (eg, a therapeutically active compound or an API, such as Compound 1 or a pharmaceutically acceptable salt thereof). For example, FSD can be performed on a mixture containing Compound I or a pharmaceutically acceptable salt thereof and one or more polymers, and optionally one or more surfactants, and optionally one or more additional excipients to obtain a direct Solid dispersions of amorphous Compound I or a pharmaceutically acceptable salt thereof compressed into oral dosage forms (eg, lozenges). Alternatively, the dispersion may be admixed with one or more excipients prior to compression.

在一個實施例中，用於製備化合物I之固體分散液之方法包括：In one embodiment, the method for preparing a solid dispersion of Compound I comprises:

a)形成化合物I或其醫藥上可接受之鹽、一或多種聚合物及一或多種溶劑之混合物；及a) forming a mixture of Compound 1 or a pharmaceutically acceptable salt thereof, one or more polymers and one or more solvents; and

b)自該溶液快速移除溶劑以形成包含化合物I或其醫藥上可接受之鹽及一或多種聚合物之固體非晶型分散液。該一或多種聚合物及一或多種溶劑可為彼等本文揭示者中之任一者。b) The solvent is rapidly removed from the solution to form a solid amorphous dispersion comprising Compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers. The one or more polymers and the one or more solvents can be any of those disclosed herein.

在一些實施例中，該方法包括在用於製備固體分散液之方法前，視需要進行將化合物I之醫藥上可接受之鹽脫鹽之步驟(以便於形成化合物I之游離鹼)。In some embodiments, the method includes, optionally, the step of desalting a pharmaceutically acceptable salt of Compound 1 (to facilitate formation of the free base of Compound 1) prior to the method used to prepare the solid dispersion.

在一些實施例中，藉由噴霧乾燥移除溶劑。在其他實施例中，使用對流盤式乾燥器盤式乾燥固體分散液。在其他實施例中，使該固體分散液過篩。In some embodiments, the solvent is removed by spray drying. In other embodiments, the solid dispersion is tray dried using a convection tray dryer. In other embodiments, the solid dispersion is sieved.

在一個實施例中，化合物I或其醫藥上可接受之鹽係結晶。在另一實施例中，化合物I或其醫藥上可接受之鹽係非晶型。In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is crystalline. In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is amorphous.

如熟習此項技術者將認知，噴霧乾燥可進行且通常在惰性氣體(諸如氮)之存在下進行。在某些實施例中，涉及噴霧乾燥之方法可在超臨界流體(涉及二氧化碳)或混合物(包括二氧化碳)之存在下進行。As will be appreciated by those skilled in the art, spray drying can be carried out and is usually carried out in the presence of an inert gas such as nitrogen. In certain embodiments, methods involving spray drying can be performed in the presence of a supercritical fluid (involving carbon dioxide) or mixtures (including carbon dioxide).

在另一實施例中，用於製備化合物I或其醫藥上可接受之鹽之固體分散液之方法包括：In another embodiment, the method for preparing a solid dispersion of Compound 1 or a pharmaceutically acceptable salt thereof comprises:

a)形成化合物I或其醫藥上可接受之鹽、至少一種聚合物及溶劑之混合物；及a) forming a mixture of Compound 1 or a pharmaceutically acceptable salt thereof, at least one polymer and a solvent; and

b)噴霧乾燥該混合物以形成包含化合物I或其醫藥上可接受之鹽及聚合物之固體分散液。b) spray drying the mixture to form a solid dispersion comprising Compound I or a pharmaceutically acceptable salt thereof and a polymer.

在一些實施例中，用於製備化合物I之醫藥上可接受之鹽之固體分散液之方法視需要包括在與至少一種聚合物及溶劑形成混合物之步驟前，將化合物I之醫藥上可接受之鹽脫鹽之步驟(以便於形成化合物I之游離鹼)。In some embodiments, the method for preparing a solid dispersion of a pharmaceutically acceptable salt of Compound 1 optionally includes mixing a pharmaceutically acceptable salt of Compound 1 with the step of forming a mixture with at least one polymer and a solvent. A step of desalting the salt (to facilitate formation of the free base of compound I).

可視需要將經濕噴霧乾燥之分散液後乾燥及/或研磨至低於ICH或殘餘溶劑之給定規格。The wet spray-dried dispersion may optionally be post-dried and/or ground below the given specification for ICH or residual solvent.

此等方法可用以製備本文揭示之醫藥組合物。該等方法中所使用組分之量及特徵可如本文揭示。These methods can be used to prepare the pharmaceutical compositions disclosed herein. The amounts and characteristics of the components used in these methods can be as disclosed herein.

在一些實施例中，溶劑包含一或多種揮發性溶劑以溶解或懸浮化合物I或其醫藥上可接受之鹽及聚合物。在其他實施例中，該一或多種溶劑完全溶解化合物I或其醫藥上可接受之鹽及聚合物。適用於噴霧乾燥方法中之溶劑將趨於彼等在乾燥方法之溫度及壓力下揮發以促進自分散液移除溶劑者。In some embodiments, the solvent comprises one or more volatile solvents to dissolve or suspend Compound 1 or a pharmaceutically acceptable salt and polymer thereof. In other embodiments, the one or more solvents completely dissolve Compound 1 or a pharmaceutically acceptable salt and polymer thereof. Solvents suitable for use in spray drying processes will tend to volatilize at the temperature and pressure of the drying process to facilitate solvent removal from the dispersion.

在一些實施例中，溶劑係揮發性溶劑。在其他實施例中，該溶劑係兩種或更多種揮發性溶劑之混合物。合適之揮發性溶劑之實例包括彼等單獨或與另一共溶劑組合溶解或懸浮治療活性化合物者。在其他實施例中，該溶劑完全溶解該治療活性化合物。In some embodiments, the solvent is a volatile solvent. In other embodiments, the solvent is a mixture of two or more volatile solvents. Examples of suitable volatile solvents include those that dissolve or suspend the therapeutically active compound, alone or in combination with another co-solvent. In other embodiments, the solvent completely dissolves the therapeutically active compound.

在一些實施例中，溶劑係非揮發性溶劑。在其他實施例中，該非揮發性溶劑係水。在其他實施例中，非揮發性溶劑係包含任何比率之兩種或更多種溶劑之混合物中之組分。例如該非揮發性溶劑可以一種組分以約1%至約20% w/w (例如，約3% w/w至約15% w/w、約4% w/w至約12% w/w、或約5% w/w至約10% w/w)存在於溶劑之混合物中。In some embodiments, the solvent is a non-volatile solvent. In other embodiments, the non-volatile solvent is water. In other embodiments, the non-volatile solvent is a component comprising a mixture of two or more solvents in any ratio. For example, the non-volatile solvent can be one component at about 1% to about 20% w/w (eg, about 3% w/w to about 15% w/w, about 4% w/w to about 12% w/w , or from about 5% w/w to about 10% w/w) in the mixture of solvents.

在一些實施例中，溶劑係溶劑之混合物。例如，該溶劑混合物可包括約0%至約30%溶劑A及約70%至約100%溶劑B，或該溶劑混合物可包括約0%至約40%溶劑A及約60%至約100%溶劑B。各種溶劑之其他例示性比率可包括80:20、75:25、70:30、60:40、55:45及50:50。In some embodiments, the solvent is a mixture of solvents. For example, the solvent mixture can include about 0% to about 30% solvent A and about 70% to about 100% solvent B, or the solvent mixture can include about 0% to about 40% solvent A and about 60% to about 100% solvent B. Other exemplary ratios of various solvents may include 80:20, 75:25, 70:30, 60:40, 55:45, and 50:50.

在一些實施例中，溶劑係溶劑之混合物，其包括至少一種非揮發性溶劑。例如，該溶劑係包括揮發性溶劑及非揮發性溶劑之組分之組合。In some embodiments, the solvent is a mixture of solvents that includes at least one non-volatile solvent. For example, the solvent is a combination of components comprising a volatile solvent and a non-volatile solvent.

在一些實施例中，溶劑係兩種或更多種揮發性溶劑及非揮發性溶劑(諸如水)之混合物。例如，該溶劑混合物可包含約40%至約80%第一揮發性溶劑、約20%至約35%第二揮發性溶劑，及約0.1%至約15%非揮發性溶劑(例如，約50%至約70%揮發性溶劑、約25%至約30%另一不同之揮發性溶劑，及約1%至約5%非揮發性溶劑)。 使用方法 In some embodiments, the solvent is a mixture of two or more volatile solvents and a non-volatile solvent such as water. For example, the solvent mixture may comprise from about 40% to about 80% of the first volatile solvent, from about 20% to about 35% of the second volatile solvent, and from about 0.1% to about 15% of the nonvolatile solvent (eg, about 50% % to about 70% volatile solvent, about 25% to about 30% another different volatile solvent, and about 1% to about 5% non-volatile solvent). Instructions

在一些實施例中，本發明中闡述之治療方法可用以治療在一或多種前線療法後已無法反應、停止反應或經歷疾病進展之病患。在其他實施例中，本發明中闡述之治療方法可用於新診斷病患(例如作為第一線療法)中。In some embodiments, the methods of treatment described in this invention can be used to treat patients who have failed to respond, stopped responding, or experienced disease progression after one or more front-line therapies. In other embodiments, the methods of treatment set forth in the present invention may be used in newly diagnosed patients (eg, as first line therapy).

在一個實施例中，本發明中闡述之治療方法可用作用於治療癌症之第二線療法。In one embodiment, the methods of treatment set forth in the present invention can be used as second line therapy for the treatment of cancer.

在另一實施例中，本發明中闡述之治療方法可用作用於治療癌症之第三線療法。In another embodiment, the methods of treatment set forth in the present invention can be used as a third line therapy for the treatment of cancer.

