TWI839921B - Cd73化合物 - Google Patents
Cd73化合物 Download PDFInfo
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- TWI839921B TWI839921B TW111141131A TW111141131A TWI839921B TW I839921 B TWI839921 B TW I839921B TW 111141131 A TW111141131 A TW 111141131A TW 111141131 A TW111141131 A TW 111141131A TW I839921 B TWI839921 B TW I839921B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Epidemiology (AREA)
Abstract
本文中提供一種式I之化合物:
Description
醣基-磷脂醯肌醇-錨定之CD73抗原(亦稱為分化簇73、外-5'-核苷酸酶、外-5'-NT、5'-NT、及NT5E)在胞外腺苷之生成中被視為速率限制酶(Stagg J, Smyth MJ.Extracellular adenosine triphosphate and adenosine in cancer.Oncogene. 2010;29:5346-58. doi:10.1038/onc.2010.292)。CD73係一種70-kDa醣基磷脂醯肌醇(glycosylphosphatidylinositol, GPI)錨定之蛋白質,通常表現於內皮細胞及造血細胞之亞群上。CD73連同CD39調控三磷酸腺苷(ATP)代謝。CD39 (NTPDase-1)將ATP轉換成AMP,僅釋放微量的ADP,而CD73催化將AMP轉化成腺苷(Ado)。
胞外Ado累積在癌性組織中且構成腫瘤免疫逃脫之重要機制。在其他作用中,腫瘤衍生之Ado顯著地抑制浸潤性效應T細胞(infiltrating effector T cell)。ATP通過在鼠類Treg(調控CD4+ T細胞)上共表現之CD39及CD73降解成Ado已顯示為造成腫瘤免疫抑制之原因。
在各種類型的癌細胞上可找到以高水平組成性表現之CD73。CD73生成之腺苷被認為抑制適應性抗腫瘤免疫反應,從而促進腫瘤生長及轉移。並且在動物模型中之研究已顯示阻斷CD73活性藉由促進抗腫瘤適應性免疫來抑制腫瘤生長並延長生存期(Forte et al. (2012) J Immunol. l89(5):2226-33)。鑒於癌症治療之需要,需要用於調控CD73活性及相關治療劑之新組成物及方法。本揭露滿足此與其他需求。
在一個實施例中,本揭露提供一種式I之化合物:
I,
或其醫藥上可接受之鹽,其中:
X係C、或N,
Y係CH、或N;
Z係C、或N;
前提是X、Y、及Z中之一者係CH、或C,且X、Y、及Z中之二者係N;
R
1係選自H、及CH
2OP(O)(OH)
2;
R
2係C
3-6環烷基、或3至8員雜環基;其中該環烷基及該雜環基係經一或多個R
4取代,
R
3係H、或鹵基;
R
4係獨立地選自H、鹵基、C
1-4烷基、-OR
5-、C
6-10芳基、或4至10員雜芳基;其中該C
1-4烷基、C
6-10芳基、或4至10員雜芳基係可選地經一或多個R
6取代;
R
5係C
1-
5烷基、C
1-
5烯基、C
1-
5炔基,該C
1-
5烷基、C
1-
5烯基、C
1-
5炔基、C
6-10芳基、或4至10員雜芳基且係可選地經一或多個R
6及鹵基取代;
R
6係C
1-
5烷基、C
3-6環烷基、C
1-
5烯基、C
1-
5炔基、或4至10員雜芳基,該C
1-
5烷基、C
3-6環烷基、C
1-
5烯基、或C
1-
5炔基係可選地經鹵基取代,且該4至10員雜芳基可選地經C
1-4烷基、或C
1-4鹵烷基取代。
在一些實施例中,R
1係H。在其他實施例中,R
1係CH
2OP(O)(OH)
2。
在一些實施例中,R
2係經一或多個R
4取代之C
3-6環烷基。
在其他實施例中,R
2係經一或多個R
4取代之3至8員雜環基。
相關申請案之交互參照
本申請案主張2021年10月29日申請且標題為「CD73 Compounds」之美國臨時專利申請案第63/273,454號之優先權,其全文以引用方式併入本文中。
I. 實例
縮寫.在描述實驗細節中使用某些縮寫及頭字語。雖然所屬技術領域中具有通常知識者會理解此等中之大多數者,但表1含有許多此等縮寫及頭字語之清單。
表1.縮寫及頭字語之清單。
通用程序1 : 製備二- 三級丁基((5-(8-(3,3- 二氟-4,4- 二甲基吡咯啶-1- 基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基) 磷酸酯
縮寫 | 定義 |
Ac | 乙酸鹽 |
Ar | 氬 |
ACN | 乙腈 |
cat | 催化劑 |
DCM | 二氯甲烷 |
DIPEA | N,N-二異丙基乙基胺 |
DMSO | 二甲基亞碸 |
DMF | 二甲基甲醯胺 |
ES/MS | 電子噴灑質譜法 |
Et | 乙基 |
EtOAc | 乙酸乙酯 |
HPLC | 高效液相層析法 |
LC | 液相層析法 |
Me | 甲基 |
MeCN | 乙腈 |
m/z | 質荷比 |
NMP | N-甲基-2-吡咯啶酮 |
NMR | 核磁共振 |
Ph | 苯基 |
Pd(dppf)Cl 2或PdCl 2(dppf) | [1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) |
Pr | 丙基 |
RP | 逆相 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TBHP | 三級丁基過氧化氫 |
δ | 參考殘留非氘化溶劑峰的百萬分點 |
向5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮(500 mg,1.38 mmol,1當量)及三乙胺(0.67 Ml,4.83 mmol,3.5當量)於DMF (16 Ml)中之溶液中添加(氯甲基)磷酸二-三級丁酯(1.07 g,4.14 mmol,3當量)。將反應混合物加熱至60℃並攪拌16小時。添加另一等分試樣的(氯甲基)磷酸二-三級丁酯(1.07 g,4.14 mmol,3當量)及三乙胺(0.67 Ml,4.83 mmol,3.5當量)並將反應再攪拌16小時。隨後將反應混合物用EtOAc/水稀釋,用EtOAc萃取兩次。將合併之有機層以MgSO4乾燥,過濾並在真空中濃縮。將粗製產物藉由矽膠層析法(100% EtOAc)純化,以提供二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯。
製備(5-(8-(3,3- 二氟-4,4- 二甲基吡咯啶-1- 基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基二氫磷酸酯
向二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯(671 mg,1.15 mmol,1當量)於DCM (15 mL)中之溶液中添加TFA (5 mL)。將反應混合物在室溫下攪拌15分鐘,之後在真空中濃縮並藉由HPLC(10至80% MeCN/水(含TFA))純化。LC-MS m/z: 473.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.25 (s, 1H), 8.08 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 6.54 (s, 1H), 5.53 (d, J = 10.7 Hz, 2H), 4.41 (s, 2H), 3.86 (s, 2H), 1.21 (s, 6H)。19F NMR (376 MHz, DMSO-d6) δ -115.33 (m, 2F)。31P NMR (162 MHz, DMSO-d6) δ -2.24 (t, J = 10.6 Hz, 1P)。
下列化合物係以類似於(5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯之方式,使用以下所列之修改製備:
二-三級丁基((2,4-二側氧基-5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯係使用5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽代替5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮製備
5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1-H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮係使用二-三級丁基((2,4-二側氧基-5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯代替二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 578.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.33 (s, 1H), 8.28 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.77 – 7.66 (m, 3H), 7.49 (s, 1H), 7.13 (dd, J = 8.6, 1.2 Hz, 1H), 5.56 (d, J = 10.8 Hz, 2H), 5.41 (q, J = 9.1 Hz, 2H), 3.09 – 3.00 (m, 1H), 2.81 (dt, J = 9.6, 5.2 Hz, 1H), 2.19 (dt, J = 9.4, 5.1 Hz, 1H), 1.89 (dt, J = 9.4, 5.3 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -70.08 (t, J = 9.1 Hz, 3F)。31P NMR (162 MHz, DMSO-d6) δ -2.22 (t, J = 11.0 Hz, 1P)。
四-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)係使用5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮代替5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮製備。
(5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基嘧啶-1,3(2H,4H)-二基)雙(亞甲基)雙(二氫磷酸酯)係使用四-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)代替二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 706.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 7.1 Hz, 1H), 7.43 (s, 1H), 7.13 (dd, J = 8.4, 1.4 Hz, 1H), 5.69 (d, J = 6.5 Hz, 2H), 5.64 (d, J = 10.8 Hz, 2H), 5.41 (q, J = 9.2 Hz, 2H), 3.02 (ddd, J = 8.9, 6.3, 4.3 Hz, 1H), 2.83 (ddd, J = 8.8, 5.9, 4.3 Hz, 1H), 2.21 – 2.09 (m, 1H), 1.91 (dt, J = 8.7, 5.5 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -70.08 (t, J = 9.1 Hz, 3F), -155.02 (d, J = 7.2 Hz, 1F)。31P NMR (162 MHz, DMSO-d6) δ -2.18 (t, J = 11.0 Hz, 1P), -3.44 (t, J = 6.5 Hz, 1P)。
通用程序2 : 製備二- 三級丁基((5-(3- 氟-8-((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吲唑-6- 基) 環丙基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基) 磷酸酯
向5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽(100 mg,0.192 mmol,1當量)於DMAc (1 mL)中之溶液中添加KHCO
3(48 mg,0.479 mmol,2.5當量)及(氯甲基)磷酸二-三級丁酯(59.5 mg,0.23 mmol,1.2當量)。將反應混合物加熱至60℃並攪拌16小時。隨後將反應混合物用EtOAc/水稀釋,用EtOAc萃取兩次。將合併之有機層以MgSO4乾燥,過濾並在真空中濃縮。將粗製產物藉由矽膠層析法(100% EtOAc)純化,以提供二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯。
製備(5-(3- 氟-8-((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吲唑-6- 基) 環丙基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基二氫磷酸酯
向二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯(90 mg,0.127 mmol,1當量)於DCM (2.5 mL)中之溶液中添加TFA (0.25 mL)。將反應混合物在室溫下攪拌15分鐘,之後在真空中濃縮並藉由HPLC(10至80% MeCN/水(含TFA))純化。LC-MS m/z: 596.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.78 – 7.68 (m, 2H), 7.58 (d, J = 7.0 Hz, 1H), 7.49 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.57 (d, J = 10.8 Hz, 2H), 5.40 (q, J = 9.1 Hz, 2H), 3.04 (ddd, J = 9.3, 6.3, 4.4 Hz, 1H), 2.79 (dt, J = 9.4, 5.2 Hz, 1H), 2.18 (dt, J = 8.8, 5.2 Hz, 1H), 1.90 (dt, J = 8.6, 5.2 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -70.08 (t, J = 9.2 Hz, 3F), -155.18 (d, J = 7.0 Hz, 1F)。
下列化合物係以類似於(5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯之方式,使用以下所列之修改製備:
二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯係使用5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮代替5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽製備。
(5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯係使用二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯代替二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 597.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.1 Hz, 1H), 7.51 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 5.57 (d, J = 10.8 Hz, 2H), 5.34 (tt, J = 9.3, 4.8 Hz, 2H), 3.24 (ddd, J = 8.6, 5.9, 4.1 Hz, 2H), 3.07 (ddd, J = 8.9, 6.1, 4.0 Hz, 1H), 2.22 (ddd, J = 8.6, 6.2, 3.9 Hz, 1H), 2.06 (ddd, J = 9.4, 5.8, 3.9 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -69.89 (t, J = 9.1 Hz, 3F), -155.18 (d, J = 7.1 Hz, 1F)。31P NMR (162 MHz, DMSO-d6) δ -2.18 (t, J = 10.8 Hz, 1P)。
二-三級丁基(2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯及四-三級丁基((2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)係使用5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-2,4(1H,3H)-二酮;三氟乙酸代替5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽製備。
及
(2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯係使用二-三級丁基((2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯代替二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 578.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.68 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.20 (dd, J = 8.4, 1.3 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 5.61 (d, J = 11.1 Hz, 2H), 5.42 (q, J = 9.1 Hz, 2H), 3.17 (ddd, J = 8.5, 6.4, 4.4 Hz, 1H), 2.82 (td, J = 7.1, 4.5 Hz, 1H), 1.97 (t, J = 8.2 Hz, 2H)。19F NMR (376 MHz, DMSO-d6) δ -70.06 (t, J = 9.1 Hz, 3F)。31P NMR (162 MHz, DMSO-d6) δ -2.17 (t, J = 11.1 Hz, 1P)。
(2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-1,3(2H,4H)-二基)雙(亞甲基)雙(二氫磷酸酯)係使用四-三級丁基((2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)代替二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 688.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 7.79 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.21 (dd, J = 8.4, 1.3 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.73 (d, J = 6.3 Hz, 2H), 5.69 (d, J = 11.1 Hz, 2H), 5.42 (q, J = 9.1 Hz, 2H), 3.21 (td, J = 7.4, 4.5 Hz, 3H), 2.83 (td, J = 7.8, 4.5 Hz, 1H), 2.00 (t, J = 7.6 Hz, 2H)。19F NMR (376 MHz, DMSO-d6) δ -70.06 (t, J = 9.1 Hz, 3F)。31P NMR (162 MHz, DMSO-d6) δ -2.15 (t, J = 11.1 Hz), -3.45 (t, J = 6.5 Hz)。
II. 定義
「烷基(alkyl)」係直鏈或支鏈飽和單價烴。例如,烷基可具有1至18個碳原子(亦即,C
1-18烷基)、或1至8個碳原子(亦即,C
1-8烷基)、或1至6個碳原子(亦即,C
1-6烷基)、或1至4個碳原子(亦即,C
1-4烷基)。烷基之實例包括但不限於甲基(Me、-CH
3)、乙基(Et、-CH
2CH
3)、1-丙基(
n-Pr、正丙基、-CH
2CH
2CH
3)、2-丙基(
i-Pr、異丙基、-CH(CH
3)
2)、1-丁基(
n-Bu、正丁基、-CH
2CH
2CH
2CH
3)、2-甲基-1-丙基(
i-Bu、異丁基、-CH
2CH(CH
3)
2)、2-丁基(
s-Bu、二級丁基、-CH(CH
3)CH
2CH
3)、2-甲基-2-丙基(
t-Bu、三級丁基、-C(CH
3)
3)、1-戊基(正戊基、-CH
2CH
2CH
2CH
2CH
3)、2-戊基(-CH(CH
3)CH
2CH
2CH
3)、3-戊基(-CH(CH
2CH
3)
2)、2-甲基-2-丁基(-C(CH
3)
2CH
2CH
3)、3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2)、3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2)、2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3)、1-己基(-CH
2CH
2CH
2CH
2CH
2CH
3)、2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3)、3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3))、2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3)、3-甲基-2-戊基(-CH(CH
3)CH(CH
3)CH
2CH
3)、4-甲基-2-戊基(-CH(CH
3)CH
2CH(CH
3)
2)、3-甲基-3-戊基(-C(CH
3)(CH
2CH
3)
2)、2-甲基-3-戊基(-CH(CH
2CH
3)CH(CH
3)