在一些實施例中，本發明闡述之治療方法中所使用之化合物劑量係藉由每日給藥一次或兩次投與。In some embodiments, the doses of compounds used in the methods of treatment described herein are administered by once or twice daily administration.

在一些實施例中，本發明闡述之治療方法中所使用之化合物劑量係經口投與。In some embodiments, the doses of compounds used in the methods of treatment described herein are administered orally.

在其中式(I)化合物以醫藥上可接受之鹽之形式投與之實施例中，將劑量量測為對應於游離形式當量之式(I)化合物之量的量。In embodiments wherein the compound of formula (I) is administered in the form of a pharmaceutically acceptable salt, the dosage amount is measured as the amount corresponding to the amount of the compound of formula (I) equivalent in free form.

針對本發明方法之實施例及態樣中之各者，該方法可進一步包括對病患投與放射療法。For each of the embodiments and aspects of the present method, the method can further comprise administering radiation therapy to the patient.

儘管未明確描述，但一或多種態樣及實施例可併入不同實施例中。即，本文描述之所有態樣及實施例可以任何方式或組合進行組合。 實例 Although not explicitly described, one or more aspects and embodiments may be incorporated into different embodiments. That is, all aspects and embodiments described herein may be combined in any manner or combination. Example

藉由參考下列實例將更充分瞭解本發明。然而，該等實例不應視為限制本發明之範圍。The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the invention.

如上文提及之式(I)化合物(亦可稱為化合物I或Cmpd I)可如國際申請案第PCT/US2017/049439號中闡述合成，該案作為WO 2018/045071公開，並以全文引用之方式併入本文中。 實例1：MAT2A抑制劑及癌症治療劑之協同篩選 Compounds of formula (I) as mentioned above (also referred to as Compound I or Cmpd I) can be synthesized as described in International Application No. PCT/US2017/049439, which is published as WO 2018/045071 and is incorporated by reference in its entirety is incorporated herein by way of. Example 1: Synergistic Screening of MAT2A Inhibitors and Cancer Therapeutics

進行協同篩選以評估組合MAT2A抑制劑與其他治療劑用於治療癌症之潛在協同效應。此等劑包括彼等極光激酶(例如ABT-348、AZD-1152)、PARP (例如奧拉帕尼、BMN673)、DNA交聯劑(例如奧沙利鉑、順鉑)、細胞週期檢查點抑制劑(例如AZD 7762、LY2603618)、MDM2路徑(例如JNJ 26854165、努特林-3)、抗代謝藥(例如吉西他濱、培美曲塞)、DNA低甲基化劑(例如氮胞苷、地西他濱)、mTOR路徑(例如依維莫司)、微管穩定化(例如紫杉醇)、ATM路徑(例如KU-60019)、CDK4/6路徑(例如PD-0332991)及PRMT5抑制劑(AGI-219及AGI-931)。在劑量矩陣中製備MAT2A抑制劑(化合物I)及組合劑之連續稀釋液並處理一組37個癌細胞系(表I)以評估對細胞生長抑制之可能協同效應。 表I：用以評估化合物I與其他癌症治療劑之間潛在協同效應之癌細胞系。 組織 細胞系 結直腸 COLO-678 結直腸 HCT-116 MTAP null 結直腸 HCT-116 MTAP wt 結直腸 SNU-1033 食道 TE-10 食道 TE-14 食道 TE-6 胃 LMSU 胃 MKN45 胃 NCC-StC-K140 胃 SNU-668 腎 CAL-54 肺 A549 肺 HCC1171 肺 HCC-15 肺 HLC-1 肺 LU-99 肺 NCI-H1437 肺 NCI-H1650 肺 NCI-H1755 肺 NCI-H2023 肺 NCI-H2126 肺 NCI-H2170 肺 NCI-H2228 肺 NCI-H647 肺 NCI-H838 肺 SK-LU-1 肺 SW1573 肺 SW900 胰臟 BxPC-3 胰臟 DAN-G 胰臟 HuP-T3 胰臟 KP-4 胰臟 MIA PaCa-2 胰臟 PK-45H 胰臟 SNU-410 胰臟 SU.86.86 Synergy screening was performed to assess potential synergistic effects of combining MAT2A inhibitors with other therapeutic agents for the treatment of cancer. Such agents include Aurora kinases (eg, ABT-348, AZD-1152), PARPs (eg, olaparib, BMN673), DNA cross-linkers (eg, oxaliplatin, cisplatin), cell cycle checkpoint inhibition Agents (eg AZD 7762, LY2603618), MDM2 pathway (eg JNJ 26854165, Nutrin-3), antimetabolites (eg gemcitabine, pemetrexed), DNA hypomethylating agents (eg azacytidine, diazepam) citabine), mTOR pathway (e.g. everolimus), microtubule stabilization (e.g. paclitaxel), ATM pathway (e.g. KU-60019), CDK4/6 pathway (e.g. PD-0332991) and PRMT5 inhibitor (AGI-219) and AGI-931). Serial dilutions of the MAT2A inhibitor (Compound I) and combination agents were prepared in dose matrices and treated with a panel of 37 cancer cell lines (Table I) to assess possible synergistic effects on cell growth inhibition. Table I: Cancer cell lines used to evaluate potential synergistic effects between Compound I and other cancer therapeutics. organize cell line colorectal COLO-678 colorectal HCT-116 MTAP null colorectal HCT-116 MTAP wt colorectal SNU-1033 esophagus TE-10 esophagus TE-14 esophagus TE-6 Stomach LMSU Stomach MKN45 Stomach NCC-StC-K140 Stomach SNU-668 kidney CAL-54 lung A549 lung HCC1171 lung HCC-15 lung HLC-1 lung LU-99 lung NCI-H1437 lung NCI-H1650 lung NCI-H1755 lung NCI-H2023 lung NCI-H2126 lung NCI-H2170 lung NCI-H2228 lung NCI-H647 lung NCI-H838 lung SK-LU-1 lung SW1573 lung SW900 pancreas BxPC-3 pancreas DAN-G pancreas HuP-T3 pancreas KP-4 pancreas MIA PaCa-2 pancreas PK-45H pancreas SNU-410 pancreas SU.86.86

在經組織培養物處理之黑色384孔盤中以每孔500至1,500個細胞將細胞接種於適當之生長培養基中。經由離心將細胞平衡於分析盤中並在培養器中在37℃下放置24小時，然後進行處理。在處理時，收集一組未處理之分析盤並針對ATP含量使用CellTiter-Glo 2.0分析。將此等盤指定為T0並使用超靈敏發光在Envision平板閱讀器(Perkin Elmer)上讀數。然後用化合物I及組合劑培養分析盤96小時，然後使用CellTiter-Glo (Promega)分析。收集所有資料點，處理並使用Horizon Discovery之專有軟體分析。使用線性內插擬合所有總結資料(包括協同效應評分)。使用Chalice分析器軟體進行資料分析。 組合益處之確定 Cells were seeded in appropriate growth medium at 500 to 1,500 cells per well in tissue culture treated black 384-well dishes. Cells were equilibrated in assay dishes via centrifugation and placed in an incubator at 37°C for 24 hours prior to processing. At the time of processing, a set of untreated assay plates were collected and analyzed for ATP content using CellTiter-Glo 2.0. The plates were designated TO and read on an Envision plate reader (Perkin Elmer) using ultrasensitive luminescence. The assay plates were then incubated with Compound I and the combination for 96 hours and then assayed using CellTiter-Glo (Promega). All data points were collected, processed and analyzed using Horizon Discovery's proprietary software. All summary data (including synergy scores) were fitted using linear interpolation. Data analysis was performed using the Chalice analyzer software. Determination of Combination Benefits

勒韋可加性模型係基於劑量且僅適用於由單一劑達成之活性程度。使用勒韋體積以評估超過該勒韋可加性模型之組合相互作用之整體量值。勒韋體積在區分表現型活性(正勒韋體積)相比於協同拮抗作用(負勒韋體積)之協同增加時特別有用。當觀測到拮抗作用時，應評估該勒韋體積以檢查拮抗作用與藥物靶標活性或細胞基因型之間是否存在任何關聯。此模型將可加性定義為非協同組合相互作用，其中組合劑量矩陣表面應無法與其自身交叉之藥物區分。勒韋可加性之計算為： 滿足(X/X I)+(Y/Y I)=1之I Loewe其中X I及Y I係觀測到之組合效應I之單一劑有效濃度。例如，若由1 µM藥物A或1 µM藥物B分別達成50%抑制，則0.5 µM藥物A及0.5 μM藥物B之組合亦應抑制50%。 The LeVert additivity model is dose-based and applies only to the degree of activity achieved by a single dose. The Lewy volume was used to assess the overall magnitude of the combined interactions beyond the Lewy additivity model. The LeVert volume is particularly useful in distinguishing synergistic increases in phenotypic activity (positive LeVert volume) versus synergistic antagonism (negative LeVert volume). When antagonism is observed, this Lewey volume should be assessed to check for any association between antagonism and drug target activity or cell genotype. This model defines additivity as a non-synergistic combination interaction, where the combination dose matrix surface should be indistinguishable from the drugs it crosses itself. Loewe additivity is calculated as: I Loewe satisfying (X/X I )+(Y/Y I )=1 where X I and Y I are the single-dose effective concentrations of the observed combined effect I. For example, if 50% inhibition is achieved by 1 µM Drug A or 1 µM Drug B, respectively, the combination of 0.5 µM Drug A and 0.5 µM Drug B should also inhibit 50%.