2)、2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2)、及3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3。其他烷基包括庚基、辛基、壬基、癸基、十一基、十二基、十五基、十六基、十七基、及十八基。
「伸烷基(alkylene)」係指直鏈或支鏈飽和脂族自由基,其具有所指示之碳原子數,並連接至少兩個其他基團,亦即二價烴自由基。連接至伸烷基之兩個部份可連接至伸烷基之相同原子或不同原子。例如,直鏈伸烷基可係-(CH
2)
n-之二價自由基,其中n係1、2、3、4、5、或6。代表性伸烷基包括但不限於亞甲基、伸乙基、伸丙基、伸異丙基、伸丁基、伸異丁基、伸二級丁基、伸戊基、及伸己基。伸烷基可經取代或未經取代。
「烯基(alkenyl)」係指具有至少2個碳原子及至少一個雙鍵之直鏈或支鏈烴。烯基可包括任何數目的碳,諸如C
2、C
2-3、C
2-4、C
2-5、C
2-6、C
2-7、C
2-8、C
2-9、C
2-10、C
3、C
3-4、C
3-5、C
3-6、C
4、C
4-5、C
4-6、C
5、C
5-6、及C
6。烯基可具有任何合適數目的雙鍵,包括但不限於1、2、3、4、5、或更多。烯基之實例包括但不限於乙烯基(vinyl/ethenyl)、丙烯基、異丙烯基、1-丁烯基、2-丁烯基、異丁烯基、丁二烯基、1-戊烯基、2-戊烯基、異戊烯基、1,3-戊二烯基、1,4-戊二烯基、1-己烯基、2-己烯基、3-己烯基、1,3-己二烯基、1,4-己二烯基、1,5-己二烯基、2,4-己二烯基、或1,3,5-己三烯基。烯基可經取代或未經取代。
「炔基(alkynyl)」係指具有至少2個碳原子及至少一個參鍵之直鏈或支鏈烴。炔基可包括任何數目的碳,諸如C
2、C
2-3、C
2-4、C
2-5、C
2-6、C
2-7、C
2-8、C
2-9、C
2-10、C
3、C
3-4、C
3-5、C
3-6、C
4、C
4-5、C
4-6、C
5、C
5-6、及C
6。炔基之實例包括但不限於乙炔基、丙炔基、1-丁炔基、2-丁炔基、丁二炔基、1-戊炔基、2-戊炔基、異戊炔基、1,3-戊二炔基、1,4-戊二炔基、1-己炔基、2-己炔基、3-己炔基、1,3-己二炔基、1,4-己二炔基、1,5-己二炔基、2,4-己二炔基、或1,3,5-己三炔基。炔基可經取代或未經取代。
「烷氧基(alkoxy)」係指具有將烷基連接至附接點:烷基-O-之氧原子的烷基。如同烷基,烷氧基可具有任何合適數目的碳原子,諸如C
1-6。烷氧基包括例如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、2-丁氧基、異丁氧基、二級丁氧基、三級丁氧基、戊氧基、己氧基等。烷氧基可進一步經本文所述之各種取代基取代。烷氧基可經取代或未經取代。
「烷氧基烷基(alkoxyalkyl)」係指連接至烷基之烷氧基,該烷基係連接至化合物之其餘部分,使得烷基係二價。烷氧基烷基可具有任何合適數目的碳,諸如2至6個(C
2-6烷氧基烷基)、2至5個(C
2-5烷氧基烷基)、2至4個(C
2-4烷氧基烷基)、或2至3個(C
2-3烷氧基烷基)。烷氧基及烷基係如上所定義,其中烷基係二價,且可包括但不限於甲氧基甲基(CH
3OCH
2-)、甲氧基乙基(CH
3OCH
2CH
2-)、及其他者。
「烷氧基-烷氧基(alkoxy-alkoxy)」係指連接至第二烷氧基之烷氧基,第二烷氧基係連接至化合物之其餘部分。烷氧基係如上所定義,且可包括但不限於甲氧基-甲氧基(CH
3OCH
2O-)、甲氧基-乙氧基(CH
3OCH
2CH
2O-)、及其他者。
如本文中所使用,「鹵基(halo)」或「鹵素(halogen)」係指氟(-F)、氯(-Cl)、溴(-Br)、及碘(-I)。
如本文中所使用,「鹵烷基(haloalkyl)」係指如本文中所定義之烷基,其中烷基之一或多個氫原子係獨立地經鹵基取代基(其可係相同或不同的)所置換。例如,C
1-4鹵烷基係C
1-4烷基,其中C
1-4烷基之一或多個氫原子已被鹵基取代基置換。鹵烷基之實例包括但不限於氟甲基、氟氯甲基、二氟甲基、二氟氯甲基、三氟甲基、1,1,1-三氟乙基、及五氟乙基。
「鹵烷氧基(haloalkoxy)」係指其中一些或全部氫原子經鹵素原子取代的烷氧基。如同烷基,鹵烷氧基可具有任何合適數目的碳原子,諸如C
1-6。烷氧基可經1、2、3、或更多個鹵素取代。當所有氫被鹵素置換時,例如被氟,化合物經全取代,例如全氟化。鹵烷氧基包括但不限於三氟甲氧基、2,2,2,-三氟乙氧基、全氟乙氧基等。
「環烷基(cycloalkyl)」係指3至20個環碳原子之單飽和或部分不飽和全碳環(亦即,C
3-20環烷基),例如3至12個環原子、例如3至10個環原子、或3至8個環原子、或3至6個環原子、或3至5個環原子、或3至4個環原子。用語「環烷基」亦包括多縮合、飽和及部分不飽和全碳環系統(例如,包含2、3或4個碳環之環系統)。因此,環烷基包括多環碳環,諸如雙環碳環(例如具有6至12個環形碳原子之雙環碳環,諸如雙環[3.1.0]己烷及雙環[2.1.1]己烷)及多烷碳環(例如具有至多20個環形碳原子之三環及四環碳環)。當價數要求允許時,多縮合環系統之環可經由稠合、螺環接、及橋聯鍵彼此連接。單環環烷基之非限制性實例包括環丙基、環丁基、環戊基、1-環戊-1-烯基、1-環戊-2-烯基、1-環戊-3-烯基、環己基、1-環己-1-烯基、1-環己-2-烯基、及1-環己-3-烯基。
「烷基-環烷基」係指具有烷基組分及環烷基組分之基團,其中烷基組分將環烷基組分連結至附接點。烷基組分係如上文所定義,除了烷基組分係至少二價的(即伸烷基)外,以連結至環烷基組分及附接點。在一些情況下,烷基組分可不存在。烷基組分可包括任何碳數,諸如C
1-6、C
1-2、C
1-3、C
1-4、C
1-5、C
2-3、C
2-4、C
2-5、C
2-6、C
3-4、C
3-5、C
3-6、C
4-5、C
4-6、及C
5-6。環烷基組分係如內文所定義。例示性烷基-環烷基包括但不限於甲基-環丙基、甲基-環丁基、甲基-環戊基、及甲基-環己基。
如本文中所使用,「雜環基(heterocyclyl)」或「雜環(heterocycle)」或「雜環烷基(heterocycloalkyl)」係指環中具有至少一個雜原子(亦即至少一個選自氧、氮、及硫之環形雜原子)之單一飽和或部分不飽和非芳族環或多環系統,其中多環系統至少包括含有至少一個雜原子之非芳環。多環系統亦可包括其他芳族環及非芳族環。除非另有指明,雜環基具有3至20個環原子、例如3至12個環原子、例如3至10個環原子、或3至8個環原子、或3至6個環原子、或3至5個環原子、或4至6個環原子、或4至5個環原子。因此,該用語包括環中具有1至6個環碳原子及1至3個選自由氧、氮、及硫所組成之群組的環雜原子之單一飽和或部分不飽和環(例如,3、4、5、6、或7員環)。雜原子可以可選地經氧化而形成–N(-OH)-、=N(-O
-)-、-S(=O)-、或–S(=O)
2-。多縮合環(例如雙環雜環基)系統之環可經由稠合、螺合、及橋聯鍵彼此連接(當價數要求允許時)。雜環包括但不限於吖呾、氮丙啶、咪唑啶、
啉、氧
(oxirane)(環氧乙烷)、氧呾、硫呾、哌
、哌啶、吡唑啶、哌啶、吡咯啶、吡咯啶酮、四氫呋喃、四氫噻吩、二氫吡啶、四氫吡啶、
啶、2-氧雜-6-氮雜螺[3.3]庚-6-基、6-氧雜-1-氮雜螺[3.3]庚-1-基、2-硫雜-6-氮雜螺[3.3]庚-6-基、2,6-二氮雜螺[3.3]庚-2-基、2-氮雜雙環[3.1.0]己-2-基、3-氮雜雙環[3.1.0]己基、2-氮雜雙環[2.1.1]己基、2-氮雜雙環[2.2.1]庚-2-基、4-氮雜螺[2.4]庚基、5-氮雜螺[2.4]庚基、吡唑啶-3-酮、哌
-2-酮、
唑啶-2-酮、及類似者。
雜環烷基環亦包括具有2、3、或更多個環之9至15員稠環雜環烷基,其中至少一個環係芳基環,且至少一個環係含有至少一個雜原子之非芳族環。代表性稠合雙環雜環烷基包括但不限於吲哚啉(二氫吲哚)、異吲哚啉(二氫異吲哚)、吲唑啉(indazoline)(二氫吲唑)、苯并[d]咪唑、二氫喹啉、二氫異喹啉、二氫苯并呋喃、二氫異苯并呋喃、苯并[d][1,3]二氧呃(benzo[d][1,3]dioxol)、二氫苯并[b]二
(dihydrobenzo[b]dioxine)、二氫苯并[d]
唑、二氫苯并[b]噻吩、二氫異苯并[c]噻吩、二氫苯并[d]噻唑、二氫苯并[c]異噻唑、螺[環丁烷-1,3'-吲哚啉]-2'-酮、螺[環丙烷-1,3'-吲哚啉]-2'-酮、2,3-二氫-1H-苯并[d]吡咯并[1,2-a]咪唑、苯并[d][1,3]二氧呃、及苯并[b][1,4]噻
,如以下結構中所示:
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
。
稠合雙環雜環烷基亦可由下列結構表示:
或
其中X
1、X
2、X
3、及X
4各自獨立地係不存在、–CH
2-、-NH-、-O-、或–S-,X
1、X
2、X
3、及X
4中之至少一者係-NH-、-O-、或–S-,且虛線圓圈代表飽和或部分不飽和非芳族環。稠合雙環雜環烷基可選地經取代。
「烷基-雜環烷基(alkyl-heterocycloalkyl)」係指具有烷基組分及雜環烷基組分之自由基,其中烷基組分將雜環烷基組分連接至附接點。烷基組分係如上所定義,惟烷基組分係至少二價(亦即伸烷基),以連接至雜環烷基組分及附接點。烷基組分可包括任何數目的碳,諸如C
0-6、C
1-2、C
1-3、C
1-4、C
1-5、C
1-6、C
2-3、C
2-4、C
2-5、C
2-6、C
3-4、C
3-5、C
3-6、C
4-5、C
4-6、及C
5-6。在一些情況下,烷基組分可不存在。雜環烷基組分係如上所定義。烷基-雜環烷基可經取代或未經取代。
如本文中所使用,「芳基(aryl)」係指單全碳芳環或多縮合全碳環系統,其中至少一個環係芳族的。例如,在一些實施例中,芳基具有6至20個碳原子、6至14個碳原子、或6至12個碳原子。芳基包括苯基自由基。芳基亦包括具有9至20個碳原子之多縮合環系統(例如,包含2、3、或4個環之環系統),其中至少一個環係芳族的且其中其他的環可係芳族的或非芳族的(亦即,碳環)。此類多縮合環系統在該多縮合環系統之任何碳環部分上可選地經一或多個(例如,1、2、或3個)側氧基取代。當價數要求允許時,多縮合環系統之環可經由稠合、螺合及橋聯鍵結來彼此連接。亦理解的是,當指稱某個原子範圍員芳基(例如,6至10員芳基)時,該原子範圍係針對該芳基之全部環原子。例如,6員芳基會包括苯基,而10員芳基會包括萘基及1,2,3,4-四氫萘基。芳基之非限制性實例包括但不限於苯基、茚基、萘基、1,2,3,4-四氫萘基、蒽基、及類似者。
「烷基-芳基」係指具有烷基組分及芳基組分之基團,其中烷基組分將芳基組分至附接點。烷基組分係如上所定義,惟烷基組分係至少二價(亦即伸烷基),以連結至芳基組分及附接點。烷基組分可包括任何數目的碳,諸如C
0-6、C
1-2、C
1-3、C
1-4、C
1-5、C
1-6、C
2-3、C
2-4、C
2-5、C
2-6、C
3-4、C
3-5、C
3-6、C
4-5、C
4-6、及C
5-6。在一些情況下,烷基組分可不存在。芳基組分係如上所定義。烷基-芳基之實例包括但不限於苄基及乙基-苯。烷基-芳基可經取代或未經取代。
如本文中所使用,「雜芳基(heteroaryl)」係指環中具有至少一個碳以外之原子的單芳族環,其中該原子係選自由氧、氮、及硫所組成之群組;「雜芳基」亦包括具有至少一個此類芳族環之多縮合環系統,多縮合環系統係進一步描述於下。因此,「雜芳基」包括1至6個碳原子及1至4個選自由氧、氮、及硫所組成之群組的雜原子之單一芳族環。硫及氮原子亦可以氧化形式存在,前提是環係芳族。例示性雜芳基環系統包括但不限於吡啶基、嘧啶基、
唑基(oxazolyl)、或呋喃基。「雜芳基」亦包括多縮合環系統(例如,包含2、3、或4個環之環系統),其中如上所定義之雜芳基係與一或多個選自雜芳基(而形成例如1,8-
啶基(1,8-naphthyridinyl))、雜環(而形成例如1,2,3,4-四氫-1,8-
啶基)、碳環(而形成例如5,6,7,8-四氫喹啉基)、及芳基(而形成例如吲哚基)之環縮合而形成多縮合環系統。因此,雜芳基(單芳族環或多縮合環系統)在雜芳基環內具有1至20個碳原子及1至6個雜原子。此類多縮合環系統可以可選地在縮合環之碳環或雜環部分上經一或多個(例如1、2、3、或4個)側氧基取代。當價數要求允許時,多縮合環系統之環可經由稠合、螺合及橋聯鍵結來彼此連接。應理解的是,多縮合環系統之個別環可相對於彼此以任何順序連接。應理解的是,雜芳基或雜芳基多縮合環系統之附接點可在包括碳原子及雜原子(例如,氮)之雜芳基或雜芳基多縮合環系統的任何合適原子處。亦應理解的是,當提及某個原子範圍員雜芳基(例如,5至10員雜芳基)時,原子範圍係針對雜芳基之環原子總數且包括碳原子及雜原子。例如,5員雜芳基會包括噻唑基而10員雜芳基會包括喹啉基。例示性雜芳基包括但不限於吡啶基、吡咯基、吡
基、嘧啶基、嗒
基、吡唑基、噻吩基、吲哚基、咪唑基、
唑基、異
唑基、噻唑基、呋喃基、
二唑基、噻二唑基、喹啉基、異喹啉基、苯并噻唑基、苯并
唑基、吲唑基、喹
啉基、喹唑啉基、5,6,7,8-四氫異喹啉基苯并呋喃基、苯并咪唑基、噻萘次甲基(thianaphthenyl)、吡咯并[2,3-b]吡啶基、喹唑啉基-4(3H)-酮、吡啶-2(1H)-酮、異喹啉-1(2H)-酮、及三唑基。
「烷基-雜芳基(alkyl-heteroaryl)」係指具有烷基組分及雜芳基組分之自由基,其中烷基組分將雜芳基組分連接至附接點。烷基組分係如上所定義,惟烷基組分係至少二價(亦即伸烷基),以連接至雜芳基組分及附接點。烷基組分可包括任何數目的碳,諸如C
0-6、C
1-2、C
1-3、C
1-4、C
1-5、C
1-6、C
2-3、C
2-4、C
2-5、C
2-6、C
3-4、C
3-5、C
3-6、C
4-5、C
4-6、及C
5-6。在一些情況下,烷基組分可不存在。雜芳基組分係如內文所定義。烷基-雜芳基可經取代或未經取代。
如本文中所使用,「組成物(composition)」意欲涵蓋以指定量包含指定成分之產品,以及直接或間接由指定成分以指定量之組合所產生的任何產品。所謂「醫藥上可接受(pharmaceutically acceptable)」,意指必須與配方之其他成分相容且對接受者有害的載劑、稀釋劑、或賦形劑。
「醫藥有效量(pharmaceutically effective amount)」係指提供所欲治療或醫藥效果的本揭露之化合物於配方或其組合中之量。
「醫藥上可接受之賦形劑」包括但不限於任何的佐藥、載劑、賦形劑、助滑劑、甜味劑、稀釋劑、防腐劑、染料/著色劑、增味劑、界面活性劑、潤濕劑、分散劑、懸浮劑、穩定劑、等張劑、溶劑、或乳化劑,其已經美國食品藥物管理局(United States Food and Drug Administration)核准可用於人類或馴養動物。
如本文中所使用之「治療(treatment/treat/treating)係指用於獲得有益或所欲結果之方法。出於本揭露之目的,有益或所欲結果包括但不限於症狀減輕、及/或症狀程度減小、及/或預防與疾病或病況相關之症狀的惡化。在一個實施例中,「治療」包括下列中之一或多者:a)抑制疾病或病況(例如減少一或多種疾病或病況所致之症狀、及/或減小疾病或病況的程度);b)延緩或停止與疾病或病況相關聯之一或多個症狀的發展(例如穩定疾病或病況、延遲疾病或病況的惡化或進展);及c)緩解疾病或病況,例如造成臨床症狀消退、改善疾病狀態、延緩疾病進展、增加生活品質、及/或延長存活期。
如本文中所使用,「治療有效量(therapeutically effective amount)」或「有效量(effective amount)」係指有效引起所欲生物或醫學反應之量,包括當投予至對象以治療疾病時,足以使該疾病治療生效的化合物量。有效量可隨化合物、疾病、及其嚴重性和所治療對象之年齡、體重等而有所變化。有效量可包括一範圍的量。如所屬技術領域中所理解,有效量可係一或多個劑量,亦即可需要單次劑量或多次劑量來達成所欲的治療終點。在投予一或多種治療劑之情況下可考慮有效量,且如果搭配一或多種其他藥劑可達成或達成所欲或有益結果,則可考慮給予有效量之單一藥劑。任何共投予的化合物之合適劑量可因化合物之組合作用(例如累加或協同效應)而可選地降低。
「投予」係指口服投予、作為栓劑投予、局部接觸、腸胃外、靜脈內、腹膜內、肌內、病灶內、鼻內、或皮下投予、鞘内投予、或植入緩釋裝置(例如微型滲透壓幫浦)至對象。投予可根據指定投予頻率、投予劑量、及其他因素之時程來進行。
如本文中所使用,「共投予(co-administration)」係指在投予單位劑量的一或多種額外治療劑之前或之後,投予單位劑量的本文所揭示之化合物,例如在投予一或多種額外治療劑之數秒、數分鐘、或數小時內投予本文所揭示之化合物。例如,在一些實施例中,先投予單位劑量的本揭露之化合物,接著在數秒或數分鐘內投予單位劑量的一或多種額外治療劑。替代地,在其他實施例中,先投予單位劑量的一或多種額外治療劑,接著在數秒或數分鐘內投予單位劑量的本揭露之化合物。在一些實施例中,先投予單位劑量的本揭露之化合物,接著在數小時(例如,1至12小時)期間之後,投予單位劑量的一或多種額外治療劑。在其他實施例中,先投予單位劑量的一或多種額外治療劑,接著在數小時(例如,1至12小時)期間之後,投予單位劑量的本揭露之化合物。本文所揭示之化合物與一或多種額外治療劑之共投予通常係指同時或依序投予本文所揭示之化合物及一或多種額外治療劑,使得治療有效量的各藥劑存在於患者體內。
「對象(subject)」係指諸如哺乳動物之動物,包括但不限於靈長動物(例如,人類)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠、及類似者。在某些實施例中,對象係人類。
「疾病(disease)」或「病況(condition)」係指能夠用本文所提供之化合物、醫藥組成物、或方法來治療的狀態或患者或對象健康狀態。在實施例中,疾病係癌症(例如肺癌、卵巢癌、骨肉瘤、膀胱癌、子宮頸癌、肝癌、腎癌、皮膚癌(例如Merkel氏細胞癌)、睪丸癌、白血病、淋巴瘤、頭頸癌、結直腸癌、前列腺癌、胰臟癌、黑色素瘤、乳癌、神經母細胞瘤)。疾病可係自體免疫、發炎性、癌症、感染性、代謝、發育、心血管、肝臟、腸、內分泌、神經、或其他疾病。
「癌症(cancer)」係指在哺乳動物中發現之所有類型的癌症、贅瘤(neoplasm)、或惡性腫瘤,包括白血病、淋巴瘤、黑色素瘤、神經內分泌腫瘤、癌(carcinoma)、及肉瘤。可用本文提供之化合物、醫藥組成物或方法治療之例示性癌症包括淋巴瘤、肉瘤、膀胱癌、骨癌、腦腫瘤、子宮頸癌、結腸癌、食道癌、胃癌、頭頸癌、腎癌、骨髓瘤、甲狀腺癌、白血病、前列腺癌、乳癌(例如三陰性、ER陽性、ER陰性、化療抗性、Herceptin抗性、HER2陽性、多柔比星(doxorubicin)抗性、他莫昔芬(tamoxifen)抗性、導管癌、小葉癌、原發性、轉移性)、卵巢癌、胰腺癌、肝癌(例如,肝細胞癌)、肺癌(例如,非小細胞肺癌、鱗狀細胞肺癌、腺癌、大細胞肺癌、小細胞肺癌、類癌、肉瘤)、多形性神經膠質母細胞瘤、神經膠質瘤、黑色素瘤、前列腺癌、去勢抵抗性前列腺癌、乳癌、三陰性乳癌、神經膠質母細胞瘤、卵巢癌、肺癌、鱗狀細胞癌(例如頭、頸或食管)、結直腸癌、白血病、急性骨髓性白血病、淋巴瘤、B細胞淋巴瘤或多發性骨髓瘤。
額外實例包括甲狀腺癌、內分泌系統癌、腦癌、乳癌、子宮頸癌、結腸癌、頭頸癌、食道癌、肝癌、腎癌、肺癌、非小細胞肺癌、黑色素瘤、間皮瘤、卵巢癌、肉瘤、胃癌、子宮癌、或髓母細胞瘤、霍奇金氏病(Hodgkin's Disease)、非霍奇金氏淋巴瘤、多發性骨髓瘤、神經母細胞瘤、神經膠質瘤、多形性神經膠質母細胞瘤、卵巢癌、橫紋肌肉瘤、原發性血小板增多症、原發性巨球蛋白血症、原發性腦腫瘤、癌症、惡性胰臟胰島素瘤、惡性類癌、膀胱癌、癌前皮膚病灶、睪丸癌、淋巴瘤、甲狀腺癌、神經母細胞瘤、食道癌、泌尿生殖道癌、惡性高血鈣症、子宮內膜癌、腎上腺皮質癌、胰臟內分泌或外分泌贅瘤、甲狀腺髓質癌(medullary thyroid cancer)、甲狀腺髓質癌(medullary thyroid carcinoma)、黑色素瘤、結腸直腸癌、乳突狀甲狀腺癌、肝細胞癌、乳頭柏哲氏病(Paget's Disease)、葉狀瘤、小葉癌、管癌、胰腺星狀細胞癌、肝臟星狀細胞癌、或前列腺癌。
「白血病(leukemia)」泛指造血器官之進行性惡性疾病,且通常以血液及骨髓中白血球及其前驅物之扭曲增生及發育為特徵。白血病通常在臨床上基於以下進行分類:(1)疾病之持續時間及特徵-急性或慢性;(2)所涉及之細胞類型;骨髓(骨髓性)、淋巴(淋巴球)、或單核球;及(3)血液中異常細胞數目之增加或不增加-白血病或非白血病(白血球缺乏性)。可用本文所提供之化合物、醫藥組成物、或方法治療之例示性白血病包括例如急性非淋巴球性白血病、慢性淋巴球性白血病、急性顆粒球性白血病、慢性顆粒球性白血病、急性前骨髓細胞性白血病、成人T細胞白血病、非白血病性白血病(aleukemic leukemia)、白血球性白血病(leukocythemic leukemia)、嗜鹼性球白血病、胚細胞白血病、牛白血病、慢性骨髓性白血病、皮膚白血病、胚胎性白血病、嗜酸性球白血病、葛氏白血病(Gross' leukemia)、毛細胞白血病、血母細胞性白血病(hemoblastic leukemia)、血母細胞性白血病(hemocytoblastic leukemia)、組織細胞白血病、幹細胞白血病、急性單核球白血病、白血球減少性白血病、淋巴性白血病、淋巴母細胞白血病、淋巴球性白血病、淋巴源性白血病(lymphogenous leukemia)、淋巴樣白血病、淋巴肉瘤細胞白血病、肥大細胞白血病、巨核細胞白血病、小骨髓母細胞性白血病、單核球白血病、骨髓母細胞性白血病、骨髓性白血病、骨髓顆粒球性白血病、骨髓單核球白血病、Naegeli氏白血病、漿細胞白血病、多發性骨髓瘤、漿細胞性白血病、前骨髓細胞性白血病、Rieder氏細胞白血病、Schilling氏白血病、幹細胞白血病、白血球缺乏性白血病、或未分化細胞白血病。
「肉瘤(sarcoma)」通常係指由類似胚胎結締組織之物質組成的腫瘤,且通常係由嵌入纖維狀或均質物質中之緊密排列的細胞構成。可用本文所提供之化合物、醫藥組成物、或方法治療之肉瘤包括軟骨肉瘤、纖維肉瘤、淋巴肉瘤、黑色素肉瘤、黏液肉瘤、骨肉瘤、Abemethy氏肉瘤、脂肪肉瘤(adipose sarcoma)、脂肉瘤(liposarcoma)、肺泡狀軟組織肉瘤、釉質母細胞肉瘤、葡萄狀肉瘤、綠色瘤肉瘤(chloroma sarcoma)、絨毛膜癌、胚胎肉瘤、威爾姆氏腫瘤肉瘤(Wilms' tumor sarcoma)、子宮內膜肉瘤、基質肉瘤、尤文氏肉瘤(Ewing's sarcoma)、筋膜肉瘤、纖維母細胞肉瘤、巨細胞肉瘤、顆粒球性肉瘤、霍奇金氏肉瘤、特發性多發性色素沉著出血性肉瘤、B細胞之免疫母細胞肉瘤、淋巴瘤、T細胞之免疫母細胞肉瘤、詹恩遜氏肉瘤(Jensen's sarcoma)、卡波西氏肉瘤(Kaposi's sarcoma)、庫佛氏細胞肉瘤(Kupffer cell sarcoma)、血管肉瘤、白血病性肉瘤、惡性間質瘤肉瘤、骨膜外肉瘤、網狀細胞肉瘤、勞氏肉瘤(Rous sarcoma)、漿液囊性肉瘤、滑膜肉瘤、或毛細管擴張性肉瘤。
「黑色素瘤(melanoma)」被認為係意指由皮膚及其他器官之黑色素細胞系統產生之腫瘤。可用本文提供之化合物、醫藥組成物、或方法治療之黑色素瘤包括例如肢端雀斑樣痣黑色素瘤、無黑色素性黑色素瘤、良性幼年性黑色素瘤、克勞德曼黑色素瘤(Cloudman's melanoma)、S91黑色素瘤、哈帕二氏黑色素瘤(Harding-Passey melanoma)、幼年性黑色素瘤、惡性雀斑樣痣黑色素瘤、惡性黑色素瘤、結節性黑色素瘤、甲下黑色素瘤、或淺表擴散性黑色素瘤。