觀測到超過勒韋可加性之活性定義潛在協同相互作用。針對此研究中之分析，將經驗推導之組合矩陣與其等由實驗收集之單一劑劑量反應曲線構建之各別勒韋可加性模型進行比較。整個劑量反應矩陣中此過度可加性之總和稱為勒韋體積。正勒韋體積表明潛在協同效應，而負勒韋體積表明潛在拮抗作用。Activity beyond LeVert additivity was observed to define potential synergistic interactions. For the analysis in this study, the empirically derived combination matrices were compared with their respective Belavir additivity models constructed from experimentally collected single-dose dose-response curves. The sum of this excess additivity across the entire dose-response matrix is called the Levay volume. A positive LeVert volume indicates a potential synergistic effect, while a negative LeVert volume indicates a potential antagonistic effect.

為量測超過勒韋可加性之組合效應，由Horizon Discovery設計之標量量度用以表徵協同相互作用之強度，稱為協同效應評分。該協同效應評分計算為： 協同效應評分=logf Xlogf YΣ max(0, I data) (I data- I Loewe) To measure combinatorial effects that exceed LeVert additivity, a scalar measure designed by Horizon Discovery to characterize the strength of synergistic interactions is called the synergy score. The synergy score is calculated as: synergy score = logf X logf Y Σ max(0, I data ) (I data - I Loewe )

相對於所有未處理/經媒介物處理之對照孔之中值，計算矩陣中各組分劑及組合點之抑制分數。協同效應評分方程將該矩陣中超過使用勒韋可加性模型自組分劑之活性數值推導之模型表面之各點處之實驗觀測之活性體積積分。協同效應評分方程中之另外術語用以標準化用於個別劑之各種稀釋因子且容許在整個實驗中比較協同效應評分。包含正抑制閘控或I data乘數消除零效應程度附近之雜訊，且導致高活性程度下發生之協同相互作用產生偏差。具有較高最大生長抑制效應之組合或彼等在低濃度下協同作用者具有較高協同效應評分。 Fractions of inhibition were calculated for each component agent and combination point in the matrix relative to the median of all untreated/vehicle-treated control wells. The synergy scoring equation integrates the experimentally observed activity volume at each point in the matrix over the surface of the model derived numerically from the activity of the component agents using the Revel additivity model. Additional terms in the synergy scoring equation are used to normalize the various dilution factors for individual agents and allow for comparison of synergy scores across experiments. The inclusion of positive inhibitory gating or I data multipliers eliminates noise near the zero effect level and leads to biases in the synergistic interactions that occur at high activity levels. Combinations with higher maximal growth inhibitory effects or those that act synergistically at low concentrations have higher synergy scores.

使用等效應圖評估效力轉移，其證實組合中達成所需效應程度所需之藥物相較於達成該效應所需之單一劑劑量少多少。藉由識別對應於跨越指定抑抑制程度之濃度軌跡繪製等效應圖。此係藉由尋找劑量矩陣中之各單一劑濃度與其他單一劑之濃度之交叉點進行。事實上，各垂直濃度(C Y)保持固定，同時使用二分演算法以鑑定水平濃度(C X)與垂直劑量之組合，該垂直劑量在反應表面Z(C X,C Y)中給定所選效應程度。然後藉由線性內插連接此等濃度以產生等效應圖顯示。針對協同相互作用，等效應圖等高線將低於可加性臨限值且接近原點，及拮抗相互作用將高於該可加性臨限值。誤差槓表示由用以產生該等效應圖之個別資料點產生之不確定性。使用二分法自反應誤差估計各交叉點之不確定性，以尋找Z-σZ(C X,C Y)及Z+σZ(C X,C Y)交叉I cut之濃度，其中σZ係效應標度上殘餘誤差之標準偏差。 Efficacy shifts were assessed using iso-effect plots, which demonstrated how much less drug in the combination is required to achieve the desired degree of effect than a single dose of the dose required to achieve that effect. Equivalent effect plots are drawn by identifying concentration trajectories that correspond to inhibition across a specified degree of inhibition. This is done by finding the intersection of each single agent concentration in the dose matrix with the concentrations of other single agents. In fact, each vertical concentration (C Y ) remains fixed, while a dichotomous algorithm is used to identify the combination of horizontal concentration (C X ) and vertical dose given given in reaction surface Z (C X ,C Y ) Select the degree of effect. These concentrations were then connected by linear interpolation to produce an isoeffect map display. For synergistic interactions, isoeffect plot contours will be below the additivity threshold and close to the origin, and antagonistic interactions will be above this additivity threshold. Error bars represent uncertainties arising from the individual data points used to generate these effect plots. Use the dichotomous self-reaction error to estimate the uncertainty at each intersection to find the concentration of the Z-σZ(C X ,C Y ) and Z+σZ(C X ,C Y ) intersections I cut , where σZ is the effect scale The standard deviation of the residual error above.

化合物I及數種劑之組合證實治療優勢。(圖15)。 實例2：與培美曲塞之組合 Compound I and the combination of several agents demonstrated therapeutic advantage. (Figure 15). Example 2: Combination with Pemetrexed

甲硫胺酸代謝與葉酸代謝相交。一致地，協同效應評分分析表明培美曲塞及化合物I組合於一些癌細胞系中之潛在組合益處(圖15)。為進一步評估培美曲塞及化合物I之組合，用化合物I及培美曲塞使用協同篩選實驗中描述之相似方法處理KP-4細胞(實例1)。在多個劑量程度上使用周-塔拉萊方法確定組合指數(CI)。所觀測到之最小CI係0.05，指示MAT2A抑制劑化合物I與培美曲塞之間的強協同效應(圖16)。Methionine metabolism intersects with folic acid metabolism. Consistently, synergy score analysis indicated potential combinatorial benefit of pemetrexed and Compound I combined in some cancer cell lines (Figure 15). To further evaluate the combination of pemetrexed and compound 1, KP-4 cells were treated with compound 1 and pemetrexed using a method similar to that described in the synergistic screening experiment (Example 1). The combination index (CI) was determined using the Zhou-Talalay method at multiple dose levels. The smallest CI observed was 0.05, indicating a strong synergistic effect between the MAT2A inhibitor Compound I and pemetrexed (Figure 16).

應注意，在攜載野生型MTAP基因之細胞系中亦觀測到化合物I與培美曲塞之間的組合益處。例如，該最小CI在HCT-116細胞中係0.45，而該最小CI在NCI-H2122細胞中係0.15 (圖16)。 實例3：由MAT2A抑制劑減少DNA甲基化 It should be noted that a combined benefit between Compound I and pemetrexed was also observed in cell lines carrying the wild-type MTAP gene. For example, the minimum CI was 0.45 in HCT-116 cells and 0.15 in NCI-H2122 cells (Figure 16). Example 3: Reduction of DNA methylation by MAT2A inhibitors

對經DMSO或化合物I處理6天之TF1白血病細胞進行全基因體亞硫酸氫鹽定序(WGBS)以評估化合物I之MAT2A抑制對DNA甲基化是否有影響。WGBS之結果揭示用化合物I處理後，CpG位點顯著減少(~8%)，指示化合物I之MAT2A抑制減少DNA甲基化且與DNA低甲基化劑組合可為有利的。結果顯示於圖12中。 實例4：細胞內西方墨點法(ICW)分析/與PRMT抑制劑之組合 Whole genome bisulfite sequencing (WGBS) was performed on TF1 leukemia cells treated with DMSO or Compound I for 6 days to assess whether MAT2A inhibition by Compound I had an effect on DNA methylation. Results from WGBS revealed that CpG sites were significantly reduced (~8%) after treatment with Compound 1, indicating that MAT2A inhibition of Compound 1 reduces DNA methylation and may be beneficial in combination with DNA hypomethylating agents. The results are shown in FIG. 12 . Example 4: Intracellular Western blot (ICW) analysis/combination with PRMT inhibitor

將TF1細胞(5000個細胞)接種於經Cell-Tak處理之96孔組織培養盤中且容許在37℃下在5% CO 2中結合整夜。以劑量反應形式在3列中添加化合物I以一式三份產生9點劑量反應曲線。劑量以2 µM最高濃度開始，以1:3連續稀釋。在DMSO中將化合物I稀釋至介質中0.2% DMSO之最終濃度。將各盤上一行指定為0.2% DMSO對照。用化合物I將細胞培養96小時。在此處理週期後，移除介質並用並用針對SDMA蛋白標識(Cell Signaling Technology #13222)、ADMA (Cell Signaling Technology #13522)之抗體及用非特異性細胞染色劑CellTag 700 (Cell Signaling Technology #926-41090)將細胞染色。藉由將各孔中之SDMA/ADMA信號標準化為CellTag 700信號計算各化合物劑量及DMSO對照之SDMA含量變化以調整化合物處理對細胞數量之影響。然後將SDMA含量變化繪製成SDMA抑制(%) (標準化為各細胞系DMSO對照樣本)相對於以莫耳(M)單位計之化合物濃度之log10。使用四參數邏輯回歸進行曲線擬合。如下計算SDMA/ADMA抑制百分比：SDMA抑制(%) =100×(1-SDMA/ADMA劑量/SDMA/ADMADMSO對照)。 TF1 cells (5000 cells) were seeded in Cell-Tak treated 96-well tissue culture dishes and allowed to bind overnight at 37°C in 5% CO2 . Compound I was added in 3 columns in a dose-response format to generate a 9-point dose-response curve in triplicate. Dosing starts with a 2 µM highest concentration and serial dilutions of 1:3. Compound 1 was diluted in DMSO to a final concentration of 0.2% DMSO in medium. The top row of each plate is designated as the 0.2% DMSO control. Cells were incubated with Compound I for 96 hours. After this treatment cycle, the medium was removed and combined with antibodies against SDMA protein marker (Cell Signaling Technology #13222), ADMA (Cell Signaling Technology #13522) and with the non-specific cell stain CellTag 700 (Cell Signaling Technology #926- 41090) to stain the cells. Changes in SDMA content for each compound dose and DMSO control were calculated by normalizing the SDMA/ADMA signal in each well to the CellTag 700 signal to adjust for the effect of compound treatment on cell number. Changes in SDMA content were then plotted as SDMA inhibition (%) (normalized to DMSO control samples for each cell line) versus log10 of compound concentration in molar (M) units. Curve fitting was performed using four-parameter logistic regression. The percent SDMA/ADMA inhibition was calculated as follows: SDMA inhibition (%) = 100 x (1-SDMA/ADMA dose/SDMA/ADMADMSO control).