「癌(carcinoma)」係指由傾向於浸潤周圍組織並引起轉移之上皮細胞組成的惡性新生長。可用本文所提供之化合物、醫藥組成物、或方法治療之例示性癌包括例如甲狀腺髓質癌、家族性甲狀腺髓質癌、腺泡癌(acinar carcinoma)、腺泡癌(acinous carcinoma)、腺囊癌、腺樣囊性癌、腺瘤性癌、腎上腺皮質癌、肺泡癌、肺泡細胞癌、基底細胞癌(basal cell carcinoma)、基底細胞癌(carcinoma basocellulare)、基底樣癌、基底鱗狀細胞癌、細支氣管肺泡癌、細支氣管癌、支氣管癌、腦狀癌、膽管細胞癌、絨毛膜癌、膠狀癌、粉刺癌、子宮體癌、篩狀癌、鎧甲狀癌、皮膚癌、柱狀癌、柱狀細胞癌、管癌(duct carcinoma)、管癌(ductal carcinoma)、硬癌(carcinoma durum)、胚胎性癌、腦樣癌(encephaloid carcinoma)、表皮樣癌、腺狀上皮癌、外植癌(exophytic carcinoma)、潰瘍性癌、纖維癌、膠樣癌(gelatiniforni carcinoma)、膠質癌(gelatinous carcinoma)、巨細胞癌(giant cell carcinoma)、巨細胞癌(carcinoma gigantocellulare)、腺癌、顆粒細胞癌、毛基質癌(hair-matrix carcinoma)、血樣癌、肝細胞癌、何氏細胞癌(Hurthle cell carcinoma)、玻質狀癌、腎上腺樣癌、幼稚型胚胎性癌、原位癌、表皮內癌、上皮內癌、Krompecher氏癌、Kulchitzky細胞癌、大細胞癌、豆狀癌(lenticular carcinoma)、豆狀癌(carcinoma lenticulare)、脂瘤癌、小葉癌、淋巴上皮癌、髓質癌(carcinoma medullare)、髓質癌(medullary carcinoma)、黑色素癌、軟癌、黏液癌(mucinous carcinoma)、黏液癌(carcinoma muciparum)、黏液細胞癌、黏液表皮樣癌、黏膜癌(carcinoma mucosum)、黏膜癌(mucous carcinoma)、黏液瘤樣癌、鼻咽癌、燕麥細胞癌、骨化性癌、骨樣癌、乳突狀癌、門脈周癌、未侵襲癌、棘細胞癌、糜爛性癌(pultaceous carcinoma)、腎臟腎細胞癌、儲備細胞癌、肉瘤樣癌、施奈德氏癌(schneiderian carcinoma)、硬癌(scirrhous carcinoma)、陰囊癌、印戒細胞癌、單純癌、小細胞癌、馬鈴薯狀癌、球狀細胞癌、梭狀細胞癌、髓狀癌、鱗狀癌、鱗狀細胞癌、繩捆癌(string carcinoma)、毛細管擴張癌(carcinoma telangiectaticum)、毛細管擴張癌(carcinoma telangiectodes)、移行細胞癌、塊狀癌、管狀癌、結節性癌、疣狀癌、或絨毛狀癌。
「轉移(metastasis)」、「轉移性(metastatic)」、及「轉移性癌症(metastatic cancer)」可互換使用,且係指增生性疾病或病症(例如癌症)自一個器官或另一不相鄰器官或身體部分之擴散。癌症在起源部位(例如乳房)發生,此部位稱為原發性腫瘤(例如原發性乳癌)。原發性腫瘤或起源部位中之一些癌細胞取得滲透及浸潤局部區域中之周圍正常組織的能力及/或滲透淋巴系統或血管系統之壁通過該系統循環至身體其他部位及組織的能力。由原發性腫瘤之癌細胞形成的繼發性臨床可偵測腫瘤稱為轉移性或繼發性腫瘤。當癌細胞轉移時,假設轉移性腫瘤及其細胞與原始腫瘤類似。因此,若肺癌轉移至乳房,則乳房部位之繼發性腫瘤係由異常肺細胞及非異常乳房細胞所組成。乳房中之繼發性腫瘤稱為轉移性肺癌。因此,詞組轉移性癌症係指其中對象具有或曾經具有原發性腫瘤且具有一或多種繼發性腫瘤之疾病。詞組非轉移性癌症或患有非轉移性癌症之對象係指其中對象具有原發性腫瘤但不具有一或多種繼發性腫瘤之疾病。例如,轉移性肺癌係指具有原發性肺腫瘤或具有原發性肺腫瘤之病史且在第二位置或多個位置(例如在乳房中)具有一或多種繼發性腫瘤之對象的疾病。
在與疾病(例如糖尿病、癌症(例如前列腺癌、腎癌、轉移性癌症、黑色素瘤、去勢抗性前列腺癌、乳癌、三陰性乳癌、神經膠質母細胞瘤、卵巢癌、肺癌、鱗狀細胞癌(例如頭部、頸部、或食道)、結腸直腸癌、白血病、急性骨髓性白血病、淋巴瘤、B細胞淋巴瘤、或多發性骨髓瘤))相關之物質或物質活性或功能的背景下,「相關(associated)」或「與…相關(associated with)」意指該疾病(例如肺癌、卵巢癌、骨肉瘤、膀胱癌、子宮頸癌、肝癌、腎癌、皮膚癌(例如Merkel氏細胞癌)、睪丸癌、白血病、淋巴瘤、頭頸癌、結腸直腸癌、前列腺癌、胰臟癌、黑色素瘤、乳癌、神經母細胞瘤)係(全部或部分)由該物質或物質活性或功能造成,或該疾病之症狀係(全部或部分)由該物質或物質活性或功能造成。
亦提供本文所述之化合物的醫藥上可接受之鹽、水合物、溶劑合物、互變異構形式、同質多形體、及前藥。「醫藥上可接受(pharmaceutically acceptable)」或「生理上可接受(physiologically acceptable)」係指適用於動物醫藥或人類醫藥用途的化合物、鹽、組成物、劑型、及其他可用於製備醫藥組成物之材料。
本文所述之化合物可經製備及/或調配為醫藥上可接受之鹽或游離鹼(當適當時)。醫藥上可接受之鹽係化合物之游離鹼形式的無毒性鹽,其具備游離鹼之所欲藥理活性。此等鹽可衍生自無機或有機酸或鹼。例如,含有鹼性氮之化合物可藉由使化合物與無機或有機酸接觸而製備為醫藥上可接受之鹽。醫藥上可接受之鹽之非限制性實例包括硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、磷酸鹽、磷酸一氫鹽、磷酸二氫鹽、偏磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物、乙酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、丙烯酸酯、甲酸鹽、異丁酸鹽、己酸鹽、庚酸鹽、丙炔酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、辛二酸鹽、癸二酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、苯甲酸鹽、氯苯甲酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、羥基苯甲酸鹽、甲氧基苯甲酸鹽、苯二甲酸鹽、磺酸鹽、甲基磺酸鹽、丙基磺酸鹽、苯磺酸鹽、二甲苯磺酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽、苯乙酸鹽、苯丙酸鹽、苯丁酸鹽、檸檬酸鹽、乳酸鹽、γ-羥基丁酸鹽、乙醇酸鹽、酒石酸鹽、及杏仁酸鹽。其他合適的醫藥上可接受之鹽的清單係見於Remington: The Science and Practice of Pharmacy, 21
stEdition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.。
本文所揭示之化合物的「醫藥上可接受之鹽(pharmaceutically acceptable salt)」的實例包括衍生自適當的鹼之鹽,適當的鹼諸如鹼金屬(例如鈉、鉀)、鹼土金屬(例如鎂)、銨、及NX
4 +(其中X係C
1-C
4烷基)。亦包括鹼加成鹽,諸如鈉或鉀鹽。
亦提供本文所述之化合物或其醫藥上可接受之鹽、異構物、或混合物,其中附接至碳原子之1至n個氫原子可被氘原子或D置換,其中n係分子中之氫原子數。如所屬技術領域中已知,氘原子係氫原子之非放射性同位素。當投予至哺乳動物時,此類化合物可增加對代謝之抗性,並因此可用於增加本文所述之化合物或其醫藥上可接受之鹽、異構物、或混合物的半衰期。參見例如Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol.Sci., 5(12):524-527 (1984)。此類化合物係藉由所屬技術領域中熟知的手段合成,例如藉由採用其中一或多個氫原子已被氘置換的起始材料。
可併入所揭示化合物的同位素之實例亦包括氫、碳、氮、氧、磷、氟、氯、及碘之同位素,諸如分別為
2H、
3H、
11C、
13C、
14C、
13N、
15N、
15O、
17O、
18O、
31P、
32P、
35S、
18F、
36Cl、
123I、及
125I。用發射正子的同位素(諸如
11C、
18F、
15O、及
13N)進行之取代可用於正子發射斷層造影(Positron Emission Topography, PET)研究中,以用於檢查受質受體佔有率。式I之經同位素標示之化合物通常可藉由所屬技術領域中具有通常知識者已知的習知技術或藉由類似於如下所提出之實例中所述之程序,使用適當的經同位素標示之試劑代替先前所採用之未經標示試劑來製備。
本文所揭示之實施例之化合物或其醫藥上可接受之鹽可含有一或多個不對稱中心,並因此可產生鏡像異構物、非鏡像異構物、及其他立體異構形式,其等可依絕對立體化學定義為(
R)-或(
S)-、或針對胺基酸定義為(D)-或(L)-。本揭露意欲包括所有此類可能的異構物、以及其外消旋及光學純形式。光學活性(+)及(-)、(
R)-及(
S)-、或(D)-及(L)-異構物可使用掌性合成組元(synthon)或掌性試劑製備,或使用例如層析法及分段結晶之習知技術解析。用於製備/單離個別鏡像異構物的習知技術包括使用例如掌性高壓液相層析法(high pressure liquid chromatography, HPLC),由合適的光學純前驅物進行掌性合成或解析外消旋物(或鹽或衍生物的外消旋物)。當本文所述之化合物含有烯烴雙鍵或其他幾何不對稱中心時,除非另有指明,否則意指該等化合物包括E及Z幾何異構物兩者。同樣地,亦意欲包括所有互變異構形式。當化合物以其掌性形式表示時,應理解的是實施例涵蓋但不限於特定的非鏡像異構或鏡像異構富集形式。當掌性未指定但存在時,應理解的是實施例係關於特定的非鏡像異構或鏡像異構富集形式;或此種(此類)化合物之外消旋或非外消混合物。如本文中所使用,「非外消旋混合物(scalemic mixture)」係立體異構物之比例非1:1之混合物。
「外消旋物(racemate)」係指鏡像異構物之混合物。此混合物可包含等量或不等量的各鏡像異構物。
「立體異構物(stereoisomer/stereoisomers)」係指一或多個立體中心之掌性有所不同的化合物。立體異構物包括鏡像異構物及非鏡像異構物。如果化合物擁有一或多個不對稱中心或具有不對稱取代之雙鍵,則其等可呈立體異構形式存在,並因而可生產為個別立體異構物或混合物。除非另有指明,此描述意欲包括個別立體異構物及混合物。立體化學之判定方法及立體異構物之分離方法在所屬技術領域中係熟知的(參見例如,Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992)。
「互變異構物(tautomer)」係指質子位置有所不同之化合物交替形式,諸如烯醇-酮及亞胺-烯胺互變異構物,或者含有同時附接至環-NH-及環=N-之環原子的雜芳基,諸如吡唑、咪唑、苯并咪唑、三唑、及四唑。
除非另有定義,否則本文中所使用之所有技術及科學用語具有與所屬技術領域中具有通常知識者一般理解的意義相同。化學基團前面或末端之破折號係為了方便起見;化學基團可用或不用一或多個破折號描繪,而不失去其通常意義。透過結構中之線繪製之波浪線指示基團之附接點。虛線表示可選的鍵。除非在化學或結構上有要求,否則化學基團之書寫順序或其附接至分子其餘部分之點非指示或暗示方向性。例如,基團「-SO
2CH
2-」等同於「-CH
2SO
2-」且皆可在任一方向連接。同樣地,「芳基烷基」基團例如可在基團之芳基或烷基部分附接至分子其餘部分。諸如「C
u-v」或(C
u-C
v)之前綴指示後述基團具有u至v個碳原子。例如,「C
1-6烷基」及「C
1-C
6烷基」皆指示烷基具有1至6個碳原子。
如本文中所使用,「溶劑合物(solvate)」係指溶劑與化合物之交互作用的結果。亦提供本文所述之化合物的鹽之溶劑合物。亦提供本文所述之化合物的水合物。
如本文中所使用,「前藥(prodrug)」係指在投予至人體後,根據某種化學或酶途徑轉化為母體藥物的藥物之衍生物。
III. 化合物 醫藥配方
在一些實施例中,本揭露提供一種醫藥配方,其包含醫藥有效量的本揭露之化合物或其醫藥上可接受之鹽、及醫藥上可接受之載劑或賦形劑。本揭露亦提供一種醫藥配方,其包含醫藥有效量的式(I)之化合物、或其醫藥上可接受之鹽、及醫藥上可接受之載劑或賦形劑。
在一些實施例中,醫藥組成物係用於治療癌症。
在一些實施例中,醫藥組成物進一步包含一或多種額外治療劑。任何合適的額外治療劑或組合療法可與式(I)之化合物、或其醫藥上可接受之鹽一起使用,諸如本文所述之劑及療法。
在一些實施例中,醫藥組成物包含式(I)之化合物、及額外治療劑,其中額外治療劑係抗癌劑。在一些實施例中,醫藥組成物係以下之醫藥組成物:其中額外治療劑獨立地係抗贅瘤劑、化學療法、放射療法、或切除療法。在一些實施例中,醫藥組成物係以下之醫藥組成物:其中額外治療劑獨立地係利妥昔單抗(rituxan)、杜薩魯比辛(doxorubicin)、吉西他濱(gemcitabine)、尼沃魯單抗(nivolumab)、派姆單抗(pembrolizumab)、尼沃魯單抗、派姆單抗、阿特珠單抗(atezolizumab)、或伊匹單抗(ipilimumab)。在一些實施例中,醫藥組成物係以下之醫藥組成物:其中額外治療劑係PD-1/PD-L1抑制劑。
在一些實施例中,醫藥組成物係以下之醫藥組成物:其中額外治療劑包含一或多種免疫細胞群,諸如自然殺手(NK)細胞、NK-T細胞、T細胞、細胞介素誘導之殺手(CIK)細胞、巨噬細胞(MAC)、腫瘤浸潤淋巴球(TIL)、及樹突細胞(DC)。
在一些實施例中,醫藥組成物係以下之醫藥組成物:其中額外治療劑包含一或多種嵌合抗原受體(CAR)。
在一些實施例中,醫藥組成物係以下之醫藥組成物:其中額外治療劑包含免疫療法、免疫刺激療法、細胞介素療法、趨化因子療法、細胞療法、基因療法、或其組合。在一些實施例中,免疫療法包括共投予針對一或多種目標或腫瘤相關抗原(TAA)之一或多種抗體或其抗原結合抗體片段、或其抗體藥物接合物、靶向CD3之多特異性分子、靶向CD16之多特異性分子、或非免疫球蛋白抗原結合域、或抗體擬似物蛋白。
在一些實施例中,本文所揭示之化合物係與習知載劑及賦形劑一起調配,其可依常規實務選擇。錠劑可含有賦形劑、滑動劑、填料、黏合劑、及類似者。水性配方可以無菌形式製備,且例如當意欲藉由口服投予以外之方式遞送時可係等張的。在一些實施例中,配方可以可選地含有賦形劑,諸如「Handbook of Pharmaceutical Excipients」(1986)中所述者。賦形劑可包括例如抗壞血酸及其他抗氧化劑、螯合劑(諸如EDTA)、碳水化合物(諸如右旋糖酐、羥烷基纖維素、羥烷基甲基纖維素)、硬脂酸、及類似者。配方之pH範圍在約3至約11,例如約7至約10。
在一些實施例中,本文所揭示之化合物係單獨投予。在一些實施例中,本文所揭示之化合物係以醫藥配方投予。在一些實施例中,用於動物醫藥及/或人類用途之配方包含至少一種式(I)之化合物、或其醫藥上可接受之鹽、連同一或多種可接受之載劑及可選地其他治療性成分,諸如本文所論述之額外治療性成分。在一些實施例中,(多種)載劑是「可接受的(acceptable)」,其意義是與配方之其他成分相容且對其接受者無害。
在一些實施例中,本揭露之配方包括適用於前述投予途徑者。在一些實施例中,配方係以單位劑型呈現。配方可藉由藥學技術領域已知的方法製備。技術及配方可見於例如Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA)。此類方法包括例如將活性成分與載劑結合之步驟,載劑包含一或多種輔助成分。在一些實施例中,配方係藉由將活性成分與液體載劑或細分固體載劑或兩者結合來製備,接著在一些實施例中將產物成形。
適用於口服投予之配方可以下列呈現:離散單位,例如膠囊、扁囊劑(cachet)、或錠劑,其各自含有預定量的活性成分,諸如式(I)之化合物、或其醫藥上可接受之鹽;粉劑或粒劑;於水性或非水性液體中之溶液或懸浮液;或水包油液體乳液或油包水液體乳液。在一些實施例中,活性成分係以大劑量(bolus)、舐劑(electuary)、或糊劑投予。
錠劑可例如藉由壓製或模製、可選地與一或多種輔助成分一起製造。壓製錠劑可例如藉由在合適機器中壓製呈自由流動形式(諸如粉劑或粒劑)之活性成分來製備,其可選地與黏合劑、潤滑劑、惰性稀釋劑、防腐劑、表面活性劑、或分散劑混合。模製錠劑可例如藉由在合適機器中將用惰性液體稀釋劑濕化之粉狀活性成分的混合物模製來製造。錠劑可以可選地經包衣或刻痕。在一些實施例中,錠劑經調配,從而自其中提供活性成分的緩慢或控制釋放。
對於眼睛或其他外部組織(例如口腔及皮膚)之感染,配方可作為含有式(I)之化合物之局部軟膏或乳膏施用,其量例如約0.075至約20% w/w(包括在約0.1%與約20%之間之範圍內的(多種)活性成分,增量為約0.1% w/w,諸如約0.6% w/w、約0.7% w/w等),諸如約0.2至約15% w/w、及諸如約0.5至約10% w/w。當以軟膏調配時,式(I)之化合物、或其醫藥上可接受之鹽可與石蠟或水混溶性軟膏基底一起採用。替代地,式(I)之化合物、或其醫藥上可接受之鹽可調配成具有水包油乳膏基底之乳膏。
若為所欲,乳膏基底之水相可包括例如至少約30% w/w的多元醇,亦即具有二或更多個羥基之醇,諸如丙二醇、1,3-丁二醇、甘露醇、山梨醇、甘油、及聚乙二醇(包括PEG 400)、及其混合物。在一些實施例中,局部配方可包括增強活性成分通過皮膚或其他受影響區域之吸收或滲透的化合物。此類皮膚滲透增強劑之實例包括二甲基亞碸及相關類似物。
乳液之油相可以已知方式由已知成分構成。雖然該相可僅包含乳化劑(亦稱為乳劑(emulgent)),其可包含例如至少一種乳化劑與脂肪或油、或與脂肪及油兩者之混合物。在一些實施例中,一起包括親水性乳化劑與作用為穩定劑之親油性乳化劑。在一些實施例中,乳液包括油及脂肪兩者。(多種)乳化劑(有或無(多種)穩定劑)一起構成所謂的乳化臘,且臘與油及脂肪一起構成所謂的乳化軟膏基底,此形成乳膏配方之油性分散相。
適用於配方中之乳劑及乳液穩定劑包括例如Tween
®60、Span
®80、鯨蠟硬脂醇、苄醇、肉豆蔻醇、單硬脂酸甘油酯、及月桂基硫酸鈉。
適用於配方之油或脂肪的選擇係基於達到所欲的性質。乳膏可係不油膩、不染色、且可清洗的產品,且具有合適稠度以避免從管子或其他容器中滲漏。可使用直鏈或支鏈、單元或二元烷基酯,諸如二異己二酸酯、硬脂酸異鯨蠟酯、椰子脂肪酸之丙二醇二酯、肉豆蔻酸異丙酯、油酸癸酯、棕櫚酸異丙酯、硬脂酸丁酯、棕櫚酸2-乙基己酯、或稱為Crodamol CAP之支鏈酯摻合物。此等可單獨或組合使用,取決於所需之性質。替代地,可使用高熔點脂質,諸如白軟石蠟及/或液體石蠟或其他礦物油。
在一些實施例中,本文中之醫藥配方包含連同一或多種醫藥上可接受之載劑或賦形劑及可選地其他治療劑之組合。含有活性成分之醫藥配方可呈任何適用於預期投予方法的形式。當例如用於口服用途時,可製備錠劑、喉錠(troche)、口含錠(lozenge)、水性或油性懸浮液、分散性粉劑或粒劑、乳液、硬或軟膠囊、溶液、糖漿、或酏劑。意欲用於口服用途之組成物可根據醫藥組成物製造技術領域已知之任何方法製備,且此類組成物可含有一或多種劑,包括甜味劑、調味劑、著色劑、及保存劑,以提供適口(palatable)製劑。含有與適用於製造錠劑的無毒性醫藥上可接受之賦形劑混合的活性成分之錠劑係可接受的。此等賦形劑可例如係惰性稀釋劑,諸如碳酸鈣或鈉、乳糖、磷酸鈣或鈉;造粒及崩解劑,諸如玉米澱粉、或藻酸;黏合劑,諸如澱粉、明膠、或阿拉伯膠;及潤滑劑,諸如硬脂酸鎂、硬脂酸、或滑石。錠劑可未包衣或可藉由已知技術(包括微囊封)進行包衣,以延遲胃腸道中之崩解及吸收,藉以在較長期間內提供持續作用。例如,可採用時間延遲材料,諸如單獨單硬脂酸甘油酯或二硬脂酸甘油酯或與蠟一起。
用於口服用途之配方亦可以硬明膠膠囊呈現,其中活性成分係與惰性固體稀釋劑混合,例如磷酸鈣或高嶺土,或以軟明膠膠囊呈現,其中活性成分係與水或油介質混合,諸如花生油、液體石蠟、或橄欖油。
水性懸浮液含有與適用於製造水性懸浮液之賦形劑混合的活性材料。此類賦形劑包括懸浮劑(諸如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠、及阿拉伯膠)及分散或潤濕劑(諸如天然存在磷脂質(例如卵磷脂)、氧化烯與脂肪酸之縮合產物(例如聚氧乙烯硬脂酸酯)、氧化乙烯與長鏈脂族醇之縮合產物(例如十七乙烯氧鯨蠟醇)、氧化乙烯與衍生自脂肪酸及己糖醇酐之部分酯之縮合產物(例如聚氧乙烯山梨醇酐單油酸酯))。水性懸浮液亦可含有一或多種保存劑(諸如對羥基苯甲酸乙酯或正丙酯)、一或多種著色劑、一或多種調味劑、及一或多種甜味劑(諸如蔗糖或糖精)。
油性懸浮液可藉由將活性成分懸浮於植物油(諸如花生油、橄欖油、芝麻油、或椰子油)中或礦物油(諸如液體石蠟)中來調配。口服懸浮液可含有增稠劑,諸如蜂蠟、硬石蠟、或鯨蠟醇。可添加甜味劑(諸如以上所述者)及調味劑以提供適口口服製劑。此等組成物可藉由添加抗氧化劑(諸如抗壞血酸)保存。
適用於藉由添加水來製備水性懸浮液的分散性粉劑及粒劑提供與分散劑或潤濕劑、懸浮劑、及一或多種防腐劑混合的活性成分。合適分散劑或潤濕劑及懸浮劑係由以上所揭示者例示。亦可存在額外賦形劑(例如甜味劑、調味劑、及著色劑)。
醫藥組成物亦可呈水包油乳液之形式。油相可係植物油(諸如橄欖油或花生油)、礦物油(諸如液體石蠟)、或此等之混合物。合適乳化劑包括天然存在膠(諸如阿拉伯膠及黃蓍膠)、天然存在磷脂質(諸如大豆卵磷脂)、衍生自脂肪酸及己糖醇酐之酯或部分酯(諸如山梨醇酐單油酸酯)、及此等部分酯與氧化乙烯之縮合產物(諸如聚氧乙烯山梨醇酐單油酸酯)。乳液亦可含有甜味劑及調味劑。糖漿及酏劑可與甜味劑(諸如甘油、山梨醇、或蔗糖)一起調配。此類配方亦可含有緩和藥、保存劑、調味劑、或著色劑。
醫藥組成物可呈無菌可注射製劑或靜脈內製劑之形式,諸如無菌可注射水性或油質懸浮液。此類懸浮液可根據已知技術使用以上已提及之合適分散劑或潤濕劑及懸浮劑調配。無菌可注射製劑或靜脈內製劑亦可包括於無毒性腸胃外可接受之稀釋劑或溶劑中的無菌可注射溶液或懸浮液(諸如於1,3-丁二醇中之溶液)或製備為凍乾粉劑。可採用之可接受媒劑及溶劑包括水、林格氏液(Ringer's solution)、及等張氯化鈉溶液。此外,習知上可採用無菌不揮發油作為溶劑或懸浮介質。為此目的,可採用任何溫和不揮發油,包括合成單酸甘油酯或二酸甘油酯。此外,脂肪酸(諸如油酸)可同樣地用於製備可注射劑。
可與載劑材料組合以生產單劑型的活性成分之量可取決於所治療之宿主及具體投予模式而變化。例如,意欲用於口服投予至人類之延時釋放配方可含有與適當及便利量的載劑材料混配之約1至約1000 mg的活性材料,載劑材料可在佔總組成物之約5至約95%(重量:重量)間變化。可製備醫藥組成物以提供用於投予的可容易測量之量。例如,意欲用於靜脈內輸注之水性溶液可含有每毫升溶液約3至約500 µg的活性成分,使得可進行約30 mL/hr之速率的合適體積輸注。
適用於局部投予至眼睛之配方亦包括點眼劑,其中活性成分係溶於或懸浮於合適載劑(尤其是活性成分之水性溶劑)中。活性成分可以約0.5至約20%之濃度存在於此類配方中,諸如約0.5至約10%,例如約1.5% w/w。
適用於在口中局部投予之配方包括例如口含錠,其包含於調味基底(諸如蔗糖及阿拉伯膠或黃蓍膠)中之活性成分;軟錠(pastille),其包含於惰性基底(諸如明膠及甘油、或蔗糖及阿拉伯膠)中之活性成分;及漱口藥水,其包含於合適液體載劑中之活性成分。
用於直腸投予之配方可以具有合適基底(包含例如可可脂或水楊酸酯)之栓劑呈現。
適用於肺內或鼻內投予之配方具有例如在約0.1至約500微米之範圍內之粒徑,諸如約0.5、約1、約30、或約35等,其係藉由通過鼻道快速吸入或藉由通過口吸入以到達肺泡囊來投予。合適配方包括活性成分之水性或油性溶液。適用於氣霧劑或乾粉劑投予之配方可根據習知方法製備,且可與其他治療劑(諸如如下所述之迄今為止用於治療癌症之化合物)一起遞送。
另一實施例提供可吸入組成物,其包含式(I)之化合物、或其醫藥上可接受之鹽。在一些實施例中,可吸入組成物適用於治療癌症。在一些實施例中,醫藥上可接受之鹽係無機酸,包括鹽酸鹽、氫溴酸鹽、硫酸鹽、或磷酸鹽。例如,相對於其他鹽,此類鹽可造成較少的肺部刺激。在一些實施例中,可吸入組成物係以氣霧劑之形式遞送至支氣管內空間,氣霧劑包含質量中數氣動直徑(MMAD)在約1與約5 µm之間的粒子。在一些實施例中,式(I)之化合物、或其醫藥上可接受之鹽經調配以用於使用霧化器、加壓計量劑量吸入器(pressurized metered dose inhaler, pMDI)、或乾粉吸入器(dry powder inhaler, DPI)進行氣霧劑遞送。
霧化器之非限制性實例包括霧化、噴射、超音波、加壓、振動多孔板、或等效霧化器,包括利用適應性氣霧劑遞送技術之霧化器(Denyer,
J. Aerosol medicine Pulmonary Drug Delivery2010,
23Supp 1, S1-S10)。噴射霧化器利用氣壓將液體溶液分解成氣溶膠液滴。超音波霧化器藉由壓電晶體工作,壓電晶體將液體剪切成小的氣溶膠液滴。加壓霧化系統迫使溶液在壓力下通過小孔以產生氣溶膠液滴。振動多孔板裝置利用快速振動以將液體流剪切成適當液滴大小。
在另一實施例中,使用能夠將式(I)之化合物、或其醫藥上可接受之鹽的配方氣霧化成所需MMAD之粒子的霧化器,將用於霧化之配方以包含MMAD主要在約1 µm與約5 µm之間的粒子之氣霧劑形式遞送至支氣管內空間。為了達到最佳治療效果且避免上呼吸道及全身性副作用,大部分氣霧化粒子不應具有大於約5 µm之MMAD。若氣霧劑含有大量MMAD大於約5 µm的粒子,則粒子會沉積在上呼吸道中,從而降低遞送至下呼吸道中發炎及支氣管收縮部位之藥物量。若氣霧劑之MMAD小於約1 µm,則在一些情況下,粒子保持懸浮在吸入的空氣中且可隨後在呼氣期間呼出。
當根據本文之方法調配及遞送時,用於霧化之氣霧劑配方將治療有效劑量的式(I)之化合物、或其醫藥上可接受之鹽遞送至治療目標,諸如癌症部位。可調整所投予之藥物之量,以反映治療有效劑量的式(I)之化合物、或其醫藥上可接受之鹽的遞送效率。在一實施例中,取決於霧化器,水性氣霧劑配方與霧化、噴射、加壓、振動多孔板、或超音波霧化器之組合允許約20至約90%(諸如約70%)的式(I)之化合物、或其醫藥上可接受之鹽之投予劑量遞送至氣道中。在一實施例中,遞送約30至約50%的活性化合物。例如,可遞送約70至約90%的活性化合物。
在另一實施例中,式(I)之化合物或其醫藥上可接受之鹽係以可吸入乾粉遞送。化合物係以乾粉配方之形式支氣管內投予,以使用乾粉或計量劑量吸入器將化合物之細粒子有效地遞送到支氣管內空間。針對藉由DPI遞送,將式(I)之化合物、或其醫藥上可接受之鹽藉由研磨噴霧乾燥、臨界流體加工、或自溶液中沉澱,加工成MMAD主要在約1 µm與約5 µm之間的粒子。能夠產生MMAD在約1 µm與約5 µm之間之粒徑的介質研磨、噴射研磨、及噴霧乾燥裝置及程序係所屬技術領域中熟知的。在一個實施例中,在加工至所需大小之粒子之前,將賦形劑添加至式(I)之化合物、或其醫藥上可接受之鹽中。在另一實施例中,將賦形劑與所需大小之粒子摻合以幫助藥物粒子之分散,例如藉由使用乳糖作為賦形劑。
使用所屬技術領域中熟知的裝置進行粒徑判定。例如,多階安德森級聯衝擊器或其他合適的方法,諸如美國藥典(US Pharmacopoeia)第601章內特別引用者,作為計量劑量及乾粉吸入器內氣霧劑的表徵裝置。
在另一實施例中,可使用諸如乾粉吸入器或其他乾粉分散裝置之裝置,將式(I)之化合物、或其醫藥上可接受之鹽以乾粉遞送。乾粉吸入器及裝置之非限制性實例包括下列中所揭示者:US5,458,135;US5,740,794;US5,775,320;US5,785,049;US3,906,950;US4,013,075;US4,069,819;US4,995,385;US5,522,385;US4,668,218;US4,667,668;US4,805,811及US5,388,572。乾粉吸入器有兩種主要設計。一種設計係計量裝置,其中藥物之貯庫係置於裝置內,且患者將一定劑量的藥物添加至吸入室中。第二種設計係工廠計量裝置,其中各個別劑量已在單獨容器中製造。兩種系統皆取決於將藥物調配成MMAD為約1 µm至約5 µm之小粒子,且常涉及與較大的賦形劑粒子(諸如但不限於乳糖)共調配。將藥物粉末置於吸入室中(藉由裝置計量或藉由破壞工廠計量劑量),且患者之吸氣流加速粉末流出裝置並進入口腔中。粉末路徑之非層流特性造成賦形劑-藥物聚集體分解,且大的賦形劑粒子之質量造成其在喉嚨後部的撞擊,而較小的藥物粒子係沉積在肺部深處。在一些實施例中,式(I)之化合物、或其醫藥上可接受之鹽係使用如本文所述之任一種類型的乾粉吸入器以乾粉遞送,其中不包括任何賦形劑之乾粉之MMAD主要在約1 µm至約5 µm之範圍內。
在另一實施例中,式(I)之化合物、或其醫藥上可接受之鹽係使用計量劑量吸入器以乾粉遞送。計量劑量吸入器及裝置之非限制性實例包括下列中所揭示者:US5,261,538;US5,544,647;US5,622,163;US4,955,371;US3,565,070;US3,361306及US6,116,234。在一些實施例中,式(I)之化合物、或其醫藥上可接受之鹽係使用計量劑量吸入器以乾粉遞送,其中不包括任何賦形劑之乾粉之MMAD主要在約1至約5 µm之範圍內。
適用於陰道投予之配方可以子宮托、棉條、乳膏、凝膠、糊劑、泡沫、或噴霧配方呈現,其除了活性成分外亦含有如所屬技術領域中已知適當之載劑。
適用於腸胃外投予之配方包括水性及非水性無菌注射溶液,其可含有抗氧化劑、緩衝劑、制菌劑、及使配方與預期接受者之血液等張的溶質;及水性及非水性無菌懸浮液,其可包括懸浮劑及增稠劑。
配方係存在於單位劑量或多劑量容器(例如密封安瓿及小瓶)中且可儲存於冷凍乾燥(freeze-dried)(凍乾(lyophilized))條件下,只需要在使用前立即添加無菌液體載劑(例如注射用水)。即時(extemporaneous)注射溶液及懸浮液係製備自先前所述種類之無菌粉劑、粒劑、及錠劑。單位劑量配方包括含有每日劑量或單位每日次劑量(如本文於上所述)或其適當部分的活性成分者。
應理解的是,除了以上特別提及之成分外,配方可包括所屬技術領域中關於所討論配方類型之習知的其他藥劑,例如適用於口服投予者可包括調味劑。
進一步提供動物醫藥組成物,其包含至少一種如上所定義之活性成分連同用於其之動物醫藥載劑。
動物醫藥載劑係可用於投予組成物之目地的材料且可係固體、液體、或氣體材料,其不是惰性的就是在動物醫藥技術領域中係可接受的且與活性成分相容。此等動物醫藥組成物可口服、腸胃外投予、或藉由任何其他所欲途徑投予。
本文之化合物係用於提供含有作為活性成分之一或多種化合物的控制釋放醫藥配方(「控制釋放配方」),其中活性成分之釋放受到控制及調控,以允許較低頻率給藥或改善給定活性成分之藥物動力學或毒性概況。
活性成分之有效劑量至少取決於待治療病況之本質、毒性、遞送方法、及醫藥配方,且可由臨床醫師使用習知劑量增量研究判定。可預期為每日約0.0001至約100 mg/kg體重;一般為每日約0.01至約10 mg/kg體重;更一般為每天約.0.01至約5 mg/kg體重;最一般為每天約.0.05至約0.5 mg/kg體重。例如,針對體重約70 kg成年人類之每日候選劑量可在約1 mg至約1000 mg之範圍內,諸如在約5 mg與約500 mg之間,且可採取單次或多次劑量之形式。
一些實施例提供一種製造用於治療有其需要之對象之癌症之藥劑之方法。在一些實施例中,用於製造用於治療癌症之藥劑之方法包括使用具有式(I)之結構之化合物、或其醫藥上可接受之鹽。一些實施例提供一種製造用於抑制有其需要之對象之癌症轉移之藥劑之方法。在一些實施例中,用於製造用於抑制癌症轉移之藥劑之方法包括使用具有式(I)之結構之化合物、或其醫藥上可接受之鹽。
在一些實施例中,本揭露提供一種具有式(I)之結構之化合物、或其醫藥上可接受之鹽在治療有其需要之對象之癌症中之用途。在一些實施例中,本揭露提供一種具有式(I)之結構之化合物、或其醫藥上可接受之鹽在抑制有其需要之對象之癌症轉移中之用途。在一些實施例中,本揭露提供一種具有式I之結構之化合物、或其醫藥上可接受之鹽供使用於療法。
IV. 投予途徑
一或多種式(I)之化合物、或其醫藥上可接受之鹽(本文稱為活性成分)係藉由適合待治療之病況的任何途徑投予。合適途徑包括口服、直腸、鼻、肺部、局部(包括經頰及舌下)、陰道、及腸胃外(包括皮下、肌內、靜脈內、皮內、鞘內、及硬膜外)、及類似者。將理解的是,途徑可隨例如接受者之病況而變化。在一些實施例中,本文所揭示之化合物係口服生體可用的且可口服給藥。
本揭露之化合物(在本文中亦稱為活性成分)可藉由適用於待治療病況的任何途徑投予。合適的途徑包括口服、直腸、鼻、局部(包括經頰及舌下)、經皮、陰道、及腸胃外(包括皮下、肌內、靜脈內、皮內、鞘內、及硬膜外)、及類似者。將理解的是,途徑可隨例如接受者之病況而變化。本文所揭示之某些化合物的優點在於其等係口服生物可用的且可口服給藥。
本揭露之化合物可根據有效給藥方案向個體投予一段所欲的時間或持續時間,諸如至少約一個月、至少約2個月、至少約3個月、至少約6個月、或至少約12個月或更久。在一些實施例中,在個體壽命之期間,以每日或間歇性排程投予化合物。
本揭露之化合物之劑量或給藥頻率可在治療過程中基於投予醫師之判斷調整。
化合物可以有效量投予至個體(例如人類)。在一些實施例中,化合物係每天投予一次。
化合物可藉由任何可用的途徑及手段投予,諸如藉由口服或腸胃外(例如靜脈內)投予。化合物之治療有效量可包括每天約0.00001 mg/kg體重至每天約10 mg/kg體重,諸如每天約0.0001 mg/kg體重至每天約10 mg/kg體重,或諸如每天約0.001 mg/kg體重至每天約1 mg/kg體重,或諸如每天約0.01 mg/kg體重至每天約1 mg/kg體重,或諸如每天約0.05 mg/kg體重至每天約0.5 mg/kg體重,或諸如每天約0.3 mg至約30 mg,或諸如每天約30 mg至約300 mg。
本揭露之化合物可與一或多種額外治療劑以任何劑量的本揭露之化合物(例如約1 mg至約1000 mg的化合物)組合。治療有效量可包括每劑量約1 mg至每劑量約1000 mg,諸如每劑量約50 mg至每劑量約500 mg,或諸如每劑量約100 mg至每劑量約400 mg,或諸如每劑量約150 mg至每劑量約350 mg,或諸如每劑量約200 mg至每劑量約300 mg。本揭露之化合物之其他治療有效量係每劑量約100、約125、約150、約175、約200、約225、約250、約275、約300、約325、約350、約375、約400、約425、約450、約475、或約500 mg。本揭露之化合物之其他治療有效量係每劑量約100 mg、或每劑量約125、約150、約175、約200、約225、約250、約275、約300、約325、約350、約375、約400、約425、約450、或約500 mg。單次劑量可每小時、每天、或每週投予。例如,單次劑量可約每1小時、約2、約3、約4、約6、約8、約12、約16投予一次、或約每24小時投予一次。單次劑量亦可約每1天、約2、約3、約4、約5、約6投予一次、或約每7天投予一次。單次劑量亦可約每1週、約2、約3投予一次、或約每4週投予一次。在一些實施例中,單次劑量可約每週投予一次。單次劑量亦可約每月投予一次。
本揭露之化合物之其他治療有效量係每劑量約20、約25、約30、約35、約40、約45、約50、約55、約60、約65、約70、約75、約80、約85、約90、約95、或約100 mg。
本揭露之化合物之劑量的頻率可由個別患者的需求判定,且可係例如每天一次、或每天兩次或更多次。只要治療疾病或病況需要,持續投予化合物。例如,可向患有癌症之人類投予化合物達約20天至約180天的期間、或例如達約20天至約90天的期間、或例如達約30天至約60天的期間。
投予可係間歇性的,其中在數天或更多天的期間內,患者接受每日劑量的本揭露之化合物,接著在數天或更多天的期間內,患者並未接受每日劑量的化合物。例如,患者可每隔一天、或每週三次接受一定劑量的化合物。再次舉實例而言,患者可每天接受一定劑量的化合物達約1至約14天的期間,接著在約7至約21天的期間內,患者並未接受一定劑量的化合物,接著在後續的期間(例如約1至約14天)內,患者再次接受每日劑量的化合物。依臨床上所需治療患者時,可重複投予化合物、接著不投予化合物之交替期。
在一個實施例中,提供醫藥組成物,其包含本揭露之化合物、或其醫藥上可接受之鹽、與一或多種(例如,一、二、三、四、一或二、一至三、或一至四種)額外治療劑、及醫藥上可接受之賦形劑之組合。
在一個實施例中,提供套組,其包含本揭露之化合物、或其醫藥上可接受之鹽、與一或多種(例如一、二、三、四、一或二、一至三、或一至四種)額外治療劑之組合。
在一些實施例中,本揭露之化合物或其醫藥上可接受之鹽係與一、二、三、四、或更多種額外治療劑組合。在一些實施例中,本揭露之化合物或其醫藥上可接受之鹽係與兩種額外治療劑組合。在其他實施例中,本揭露之化合物或其醫藥上可接受之鹽係與三種額外治療劑組合。在進一步實施例中,本揭露之化合物、或其醫藥上可接受之鹽係與四種額外治療劑組合。一、二、三、四、或更多種額外治療劑可為選自相同類型治療劑之不同治療劑,及/或其可為選自不同類型之治療劑。
在一些實施例中,當本揭露之化合物係與一或多種如本文所述之額外治療劑組合時,該組成物之組分係以同時或依序方案投予。當依序投予時,組合可在二或更多次投予中投予。
在一些實施例中,本揭露之化合物係與一或多種額外治療劑組合成單位劑型(unitary dosage form),以同時投予至患者,例如作為用於口服投予之固體劑型。
在一些實施例中,本揭露之化合物係與一或多種額外治療劑共投予。
為了延長本揭露之化合物的效應,通常所欲的是減緩皮下或肌肉內注射之化合物之吸收。此可藉由使用具有不良水溶性之結晶或非晶材料之液體懸浮液來達成。化合物之吸收速率因而取決於其溶解速率,而溶解速率又可取決於晶體大小及晶形。替代地,腸胃外投予之化合物形式之延遲吸收係藉由將化合物溶解或懸浮於油媒劑中來達成。藉由在可生物降解聚合物(諸如聚乳酸-聚甘醇酸)中形成化合物之微囊基質來製造可注射貯劑(depot)形式。取決於化合物與聚合物之比率及所採用之具體聚合物之本質,可控制化合物釋放速率。其他可生物降解聚合物之實例包括聚(原酸酯)及聚(酸酐)。貯劑可注射配方亦藉由將化合物包埋在與身體組織相容的微脂體或微乳液中來製備。
V. 組合療法
式I之化合物、其醫藥上可接受之鹽、及/或本文所提供之組成物亦可與其他活性治療劑組合使用以用於治療癌症。
在一些實施例中,本文所提供之化合物、或醫藥組成物係與一或多種(例如,一、二、三、或四種)額外治療劑一起投予。在一些實施例中,額外治療劑包括例如抑制性免疫檢查點阻斷劑或抑制劑、刺激性免疫檢查點刺激劑、促效劑或活化劑、化學治療劑、抗癌劑、放射治療劑、抗贅瘤劑、抗增生劑、抗血管生成劑、消炎劑、免疫治療劑、治療性抗原結合分子(例如呈任何形式之單及多特異性抗體或其片段,諸如DART
®、Duobody
®、BiTE
®、BiKE、TriKE、XmAb
®、TandAb
®、scFv、Fab、Fab衍生物)、雙特異性抗體、非免疫球蛋白抗體擬似物(例如包括阿德耐汀(adnectin)、親和抗體(affibody)、阿菲林(affilin)、黏合素(affimer)、阿非汀(affitin)、α抗體(alphabody)、抗運載蛋白(anticalin)、肽適體、犰狳重複蛋白(ARM)、阿去末(atrimer)、親和性多聚體(avimer)、經設計錨蛋白重複蛋白(DARPin
®)、非諾莫(fynomer)、打結素(knottin)、Kunitz域肽、單抗體(monobody)、及nanoCLAMP)、抗體藥物接合物(ADC)、抗體-肽接合物)、溶瘤病毒、基因修飾劑或編輯器、包含嵌合抗原受體(CAR)之細胞(例如包括T細胞免疫治療劑、NK細胞免疫治療劑、或巨噬細胞免疫治療劑)、包含經工程改造T細胞受體(TCR-T)之細胞、或其任何組合。
說明性目標
在一些實施例中,一或多種額外治療劑包括例如目標(例如多肽或多核苷酸)之抑制劑、促效劑、拮抗劑、配體、調節劑、刺激劑、阻斷劑、活化劑、或抑制劑,該目標諸如:2'-5'-寡腺苷酸合成酶(OAS1;NCBI基因ID:4938);5'-3'外切核醣核酸酶1(XRN1;NCBI基因ID:54464);胞外5'-核苷酸酶(NT5E、CD73;NCBI基因ID:4907);ABL原致癌基因1(非受體酪胺酸激酶)(ABL1、BCR-ABL、c-ABL、v-ABL;NCBI基因ID:25);黑色素瘤2中不存在(AIM2;NCBI基因ID:9447);乙醯CoA醯基轉移酶2(ACAA2;NCBI基因ID:10499);酸性磷酸酶3(ACP3;NCBI基因ID:55);腺苷去胺酶(ADA、ADA1;NCBI基因ID:100);腺苷受體(例如ADORA1 (A1)、ADORA2A (A2a, A2AR)、ADORA2B (A2b, A2BR)、ADORA3 (A3);NCBI基因ID:134、135、136、137);AKT絲胺酸/蘇胺酸激酶1(AKT1、AKT、PKB;NCBI基因ID:207);丙胺醯基胺肽酶(膜)(ANPEP、CD13;NCBI基因ID:290);ALK受體酪胺酸激酶(ALK、CD242;NCBI基因ID:238);α胎兒蛋白(AFP;NCBI基因ID:174);含銅胺氧化酶(例如AOC1 (DAO1)、AOC2、AOC3 (VAP1);NCBI基因ID:26、314、8639);雄性激素受體(AR;NCBI基因ID:367);血管生成素(ANGPT1、ANGPT2;NCBI基因ID:284、285);血管收縮素II受體1型(AGTR1;NCBI基因ID:185);血管張力素原(AGT;NCBI基因ID:183);載脂蛋白A1(APOA1;NCBI基因ID:335);細胞凋亡誘導因子粒線體相關1(AIFM1、AIF;NCBI基因ID:9131);花生四烯酸5-脂氧合酶(ALOX55;NCBI基因ID:240);天冬醯胺酶(ASPG;NCBI基因ID:374569);星狀同源物1(ASTE1;NCBI基因ID:28990);ATM絲胺酸/蘇胺酸激酶(ATM;NCBI基因ID:472);ATP結合匣亞家族B成員1(ABCB1、CD243、GP170;NCBI基因ID:5243);ATP依賴性Clp蛋白酶(CLPP;NCBI基因ID:8192);ATR絲胺酸/蘇胺酸激酶(ATR;NCBI基因ID:545);AXL受體酪胺酸激酶(AXL;NCBI基因ID:558);B及T淋巴球相關(BTLA、CD272;NCBI基因ID:151888);含桿狀病毒IAP重複序列之蛋白質(BIRC2 (cIAP1)、BIRC3 (cIAP2)、XIAP (BIRC4, IAP3)、BIRC5(生存素(survivin));NCBI基因ID:329、330、331、332);basigin(Ok血型)(BSG、CD147;NCBI基因ID:682);B細胞淋巴瘤2(BCL2;NCBI基因ID:596);BCL2結合組分3(BBC3、PUMA;NCBI基因ID:27113);BCL2樣(例如BCL2L1 (Bcl-x)、BCL2L2 (BIM);Bcl-x;NCBI基因ID:598、10018);β3-腎上腺素受體(ADRB3;NCBI基因ID:155);骨γ-羧基麩胺酸蛋白(BGLAP;NCBI基因ID:632);骨形成蛋白10配體(BMP10;NCBI基因ID:27302);緩激肽受體(例如BDKRB1、BDKRB2;NCBI基因ID:623、624);B-RAF(BRAF;NCBI基因ID:273);斷點簇集區(BCR;NCBI基因ID:613);布羅莫域(Bromodomain)及外域(BET)含布羅莫域蛋白(例如BRD2、BRD3、BRD4、BRDT;NCBI基因ID:6046、8019、23476、676);布魯頓氏(Bruton)酪胺酸激酶(BTK;NCBI基因ID:695);鈣黏素(例如CDH3(p-鈣黏素)、CDH6(k-鈣黏素);NCBI基因ID:1001、1004);癌症/睪丸抗原(例如CTAG1A、CTAG1B、CTAG2;NCBI基因ID:1485、30848、246100);大麻素受體(例如CNR1 (CB1)、CNR2 (CB2);NCBI基因ID:1268、1269);碳水化合物磺基轉移酶15(CHST15;NCBI基因ID:51363);碳酸酐酶(例如CA1、CA2、CA3、CA4、CA5A、CA5B、CA6、CA7、CA8、CA9、CA10、CA11、CA12、CA13、CA14);NCBI基因ID:759、760、761、762、763、765、766、767、768、770、771、11238、23632、56934、377677);癌胚抗原相關細胞黏附分子(例如,CEACAM3 (CD66d)、CEACAM5 (CD66e)、CEACAM6 (CD66c);NCBI基因ID:1048、1084、4680);酪蛋白激酶(例如,CSNK1A1 (CK1)、CSNK2A1 (CK2);NCBI基因ID:1452、1457);凋亡蛋白酶(例如,CASP3、CASP7、CASP8;NCBI基因ID:836、840、841、864);連環蛋白β1(CTNNB1;NCBI基因ID:1499);組織蛋白酶G(CTSG;NCBI基因ID:1511);Cbl原致癌基因B(CBLB,Cbl-b;NCBI基因ID:868);C-C模體趨化因子配體21(CCL21;NCBI基因ID:6366);C-C模體趨化因子受體2(CCR2;NCBI基因ID:729230);C-C模體趨化因子受體(例如,CCR3 (CD193)、CCR4 (CD194)、CCR5 (CD195)、CCR8 (CDw198);NCBI基因ID:1232、1233、1234、1237);CCAAT增強子結合蛋白α(CEBPA、CEBP;NCBI基因ID:1050);細胞黏附分子1(CADM1;NCBI基因ID:23705);細胞分裂週期7(CDC7;NCBI基因ID:8317);細胞通訊網路因子2(CCN2;NCBI基因ID:1490);塞勒布隆(CRBN;NCBI基因ID:51185);檢查點激酶(例如,CHEK1 (CHK1)、CHEK2 (CHK2);NCBI基因ID:1111、11200);膽囊收縮素B受體(CCKBR;NCBI基因ID:887);絨毛膜促體乳素荷爾蒙1(CSH1;NCBI基因ID:1442);密連蛋白(例如,CLDN6、CLDN18;NCBI基因ID:9074、51208);分化簇標記(例如,CD1A、CD1C、CD1D、CD1E、CD2、CD3 α (TRA)、CD β (TRB)、CD γ (TRG)、CD δ (TRD)、CD4、CD8A、CD8B、CD19、CD20 (MS4A1)、CD22、CD24、CD25 (IL2RA, TCGFR)、CD28、CD33 (SIGLEC3)、CD37、CD38、CD39 (ENTPD1)、CD40 (TNFRSF5)、CD44 (MIC4, PGP1)、CD47 (IAP)、CD48 (BLAST1)、CD52、CD55 (DAF)、CD58 (LFA3)、CD74,CD79a、CD79b、CD80 (B7-1)、CD84、CD86 (B7-2)、CD96 (TACTILE)、CD99 (MIC2)、CD115 (CSF1R)、CD116 (GMCSFR, CSF2RA)、CD122 (IL2RB)、CD123 (IL3RA)、CD128 (IL8R1)、CD132 (IL2RG)、CD135 (FLT3)、CD137 (TNFRSF9, 4-1BB)、CD142 (TF, TFA)、CD152 (CTLA4)、CD160、CD182 (IL8R2)、CD193 (CCR3)、CD194 (CCR4)、CD195 (CCR5)、CD207、CD221 (IGF1R)、CD222 (IGF2R)、CD223 (LAG3)、CD226 (DNAM1)、CD244、CD247、CD248、CD276 (B7-H3)、CD331 (FGFR1)、CD332 (FGFR2)、CD333 (FGFR3)、CD334 (FGFR4);NCBI基因ID:909、911、912、913、914、919、920、923、925、926、930、931、933、940、941、942、945、951、952、953、958,960、961、962、965、972、973、974、1043、1232、1233、1234、1237、1436、1438、1493、1604、2152、2260、2261、2263、2322、3480、3482、3559、3560、3561、3563、3577、3579、3604、3902、4267、6955、6957、6964、6965、8832、10666、11126、50489、51744、80381、100133941);群集素(CLU;NCBI基因ID:1191);凝血因子(例如,F7、FXA、;NCBI基因ID:2155、2159);膠原蛋白IV型α鏈(例如,COL4A1、COL4A2、COL4A3、COL4A4、COL4A5;NCBI基因ID:1282、1284、1285、1286、1287);膠凝素亞家族成員10(COLEC10;NCBI基因ID:10584);群落刺激因子(例如,CSF1 (MCSF)、CSF2 (GMCSF)、CSF3 (GCSF);NCBI基因ID:1435、1437、1440);補體因子(例如,C3、C5;NCBI基因ID:718、727);COP9信號小體次單元5(COPS5;NCBI基因ID:10987);C型凝集素域家族成員(例如,CLEC4C (CD303)、CLEC9A (CD370)、CLEC12A (CD371);CD371;NCBI基因ID:160364、170482、283420);C-X-C模體趨化因子配體12(CXCL12;NCBI基因ID:6387);C-X-C模體趨化因子受體(CXCR1 (IL8R1, CD128)、CXCR2 (IL8R2, CD182)、CXCR3 (CD182, CD183, IP-10R)、CXCR4 (CD184);NCBI基因ID:2833、3577、3579、7852);週期蛋白D1(CCND1、BCL1;NCBI基因ID:595);週期蛋白依賴性激酶(例如CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8、CDK9、CDK10、CDK12;NCBI基因ID:983、1017、1018、1019、1020、1021、1022、1024、1025、8558、51755);週期蛋白G1(CCNG1;NCBI基因ID:900);細胞色素P450家族成員(例如,CYP2D6、CYP3A4、CYP11A1、CYP11B2、CYP17A1、CYP19A1、CYP51A1;NCBI基因ID:1565、1576、1583、1585、1586、1588、1595);細胞色素P450氧化還原酶(POR;NCBI基因ID:5447);含細胞介素誘導性SH2蛋白(CISH;NCBI基因ID:1154);細胞毒性T淋巴細胞相關蛋白4(CTLA4、CD152;NCBI基因ID:1493);死亡盒(DEAD-box)解螺旋酶(例如,DDX5、DDX6、DDX58;NCBI基因ID:1655、1656、23586);δ樣典型Notch配體(例如,DLL3、DLL4;NCBI基因ID:10683、54567);diablo IAP結合粒線體蛋白(DIABLO、SMAC;NCBI基因ID:56616);二醯基甘油激酶(例如,DGKA、DGKZ;NCBI基因ID:1606、8525);dickkopf WNT信號傳導路徑抑制劑(例如,DKK1、DKK3;NCBI基因ID:22943、27122);二氫葉酸還原酶(DHFR;NCBI基因ID:1719);二氫嘧啶去氫酶(DPYD;NCBI基因ID:1806);二肽基肽酶4(DPP4;NCBI基因ID:1803);盤狀蛋白域受體酪胺酸激酶(例如,DDR1 (CD167)、DDR2;CD167;NCBI基因ID:780、4921);DNA依賴性蛋白激酶(PRKDC;NCBI基因ID:5591);DNA拓樸異構酶(例如,TOP1、TOP2A、TOP2B、TOP3A、TOP3B;NCBI基因ID:7150、7153、7155、7156、8940);多巴色素互變異構酶(DCT;NCBI基因ID:1638);多巴胺受體D2(DRD2;NCBI基因ID:1318);DOT1樣組蛋白離胺酸甲基轉移酶(DOT1L;NCBI基因ID:84444);外核苷酸焦磷酸酶/磷酸二酯酶3(ENPP3、CD203c;NCBI基因ID:5169);EMAP樣4(EML4;NCBI基因ID:27436);內皮糖蛋白(ENG;NCBI基因ID:2022);內質網胺基肽酶(例如,ERAP1、ERAP2;NCBI基因ID:51752、64167);zeste 2多梳蛋白抑制複合體2次單元之增強子(EZH2;NCBI基因ID:2146);蝶素受體(例如,EPHA1、EPHA2EPHA3、EPHA4、EPHA5、EPHA7、EPHB4;NCBI基因ID:1969、2041、2042、2043、2044、2045、2050);蝶素(例如,EFNA1、EFNA4、EFNB2;NCBI基因ID:1942、1945、1948);表皮生長因子受體(例如,ERBB1 (HER1, EGFR)、ERBB1變體III (EGFRvIII)、ERBB2 (HER2, NEU, CD340)、ERBB3 (HER3)、ERBB4 (HER4);NCBI基因ID:1956、2064、2065、2066);上皮細胞黏附分子(EPCAM;NCBI基因ID:4072);上皮促分裂原(EPGN;NCBI基因ID:255324);真核轉譯伸長因子(例如,EEF1A2、EEF2;NCBI基因ID:1917、1938);真核轉譯起始因子(例如,EIF4A1、EIF5A;NCBI基因ID:1973、1984);外輸蛋白-1(XPO1;NCBI基因ID:7514);法尼醇X受體(NR1H4、FXR;NCBI基因ID:9971);Fas配體(FASLG、FASL、CD95L、CD178、TNFSF6;NCBI基因ID:356);脂肪酸醯胺水解酶(FAAH;NCBI基因ID:2166);脂肪酸合成酶(FASN;FAS;NCBI基因ID:2194);Ig受體之Fc片段(例如,FCER1A、FCGRT、FCGR3A (CD16);NCBI基因ID:2205、2214、2217);Fc受體樣5(FCRL5、CD307;NCBI基因ID:83416);纖維母細胞活化蛋白α (FAP);NCBI基因ID:2191);纖維母細胞生長因子受體(例如FGFR1 (CD331)、FGFR2 (CD332)、FGFR3 (CD333)、FGFR4 (CD334);NCBI基因ID:2260、2261、2263、2264);纖維母細胞生長因子(例如FGF1 (FGFα)、FGF2 (FGFβ)、FGF4、FGF5;NCBI基因ID:2246、2247、2249、2250);纖連蛋白1(FN1、MSF;NCBI基因ID:2335);fms相關受體酪胺酸激酶(例如FLT1 (VEGFR1)、FLT3 (STK1, CD135)、FLT4 (VEGFR2);NCBI基因ID:2321、2322、2324);fms相關受體酪胺酸激酶3配體(FLT3LG;NCBI基因ID:2323);黏著斑激酶2(PTK2、FAK1;NCBI基因ID:5747);葉酸水解酶1(FOLH1、PSMA;NCBI基因ID:2346);葉酸受體1(FOLR1;NCBI基因ID:2348);叉頭盒蛋白M1(FOXM1;NCBI基因ID:2305);FURIN(FURIN、PACE;NCBI基因ID:5045);FYN酪胺酸激酶(FYN、SYN;NCBI基因ID:2534);半乳糖凝集素(例如,LGALS3、LGALS8 (PCTA1)、LGALS9;NCBI基因ID:3958、3964、3965);糖皮質激素受體(NR3C1、GR;NCBI基因ID:2908);葡萄醣醛酸酶β(GUSB;NCBI基因ID:2990);麩胺酸代謝型受體1(GRM1;NCBI基因ID:2911);麩醯胺酸酶(GLS;NCBI基因ID:2744);麩胱甘肽S-轉移酶Pi(GSTP1;NCBI基因ID:2950);肝醣合成酶激酶3 β(GSK3B;NCBI基因ID:2932);磷脂肌醇聚糖3(GPC3;NCBI基因ID:2719);促性腺激素釋放激素1(GNRH1;NCBI基因ID:2796);促性腺激素釋放荷爾蒙受體(GNRHR;NCBI基因ID:2798);GPNMB醣蛋白nmb(GPNMB、骨活素(osteoactivin);NCBI基因ID:10457);生長分化因子2(GDF2、BMP9;NCBI基因ID:2658);生長因子受體結合蛋白2(GRB2、ASH;NCBI基因ID:2885);鳥苷酸環化酶2C(GUCY2C、STAR、MECIL、MUCIL,NCBI基因ID:2984);H19母系印跡表現轉錄物(H19;NCBI基因ID:283120);HCK原致癌基因,Src家族酪胺酸激酶(HCK;NCBI基因ID:3055);熱休克蛋白(例如HSPA5 (HSP70, BIP, GRP78)、HSPB1 (HSP27)、HSP90B1 (GP96);NCBI基因ID:3309、3315、7184);血紅素加氧酶(例如,HMOX1 (HO1)、HMOX2 (HO1);NCBI基因ID:3162、3163);肝素酶(HPSE;NCBI基因ID:10855);A型肝炎病毒細胞性受體2(HAVCR2、TIM3、CD366;NCBI基因ID:84868);肝細胞生長因子(HGF;NCBI基因ID:3082);HERV-H LTR關聯2(HHLA2、B7-H7;NCBI基因ID:11148);組織胺受體H2(HRH2;NCBI基因ID:3274);組蛋白去乙醯酶(例如,HDAC1、HDAC7、HDAC9;NCBI基因ID:3065、9734、51564);HRas原致癌基因(GTP酶)(HRAS;NCBI基因ID:3265);缺氧誘導因子(例如HIF1A、HIF2A (EPAS1);NCBI基因ID:2034、3091);I-κ-B激酶(IKK β;NCBI基因ID:3551、3553);IKAROS家族鋅指(IKZF1 (LYF1)、IKZF3;NCBI基因ID:10320、22806);免疫球蛋白超家族成員11(IGSF11;NCBI基因ID:152404);吲哚胺2,3-二加氧酶(例如,IDO1、IDO2;NCBI基因ID:3620、169355);可誘導T細胞共刺激劑(ICOS、CD278;NCBI基因ID:29851);可誘導T細胞共刺激劑配體(ICOSLG、B7-H2;NCBI基因ID:23308);胰島素樣生長因子受體(例如,IGF1R、IGF2R;NCBI基因ID:3480’3482);胰島素樣生長因子(例如,IGF1、IGF2;NCBI基因ID:3479、3481);胰島素受體(INSR、CD220;NCBI基因ID:3643);整合素次單元(例如,ITGA5 (CD49e)、ITGAV (CD51)、ITGB1 (CD29)、ITGB2 (CD18, LFA1, MAC1)、ITGB7;NCBI基因ID:3678、3685、3688、3695、3698);細胞間黏附分子1(ICAM1、CD54;NCBI基因ID:3383);介白素1受體相關激酶4(IRAK4;NCBI基因ID:51135);介白素受體(例如,IL2RA (TCGFR, CD25)、IL2RB (CD122)、IL2RG (CD132)、IL3RA、IL6R、IL13RA2 (CD213A2)、IL22RA1;NCBI基因ID:3598、3559、3560、3561、3563、3570、58985);介白素(例如,IL1A、IL1B、IL2、IL3、IL6 (HGF)、IL7、IL8 (CXCL8)、IL10 (TGIF)、IL12A、IL12B, IL15、IL17A (CTLA8)、IL18、IL23A、IL24、IL-29 (IFNL1);NCBI基因ID:3552、3553、3558、3562、3565、3569、3574、3586、3592、3593、3600、3605、3606、11009、51561、282618);異檸檬酸去氫酶(NADP(+)1)(例如,IDH1、IDH2;NCBI基因ID:3417、3418);Janus激酶(例如,JAK1、JAK2、JAK3;NCBI基因ID:3716、3717、3718);血管舒緩素相關肽酶3(KLK3;NCBI基因ID:354);殺手細胞免疫球蛋白樣受體、Ig域及長細胞質尾(例如,KIR2DL1 (CD158A)、KIR2DL2 (CD158B1)、KIR2DL3 (CD158B)、KIR2DL4 (CD158D)、KIR2DL5A (CD158F)、KIR2DL5B, KIR3DL1 (CD158E1)、KIR3DL2 (CD158K)、KIR3DP1 (CD158c)、KIR2DS2 (CD158J;NCBI基因ID:3802、3803、3804、3805、3811、3812、57292、553128、548594、100132285);殺手細胞凝集素樣受體(例如,KLRC1 (CD159A)、KLRC2 (CD159c)、KLRC3、KLRRC4、KLRD1 (CD94)、KLRG1、KLRK1 (NKG2D, CD314);NCBI基因ID:3821、3822、3823、3824、8302、10219、22914);激酶插入域受體(KDR、CD309、VEGFR2;NCBI基因ID:3791);驅動蛋白家族成員11(KIF11;NCBI基因ID:3832);KiSS-1轉移抑制劑(KISS1;NCBI基因ID:3814);KIT原致癌基因(受體酪胺酸激酶)(KIT、C-KIT、CD117;NCBI基因ID:3815);KRAS原致癌基因(GTP酶)(KRAS;NCBI基因ID:3845);乳轉鐵蛋白(LTF;NCBI基因ID:4057);LCK原致癌基因,Src家族酪胺酸激酶(LCK;NCBI基因ID:3932);LDL受體相關蛋白1(LRP1、CD91、IGFBP3R;NCBI基因ID:4035);含富白胺酸重複序列15(LRRC15;NCBI基因ID:131578);白血球免疫球蛋白樣受體(例如,LILRB1 (ILT2, CD85J)、LILRB2 (ILT4, CD85D);NCBI基因ID:10288、10859);白三烯A4水解酶(LTA4H;NCBI基因ID:4048);用於活化T細胞之連接子(LAT;NCBI基因ID:27040);黃體成長荷爾蒙/絨毛膜促性腺激素受體(LHCGR;NCBI基因ID:3973);含LY6/PLAUR域3(LYPD3;NCBI基因ID:27076);淋巴球活化3 (LAG3);CD223;NCBI基因ID:3902);淋巴球抗原(例如,LY9 (CD229)、LY75 (CD205);NCBI基因ID:4063、17076);LYN原致癌基因,Src家族酪胺酸激酶(LYN;NCBI基因ID:4067);淋巴球胞溶質蛋白2(LCP2;NCBI基因ID:3937);離胺酸去甲基酶1A(KDM1A;NCBI基因ID:23028);溶血磷脂酸受體1(LPAR1、EDG2、LPA1、GPR26;NCBI基因ID:1902);離胺醯基氧化酶(LOX;NCBI基因ID:4015);離胺醯基氧化酶樣2(LOXL2;NCBI基因ID:4017);巨噬細胞移動抑制因子(MIF、GIF;NCBI基因ID:4282);巨噬刺激1受體(MST1R、CD136;NCBI基因ID:4486);MAGE家族成員(例如,MAGEA1、MAGEA2、MAGEA2B、MAGEA3、MAGEA4、MAGEA5、MAGEA6、MAGEA10、MAGEA11、MAGEC1、MAGEC2、MAGED1、MAGED2;NCBI基因ID:4100、4101、4102、4103、4104、4105、4109、4110、9500、9947、10916、51438、266740);主要組織相容性複合體(例如,HLA-A、HLA-E、HLA-F、HLA-G;NCBI基因ID:3105、3133、3134、3135);穹窿體主蛋白(MVP、VAULT1;NCBI基因ID:9961);MALT1對凋亡蛋白酶(MALT1;NCBI基因ID:10892);MAPK活化蛋白激酶2(MAPKAPK2;NCBI基因ID:9261);MAPK交互作用型絲胺酸/蘇胺酸激酶(例如,MKNK1、MKNK2;NCBI基因ID:2872、8569);基質金屬肽酶(例如,MMP1、MMP2、MMP3、MMP7、MMP8、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、MMP15、MMP16、MMP17、MMP19、MMP20、MMP21,MMP24、MMP25、MMP26、MMP27、MMP28;NCBI基因ID:4312、4313、4314、4316、4317、4318、4319、4320、4321、4322、4323、4324、4325、4326、4327、9313、10893、56547、64066、64386、79148、118856);MCL1細胞凋亡調控子,BCL2家族成員(MCL1;NCBI基因ID:4170);MDM2原致癌基因(MDM2;NCBI基因ID:4193);p53之MDM4調控子(MDM4;BMFS6;NCBI基因ID:4194);機制性雷帕黴素激酶目標(MTOR、FRAP1;NCBI基因ID:2475);melan-A(MLANA;NCBI基因ID:2315);黑皮質素受體(MC1R、MC2R;NCBI基因ID:4157、4148);MER原致癌基因(酪胺酸激酶)(MERTK;NCBI基因ID:10461);間皮素(MSLN;NCBI基因ID:10232);MET原致癌基因(受體酪胺酸激酶)(MET、c-Met、HGFR;NCBI基因ID:4233);甲硫胺醯基胺基肽酶2(METAP2、MAP2;NCBI基因ID:10988);MHC第I型多肽相關序列(例如,MICA、MICB;NCBI基因ID:4277、100507436);促分裂原活化蛋白激酶(例如MAPK1 (ERK2)、MAPK3 (ERK1)、MAPK8 (JNK1)、MAPK9 (JNK2)、MAPK10 (JNK3)、MAPK11 (p38β)、MAPK12;NCBI基因ID:5594、5595、5599、5600、5601、5602、819251);促分裂原活化蛋白激酶激酶激酶(例如MAP3K5 (ASK1)、MAP3K8 (TPL2, AURA2);NCBI基因ID:4217、1326);促分裂原活化蛋白激酶激酶激酶激酶1(MAP4K1,HPK1;NCBI基因ID:11184);促分裂原活化蛋白激酶激酶(例如MAP2K1 (MEK1)、MAP2K2 (MEK2)、MAP2K7 (MEK7);NCBI基因ID:5604、5605、5609);MPL原致癌基因,血小板生成素受體(MPL;NCBI基因ID:4352);黏液素(例如,MUC1(包括其剪接變體(例如,包括MUC1/A、C、D、X、Y、Z、及REP))、MUC5AC、MUC16 (CA125);NCBI基因ID:4582、4586、94025);MYC原致癌基因,bHLH轉錄因子(MYC;NCBI基因ID:4609);肌肉生長抑制素(MSTN、GDF8;NCBI基因ID:2660);富肉豆蔻醯基化丙胺酸蛋白激酶C受質(MARCKS;NCBI基因ID:4082);利尿鈉肽受體3(NPR3;NCBI基因ID:4883);自然殺手細胞細胞毒性受體3配體1(NCR3LG1、B7-H6;NCBI基因ID:374383);神經細胞生長抑制因子(necdin),MAGE家族成員(NDN;NCBI基因ID:4692);連黏蛋白細胞黏附分子(例如,NECTIN2 (CD112, PVRL2)、NECTIN4 (PVRL4);NCBI基因ID:5819、81607);神經細胞黏附分子1(NCAM1、CD56;NCBI基因ID:4684);神經纖毛蛋白(例如,NRP1 (CD304, VEGF165R)、NRP2 (VEGF165R2);NCBI基因ID:8828、8829);神經營養受體酪胺酸激酶(例如,NTRK1 (TRKA)、NTRK2 (TRKB)、NTRK3 (TRKC);NCBI基因ID:4914、4915、4916);NFKB活化蛋白(NKAP;NCBI基因ID:79576);NIMA相關激酶9(NEK9;NCBI基因ID:91754);含NLR家族膿素域3(NLRP3、NALP3;NCBI基因ID:114548);notch受體(例如,NOTCH1、NOTCH2、NOTCH3、NOTCH4;NCBI基因ID:4851、4853、4854、4855);NRAS原致癌基因(GTP酶)(NRAS;NCBI基因ID:4893);核因子κ B(NFKB1、NFKB2;NCBI基因ID:4790、4791);核因子,類紅血球2樣2(NFE2L2;NRF2;NCBI基因ID:4780);核受體亞家族4 A組成員1(NR4A1;NCBI基因ID:3164);核仁素(NCL;NCBI基因ID:4691);核仁磷酸蛋白1(NPM1;NCBI基因ID:4869);含核苷酸結合寡聚域2(NOD2;NCBI基因ID:64127);nudix水解酶1(NUDT1;NCBI基因ID:4521);O-6-甲基鳥嘌呤-DNA甲基轉移酶(MGMT;NCBI基因ID:4255);類鴉片受體δ 1(OPRD1;NCBI基因ID:4985);鳥胺酸去羧酶1(ODC1;NCBI基因ID:4953);側氧戊二酸去氫酶(OGDH;NCBI基因ID:4967);副甲狀腺荷爾蒙(PTH;NCBI基因ID:5741);PD-L1(CD274;NCBI基因ID:29126);骨膜素(POSTN;NCBI基因ID:10631);過氧化體增殖物活化受體(例如,PPARA (PPAR α)、PPARD (PPAR δ)、PPARG (PPAR γ);NCBI基因ID:5465、5467、5468);磷酸酶及張力蛋白同源物(PTEN;NCBI基因ID:5728);磷脂醯肌醇-4,5-雙磷酸3-激酶(PIK3CA (PI3Kα)、PIK3CB (PI3Kβ)、PIK3CD (PI3Kδ)、PIK3CG (PI3Kγ);NCBI基因ID:5290、5291、5293、5294);磷脂酶(例如,PLA2G1B、PLA2G2A、PLA2G2D、PLA2G3、PLA2G4A、PLA2G5、PLA2G7、PLA2G10、PLA2G12A、PLA2G12B、PLA2G15;NCBI基因ID:5319、5320、5321、5322、7941、8399、50487、23659、26279、81579、84647);Pim原致癌基因、絲胺酸/蘇胺酸激酶(例如,PIM1、PIM2、PIM3;NCBI基因ID:5292、11040、415116);胎盤生長因子(PGF;NCBI基因ID:5228);纖維蛋白溶酶原活化子,尿激酶(PLAU,u-PA,ATF;NCBI基因ID:5328);血小板衍生生長因子受體(例如PDGFRA (CD140A, PDGFR2)、FDGFRB (CD140B, PDGFR1);NCBI基因ID:5156、5159);叢蛋白B1(PLXNB1;NCBI基因ID:5364);脊髓灰白質炎病毒受體(PVR)細胞黏附分子(PVR, CD155);NCBI基因ID:5817);polo樣激酶1(PLK1;NCBI基因ID:5347);聚(ADP-核糖)聚合酶(例如,PARP1、PARP2、PARP3;NCBI基因ID:142、10038、10039);多梳蛋白EED(EED;NCBI基因ID:8726);豪豬O-醯基轉移酶(PORCN;NCBI基因ID:64840);PRAME核受體轉錄調控子(PRAME;NCBI基因ID:23532);前黑色素體蛋白(PMEL;NCBI基因ID:6490);助孕素受體(PGR;NCBI基因ID:5241);程序性細胞死亡1(PDCD1、PD-1、CD279;NCBI基因ID:5133);程式性細胞死亡1配體2(PDCD1LG2、CD273、PD-L2;NCBI基因ID:80380);凸素1 (prominin 1)(PROM1、CD133;NCBI基因ID:8842);前骨髓細胞性白血病(PML;NCBI基因ID:5371);鞘脂激活蛋白原(PSAP;NCBI基因ID:5660);前列腺素E受體4(PTGER4;NCBI基因ID:5734);前列腺素E合成酶(PTGES;NCBI基因ID:9536);前列腺素-內過氧化物合成酶(PTGS1 (COX1)、PTGS2 (COX2);NCBI基因ID:5742、5743);蛋白酶體20S次單元β 9(PSMB9;NCBI基因ID:5698);蛋白質精胺酸甲基轉移酶(例如,PRMT1,PRMT5;NCBI基因ID:3276、10419);蛋白激酶N3(PKN3;NCBI基因ID:29941);蛋白質磷酸酶2A(PPP2CA;NCBI基因ID:5515);蛋白酪胺酸激酶7(非活性)(PTK7;NCBI基因ID:5754);蛋白質酪胺酸磷酸酶受體(PTPRB (PTPB)、PTPRC (CD45R);NCBI基因ID:5787、5788);前胸腺素α(PTMA;NCBI基因ID:5757);嘌呤核苷磷酸化酶(PNP;NCBI基因ID:4860);嘌呤系受體(purinergic receptor) P2X 7(P2RX7;NCBI基因ID:5027);含PVR相關免疫球蛋白域(PVRIG、CD112R;NCBI基因ID:79037);Raf-1原致癌基因,絲胺酸/蘇胺酸激酶(RAF1、c-Raf;NCBI基因ID:5894);RAR相關孤兒受體γ(RORC;NCBI基因ID:6097);Ras同源物家族成員C (RhoC);NCBI基因ID:389);Ras同源物,mTORC1結合(RHEB;NCBI基因ID:6009);RB轉錄輔阻抑子1(RB1;NCBI基因ID:5925);受體交互作用型絲胺酸/蘇胺酸蛋白激酶1(RIPK1;NCBI基因ID:8737);ret原致癌基因(RET;NCBI基因ID:5979);視黃酸早期轉錄物(例如RAET1E、RAET1G、RAET1L;NCBI基因ID:135250、154064、353091);視黃酸受體α(例如,RARA、RARG;NCBI基因ID:5914、5916);類視色素X受體(例如,RXRA、RXRB、RXRG;NCBI基因ID:6256、6257、6258);含Rho相關捲曲螺旋之蛋白激酶(例如,ROCK1、ROCK2;NCBI基因ID:6093、9475);核糖體蛋白S6激酶B1(RPS6KB1、S6K-β 1;NCBI基因ID:6198);指環蛋白128(RNF128、GRAIL;NCBI基因ID:79589);ROS原致癌基因1,受體酪胺酸激酶(ROS1;NCBI基因ID:6098);圓環指引受體4(ROBO4;NCBI基因ID:54538);RUNX家族轉錄因子3(RUNX3;NCBI基因ID:864);S100鈣結合蛋白A9(S100A9;NCBI基因ID:6280);分泌之捲曲相關蛋白2(SFRP2;NCBI基因ID:6423);分泌之磷蛋白1(SPP1;NCBI基因ID:6696);食道鱗癌分泌素家族1A成員1(SCGB1A1;NCBI基因ID:7356);選擇素(例如,SELE、SELL (CD62L)、SELP (CD62);NCBI基因ID:6401、6402、6403);信號素(semaphorin) 4D(SEMA4D;CD100;NCBI基因ID:10507);唾液酸結合Ig樣凝集素(SIGLEC7 (CD328)、SIGLEC9 (CD329)、SIGLEC10;NCBI基因ID:27036、27180、89790);信號調控蛋白α(SIRPA、CD172A;NCBI基因ID:140885);信號轉導及轉錄活化子(例如,STAT1、STAT3、STAT5A、STAT5B;NCBI基因ID:6772、6774、6776、6777);長壽蛋白-3(SIRT3;NCBI基因ID:23410);傳訊淋巴球性活化分子(signaling lymphocytic activation molecule, SLAM)家族成員(例如,SLAMF1 (CD150)、SLAMF6 (CD352)、SLAMF7 (CD319)、SLAMF8 (CD353)、SLAMF9;NCBI基因ID:56833、57823、89886、114836);SLIT及NTRK樣家族成員6(SLITRK6;NCBI基因ID:84189);平滑化捲曲類型受體(SMO;NCBI基因ID:6608);可溶性環氧化物水解酶2(EPHX2;NCBI基因ID:2053);溶質載運體家族成員(例如,C3A2 (CD98)、SLC5A5、SLC6A2、SLC10A3、SLC34A2、SLC39A6、SLC43A2 (LAT4)、SLC44A4;NCBI基因ID:6520、6528、6530、8273、10568、25800、80736、124935);體抑素受體(例如,SSTR1、SSTR2、SSTR3、SSTR4、SSTR5;NCBI基因ID:6751、6752、6753、6754、6755);聲波刺蝟蛋白傳訊分子(SHH;NCBI基因ID:6469);Sp1轉錄因子(SP1;NCBI基因ID:6667);神經鞘胺醇激酶(例如,SPHK1、SPHK2;NCBI基因ID:8877、56848);神經鞘胺醇-1-磷酸酯受體1(S1PR1、CD363;NCBI基因ID:1901);脾臟相關酪胺酸激酶(SYK;NCBI基因ID:6850);剪接因子3B因子1(SF3B1;NCBI基因ID:23451);SRC原致癌基因,非受體酪胺酸激酶(SRC;NCBI基因ID:6714);穩定素1(STAB1、CLEVER-1;NCBI基因ID:23166);STEAP家族成員1(STEAP1;NCBI基因ID:26872);類固醇硫酸酯酶(STS;NCBI基因ID:412);干擾素反應cGAMP互作蛋白刺激因子1(STING1;NCBI基因ID:340061);超氧化物歧化酶1(SOD1、ALS1;NCBI基因ID:6647);細胞介素信號傳導抑制劑(SOCS1 (CISH1)、SOCS3 (CISH3);NCBI基因ID:8651、9021);突觸蛋白3(SYN3;NCBI基因ID:8224);多配體蛋白聚糖1(SDC1、CD138,多配體蛋白聚糖;NCBI基因ID:6382);共核蛋白α(SNCA、PARK1;NCBI基因ID:6622);含T細胞免疫球蛋白及黏蛋白域4(TIMD4、SMUCKLER;NCBI基因ID:91937);具Ig及ITIM域之T細胞免疫受體(TIGIT;NCBI基因ID:201633);速激肽受體(例如,TACR1、TACR3;NCBI基因ID:6869、6870);TANK結合激酶1(TBK1;NCBI基因ID:29110);端錨聚合酶(TNKS;NCBI基因ID:8658);TATA盒結合蛋白相關因子,RNA聚合酶I次單元B(TAF1B;NCBI基因ID:9014);T盒轉錄因子T(TBXT;NCBI基因ID:6862);TCDD誘導性聚(ADP-核糖)聚合酶(TIPARP、PAPR7;NCBI基因ID:25976);tec蛋白酪胺酸激酶(TEC;NCBI基因ID:7006);TEK受體酪胺酸激酶(TEK、CD202B、TIE2;NCBI基因ID:7010);端粒酶反轉錄酶(TERT;NCBI基因ID:7015);生腱蛋白C(TNC;NCBI基因ID:3371);三素修復核酸外切酶(例如,TREX1、TREX2;NCBI基因ID:11277、11219);血栓調節蛋白(THBD,CD141;NCBI基因ID:7056);胸苷激酶(例如,TK1,TK2;NCBI基因ID:7083、7084);胸苷磷酸化酶(TYMP;NCBI基因ID:1890);胸苷酸合成酶(TYMS;NCBI基因ID:7298);甲狀腺荷爾蒙受體(THRA、THRB;NCBI基因ID:7606、7608);促甲狀腺荷爾蒙受體(TSHR;NCBI基因ID:7253);TNF超家族成員(例如,TNFSF4 (OX40L, CD252)、TNFSF5 (CD40L)、TNFSF7 (CD70)、TNFSF8 (CD153, CD30L)、TNFSF9 (4-1BB-L, CD137L)、TNFSF10 (TRAIL, CD253, APO2L)、TNFSF11 (CD254, RANKL2, TRANCE)、TNFSF13 (APRIL, CD256, TRAIL2)、TNFSF13b (BAFF, BLYS, CD257)、TNFSF14 (CD258, LIGHT)、TNFSF18 (GITRL);NCBI基因ID:944、959、970、7292、8600、8740、8741、8743、8744、8995);類鐸受體(例如,TLR1 (CD281)、TLR2 (CD282)、TLR3 (CD283)、TLR4 (CD284)、TLR5、TLR6 (CD286)、TLR7、TLR8 (CD288)、TLR9 (CD289)、TLR10 (CD290);NCBI基因ID:7096、7097、7098、7099、10333、51284、51311、54106、81793);轉鐵蛋白(TF;NCBI基因ID:7018);轉鐵蛋白受體(TFRC,CD71;NCBI基因ID:7037);轉形生長因子(例如,TGFA、TGFB1;NCBI基因ID:7039、7040);轉形生長因子受體(例如,TGFBR1、TGFBR2、TGFBR3;NCBI基因ID:7046、7048、7049);轉形蛋白E7(E7;NCBI基因ID:1489079);轉麩醯胺酸酶5 (TGM5);NCBI基因ID:9333);瞬時受體電位陽離子通道亞家族V成員1(TRPV1、VR1;NCBI基因ID:7442);含跨膜及免疫球蛋白域2(TMIGD2、CD28H、IGPR1;NCBI基因ID:126259);骨髓細胞表現之觸發受體(例如,TREM1 (CD354)、TREM2;NCBI基因ID:54209、54210);滋養蛋白(TRO、MAGED3;NCBI基因ID:7216);滋養層糖蛋白(TPBG;NCBI基因ID:7162);色胺酸2,3-二加氧酶(TDO2;NCBI基因ID:6999);色胺酸羥化酶(例如,TPH1、TPH2;NCBI基因ID:7166、121278);腫瘤相關鈣信號轉導子2(TACSTD2、TROP2、EGP1;NCBI基因ID:4070);腫瘤壞死因子(TNF;NCBI基因ID:7124);腫瘤壞死因子(TNF)受體超家族成員(例如,TNFRSF1A (CD120a)、TNFRSF1B (CD120b)、TNFRSF4 (OX40)、TNFRSF5 (CD40)、TNFRSF6(CD95,FAS受體)、TNFRSF7 (CD27)、TNFRSF8 (CD30)、TNFRSF9 (CD137, 4-1BB)、TNFRSF10A (CD261)、TNFRSF10B (TRAIL, DR5, CD262)、TNFRSF10C、TNFRSF10D、TNFRSF11A、TNFRSF11B (OPG)、TNFRSF12A、TNFRSF13B、TNFR13C (, CD268, BAFFR)、TNFRSF14 (CD270, LIGHTR)、TNFRSF16、TNFRSF17 (CD269, BCMA)、TNFRSF18 (GITR, CD357)、TNFRSF19、TNFRSF21、TNFRSF25、; NCBI基因ID:355、608、939、943、958、3604、4804、4982、7132、7133、7293、8718、8764、8784、8792、8793、8794、8795、8797、23495、27242、51330、55504);腫瘤蛋白p53(TP53;NCBI基因ID:7157);腫瘤抑制劑2,粒線體鈣調控子(TUSC2;NCBI基因ID:11334);TYRO3蛋白酪胺酸激酶(TYRO3;BYK;NCBI基因ID:7301);酪胺酸酶(TYR;NCBI基因ID:7299);酪胺酸羥化酶(TH;NCBI基因ID:7054);具免疫球蛋白樣及EGF樣域1之酪胺酸激酶(例如,TIE1、TIE1;NCBI基因ID:7075);酪胺酸蛋白磷酸酶非受體11型(PTPN11、SHP2;NCBI基因ID:5781);泛素接合酶E2 I(UBE2I、UBC9;NCBI基因ID:7329);泛素C端水解酶L5(UCHL5;NCBI基因ID:51377);泛素特異性肽酶7(USP7;NCBI基因ID:7874);泛素樣改質劑活化酶1(UBA1;NCBI基因ID:7317);UL16結合蛋白(例如,ULBP1、ULBP2、ULBP3;NCBI基因ID:79465、80328、80328);含纈酪胺酸之蛋白質(VCP、CDC48;NCBI基因ID:7415);血管細胞黏附分子1(VCAM1、CD106;NCBI基因ID:7412);血管內皮生長因子(例如,VEGFA、VEGFB;NCBI基因ID:7422、7423);波形蛋白(VIM;NCBI基因ID:7431);維生素D受體(VDR;NCBI基因ID:7421);含V-set域T細胞活化抑制子1(TCN1、B7-H4;NCBI基因ID:79679);V-set免疫調控受體(VSIR、VISTA、B7H5;NCBI基因ID:64115);WEE1 G2檢查點激酶(WEE1;NCBI基因ID:7465);WRN類RecQ解螺旋酶(WRN;RECQ3;NCBI基因ID:7486);WT1轉錄因子(WT1;NCBI基因ID:7490);含WW域轉錄調控子1(WWTR1;TAZ;NCBI基因ID:25937);X-C模體趨化因子配體1(XCL1、ATAC;NCBI基因ID:6375);X-C模體趨化因子受體1(XCR1、GPR5、CCXCR1;NCBI基因ID:2829);Yes1相關轉錄調控子(YAP1;NCBI基因ID:10413);ζ鏈相關蛋白激酶70(ZAP70;NCBI基因ID:7535)。
在一些實施例中,一或多種額外治療劑包括例如靶向下列之藥劑:胞外5'-核苷酸酶(NT5E或CD73;NCBI基因ID:4907);腺苷A
2A受體(ADORA2A;NCBI基因ID:135);腺苷A
2B受體(ADORA2B;NCBI基因ID:136);C-C模體趨化因子受體8(CCR8、CDw198;NCBI基因ID:1237);含細胞介素誘導性SH2蛋白(CISH;NCBI基因ID:1154);二醯基甘油激酶α(DGKA、DAGK、DAGK1、或DGK-α;NCBI基因ID:1606);fms樣酪胺酸激酶3(FLT3、CD135;NCBI基因ID:2322);整合素相關蛋白(IAP、CD47;NCBI基因ID:961);介白素2(IL2;NCBI基因ID:3558);介白素2受體(IL2RA、IL2RB、IL2RG;NCBI基因ID:3559、3560、3561);Kirsten大鼠肉瘤病毒(KRAS;NCBI基因ID:3845;包括突變,諸如KRAS G12C或G12D);促分裂原活化蛋白激酶激酶激酶激酶1 (MAP4K1)(亦稱為造血祖細胞激酶1 (HPK1),NCBI基因ID:11184);骨髓細胞白血病序列1細胞凋亡調控子(MCL1;NCBI基因ID:4170);磷脂醯肌醇-4,5-雙膦酸鹽3-激酶,酶催化性次單元δ(PIK3CD;NCBI基因ID:5293);程序性死亡配體1(PD-L1、CD274;NCBI基因ID:29126);程序性細胞死亡蛋白1(PD-1、CD279;NCBI基因ID:5133);原致癌基因c-KIT(KIT、CD117;NCBI基因ID:3815);信號調控蛋白α(SIRPA、CD172A;NCBI基因ID:140885);TCDD誘導性聚(ADP-核糖)聚合酶(TIPARP、PARP7;NCBI基因ID:25976);具Ig及ITIM域之T細胞免疫受體(TIGIT;NCBI基因ID:201633);骨髓細胞表現之觸發受體1(TREM1;NCBI基因ID:54210);骨髓細胞表現之觸發受體2(TREM2;NCBI基因ID:54209);腫瘤相關鈣信號轉導子2(TACSTD2、TROP2、EGP1;NCBI基因ID:4070);腫瘤壞死因子受體超家族成員4(TNFRSF4、CD134、OX40;NCBI基因ID:7293);腫瘤壞死因子受體超家族成員9(TNFRSF9、4-1BB、CD137;NCBI基因ID:3604);腫瘤壞死因子受體超家族成員18(TNFRSF18、CD357、GITR;NCBI基因ID:8784);WRN類RecQ解螺旋酶(WRN;NCBI基因ID:7486);鋅指蛋白Helios(IKZF2;NCBI基因ID:22807)。
說明性作用機轉免疫檢查點調節劑
在一些實施例中,本文所提供之化合物係與抑制性免疫檢查點蛋白或受體之一或多種阻斷劑或抑制劑及/或與一或多種刺激性免疫檢查點蛋白或受體之一或多種刺激劑、活化劑、或促效劑一起投予。抑制性免疫檢查點之阻斷或抑制可正向調控T細胞或NK細胞活化並防止腫瘤微環境內之細胞免疫逃脫。活化或刺激刺激性免疫檢查點可放大免疫檢查點抑制劑在癌症治療劑中之效應。在一些實施例中,免疫檢查點蛋白或受體調控T細胞反應(例如綜述於Xu,
et al.,
J Exp Clin Cancer Res.(2018) 37:110)。在一些實施例中,免疫檢查點蛋白或受體調節NK細胞反應(例如綜述於Davis,
et al.,
Semin Immunol.(2017) 31:64–75及Chiossone,
et al.,
Nat Rev Immunol.(2018) 18(11):671-688)。調控T細胞(Treg)之抑制或Treg除盡可減輕其對抗腫瘤免疫反應之抑制且具有抗癌效應(例如綜述於Plitas and Rudensky,
Annu.Rev. Cancer Biol.(2020) 4:459-77;Tanaka and Sakaguchi,
Eur.J. Immunol.(2019) 49:1140-1146)。
免疫檢查點蛋白或受體之實例包括CD27(NCBI基因ID:939)、CD70(NCBI基因ID:970);CD40(NCBI基因ID:958)、CD40LG(NCBI基因ID:959);CD47(NCBI基因ID:961)、SIRPA(NCBI基因ID:140885);CD48(SLAMF2;NCBI基因ID:962)、含跨膜及免疫球蛋白域2(TMIGD2、CD28H;NCBI基因ID:126259)、CD84(LY9B、SLAMF5;NCBI基因ID:8832)、CD96(NCBI基因ID:10225)、CD160(NCBI基因ID:11126)、MS4A1(CD20;NCBI基因ID:931)、CD244(SLAMF4;NCBI基因ID:51744);CD276(B7H3;NCBI基因ID:80381);含V-set域T細胞活化抑制子1 (VTCN1, B7H4);V-set免疫調控受體(VSIR、B7H5、VISTA;NCBI基因ID:64115);免疫球蛋白超家族成員11(IGSF11、VSIG3;NCBI基因ID:152404);自然殺手細胞細胞毒性受體3配體1(NCR3LG1、B7H6;NCBI基因ID:374383);HERV-H LTR關聯2(HHLA2、B7H7;NCBI基因ID:11148);誘導性T細胞共刺激子(ICOS、CD278;NCBI基因ID:29851);誘導性T細共刺激子配體(ICOSLG、B7H2;NCBI基因ID:23308);TNF受體超家族成員4(TNFRSF4、OX40;NCBI基因ID:7293);TNF超家族成員4(TNFSF4、OX40L;NCBI基因ID:7292);TNFRSF8(CD30;NCBI基因ID:943)、TNFSF8(CD30L;NCBI基因ID:944);TNFRSF10A(CD261、DR4、TRAILR1;NCBI基因ID:8797)、TNFRSF9(CD137;NCBI基因ID:3604)、TNFSF9(CD137L;NCBI基因ID:8744);TNFRSF10B(CD262、DR5、TRAILR2;NCBI基因ID:8795)、TNFRSF10(TRAIL;NCBI基因ID:8743);TNFRSF14(HVEM、CD270;NCBI基因ID:8764)、TNFSF14(HVEML;NCBI基因ID:8740);CD272(B及T淋巴細胞相關(BTLA);NCBI基因ID:151888);TNFRSF17(BCMA、CD269;NCBI基因ID:608)、TNFSF13B(BAFF;NCBI基因ID:10673);TNFRSF18(GITR;NCBI基因ID:8784)、TNFSF18(GITRL;NCBI基因ID:8995);MHC第I型多肽相關序列A(MICA;NCBI基因ID:100507436);MHC第I型多肽相關序列B(MICB;NCBI基因ID:4277);CD274(CD274、PDL1、PD-L1;NCBI基因ID:29126);程序性細胞死亡1(PDCD1、PD1、PD-1;NCBI基因ID:5133);細胞毒性T淋巴細胞相關蛋白4(CTLA4、CD152;NCBI基因ID:1493);CD80(B7-1;NCBI基因ID:941)、CD28(NCBI基因ID:940);連接蛋白細胞黏附分子2(NECTIN2、CD112;NCBI基因ID:5819);CD226(DNAM-1;NCBI基因ID:10666);脊髓灰白質炎病毒受體(PVR)細胞黏附分子(PVR、CD155;NCBI基因ID:5817);含PVR相關免疫球蛋白域(PVRIG、CD112R;NCBI基因ID:79037);具Ig及ITIM域之T細胞免疫受體(TIGIT;NCBI基因ID:201633);含T細胞免疫球蛋白及黏液素域4 (TIMD4; TIM4;NCBI基因ID:91937);A型肝炎病毒細胞性受體2(HAVCR2、TIMD3、TIM3;NCBI基因ID:84868);半乳糖凝集素9(LGALS9;NCBI基因ID:3965);淋巴細胞活化3(LAG3、CD223;NCBI基因ID:3902);傳訊淋巴球性活化分子家族成員1(SLAMF1、SLAM、CD150;NCBI基因ID:6504);淋巴球抗原9(LY9、CD229、SLAMF3;NCBI基因ID:4063);SLAM家族成員6(SLAMF6、CD352;NCBI基因ID:114836);SLAM家族成員7(SLAMF7、CD319;NCBI基因ID:57823);UL16結合蛋白1(ULBP1;NCBI基因ID:80329);UL16結合蛋白2(ULBP2;NCBI基因ID:80328);UL16結合蛋白3(ULBP3;NCBI基因ID:79465);視黃酸早期轉錄物1E (RAET1E; ULBP4;NCBI基因ID:135250);視黃酸早期轉錄物1G (RAET1G; ULBP5;NCBI基因ID:353091);視黃酸早期轉錄物1L (RAET1L; ULBP6;NCBI基因ID:154064);殺手細胞免疫球蛋白樣受體、三個Ig域、及長細胞質尾1(KIR、CD158E1;NCBI基因ID:3811,例如利瑞路單抗(IPH-2102, IPH-4102));殺手細胞凝集素樣受體C1(KLRC1、NKG2A、CD159A;NCBI基因ID:3821);殺手細胞凝集素樣受體K1(KLRK1、NKG2D、CD314;NCBI基因ID:22914);殺手細胞凝集素樣受體C2(KLRC2、CD159c、NKG2C;NCBI基因ID:3822);殺手細胞凝集素樣受體C3(KLRC3、NKG2E;NCBI基因ID:3823);殺手細胞凝集素樣受體C4(KLRC4、NKG2F;NCBI基因ID:8302);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾1(KIR2DL1;NCBI基因ID:3802);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾2(KIR2DL2;NCBI基因ID:3803);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾3(KIR2DL3;NCBI基因ID:3804);殺手細胞免疫球蛋白樣受體、三個Ig域、及長細胞質尾1 (KIR3DL1);殺手細胞凝集素樣受體D1(KLRD1;NCBI基因ID:3824);殺手細胞凝集素樣受體G1(KLRG1;CLEC15A、MAFA、2F1;NCBI基因ID:10219);唾液酸結合Ig樣凝集素7(SIGLEC7;NCBI基因ID:27036);及唾液酸結合Ig樣凝集素9(SIGLEC9;NCBI基因ID:27180)。