為評估MAT2A抑制是否改變蛋白質精胺酸甲基轉移酶PRMT5及PRMT1之酶活性，在DMSO之存在下或以劑量增加之化合物I將TF1細胞培養96 h。然後將該等細胞固定並用識別PRMT5依賴性SDMA或PRMT1依賴性ADMA之抗體染色。使用LI- COR成像系統定量分析ADMA及SDMA之染色強度(圖18)。此分析揭示化合物I處理以劑量依賴性方式降低ADMA含量，而不改變SDMA含量。 實例5：化合物I與PRMT1抑制劑之間的組合 To assess whether MAT2A inhibition alters the enzymatic activities of the protein arginine methyltransferases PRMT5 and PRMT1, TF1 cells were cultured for 96 h in the presence of DMSO or with increasing doses of Compound I. The cells were then fixed and stained with antibodies recognizing PRMT5-dependent SDMA or PRMT1-dependent ADMA. The staining intensity of ADMA and SDMA was quantified using the LI-COR imaging system (Figure 18). This analysis revealed that Compound I treatment decreased ADMA levels in a dose-dependent manner, but did not alter SDMA levels. Example 5: Combination between Compound I and a PRMT1 inhibitor

為評估MAT2A抑制劑是否可與PRMT1抑制劑組合並增強其活體外效力，對TF1及MV4-11細胞系進行細胞生長抑制分析。將此等細胞接種於96孔盤中並用濃度增加之PRMT1抑制劑(GSK3368715)，在DMSO或1 µMol/L化合物I之存在下培養96小時。使用Cell Titer Glo分析量測細胞生長抑制。此分析證實MAT2A抑制劑可增強PRMT1抑制劑延遲TF1及MV4-11細胞生長之能力(圖19)。 實例6：AML THP-1異種移植模型中式(I)化合物及維奈托克/阿紮胞苷之組合 To assess whether MAT2A inhibitors can be combined with PRMT1 inhibitors and enhance their in vitro potency, cytostatic assays were performed on TF1 and MV4-11 cell lines. These cells were seeded in 96-well plates and incubated with increasing concentrations of PRMT1 inhibitor (GSK3368715) in the presence of DMSO or 1 µMol/L Compound I for 96 hours. Cell growth inhibition was measured using the Cell Titer Glo assay. This analysis demonstrated that MAT2A inhibitors enhanced the ability of PRMT1 inhibitors to delay the growth of TF1 and MV4-11 cells (Figure 19). Example 6: Combination of compound of formula (I) and venetoclax/azacitidine in AML THP-1 xenograft model

研究目的：此研究之目的係評估以下潛在效用：1)每天一次(PO)單獨給藥之式(I)化合物，2)式(I)化合物與維奈托克/阿紮胞苷之組合，3)在維奈托克/阿紮胞苷組合雙聯體中用式(I)化合物代替阿紮胞苷，均在既定MTAP缺陷型AML異種移植腫瘤(THP-1)中，在雌性NOD SCID小鼠中。OBJECTIVES OF THE STUDY: The purpose of this study was to evaluate the potential utility of: 1) a compound of formula (I) administered once daily (PO) alone, 2) a combination of a compound of formula (I) with venetoclax/azacitidine, 3) Substitution of azacitidine with a compound of formula (I) in the venetoclax/azacitidine combination doublet, both in established MTAP-deficient AML xenograft tumors (THP-1), in female NOD SCID in mice.

研究設計：對20至22公克雌性NOD SCID小鼠皮下接種於無血清培養基+基質膠(1:1)中之5x10 6個THP-1細胞。腫瘤一經平均為144 mm 3，即在第14天將小鼠隨機分成處理組並如表2中概述給藥。 表2：研究設計/治療時間表 組 動物編號 處理 途徑 劑量及時間表 1 12 媒介物#1：5%DMSO+50%PEG300+5%Tween80+40%H 2O+媒介物#2：2.86% w/w聚合物A、1% w/w聚合物B、2% w/w表面活性劑、0.1%賦形劑+媒介物#3：無菌鹽水 PO       PO             IP (QDx18)       (QDx18)             (Q3Dx6) 2 12 式(I)化合物 PO 100 mg/kg，(QDx28) 3 12 阿紮胞苷 IP 3 mg/kg，(Q3Dx7) 4 12 維奈托克 PO 50 mg/kg，(QDx19) 5 12 維奈托克+阿紮胞苷 PO IP 50 mg/kg，(QDx22) 3 mg/kg，(Q3Dx8) 6 12 維奈托克+式(I)化合物 PO    PO 50 mg/kg，(QDx34)    100 mg/kg，(QDx34) 7 12 維奈托克+阿紮胞苷+式(I)化合物 PO IP    PO 50 mg/kg，(QDx34) 3 mg/kg，(Q3Dx12)    100 mg/kg，(QDx34) Study Design: 20 to 22 grams of female NOD SCID mice were inoculated subcutaneously with 5x106 THP-1 cells in serum free medium + Matrigel (1:1). Once tumors averaged 144 mm3 , mice were randomized into treatment groups on day 14 and dosed as outlined in Table 2. Table 2: Study Design/Treatment Schedule Group animal number deal with way Dosage and Schedule 1 12 Vehicle #1: 5% DMSO + 50% PEG300 + 5% Tween80 + 40% H 2 O + Vehicle #2: 2.86% w/w Polymer A, 1% w/w Polymer B, 2% w/w Surfactant, 0.1% Excipient + Vehicle #3: Sterile Saline PO PO IP (QDx18) (QDx18) (Q3Dx6) 2 12 Compounds of formula (I) PO 100 mg/kg, (QDx28) 3 12 azacitidine IP 3 mg/kg, (Q3Dx7) 4 12 Venetok PO 50 mg/kg, (QDx19) 5 12 venetoclax + azacitidine PO IP 50 mg/kg, (QDx22) 3 mg/kg, (Q3Dx8) 6 12 Venetoclax + compound of formula (I) PO PO 50 mg/kg, (QDx34) 100 mg/kg, (QDx34) 7 12 Venetoclax + azacitidine + compound of formula (I) PO IP PO 50 mg/kg, (QDx34) 3 mg/kg, (Q3Dx12) 100 mg/kg, (QDx34)

材料及方法：在兩個維度上使用游標尺每週兩次量測腫瘤體積，且體積係使用下式以mm 3計表示：V = (L x W x W)/2，其中V係腫瘤體積，L係腫瘤長度(最長腫瘤維度)及W係腫瘤寬度(垂直於L)。每週兩次量測體重。 Materials and methods: Tumor volume was measured twice weekly using a vernier scale in two dimensions, and volume was expressed in mm using the formula : V = (L x W x W)/2, where V is the tumor volume , L is for tumor length (longest tumor dimension) and W is for tumor width (perpendicular to L). Measure body weight twice a week.

式(I)化合物以包含非晶型式(I)之調配物之形式供應。該化合物在4℃下避光保存。將該式(I)化合物每天調配於由2.86% w/w聚合物A、1% w/w聚合物B、2% w/w表面活性劑及0.1%賦形劑構成之媒介物中。當在4℃下避光保存時，經調配之式(I)化合物係穩定24小時。The compound of formula (I) is supplied in a formulation comprising amorphous form (I). The compound was stored at 4°C in the dark. The compound of formula (I) was formulated daily in a vehicle consisting of 2.86% w/w polymer A, 1% w/w polymer B, 2% w/w surfactant and 0.1% excipient. The formulated compounds of formula (I) are stable for 24 hours when stored in the dark at 4°C.

針對第2、6及7組，以100 mg/kg每天經口給藥式(I)化合物。For groups 2, 6 and 7, the compound of formula (I) was administered orally daily at 100 mg/kg.

阿紮胞苷購買自Selleck (中國，目錄號S1782)並調配於無菌鹽水中。針對第3、5及7組，使用3 mg/kg IP給藥阿紮胞苷。Azacitidine was purchased from Selleck (China, catalog number S1782) and formulated in sterile saline. For Groups 3, 5, and 7, azacitidine was administered IP at 3 mg/kg.

維奈托克購買自Selleck (中國，目錄號8048)並調配於5% DMSO+50% PEG300+5% Tween80+40% H 2O中。針對第4、5、6及7組，使用50 mg/kg PO給藥維奈托克。 Venetoclax was purchased from Selleck (China, catalog number 8048) and formulated in 5% DMSO+50% PEG300+5% Tween80+40% H2O . For Groups 4, 5, 6, and 7, venetoclax was administered at 50 mg/kg PO.

第1組之媒介物製劑(僅媒介物)分別與式(I)化合物調配物、阿紮胞苷及維奈托克媒介物匹配。 結果： Vehicle formulations of Group 1 (vehicle only) were matched to the compound formulation of formula (I), azacitidine and venetoclax vehicles, respectively. result:

在研究期間，使用媒介物之治療係耐受性良好及0%體重損失(BWL)。腫瘤體積在治療第17天達成1571.95 mm 3之中值(表2)，此組之最後一次腫瘤量測。 Treatment with vehicle was well tolerated and 0% body weight loss (BWL) during the study period. Tumor volume reached a median of 1571.95 mm3 on treatment day 17 (Table 2), the last tumor measurement for this group.