在一些實施例中,本文所提供之化合物係與一或多種T細胞抑制性免疫檢查點蛋白或受體之一或多種阻斷劑或抑制劑一起投予。說明性T細胞抑制性免疫檢查點蛋白或受體包括CD274 (CD274, PDL1, PD-L1);程式性細胞死亡1配體2 (PDCD1LG2, PD-L2, CD273);程式性細胞死亡1 (PDCD1, PD1, PD-1);細胞毒性T淋巴細胞相關蛋白4 (CTLA4, CD152);CD276 (B7H3);含V-set域T細胞活化抑制子1 (VTCN1, B7H4);V-set免疫調控受體(VSIR, B7H5, VISTA);免疫球蛋白超家族成員11 (IGSF11, VSIG3);TNFRSF14 (HVEM, CD270)、TNFSF14 (HVEML);CD272(B及T淋巴細胞相關(BTLA));含PVR相關免疫球蛋白域(PVRIG, CD112R);具Ig及ITIM域之T細胞免疫受體(TIGIT);淋巴細胞活化3 (LAG3, CD223);A型肝炎病毒細胞性受體2 (HAVCR2, TIMD3, TIM3);半乳糖凝集素9 (LGALS9);殺手細胞免疫球蛋白樣受體、三個Ig域、及長細胞質尾1 (KIR, CD158E1);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾1 (KIR2DL1);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾2 (KIR2DL2);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾3 (KIR2DL3);及殺手細胞免疫球蛋白樣受體、三個Ig域、及長細胞質尾1 (KIR3DL1)。在一些實施例中,本文所提供之化合物係與一或多種T細胞刺激性免疫檢查點蛋白或受體之一或多種促效劑或活化劑一起投予。說明性T細胞刺激性免疫檢查點蛋白或受體包括但不限CD27、CD70;CD40、CD40LG;誘導性T細胞共刺激子(ICOS, CD278);誘導性T細胞共刺激子配體(ICOSLG, B7H2);TNF受體超家族成員4 (TNFRSF4, OX40);TNF超家族成員4 (TNFSF4, OX40L);TNFRSF9 (CD137)、TNFSF9 (CD137L);TNFRSF18 (GITR)、TNFSF18 (GITRL);CD80 (B7-1)、CD28;連接蛋白細胞黏附分子2 (NECTIN2, CD112);CD226 (DNAM-1);CD244 (2B4, SLAMF4)、脊髓灰白質炎病毒受體(PVR)細胞黏附分子(PVR, CD155)。見例如Xu,
et al.,
J Exp Clin Cancer Res.(2018) 37:110。
在一些實施例中,本文所提供之化合物係與一或多種NK細胞抑制性免疫檢查點蛋白或受體之一或多種阻斷劑或抑制劑一起投予。說明性NK細胞抑制性免疫檢查點蛋白或受體包括殺手細胞免疫球蛋白樣受體、三個Ig域、及長細胞質尾1 (KIR, CD158E1);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾1 (KIR2DL1);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾2 (KIR2DL2);殺手細胞免疫球蛋白樣受體、二個Ig域、及長細胞質尾3 (KIR2DL3);殺手細胞免疫球蛋白樣受體、三個Ig域、及長細胞質尾1 (KIR3DL1);殺手細胞凝集素樣受體C1 (KLRC1, NKG2A, CD159A);殺手細胞凝集素樣受體D1 (KLRD1, CD94)、殺手細胞凝集素樣受體G1 (KLRG1; CLEC15A, MAFA, 2F1);唾液酸結合Ig樣凝集素7 (SIGLEC7);及唾液酸結合Ig樣凝集素9 (SIGLEC9)。在一些實施例中,本文所提供之化合物係與一或多種NK細胞刺激性免疫檢查點蛋白或受體之一或多種促效劑或活化劑一起投予。說明性NK細胞刺激性免疫檢查點蛋白或受體包括CD16、CD226 (DNAM-1);CD244 (2B4, SLAMF4);殺手細胞凝集素樣受體K1 (KLRK1, NKG2D, CD314);SLAM家族成員7 (SLAMF7)。見例如Davis,
et al.,
Semin Immunol.(2017) 31:64–75;Fang,
et al.,
Semin Immunol.(2017) 31:37-54;及Chiossone,
et al.,
Nat Rev Immunol.(2018) 18(11):671-688。
在一些實施例中,一或多種免疫檢查點抑制劑包含PD-L1 (CD274)、PD-1 (PDCD1)、CTLA4、或TIGIT之蛋白質(例如抗體或其片段、或抗體擬似物)抑制劑。在一些實施例中,一或多種免疫檢查點抑制劑包含PD-L1 (CD274)、PD-1 (PDCD1)、CTLA4、或TIGIT之有機小分子抑制劑。在一些實施例中,一或多種免疫檢查點抑制劑包含LAG3之蛋白質(例如抗體或其片段、或抗體擬似物)抑制劑。
可共投予的CTLA4之抑制劑之實例包括伊匹單抗(ipilimumab)、曲美木單抗(tremelimumab)、BMS-986218、AGEN1181、澤弗利單抗(zalifrelimab) (AGEN1884)、BMS-986249、MK-1308、REGN-4659、ADU-1604、CS-1002(伊匹單抗生物相似藥(biosimilar))、BCD-145、APL-509、JS-007、BA-3071、ONC-392、AGEN-2041、HBM-4003、JHL-1155、KN-044、CG-0161、ATOR-1144、PBI-5D3H5、BPI-002、以及多特異性抑制劑FPT-155 (CTLA4/PD-L1/CD28)、PF-06936308 (PD-1/ CTLA4)、MGD-019 (PD-1/CTLA4)、KN-046 (PD-1/CTLA4)、MEDI-5752 (CTLA4/PD-1)、XmAb-20717 (PD-1/CTLA4)、及AK-104 (CTLA4/PD-1)。
可共投予的PD-L1 (CD274)或PD-1 (PDCD1)之抑制劑之實例包括派姆單抗(pembrolizumab)、納武單抗(nivolumab)、西米普利單抗(cemiplimab)、皮地利珠單抗(pidilizumab)、AMP-224、MEDI0680 (AMP-514)、斯巴達珠單抗(spartalizumab)、阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)、德瓦魯單抗(durvalumab)、BMS-936559、柯希利單抗(cosibelimab) (CK-301)、薩善利單抗(sasanlimab) (PF-06801591)、緹勒珠單抗(tislelizumab) (BGB-A317)、GLS-010 (WBP-3055)、AK-103 (HX-008)、AK-105、CS-1003、HLX-10、瑞弗利單抗(retifanlimab) (MGA-012)、BI-754091、巴替利單抗(balstilimab) (AGEN-2034)、AMG-404、特瑞普利單抗(toripalimab) (JS-001)、西利單抗(cetrelimab) (JNJ-63723283)、傑諾珠單抗(genolimzumab) (CBT-501)、LZM-009、帕洛利單抗(prolgolimab) (BCD-100)、洛達利單抗(lodapolimab) (LY-3300054)、SHR-1201、坎立珠單抗(camrelizumab) (SHR-1210)、Sym-021、布格利單抗(budigalimab) (ABBV-181)、PD1-PIK、BAT-1306、阿維魯單抗(MSB0010718C)、CX-072、CBT-502、多斯利單抗(dostarlimab) (TSR-042)、MSB-2311、JTX-4014、BGB-A333、SHR-1316、CS-1001 (WBP-3155)、恩伐利單抗(envafolimab) (KN-035)、斯迪利單抗(sintilimab) (IBI-308)、HLX-20、KL-A167、STI-A1014、STI-A1015 (IMC-001)、BCD-135、FAZ-053、TQB-2450、MDX1105-01、GS-4224、GS-4416、INCB086550、MAX10181、賽帕利單抗(zimberelimab) (AB122)、斯巴達珠單抗(PDR-001)、及揭示於WO2018195321、WO2020014643、WO2019160882、或WO2018195321中之化合物、以及多特異性抑制劑FPT-155 (CTLA4/PD-L1/CD28)、PF-06936308 (PD-1/ CTLA4)、MGD-013 (PD-1/LAG-3)、FS-118 (LAG-3/PD-L1)、RO-7247669 (PD-1/LAG-3)、MGD-019 (PD-1/CTLA4)、KN-046 (PD-1/CTLA4)、MEDI-5752 (CTLA4/PD-1)、RO-7121661 (PD-1/TIM-3)、RG7769 (PD-1/TIM-3)、TAK-252 (PD-1/OX40L)、XmAb-20717 (PD-1/CTLA4)、AK-104 (CTLA4/PD-1)、FS-118 (LAG-3/PD-L1)、FPT-155 (CTLA4/PD-L1/CD28)、GEN-1046 (PD-L1/4-1BB)、濱他福α (bintrafusp alpha)(M7824;PD-L1/TGFβ-EC域)、CA-170 (PD-L1/VISTA)、CDX-527 (CD27/PD-L1)、LY-3415244 (TIM3/PDL1)、及INBRX-105 (4-1BB/PDL1)。在一些實施例中,PD-L1抑制劑係小分子抑制劑,諸如CA-170、GS-4224、GS-4416、及拉澤替尼(lazertinib) (GNS-1480; PD-L1/EGFR)。
可共投予的TIGIT之抑制劑之實例包括替瑞利尤單抗(tiragolumab) (RG-6058)、維博利單抗(vibostolimab)、多伐那利單抗(domvanalimab)、多伐那利單抗(AB154)、AB308、BMS-986207、AGEN-1307、COM-902、或厄提吉利單抗(etigilimab)。
可共投予的LAG3之抑制劑之實例包括雷拉米立單抗(leramilimab) (LAG525)。
調控T細胞(Treg)活性之抑制或Treg除盡可減輕其對抗腫瘤免疫反應之抑制且具有抗癌效應。參見例如Plitas and Rudensky,
Annu.Rev. Cancer Biol.(2020) 4:459-77;Tanaka and Sakaguchi,
Eur.J. Immunol.(2019) 49:1140-1146。在一些實施例中,本文所提供之化合物係與Treg活性之一或多種抑制劑或Treg除盡劑一起投予。Treg抑制或除盡可放大免疫檢查點抑制劑在癌症治療劑中之效應。
在一些實施例中,本文所提供之化合物係與一或多種Treg抑制劑一起投予。在一些實施例中,Treg抑制劑可抑制Treg至腫瘤微環境中之遷移。在一些實施例中,Treg抑制劑可降低Treg之免疫抑制功能。在一些實施例中,Treg抑制劑可調節細胞表型及誘導促發炎細胞介素之生產。例示性Treg抑制劑包括但不限於CCR4(NCBI基因ID:1233)拮抗劑及下列之降解劑:Ikaros鋅指蛋白(例如Ikaros(IKZF1;NCBI基因ID:10320)、Helios(IKZF2;NCBI基因ID:22807)、Aiolos(IKZF3;NCBI基因ID:22806)、及Eos(IKZF4;NCBI基因ID:64375)。
可共投予的Helios降解劑之實例包括但不限於I-57 (Novartis)及揭示於WO2019038717、WO2020012334、WO20200117759、及WO2021101919中之化合物。
在一些實施例中,本文所揭示之化合物係與一或多種Treg除盡劑一起投予。在一些實施例中,Treg除盡劑係抗體。在一些實施例中,Treg除盡抗體具有抗體依賴性細胞毒性(ADCC)活性。在一些實施例中,Treg除盡抗體係經Fc工程改造以具有增強ADCC活性。在一些實施例中,Treg除盡抗體係抗體藥物接合物(ADC)。Treg除盡劑之說明性目標包括但不限於CD25(IL2RA;NCBI基因ID:3559)、CTLA4(CD152;NCBI基因ID:1493);GITR(TNFRSF18;NCBI基因ID:8784);4-1BB(CD137;NCBI基因ID:3604)、OX-40(CD134;NCBI基因ID:7293)、LAG3(CD223;NCBI基因ID:3902)、TIGIT(NCBI基因ID:201633)、CCR4(NCBI基因ID:1233)、及CCR8(NCBI基因ID:1237)。
在一些實施例中,可共投予之Treg抑制劑或Treg除盡劑包含選擇性地結合至選自由下列所組成之群組的細胞表面受體的抗體或其抗原結合片段:C-C模體趨化因子受體4 (CCR4)、C-C模體趨化因子受體7 (CCR7)、C-C模體趨化因子受體8 (CCR8)、C-X-C模體趨化因子受體4 (CXCR4; CD184)、TNFRSF4 (OX40)、TNFRSF18 (GITR, CD357)、TNFRSF9 (4-1BB, CD137)、細胞毒性T淋巴細胞相關蛋白4 (CTLA4, CD152)、程式性細胞死亡1 (PDCD1, PD-1)、唾液酸基Lewis x (CD15s)、CD27、胞外核苷三磷酸二磷酸水解酶1 (ENTPD1; CD39)、蛋白酪胺酸磷酸酶受體C型(PTPRC; CD45)、神經細胞黏附分子1 (NCAM1; CD56)、選擇素L (SELL; CD62L)、整合素次單元αE (ITGAE; CD103)、介白素7受體(IL7R; CD127)、CD40配體(CD40LG; CD154)、葉酸受體α (FOLR1)、葉酸受體β (FOLR2)、含富白胺酸重複32 (LRRC32; GARP)、IKAROS家族鋅指2 (IKZF2; HELIOS)、誘導性T細胞共刺激子(ICOS; CD278)、淋巴細胞活化3 (LAG3; CD223)、轉形生長因子β1 (TGFB1)、A型肝炎病毒細胞性受體2 (HAVCR2;;CD366;TIM3)、具Ig及ITIM域之T細胞免疫受體(TIGIT)、TNF受體超家族成員1B (CD120b; TNFR2)、IL2RA (CD25)、或其組合。
可投予之Treg除盡抗CCR8抗體之實例包括但不限於JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences)、BMS-986340 (Bristol Meyers Squibb)、S-531011 (Shionogi)、FPA157 (Five Prime Therapeutics)、SRF-114 (Surface Oncology)、HBM1022 (Harbor BioMed)、IO-1 (Oncurious),及揭示於WO2021163064、WO2020138489、及WO2021152186中之抗體。
可投予之Treg除盡性抗CCR4抗體之實例包括莫格利珠單抗。
抑制、除盡、或重編程腫瘤微環境中之非刺激性骨髓細胞可增強抗癌免疫反應(參見例如Binnewies
et al.,
Nat. Med.(2018) 24(5): 541-550;WO2016049641)。用於除盡或重編程非刺激性骨髓細胞之說明性目標包括骨髓細胞上表現之觸發受體TREM-1(CD354,NCBI基因ID:54210)及TREM-2(NCBI基因ID:54209)。在一些實施例中,本文所提供之化合物係與一或多種骨髓細胞除盡或重編程劑一起投予,諸如抗TREM-1抗體(例如PY159;揭示於WO2019032624中之抗體)或抗TREM-2抗體(例如PY314;揭示於WO2019118513中之抗體)。
分化簇促效劑或活化劑
在一些實施例中,本文所提供之化合物係與靶向分化簇(CD)標記之劑一起投予。可共投予之例示性CD標記靶向劑包括但不限於A6、AD-IL24、來那替尼(neratinib)、圖卡替尼(tucatinib) (ONT-380)、莫泊替尼(mobocertinib)(TAK-788)、特伐替尼(tesevatinib)、曲妥珠單抗(trastuzumab) (HERCEPTIN
®)、曲妥珠單抗百思米(rastuzumab biosimimar) (HLX-02)、馬妥昔單抗(margetuximab)、BAT-8001、帕妥珠單抗(pertuzumab) (Perjeta)、派非格司亭(pegfilgrastim)、RG6264、贊達單抗(zanidatamab) (ZW25)、卡瓦塔克(cavatak)、AIC-100、塔格索夫(tagraxofusp) (SL-401)、HLA-A2402/HLA-A0201限制性表位肽疫苗、達沙替尼(dasatinib)、伊馬替尼(imatinib)、尼羅替尼(nilotinib)、索拉非尼(sorafenib)、樂伐替尼甲磺酸鹽(lenvatinib mesylate)、奧巴-奧雷呐近(ofranergene obadenovec)、卡博替尼蘋果酸鹽(cabozantinib malate)、AL-8326、ZLJ-33、KBP-7018、舒尼替尼蘋果酸鹽(sunitinib malate)、帕佐泮尼衍生物(pazopanib derivatives)、AGX-73、瑞巴替尼(rebastinib)、NMS-088、盧西替尼鹽酸鹽(lucitanib hydrochloride)、米哚妥林(midostaurin)、西地尼布(cediranib)、多韋替尼(dovitinib)、斯特替尼(sitravatinib)、替沃紮尼(tivozanib)、馬賽替尼(masitinib)、瑞戈非尼(regorafenib)、奧氟替尼二甲磺酸鹽(olverembatinib dimesylate) (HQP-1351)、卡博替尼(cabozantinib)、普納替尼(ponatinib)、及法米替尼L-蘋果酸鹽(famitinib L-malate)、CX-2029 (ABBV-2029)、SCB-313、CA-170、COM-701、CDX-301、GS-3583、阿蘇賽普(asunercept)(APG-101)、APO-010、及揭示於下列文獻中之化合物:WO2016196388、WO2016033570、WO2015157386、WO199203459、WO199221766、WO2004080462、WO2005020921、WO2006009755、WO2007078034、WO2007092403、WO2007127317、WO2008005877、WO2012154480、WO2014100620、WO2014039714、WO2015134536、WO2017167182、WO2018112136、WO2018112140、WO2019155067、WO2020076105、PCT/US2019/063091、WO19173692、WO2016179517、WO2017096179、WO2017096182、WO2017096281、WO2018089628、WO2017096179、WO2018089628、WO2018195321、WO2020014643、WO2019160882、WO2018195321、WO200140307、WO2002092784、WO2007133811、WO2009046541、WO2010083253、WO2011076781、WO2013056352、WO2015138600、WO2016179399、WO2016205042、WO2017178653、WO2018026600、WO2018057669、WO2018107058、WO2018190719、WO2018210793、WO2019023347、WO2019042470、WO2019175218、WO2019183266、WO2020013170、WO2020068752、Cancer Discov.2019 Jan 9(1):8;及Gariepy J., et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5)。