使用100 mg/kg單獨式(I)化合物之治療(第2組)係耐受性良好及在治療第14天達成2%之最大中值BWL。腫瘤體積在治療第28天達成1123.94 mm 3之中值，此組之最後一次腫瘤量測。 Treatment with 100 mg/kg of compound of formula (I) alone (Group 2) was well tolerated and achieved a maximum median BWL of 2% on day 14 of treatment. Tumor volume reached a median of 1123.94 mm3 on day 28 of treatment, the last tumor measurement in this group.

在研究期間使用3 mg/kg單獨阿紮胞苷之治療(第3組)係耐受性良好，及0% BWL。腫瘤體積在治療第17天達成1319.61 mm 3之中值，此組之最後一次腫瘤量測。 Treatment with 3 mg/kg of azacitidine alone (Group 3) was well tolerated with 0% BWL during the study. Tumor volume reached a median of 1319.61 mm3 on day 17 of treatment, the last tumor measurement in this group.

使用50 mg/kg單獨維奈托克之治療(第4組)係耐受性良好，及在治療第3天達成2%之最大平均BWL。腫瘤體積在治療第17天達成1319.61 mm 3之中值，此組之最後一次腫瘤量測。 Treatment with venetoclax at 50 mg/kg alone (Group 4) was well tolerated and achieved a maximum mean BWL of 2% on day 3 of treatment. Tumor volume reached a median of 1319.61 mm3 on day 17 of treatment, the last tumor measurement in this group.

使用50 mg/kg維奈托克及3 mg/kg阿紮胞苷之組合之治療(第5組)係耐受性良好，及在治療第14天達成2%之中值BWL。腫瘤體積在治療第21天達成925.92 mm 3之中值，此組之最後一次腫瘤量測。 Treatment with the combination of 50 mg/kg venetoclax and 3 mg/kg azacitidine (Group 5) was well tolerated and achieved a median BWL of 2% on treatment day 14. Tumor volume reached a median of 925.92 mm3 on day 21 of treatment, the last tumor measurement for this group.

使用50 mg/kg維奈托克及100 mg/kg式(I)化合物之組合之治療(第6組)係耐受性良好，及在治療第17天達成6%之中值BWL。腫瘤體積在治療第34天達成478.03 mm 3之中值，此組之最後一次腫瘤量測。 Treatment with the combination of 50 mg/kg venetoclax and 100 mg/kg compound of formula (I) (Group 6) was well tolerated and achieved a median BWL of 6% on treatment day 17. Tumor volume reached a median value of 478.03 mm3 on day 34 of treatment, the last tumor measurement in this group.

使用50 mg/kg維奈托克+ 3 mg/kg阿紮胞苷+ 100 mg/kg式(I)化合物之組合之治療(第7組)係耐受性良好，及在治療第34天達成13%之中值BWL。腫瘤體積在治療第34天達成119.84 mm 3之中值，此組之最後一次腫瘤量測。 Treatment with the combination of 50 mg/kg venetoclax + 3 mg/kg azacitidine + 100 mg/kg compound of formula (I) (group 7) was well tolerated and achieved on day 34 of treatment 13% median BWL. Tumor volume reached a median of 119.84 mm3 on day 34 of treatment, the last tumor measurement in this group.

來自各組之腫瘤體積顯示於表3中並在圖20中以圖表闡述，且組結果顯示於表3中。使用化合物I、維奈托克及阿紮西汀(Azaciditine)之組合療法證實可加性抗腫瘤活性，且維奈托克及式(I)化合物之組合證實協同效應。 表3：量測之腫瘤體積及SEM          天(治療後開始) 第1組 第2組 第3組 第4組 第5組 第6組 第7組 中值(SEM) 中值(SEM) 中值(SEM) 中值(SEM) 中值(SEM) 中值(SEM) 中值(SEM) 0 143.5 (6.4) 143.7 (4.7) 144.0 (4.7) 145.0 (6.2) 143.8 (5.8) 144.3 (5.2) 143.2 (6.4) 3 237.1 (16.8) 193.6 (12.2) 206.5 (14.9) 195.8 (22.0) 188.5 (16.6) 180.3 (14.8) 175.1 (9.8) 7 510.0 (45.2) 324.2 (30.0) 400.1 (34.0) 388.7 (40.0) 250.9 (29.5) 203.8 (18.0) 171.3 (19.6) 10 673.2 (58.1) 364.4 (26.4) 567.6 (49.1) 623.9 (88.1) 321.3 (40.2) 222.5 (18.9) 135.1 (16.3) 14 1143.0 (77.6) 471.8 (30.0) 889.8 (79.8) 951.6 (106.8) 552.9 (63.0) 267.6 (27.6) 121.5 (13.6) 17 1572.0 (114.3) 542.3 (42.4) 1319.6 (121.0) 1284.8 (118.9) 649.2 (97.7) 202.0 (19.8) 110.0 (12.4) 21       710.6 (55.8)       925.9 (142.0) 213.0 (21.3) 90.9 (10.8) 24    846.6 (87.4)          297.7 (30.1) 93.0 (15.2) 28    1123.9 (88.8)          328.7 (37.7) 92.5 (15.6) 31                396.0 (36.4) 98.2 (16.6) 34                478.0 (50.0) 119.8 (17.8) 表4：第0至21天維奈托克與阿紮胞苷組合之統計分析 平均AUC第1組= 13.68087 平均AUC第3組= 11.86053 平均AUC第4組= 11.69741 平均AUC第5組= 7.85588 活體內協同效應評分：-14.7738747232625 p值：0.148273252091063 表5：第0至34天維奈托克與式(I)化合物組合之統計分析 平均AUC第1組= 27.060137 平均AUC第2組= 18.742613 平均AUC第4組= 23.754321 平均AUC第6組= 7.237104 活體內協同效應評分：-30.3017441545198 p值：0.00102017578810998 Tumor volumes from each group are shown in Table 3 and graphically illustrated in Figure 20, and group results are shown in Table 3. Additive antitumor activity was demonstrated with the combination therapy of Compound I, venetoclax and Azaciditine, and the combination of venetoclax and the compound of formula (I) demonstrated a synergistic effect. Table 3: Measured tumor volume and SEM days (start after treatment) Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 Median (SEM) Median (SEM) Median (SEM) Median (SEM) Median (SEM) Median (SEM) Median (SEM) 0 143.5 (6.4) 143.7 (4.7) 144.0 (4.7) 145.0 (6.2) 143.8 (5.8) 144.3 (5.2) 143.2 (6.4) 3 237.1 (16.8) 193.6 (12.2) 206.5 (14.9) 195.8 (22.0) 188.5 (16.6) 180.3 (14.8) 175.1 (9.8) 7 510.0 (45.2) 324.2 (30.0) 400.1 (34.0) 388.7 (40.0) 250.9 (29.5) 203.8 (18.0) 171.3 (19.6) 10 673.2 (58.1) 364.4 (26.4) 567.6 (49.1) 623.9 (88.1) 321.3 (40.2) 222.5 (18.9) 135.1 (16.3) 14 1143.0 (77.6) 471.8 (30.0) 889.8 (79.8) 951.6 (106.8) 552.9 (63.0) 267.6 (27.6) 121.5 (13.6) 17 1572.0 (114.3) 542.3 (42.4) 1319.6 (121.0) 1284.8 (118.9) 649.2 (97.7) 202.0 (19.8) 110.0 (12.4) twenty one 710.6 (55.8) 925.9 (142.0) 213.0 (21.3) 90.9 (10.8) twenty four 846.6 (87.4) 297.7 (30.1) 93.0 (15.2) 28 1123.9 (88.8) 328.7 (37.7) 92.5 (15.6) 31 396.0 (36.4) 98.2 (16.6) 34 478.0 (50.0) 119.8 (17.8) Table 4: Statistical analysis of the combination of venetoclax and azacitidine from days 0 to 21 Mean AUC Group 1 = 13.68087 Mean AUC Group 3 = 11.86053 Mean AUC Group 4 = 11.69741 Mean AUC Group 5 = 7.85588 In vivo synergy score: -14.7738747232625 p-value: 0.148273252091063 Table 5: Statistical analysis of venetoclax in combination with compounds of formula (I) from days 0 to 34 Mean AUC Group 1 = 27.060137 Mean AUC Group 2 = 18.742613 Mean AUC Group 4 = 23.754321 Mean AUC Group 6 = 7.237104 In vivo synergy score: -30.3017441545198 p-value: 0.00102017578810998

本說明書中引用之所有公開案、專利及專利申請案係以引用之方式併入本文中用於使用此引用之教示。All publications, patents, and patent applications cited in this specification are incorporated herein by reference for the teachings of the use of such citations.

所觀測到之特定反應可根據並取決於所選特定活性化合物或組合之給藥及調配物之類型及採用之投與模式而變化，且根據本發明之實務審慎考慮結果中之此等預期變化或差異。The particular responses observed may vary according to and depend upon the administration of the particular active compound or combination selected and the type of formulation and mode of administration employed, and such expected variations in results are carefully considered in accordance with the practice of the present invention. or difference.

儘管本文闡述並詳細描述本申請案之特定實施例，但本申請案不限於此。上文實施方式作為例示提供且不應視為限制。熟習此項技術者將顯而易見修飾，且不背離本申請案精神之所有修飾意欲包含在隨附申請專利範圍之範圍內。Although specific embodiments of the present application are set forth and described in detail herein, the present application is not limited thereto. The above embodiments are provided by way of illustration and should not be considered limiting. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of this application are intended to be included within the scope of the appended claims.

圖1A及1B顯示可用於本文所述方法中之例示性PARP抑制劑之化學結構。1A and 1B show the chemical structures of exemplary PARP inhibitors useful in the methods described herein.

圖2顯示可用於本文所述方法中之例示性Chk1抑制劑之化學結構。Figure 2 shows the chemical structures of exemplary Chkl inhibitors useful in the methods described herein.

圖3顯示可用於本文所述方法中之例示性MDM2抑制劑之化學結構。Figure 3 shows the chemical structures of exemplary MDM2 inhibitors useful in the methods described herein.

圖4A及4B顯示可用於本文所述方法中之例示性低甲基化劑之化學結構。4A and 4B show the chemical structures of exemplary hypomethylating agents that can be used in the methods described herein.

圖5A至5E顯示可用於本文所述方法中之例示性mTOR抑制劑之化學結構。Figures 5A-5E show the chemical structures of exemplary mTOR inhibitors useful in the methods described herein.

圖6顯示可用於本文所述方法中之例示性ATM抑制劑之化學結構。Figure 6 shows the chemical structures of exemplary ATM inhibitors useful in the methods described herein.

圖7A及7B顯示可用於本文所述方法中之例示性CDK 4/6抑制劑之化學結構。Figures 7A and 7B show chemical structures of exemplary CDK 4/6 inhibitors useful in the methods described herein.

圖8顯示可用於本文所述方法中之例示性PRMT5抑制劑之化學結構。Figure 8 shows the chemical structures of exemplary PRMT5 inhibitors useful in the methods described herein.

圖9顯示可用於本文所述方法中之例示性PRMT1抑制劑之化學結構。Figure 9 shows the chemical structures of exemplary PRMTl inhibitors useful in the methods described herein.

圖10A及10B顯示可用於本文所述方法中之例示性BCL-2抑制劑之化學結構。Figures 10A and 10B show the chemical structures of exemplary BCL-2 inhibitors useful in the methods described herein.

圖11顯示可用於本文所述方法中之例示性抗代謝藥之化學結構。Figure 11 shows the chemical structures of exemplary antimetabolites that can be used in the methods described herein.

圖12A至12C顯示可用於本文所述方法中之例示性極光抑制劑之化學結構。12A-12C show the chemical structures of exemplary aurora inhibitors useful in the methods described herein.

圖13顯示可用於本文所述方法中之例示性微管穩定劑之化學結構。Figure 13 shows the chemical structures of exemplary microtubule stabilizers useful in the methods described herein.

圖14顯示可用於本文所述方法中之例示性DNA交聯劑之化學結構。Figure 14 shows the chemical structures of exemplary DNA cross-linkers that can be used in the methods described herein.

圖15顯示在各種癌細胞系中與組合式(I)化合物及多種癌症治療劑相關聯之協同效應評分。Figure 15 shows the synergy scores associated with combining a compound of formula (I) and various cancer therapeutics in various cancer cell lines.

圖16顯示KP-4細胞中式(I)化合物及培美曲塞(Pemetrexed)組合之協同效應。Figure 16 shows the synergistic effect of the combination of the compound of formula (I) and Pemetrexed in KP-4 cells.

圖17顯示經式(I)化合物處理之TF1細胞中之全基因體亞硫酸氫鹽定序(WGBS)分析。Figure 17 shows whole genome bisulfite sequencing (WGBS) analysis in TF1 cells treated with compounds of formula (I).

圖18顯示證實式(I)化合物抑制TF1細胞中PRMT1依賴性ADMA標識之表現之細胞內西方墨點法分析。Figure 18 shows intracellular western blot analysis demonstrating that compounds of formula (I) inhibit expression of PRMT1-dependent ADMA labeling in TF1 cells.

圖19顯示細胞生長抑制分析以評估式(I)化合物與PRMT1抑制劑之組合對TF1及MV4-11細胞系之生長之影響。Figure 19 shows a cytostatic assay to assess the effect of the combination of a compound of formula (I) and a PRMT1 inhibitor on the growth of TF1 and MV4-11 cell lines.

圖20顯示式(I)化合物；維奈托克(ventoclax)及式(I)化合物；及維奈托克/氮胞苷(azacytidine)/式(I)化合物所對應的隨時間而變化的腫瘤體積。Figure 20 shows tumors of formula (I); venetoclax and compounds of formula (I); and venetoclax/azacytidine/compound of formula (I) as a function of time volume.

Figure 110129858-A0101-11-0002-1
Figure 110129858-A0101-11-0002-1

Claims (65)

一種用於治療有需要病患中癌症之方法，其包括對該病患投與： (a)治療有效量之式(I)化合物：
Figure 03_image002
式(I) 或其醫藥上可接受之鹽；及 (b)治療有效量之治療劑，其中該治療劑係PARP抑制劑、Chk1抑制劑、MDM2抑制劑、低甲基化劑、mTOR抑制劑、ATM抑制劑、CDK 4/6抑制劑、BCL-2抑制劑、PRMT5抑制劑或PRMT1抑制劑。 A method for treating cancer in a patient in need thereof, comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I):
Figure 03_image002
Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a PARP inhibitor, a Chk1 inhibitor, an MDM2 inhibitor, a hypomethylating agent, an mTOR inhibitor , ATM inhibitor, CDK 4/6 inhibitor, BCL-2 inhibitor, PRMT5 inhibitor or PRMT1 inhibitor. 如請求項1之方法，其中該治療劑係PARP抑制劑。The method of claim 1, wherein the therapeutic agent is a PARP inhibitor. 如請求項2之方法，其中該PARP抑制劑係奧拉帕尼(Olaparib) (AZD2281)、維利帕利布(Veliparib) (ABT-888)、磷酸魯卡帕裡布(Rucaparib) (AG-014699)、他拉唑帕尼(Talazoparib) (BMN 673)、AG-14361、INO-1001 (3-胺基苯甲醯胺)、A-966492、PJ34 HCl、尼拉帕裡布(Niraparib) (MK-4827)、UPF 1069、ME0328、RK-287107、帕米帕利布(Pamiparib) (BGB-290)、NMS-P118、E7449、吡啶甲醯胺(Picolinamide)、苯甲醯胺、甲苯磺酸尼拉帕裡布(Niraparib) (MK-4827)、NU1025、尼帕利布(Iniparib) (BSI-201)、AZD2461、BGP-15 2HCl、XAV-939、4-羥基喹唑啉、NVP-TNKS656、MN 64或G007-LK；或其醫藥上可接受之鹽。The method of claim 2, wherein the PARP inhibitor is Olaparib (AZD2281), Veliparib (ABT-888), Rucaparib phosphate (AG- 014699), Talazoparib (BMN 673), AG-14361, INO-1001 (3-aminobenzamide), A-966492, PJ34 HCl, Niraparib ( MK-4827), UPF 1069, ME0328, RK-287107, Pamiparib (BGB-290), NMS-P118, E7449, Picolinamide, benzamide, toluenesulfonic acid Niraparib (MK-4827), NU1025, Iniparib (BSI-201), AZD2461, BGP-15 2HCl, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656 , MN 64 or G007-LK; or a pharmaceutically acceptable salt thereof. 如請求項3之方法，其中該PARP抑制劑係奧拉帕尼(AZD2281)或他拉唑帕尼(BMN 673)；或其醫藥上可接受之鹽。The method of claim 3, wherein the PARP inhibitor is olaparib (AZD2281) or tarazopanib (BMN 673); or a pharmaceutically acceptable salt thereof. 如請求項4之方法，其中該PARP抑制劑係奧拉帕尼(AZD2281)或其醫藥上可接受之鹽。The method of claim 4, wherein the PARP inhibitor is olaparib (AZD2281) or a pharmaceutically acceptable salt thereof. 如請求項4之方法，其中該PARP抑制劑係他拉唑帕尼(BMN 673)；或其醫藥上可接受之鹽。The method of claim 4, wherein the PARP inhibitor is tarazopanib (BMN 673); or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係Chk1抑制劑。The method of claim 1, wherein the therapeutic agent is a Chk1 inhibitor. 如請求項7之方法，其中該Chk1抑制劑係AZD7762、拉布塞蒂布(Rabusertib) (LY2603618)、MK-8776 (SCH 900776)、CHIR-124、PF-477736、VX-803 (M4344)、GDC-0575 (ARRY-575)、SAR-020106、CCT245737、PD0166285或普雷沙替鹽酸鹽(Prexasertib HCl) (LY2606368)；或其醫藥上可接受之鹽。The method of claim 7, wherein the Chk1 inhibitor is AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC-0575 (ARRY-575), SAR-020106, CCT245737, PD0166285, or Prexasertib HCl (LY2606368); or a pharmaceutically acceptable salt thereof. 如請求項8之方法，其中該Chk1抑制劑係AZD7762或拉布塞蒂布(LY2603618)或其醫藥上可接受之鹽。The method of claim 8, wherein the Chk1 inhibitor is AZD7762 or Labsetib (LY2603618) or a pharmaceutically acceptable salt thereof. 如請求項9之方法，其中該Chk1抑制劑係AZD7762或其醫藥上可接受之鹽。The method of claim 9, wherein the Chk1 inhibitor is AZD7762 or a pharmaceutically acceptable salt thereof. 如請求項9之方法，其中該Chk1抑制劑係拉布塞蒂布(LY2603618)或其醫藥上可接受之鹽。The method of claim 9, wherein the Chk1 inhibitor is labsetib (LY2603618) or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係MDM2抑制劑。The method of claim 1, wherein the therapeutic agent is an MDM2 inhibitor. 如請求項12之方法，其中該MDM2抑制劑係努特林(Nutlin)-3、NSC 207895、努特林-3a、努特林-3b、MX69、NVP-CGM097、MI-773 (SAR405838)、伊達沙努特林(Idasanutlin) (RG-7388)、RG-7112、HDM201 (西雷馬德林(Siremadlin))、YH239-EE、(-)-小白菊內酯(Parthenolide)或色地美坦(Serdemetan) (JNJ-26854165)；或其醫藥上可接受之鹽。The method of claim 12, wherein the MDM2 inhibitor is Nutlin-3, NSC 207895, Nutlin-3a, Nutlin-3b, MX69, NVP-CGM097, MI-773 (SAR405838), Idasanutlin (RG-7388), RG-7112, HDM201 (Siremadlin), YH239-EE, (-)-Parthenolide or Serdemetan ) (JNJ-26854165); or a pharmaceutically acceptable salt thereof. 如請求項13之方法，其中該MDM2抑制劑係努特林-3或色地美坦(JNJ-26854165)或其醫藥上可接受之鹽。The method of claim 13, wherein the MDM2 inhibitor is nutrin-3 or sedimetane (JNJ-26854165) or a pharmaceutically acceptable salt thereof. 如請求項14之方法，其中該MDM2抑制劑係努特林-3或其醫藥上可接受之鹽。The method of claim 14, wherein the MDM2 inhibitor is Nutrin-3 or a pharmaceutically acceptable salt thereof. 如請求項14之方法，其中該MDM2抑制劑係色地美坦(JNJ-26854165)或其醫藥上可接受之鹽。The method of claim 14, wherein the MDM2 inhibitor is sedemestane (JNJ-26854165) or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係低甲基化劑。The method of claim 1, wherein the therapeutic agent is a hypomethylating agent. 如請求項17之方法，其中該低甲基化劑係地西他濱(Decitabine)、阿紮胞苷(Azacitidine) (5-氮胞苷)、RG108、硫鳥嘌呤(Thioguanine)、西布拉林(Zebularine)、SGI-1027、CM272、2'-脫氧-5-氟胞苷、普魯卡因胺鹽酸鹽(Procainamide HCl)、Bobcat339鹽酸鹽、γ-米糠醇(Gamma-Oryzanol)、β-檜酚酮(β-thujaplicin)或(-)-表沒食子兒茶素沒食子酸酯(Epigallocatechin Gallate)；或其醫藥上可接受之鹽。The method of claim 17, wherein the hypomethylating agent is Decitabine, Azacitidine (5-azacytidine), RG108, Thioguanine, Sibra Zebularine, SGI-1027, CM272, 2'-deoxy-5-fluorocytidine, Procainamide HCl, Bobcat339 hydrochloride, Gamma-Oryzanol, β-thujaplicin or (-)-epigallocatechin gallate; or a pharmaceutically acceptable salt thereof. 如請求項18之方法，其中該低甲基化劑係地西他濱或阿紮胞苷(5-氮胞苷)或其醫藥上可接受之鹽。The method of claim 18, wherein the hypomethylating agent is decitabine or azacitidine (5-azacytidine) or a pharmaceutically acceptable salt thereof. 如請求項19之方法，其中該低甲基化劑係地西他濱或其醫藥上可接受之鹽。The method of claim 19, wherein the hypomethylating agent is decitabine or a pharmaceutically acceptable salt thereof. 如請求項19之方法，其中該低甲基化劑係阿紮胞苷(5-氮胞苷)或其醫藥上可接受之鹽。The method of claim 19, wherein the hypomethylating agent is azacitidine (5-azacytidine) or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係mTOR抑制劑。The method of claim 1, wherein the therapeutic agent is an mTOR inhibitor. 如請求項22之方法，其中該mTOR抑制劑係達克利司(Dactolisib) (BEZ235)、雷帕黴素(Rapamycin) (西羅莫司(Sirolimus))、依維莫司(Everolimus) (RAD001)、AZD8055、替西羅莫司(Temsirolimus) (CCI-779)、PI-103、KU-0063794、托基尼布(Torkinib) (PP242)、利達福莫司(Ridaforolimus) (地福莫司(Deforolimus)、MK-8669)、沙帕舍替(Sapanisertib) (MLN0128)、沃他利司(Voxtalisib) (XL765)類似物、通潤1 (Torin 1)、奧帕利司(Omipalisib) (GSK2126458)、OSI-027、PF-04691502、阿托利司(Apitolisib) (GDC-0980)、GSK1059615、吉托利司(Gedatolisib) (PKI-587)、WYE-354、維妥色替(Vistusertib) (AZD2014)、通潤2、WYE-125132 (WYE-132)、PP121、WYE-687、WAY-600、ETP-46464、GDC-0349、XL388、GNE-477、比米利司(Bimiralisib) (PQR309)、SF2523、CZ415、派克利塞(Paxalisib) (GDC-0084)、CC-115、奧納塔塞爾蒂布(Onatasertib) (CC 223)、沃他利司(XL765)、佐他莫司(Zotarolimus) (ABT-578)、他克莫司(Tacrolimus) (FK506)、馬來酸BGT226 (馬來酸NVP-BGT226)、帕羅米德529 (Palomid 529) (P529)、LY3023414(沙托利塞(Samotolisib))或大黃酸(Chrysophanic Acid)；或其醫藥上可接受之鹽。The method of claim 22, wherein the mTOR inhibitor is Dactolisib (BEZ235), Rapamycin (Sirolimus), Everolimus (RAD001) , AZD8055, Temsirolimus (CCI-779), PI-103, KU-0063794, Torkinib (PP242), Ridaforolimus (Deforolimus) , MK-8669), Sapanisertib (MLN0128), Voxtalisib (XL765) analogs, Torin 1, Omipalisib (GSK2126458), OSI -027, PF-04691502, Apitolisib (GDC-0980), GSK1059615, Gedatolisib (PKI-587), WYE-354, Vistusertib (AZD2014), Tongrun 2, WYE-125132 (WYE-132), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, Bimiralisib (PQR309), SF2523, CZ415 , Paxalisib (GDC-0084), CC-115, Onatasertib (CC 223), Votalis (XL765), Zotarolimus (ABT- 578), Tacrolimus (FK506), BGT226 maleate (NVP-BGT226 maleate), Palomid 529 (P529), LY3023414 (Samotolisib) Or rhein (Chrysophanic Acid); or its pharmaceutically acceptable salt. 如請求項23之方法，其中該mTOR抑制劑係依維莫司(RAD001)或其醫藥上可接受之鹽。The method of claim 23, wherein the mTOR inhibitor is everolimus (RAD001) or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係ATM抑制劑。The method of claim 1, wherein the therapeutic agent is an ATM inhibitor. 如請求項25之方法，其中該ATM抑制劑係KU-55933、KU-60019、渥曼青黴素(Wortmannin)、通潤2、CP-466722、ETP-46464、CGK 733、AZ32、AZD1390、AZ31或AZD0156；或其醫藥上可接受之鹽。The method of claim 25, wherein the ATM inhibitor is KU-55933, KU-60019, Wortmannin, Tongrun 2, CP-466722, ETP-46464, CGK 733, AZ32, AZD1390, AZ31 or AZD0156 ; or a pharmaceutically acceptable salt thereof. 如請求項26之方法，其中該ATM抑制劑係KU-60019或其醫藥上可接受之鹽。The method of claim 26, wherein the ATM inhibitor is KU-60019 or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係CDK 4/6抑制劑。The method of claim 1, wherein the therapeutic agent is a CDK 4/6 inhibitor. 如請求項28之方法，其中該CDK 4/6抑制劑係帕博西尼(Palbociclib) (PD-0332991)、帕博西尼鹽酸鹽(PD-0332991)、氟哌啶醇(Flavopiridol) (夫拉平度(Alvocidib))、AT7519、氟哌啶醇鹽酸鹽、JNJ-7706621、PHA-793887、羥乙基磺酸帕博西尼(PD0332991)、甲磺酸阿貝西利(abemaciclib mesylate) (LY2835219)、BMS-265246、米爾西利(Milciclib) (PHA-848125)、R547、利維昔布鹽酸鹽(Riviciclib hydrochloride) (P276-00)、MC180295、G1T38、阿貝西利、ON123300、AT7519 HCl、嘌呤醇A (Purvalanol A)、SU9516、瑞波西尼(Ribociclib) (LEE011)或BSJ-03-123；或其醫藥上可接受之鹽。The method of claim 28, wherein the CDK 4/6 inhibitor is Palbociclib (PD-0332991), Palbociclib hydrochloride (PD-0332991), Flavopiridol ( Alvocidib), AT7519, Haloperidol hydrochloride, JNJ-7706621, PHA-793887, Palbociclib isethionate (PD0332991), abemaciclib mesylate ( LY2835219), BMS-265246, Mirciclib (PHA-848125), R547, Riviciclib hydrochloride (P276-00), MC180295, G1T38, Abeccil, ON123300, AT7519 HCl, Purinol A (Purvalanol A), SU9516, Ribociclib (LEE011) or BSJ-03-123; or a pharmaceutically acceptable salt thereof. 如請求項29之方法，其中該CDK 4/6抑制劑係帕博西尼(PD-0332991)或其醫藥上可接受之鹽。The method of claim 29, wherein the CDK 4/6 inhibitor is palbociclib (PD-0332991) or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係BCL-2抑制劑。The method of claim 1, wherein the therapeutic agent is a BCL-2 inhibitor. 如請求項31之方法，其中該BCL-2抑制劑係ABT-737、納維托克(Navitoclax) (ABT-263)、甲磺酸奧巴克拉(Obatoclax Mesylate) (GX15-070)、TW-37、維奈托克(Venetoclax) (ABT-199)、AT101、HA14-1、沙布托克(Sabutoclax)、S55746或藤黃酸(Gambogic Acid)；或其醫藥上可接受之鹽。The method of claim 31, wherein the BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW- 37. Venetoclax (ABT-199), AT101, HA14-1, Sabutoclax, S55746 or Gambogic Acid; or a pharmaceutically acceptable salt thereof. 如請求項32之方法，其中該BCL-2抑制劑係維奈托克(ABT-199)或其醫藥上可接受之鹽。The method of claim 32, wherein the BCL-2 inhibitor is venetoclax (ABT-199) or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係PRMT5抑制劑。The method of claim 1, wherein the therapeutic agent is a PRMT5 inhibitor. 如請求項34之方法，其中該PRMT5抑制劑係JNJ-64619178 (AGI-931)、HLCL-61、GSK591、EPZ015666(GSK3235025)、GSK3326595 (EPZ015938；AGI-219)；或其醫藥上可接受之鹽。The method of claim 34, wherein the PRMT5 inhibitor is JNJ-64619178 (AGI-931), HLCL-61, GSK591, EPZ015666 (GSK3235025), GSK3326595 (EPZ015938; AGI-219); or a pharmaceutically acceptable salt thereof . 如請求項35之方法，其中該PRMT5抑制劑係GSK3326595 (EPZ015938；AGI-219)或JNJ-64619178 (AGI-931)；或其醫藥上可接受之鹽。The method of claim 35, wherein the PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or JNJ-64619178 (AGI-931); or a pharmaceutically acceptable salt thereof. 如請求項36之方法，其中該PRMT5抑制劑係GSK3326595 (EPZ015938；AGI-219)或其醫藥上可接受之鹽。The method of claim 36, wherein the PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or a pharmaceutically acceptable salt thereof. 如請求項36之方法，其中該PRMT5抑制劑係JNJ-64619178 (AGI-931)或其醫藥上可接受之鹽。The method of claim 36, wherein the PRMT5 inhibitor is JNJ-64619178 (AGI-931) or a pharmaceutically acceptable salt thereof. 如請求項1之方法，其中該治療劑係PRMT1抑制劑。The method of claim 1, wherein the therapeutic agent is a PRMT1 inhibitor. 如請求項39之方法，其中該PRMT1抑制劑係GSK3368715 (EPZ019997)、C7280948、EPZ020411 2HCl、MS023或AMI-1；或所列舉化合物之醫藥上可接受之鹽。The method of claim 39, wherein the PRMT1 inhibitor is GSK3368715 (EPZ019997), C7280948, EPZ020411 2HCl, MS023 or AMI-1; or a pharmaceutically acceptable salt of the enumerated compound. 如請求項40之方法，其中該PRMT1抑制劑係GSK3368715 (EPZ019997)或其醫藥上可接受之鹽。The method of claim 40, wherein the PRMT1 inhibitor is GSK3368715 (EPZ019997) or a pharmaceutically acceptable salt thereof. 如請求項1至41中任一項之方法，其進一步包括對該病患投與另一治療劑。The method of any one of claims 1 to 41, further comprising administering to the patient another therapeutic agent. 如請求項42之方法，其中該另一治療劑係PARP抑制劑、Chk1抑制劑、MDM2抑制劑、低甲基化劑、mTOR抑制劑、ATM抑制劑、CDK 4/6抑制劑、PRMT5抑制劑、PRMT1抑制劑、抗代謝藥、極光(Aurora)抑制劑、微管穩定劑、DNA交聯劑或BCL-2抑制劑。The method of claim 42, wherein the other therapeutic agent is a PARP inhibitor, a Chk1 inhibitor, an MDM2 inhibitor, a hypomethylating agent, an mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a PRMT5 inhibitor , PRMT1 inhibitors, antimetabolites, Aurora inhibitors, microtubule stabilizers, DNA cross-linkers or BCL-2 inhibitors. 如請求項1至43中任一項之方法，其中該癌症係MTAP缺陷型癌症。The method of any one of claims 1 to 43, wherein the cancer is an MTAP-deficient cancer. 如請求項1至43中任一項之方法，其中該癌症係MTAP野生型癌症。The method of any one of claims 1 to 43, wherein the cancer is an MTAP wild-type cancer. 如請求項1至45中任一項之方法，其中該癌症係對由於投與MAT2A抑制劑所致之SAM減少產生反應之癌症。The method of any one of claims 1 to 45, wherein the cancer is a cancer responsive to a reduction in SAM due to administration of a MAT2A inhibitor. 如請求項1至46中任一項之方法，其中該癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(acute myeloid leukemia；AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(non-small cell lung cancer；NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤(non-Hodgkin lymphoma)或間皮瘤。The method of any one of claims 1 to 46, wherein the cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, Non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, intrauterine cancer Membranous cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma. 一種用於治療有需要病患中癌症之方法，其包括對該病患投與： (a)治療有效量之式(I)化合物：
Figure 03_image002
式(I) 或其醫藥上可接受之鹽；及 (b)治療有效量之治療劑，其中該治療劑係抗代謝藥、極光抑制劑、DNA交聯劑或微管穩定劑； 其中該癌症係MTAP野生型癌症。 A method for treating cancer in a patient in need thereof, comprising administering to the patient: (a) a therapeutically effective amount of a compound of formula (I):
Figure 03_image002
Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is an antimetabolite, aurora inhibitor, DNA cross-linking agent or microtubule stabilizer; wherein the cancer Line MTAP wild-type cancer. 如請求項48之方法，其中該癌症係原發性白血病、血液系統惡性腫瘤、急性骨髓性白血病(AML)、神經膠質瘤、黑色素瘤、胰臟癌、非小細胞肺癌(NSCLC)、膀胱癌、腎癌、結腸直腸癌、食道癌、星細胞瘤、骨肉瘤、頭頸癌、骨外黏液樣軟骨肉瘤、卵巢癌、子宮內膜癌、乳癌、軟組織肉瘤、非何傑金氏淋巴瘤或間皮瘤。The method of claim 48, wherein the cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer , kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, extraosseous myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma or skin tumor. 如請求項48或請求項49之方法，其中該治療劑係抗代謝藥。The method of claim 48 or claim 49, wherein the therapeutic agent is an antimetabolite. 如請求項50之方法，其中該抗代謝藥係培美曲塞(pemetrexed)。The method of claim 50, wherein the antimetabolite is pemetrexed. 如請求項50之方法，其中該抗代謝藥係吉西他濱(gemcitabine)或其醫藥上可接受之鹽。The method of claim 50, wherein the antimetabolite is gemcitabine or a pharmaceutically acceptable salt thereof. 如請求項48或請求項49之方法，其中該治療劑係極光抑制劑。The method of claim 48 or claim 49, wherein the therapeutic agent is an aurora inhibitor. 如請求項48或請求項49之方法，其中該治療劑係微管穩定劑。The method of claim 48 or claim 49, wherein the therapeutic agent is a microtubule stabilizer. 如請求項48或請求項49之方法，其中該治療劑係DNA交聯劑。The method of claim 48 or claim 49, wherein the therapeutic agent is a DNA cross-linking agent. 一種用於治療有需要病患中癌症之方法，其包括對該病患投與： 治療有效量之式(I)化合物：
Figure 03_image002
式(I) 或其醫藥上可接受之鹽；其中該癌症係急性骨髓性白血病(AML)。 A method for treating cancer in a patient in need thereof, comprising administering to the patient: a therapeutically effective amount of a compound of formula (I):
Figure 03_image002
Formula (I) or a pharmaceutically acceptable salt thereof; wherein the cancer is acute myeloid leukemia (AML). 如請求項56之方法，其中該AML係MTAP缺陷型。The method of claim 56, wherein the AML is MTAP deficient. 如請求項56之方法，其中該AML係MTAP野生型。The method of claim 56, wherein the AML is MTAP wild-type. 如請求項56至58中任一項之方法，其中該AML對由於投與MAT2A抑制劑所致之SAM減少產生反應。The method of any one of claims 56 to 58, wherein the AML is responsive to a reduction in SAM due to administration of a MAT2A inhibitor. 如請求項56至59中任一項之方法，其進一步包括對該病患投與治療有效量之BCL-2抑制劑。The method of any one of claims 56 to 59, further comprising administering to the patient a therapeutically effective amount of a BCL-2 inhibitor. 如請求項60之方法，其中該BCL-2抑制劑係ABT-737、納維托克(ABT-263)、甲磺酸奧巴克拉(GX15-070)、TW-37、維奈托克(ABT-199)、AT101、HA14-1、沙布托克、S55746或藤黃酸；或其醫藥上可接受之鹽。The method of claim 60, wherein the BCL-2 inhibitor is ABT-737, Navitas (ABT-263), Obacela mesylate (GX15-070), TW-37, Venetoclax ( ABT-199), AT101, HA14-1, Sabutok, S55746 or gambogic acid; or a pharmaceutically acceptable salt thereof. 如請求項61之方法，其中該BCL-2抑制劑係維奈托克或其醫藥上可接受之鹽。The method of claim 61, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. 如請求項60至62中任一項之方法，其進一步包括對該病患投與治療有效量之低甲基化劑。The method of any one of claims 60 to 62, further comprising administering to the patient a therapeutically effective amount of a hypomethylating agent. 如請求項63之方法，其中該低甲基化劑係地西他濱、阿紮胞苷(5-氮胞苷)、RG108、硫鳥嘌呤、西布拉林、SGI-1027、CM272、2'-脫氧-5-氟胞苷、普魯卡因胺鹽酸鹽、Bobcat339鹽酸鹽、γ-米糠醇、β-檜酚酮或(-)-表沒食子兒茶素沒食子酸酯；或其醫藥上可接受之鹽。The method of claim 63, wherein the hypomethylating agent is decitabine, azacitidine (5-azacytidine), RG108, thioguanine, sibraline, SGI-1027, CM272, 2 '-Deoxy-5-fluorocytidine, procainamide hydrochloride, Bobcat339 hydrochloride, γ-ricefuryl alcohol, β-cypressone or (-)-epigallocatechin gallic acid ester; or a pharmaceutically acceptable salt thereof. 如請求項64之方法，其中該低甲基化劑係阿紮胞苷(5-氮胞苷)或其醫藥上可接受之鹽。The method of claim 64, wherein the hypomethylating agent is azacitidine (5-azacytidine) or a pharmaceutically acceptable salt thereof.
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