在一些實施例中,可共投予的CD標記靶向劑包括小分子抑制劑,諸如PBF-1662、BLZ-945、培米替尼(pemigatinib) (INCB-054828)、羅加替尼(rogaratinib) (BAY-1163877)、AZD4547、羅利替尼(roblitinib) (FGF-401)、喹雜替尼(quizartinib)二鹽酸鹽、SX-682、AZD-5069、PLX-9486、阿伐替尼(avapritinib) (BLU-285)、瑞普替尼(ripretinib) (DCC-2618)、甲磺酸伊馬替尼、JSP-191、BLU-263、CD117-ADC、AZD3229、替拉替尼(telatinib)、沃羅拉尼(vorolanib)、GO-203-2C、AB-680、PSB-12379、PSB-12441、PSB-12425、CB-708、HM-30181A、莫替福泰(motixafortide) (BL-8040)、LY2510924、布利沙福(burixafor) (TG-0054)、X4P-002、馬沃瑞福(mavorixafor) (X4P-001-IO)、普樂沙福(plerixafor)、CTX-5861、或REGN-5678 (PSMA/CD28)。
在一些實施例中,可共投予的CD標記靶向劑包括小分子促效劑,諸如介白素2受體次單元γ、艾曲波帕(eltrombopag)、瑞他立德(rintatolimod)、poly-ICLC (NSC-301463)、Riboxxon、Apoxxim、RIBOXXIM
®、MCT-465、MCT-475、G100、PEPA-10、氟妥占敏α (eftozanermin alfa) (ABBV-621)、E-6887、莫托莫德(motolimod)、雷西莫特(resiquimod)、賽爾甘托莫德(selgantolimod) (GS-9688)、VTX-1463、NKTR-262、AST-008、CMP-001、庫比莫德(cobitolimod)、替索莫德(tilsotolimod)、利騰莫特(litenimod)、MGN-1601、BB-006、IMO-8400、IMO-9200、阿托莫特(agatolimod)、DIMS-9054、DV-1079、利福莫特(lefitolimod) (MGN-1703)、CYT-003、及PUL-042。
在一些實施例中,可共投予的CD標記靶向劑包括抗體,諸如他法替他單抗(tafasitamab) (MOR208; MorphoSys AG)、英比珠單抗(Inebilizumab) (MEDI-551)、奧必珠單抗(obinutuzumab)、IGN-002、利妥昔單抗生物類似物(rituximab biosimilar) (PF-05280586)、瓦里木單抗(varlilumab) (CDX-1127)、AFM-13 (CD16/CD30)、AMG330、奧樂妥珠單抗(otlertuzumab) (TRU-016)、艾薩妥昔單抗(isatuximab)、非乍單抗(felzartamab) (MOR-202)、TAK-079、TAK573、達土木單抗(daratumumab) (DARZALEX
®)、TTX-030、塞立路單抗(selicrelumab) (RG7876)、APX-005M、ABBV-428、ABBV-927、米佐利單抗(mitazalimab) (JNJ-64457107)、朗齊魯嗎(lenziluma)、阿來圖珠嗎(alemtuzuma)、艾瑪圖單抗(emactuzumab)、AMG-820、FPA-008(卡比拉單抗(cabiralizumab))、PRS-343 (CD-137/Her2)、AFM-13 (CD16/CD30)、貝蘭單抗馬佛多坦(belantamab mafodotin) (GSK-2857916)、AFM26 (BCMA/CD16A)、辛魯卡α (simlukafusp alfa) (RG7461)、烏瑞魯單抗(urelumab)、烏圖木單抗(utomilumab) (PF-05082566)、AGEN2373、ADG-106、BT-7480、PRS-343 (CD-137/HER2)、FAP-4-IBBL (4-1BB/FAP)、雷莫蘆單抗(ramucirumab)、CDX-0158、CDX-0159及FSI-174、瑞拉單抗(relatlimab) (ONO-4482)、LAG-525、MK-4280、飛利單抗(fianlimab) (REGN-3767)、INCAGN2385、恩斯單抗(encelimab) (TSR-033)、替普珠單抗(atipotuzumab)、BrevaRex (Mab-AR-20.5)、MEDI-9447(奧勒魯單抗(oleclumab))、CPX-006、IPH-53、BMS-986179、NZV-930、CPI-006、PAT-SC1、利瑞路單抗(lirilumab) (IPH-2102)、拉庫單抗(lacutamab) (IPH-4102)、莫納珠單抗(monalizumab)、BAY-1834942、NEO-201 (CEACAM 5/6)、碘(131I)阿帕米單抗(apamistamab) (131I-BC8 (lomab-B))、MEDI0562(塔伏利西單抗(tavolixizumab))、GSK-3174998、INCAGN1949、BMS-986178、GBR-8383、ABBV-368、地諾單抗(denosumab)、BION-1301、MK-4166、INCAGN-1876、TRX-518、BMS-986156、MK-1248、GWN-323、CTB-006、INBRX-109、GEN-1029、培品單抗(pepinemab) (VX-15)、沃普瑞單抗(vopratelimab) (JTX-2011)、GSK3359609、考波力單抗(cobolimab) (TSR-022)、MBG-453、INCAGN-2390、及揭示於下列文獻中之化合物:WO2017096179、WO2017096276、WO2017096189、及WO2018089628。
在一些實施例中,可共投予之CD標記靶向劑包括細胞療法,諸如CD19-ARTEMIS、TBI-1501、CTL-119 huCART-19 T細胞、l iso-cel、利基邁崙賽(lisocabtagene maraleucel) (JCAR-017)、西卡思羅(axicabtagene ciloleucel) (KTE-C19, Yescarta
®)、西卡思羅(KTE-X19)、US7741465、US6319494、UCART-19、肽貝魯塞(tabelecleucel) (EBV-CTL)、T替薩金魯-T (T tisagenlecleucel-T) (CTL019)、CD19CAR-CD28-CD3ζ-EGFRt-表現T細胞、CD19/4-1BBL武裝之CAR T細胞療法、C-CAR-011、CIK-CAR.CD19、CD19CAR-28-ζ T細胞、PCAR-019、MatchCART、DSCAR-01、IM19 CAR-T、TC-110、抗CD19 CAR T細胞療法(B細胞急性淋巴母細胞性白血病,Universiti Kebangsaan Malaysia)、抗CD19 CAR T細胞療法(急性淋巴母細胞性白血病/非霍奇金氏淋巴瘤,University Hospital Heidelberg)、抗CD19 CAR T細胞療法(靜默IL-6表現,癌症,Shanghai Unicar-Therapy Bio-medicine Technology)、MB-CART2019.1 (CD19/CD20)、GC-197 (CD19/CD7)、CLIC-1901、ET-019003、抗CD19-STAR-T細胞、AVA-001、BCMA-CD19 cCAR (CD19/APRIL)、ICG-134、ICG-132 (CD19/CD20)、CTA-101、WZTL-002、雙重抗CD19/抗CD20 CAR T細胞(慢性淋巴球性白血病/B細胞淋巴瘤)、HY-001、ET-019002、YTB-323、GC-012 (CD19/APRIL)、GC-022 (CD19/CD22)、CD19CAR-CD28-CD3ζ-EGFRt-表現Tn/mem、UCAR-011、ICTCAR-014、GC-007F、PTG-01、CC-97540、GC-007G、TC-310、GC-197、替薩金魯-T、CART-19、替薩金魯(CTL-019))、抗CD20 CAR T細胞療法(非霍奇金氏淋巴瘤)、MB-CART2019.1 (CD19/CD20)、WZTL-002雙重抗CD19/抗CD20 CAR-T細胞、ICG-132 (CD19/CD20)、ACTR707 ATTCK-20、PBCAR-20A、LB-1905、CIK-CAR.CD33、CD33CART、雙重抗BCMA/抗CD38 CAR T細胞療法、CART-ddBCMA、MB-102、IM-23、JEZ-567、UCART-123、PD-1剔除T細胞療法(食道癌/NSCLC)、ICTCAR-052、Tn MUC-1 CAR-T、ICTCAR-053、PD-1剔除T細胞療法(食道癌/NSCLC)、AUTO-2、抗BCMA CAR T細胞療法、Descartes-011、抗BCMA/抗CD38 CAR T細胞療法、CART-ddBCMA、BCMA-CS1 cCAR、CYAD-01 (NKG2D LIGAND MODULATOR)、KD-045、PD-L1 t-haNK、BCMA-CS1 cCAR、MEDI5083、抗CD276 CART、及揭示於WO2012079000或WO2017049166中之療法。
分化簇
47 (CD47)抑制劑
在一些實施例中,本文所提供之化合物係與CD47(IAP、MER6、OA3;NCBI基因ID:961)之抑制劑一起投予。CD47抑制劑之實例包括抗CD47 mAb (Vx-1004)、抗人類CD47 mAb (CNTO-7108)、CC-90002、CC-90002-ST-001、人源化抗CD47抗體或CD47阻斷劑、NI-1701、NI-1801、RCT-1938、ALX148、SG-404、SRF-231、及TTI-621。額外例示性抗CD47抗體包括CC-90002、馬格羅單抗(magrolimab) (Hu5F9-G4)、AO-176 (Vx-1004)、來那普利單抗(letaplimab) (IBI-188(來那普利單抗)、利佐帕單抗(lemzoparlimab) (TJC-4)、SHR-1603、HLX-24、LQ-001、IMC-002、ZL-1201、IMM-01、B6H12、GenSci-059、TAY-018、PT-240、1F8-GMCSF、SY-102、KD-015、ALX-148、AK-117、TTI-621、TTI-622、或揭示於下列中之化合物:WO199727873、WO199940940、WO2002092784、WO2005044857、WO2009046541、WO2010070047、WO2011143624、WO2012170250、WO2013109752、WO2013119714、WO2014087248、WO2015191861、WO2016022971、WO2016023040、WO2016024021、WO2016081423、WO2016109415、WO2016141328、WO2016188449、WO2017027422、WO2017049251、WO2017053423、WO2017121771、WO2017194634、WO2017196793、WO2017215585、WO2018075857、WO2018075960、WO2018089508、WO2018095428、WO2018137705、WO2018233575、WO2019027903、WO2019034895、WO2019042119、WO2019042285、WO2019042470、WO2019086573、WO2019108733、WO2019138367、WO2019144895、WO2019157843、WO2019179366、WO2019184912、WO2019185717、WO2019201236、WO2019238012、WO2019241732、WO2020019135、WO2020036977、WO2020043188、及WO2020009725。在一些實施例中,CD47抑制劑係RRx-001、DSP-107、VT-1021、IMM-02、SGN-CD47M、或SIRPa‐Fc‐CD40L (SL-172154)。在一些實施例中,CD47抑制劑係馬格羅單抗。
在一些實施例中,CD47抑制劑係靶向CD47之雙特異性抗體,諸如IBI-322 (CD47/PD-L1)、IMM-0306 (CD47/CD20)、TJ-L1C4 (CD47/PD-L1)、HX-009 (CD47/PD-1)、PMC-122 (CD47/PD-L1)、PT-217、(CD47/DLL3)、IMM-26011 (CD47/FLT3)、IMM-0207 (CD47/VEGF)、IMM-2902 (CD47/HER2)、BH29xx (CD47/PD-L1)、IMM-03 (CD47/CD20)、IMM-2502 (CD47/PD-L1)、HMBD-004B (CD47/BCMA)、HMBD-004A (CD47/CD33)、TG-1801 (NI-1701)、或NI-1801。
SIRPa靶向劑
在一些實施例中,本文所提供之化合物係與下列一起投予:SIRPa靶向劑(NCBI基因ID:140885;UniProt P78324)。SIRPa靶向劑之實例包括SIRPa抑制劑,諸如AL-008、RRx-001、及CTX-5861,及抗SIRPa抗體,諸如FSI-189 (GS-0189)、ES-004、BI-765063、ADU1805、CC-95251、及Q-1801 (SIRPa/PD-L1)。使用之額外SIRPα靶向劑係描述於例如WO200140307、WO2002092784、WO2007133811、WO2009046541、WO2010083253、WO2011076781、WO2013056352、WO2015138600、WO2016179399、WO2016205042、WO2017178653、WO2018026600、WO2018057669、WO2018107058、WO2018190719、WO2018210793、WO2019023347、WO2019042470、WO2019175218、WO2019183266、WO2020013170、及WO2020068752。
FLT3R促效劑
在一些實施例中,本文所提供之化合物係與FLT3R促效劑一起投予。在一些實施例中,本文所提供之化合物係與FLT3配體一起投予。在一些實施例中,本文所提供之化合物與例如描述於WO2020263830中之FLT3L-Fc融合蛋白一起投予。在一些實施例中,本文所提供之化合物係與GS-3583、或CDX-301一起投予。在一些實施例中,本文所提供之化合物係與GS-3583一起投予。
TNF受體超家族
(TNFRSF)成員促效劑或活化劑
在一些實施例中,本文所提供之化合物係與一或多種TNF受體超家族(TNFRSF)成員之促效劑一起投予,例如下列中之一或多者之促效劑:TNFRSF1A(NCBI基因ID:7132)、TNFRSF1B(NCBI基因ID:7133)、TNFRSF4(OX40、CD134;NCBI基因ID:7293)、TNFRSF5(CD40;NCBI基因ID:958)、TNFRSF6(FAS、NCBI基因ID:355)、TNFRSF7(CD27、NCBI基因ID:939)、TNFRSF8(CD30、NCBI基因ID:943)、TNFRSF9(4-1BB、CD137、NCBI基因ID:3604)、TNFRSF10A(CD261、DR4、TRAILR1、NCBI基因ID:8797)、TNFRSF10B(CD262、DR5、TRAILR2、NCBI基因ID:8795)、TNFRSF10C(CD263、TRAILR3、NCBI基因ID:8794)、TNFRSF10D(CD264、TRAILR4、NCBI基因ID:8793)、TNFRSF11A(CD265、RANK、NCBI基因ID:8792)、TNFRSF11B(NCBI基因ID:4982)、TNFRSF12A(CD266、NCBI基因ID:51330)、TNFRSF13B(CD267、NCBI基因ID:23495)、TNFRSF13C(CD268、NCBI基因ID:115650)、TNFRSF16(NGFR、CD271、NCBI基因ID:4804)、TNFRSF17(BCMA、CD269、NCBI基因ID:608)、TNFRSF18(GITR、CD357、NCBI基因ID:8784)、TNFRSF19(NCBI基因ID:55504)、TNFRSF21(CD358、DR6、NCBI基因ID:27242)、及TNFRSF25(DR3、NCBI基因ID:8718)。
可共投予的例示性抗TNFRSF4 (OX40)抗體包括MEDI6469、MEDI6383、塔沃西單抗(MEDI0562)、MOXR0916、PF-04518600、RG-7888、GSK-3174998、INCAGN1949、BMS-986178、GBR-8383、ABBV-368、及描述於WO2016179517、WO2017096179、WO2017096182、WO2017096281、及WO2018089628中者。
可共投予的例示性抗TNFRSF5 (CD40)抗體包括RG7876、SEA-CD40、APX-005M、及ABBV-428。
在一些實施例中,抗TNFRSF7 (CD27)抗體瓦里木單抗(varlilumab) (CDX-1127)係可共投予。
可共投予的例示性抗TNFRSF9 (4-1BB, CD137)抗體包括烏瑞魯單抗(urelumab)、烏圖木單抗(utomilumab) (PF-05082566)、AGEN-2373、及ADG-106。
在一些實施例中,共投予抗TNFRSF17 (BCMA)抗體GSK-2857916。
可共投予的例示性抗TNFRSF18 (GITR)抗體包括MEDI1873、FPA-154、INCAGN-1876、TRX-518、BMS-986156、MK-1248、GWN-323、及描述於WO2017096179、WO2017096276、WO2017096189、及WO2018089628中者。在一些實施例中,共靶向TNFRSF4 (OX40)及TNFRSF18 (GITR)之抗體或其片段係經共投予。此類抗體係描述於例如WO2017096179及WO2018089628。
可共投予的靶向TNFRSF家族成員之雙特異性抗體包括PRS-343 (CD-137/HER2)、AFM26 (BCMA/CD16A)、AFM-13 (CD16/CD30)、奧卓尼單抗(REGN-1979; CD20/CD3)、AMG-420 (BCMA/CD3)、INHIBRX-105 (4-1BB/PDL1)、FAP-4-IBBL (4-1BB/FAP)、普拉莫單抗(plamotamab) (XmAb-13676; CD3/CD20)、RG-7828 (CD20/CD3)、CC-93269 (CD3/BCMA)、REGN-5458 (CD3/BCMA)、及IMM-0306 (CD47/CD20)。
雙特異性
T細胞銜接器
在一些實施例中,本文所提供之化合物係與雙特異性T細胞銜接器(例如不具有Fc)或抗CD3雙特異性抗體(例如具有Fc)一起投予。可共投予的說明性抗CD3雙特異性抗體或BiTE包括杜沃土單抗(duvortuxizumab) (JNJ-64052781; CD19/CD3)、AMG-211 (CEA/CD3)、AMG-160 (PSMA/CD3)、RG7802 (CEA/CD3)、ERY-974 (CD3/GPC3)、PF-06671008(鈣黏素/CD3)、APVO436 (CD123/CD3)、弗圖珠單抗(flotetuzumab) (CD123/CD3)、奧卓尼單抗(REGN-1979; CD20/CD3)、MCLA-117 (CD3/CLEC12A)、JNJ-0819(血基質/CD3)、JNJ-7564(CD3/血基質)、AMG-757 (DLL3-CD3)、AMG-330 (CD33/CD3)、AMG-420 (BCMA/CD3)、AMG-427 (FLT3/CD3)、AMG-562 (CD19/CD3)、AMG-596 (EGFRvIII/CD3)、AMG-673 (CD33/CD3)、AMG-701 (BCMA/CD3)、AMG-757 (DLL3/CD3)、AMG-211 (CEA/CD3)、蘭妥莫單抗(blinatumomab) (CD19/CD3)、huGD2-BsAb (CD3/GD2)、ERY974 (GPC3/CD3)、GEMoab (CD3/PSCA)、RG6026 (CD20/CD3)、RG6194 (HER2/CD3)、PF-06863135 (BCMA/CD3)、SAR440234 (CD3/CDw123)、JNJ-9383 (MGD-015)、AMG-424 (CD38/CD3)、替圖單抗(tidutamab) (XmAb-18087 (SSTR2/CD3))、JNJ-63709178 (CD123/CD3)、MGD-007 (CD3/gpA33)、MGD-009 (CD3/B7H3)、IMCgp100 (CD3/gp100)、XmAb-14045 (CD123/CD3)、XmAb-13676 (CD3/CD20)、替圖單抗(XmAb-18087; SSTR2/CD3)、卡托莫西單抗(CD3/EpCAM)、REGN-4018 (MUC16/CD3)、莫遜圖單抗(mosunetuzumab) (RG-7828; CD20/CD3)、CC-93269 (CD3/BCMA)、REGN-5458 (CD3/BCMA)、GRB-1302 (CD3/Erbb2)、GRB-1342 (CD38/CD3)、GEM-333 (CD3/CD33)。視情況,抗CD3結合雙特異性分子可具有或可不具有Fc。可共投予的說明性雙特異性T細胞銜接器靶向CD3及如本文所述之腫瘤相關抗原,包括例如CD19(例如蘭妥莫單抗);CD33(例如AMG330);CEA(例如MEDI-565);受體酪胺酸激酶樣孤兒受體1 (ROR1) (Gohil,
et al.,
Oncoimmunology.(2017) May 17; 6(7):e1326437);PD-L1 (Horn,
et al.,
Oncotarget.2017 Aug 3; 8(35):57964-57980);及EGFRvIII (Yang,
et al.,
Cancer Lett.2017 Sep 10; 403:224-230)。
雙特異性及三特異性自然殺手
(NK)細胞銜接器
在一些實施例中,本文所提供之化合物係與針對下列之雙特異性NK細胞銜接器(bi-specific NK-cell engager, BiKE)或三特異性NK細胞銜接器(tri-specific NK-cell engager, TriKE)(例如不具有Fc)或雙特異性抗體(例如具有Fc)一起投予:NK細胞活化受體(例如CD16A)、C型凝集素受體(CD94/NKG2C、NKG2D、NKG2E/H、及NKG2F)、天然細胞毒性受體(NKp30、NKp44、及NKp46)、殺手細胞C型凝集素樣受體(NKp65、NKp80)、Fc受體FcγR(其介導抗體依賴性細胞毒性)、SLAM家族受體(例如2B4、SLAM6、及SLAM7)、殺手細胞免疫球蛋白樣受體(KIR)(KIR-2DS及KIR-3DS)、DNAM-1、及CD137 (41BB)。可共投予的說明性抗CD16雙特異性抗體、BiKE、或TriKE包括AFM26 (BCMA/CD16A)及AFM-13 (CD16/CD30)。視情況,抗CD16結合雙特異性分子可具有或可不具有Fc。可共投予的說明性雙特異性NK細胞銜接器靶向CD16及如本文所述之一或多種腫瘤相關抗原,包括例如CD19、CD20、CD22、CD30、CD33、CD123、EGFR、EpCAM、神經節苷酯GD2、HER2/neu、HLA第II型、及FOLR1。BiKE及TriKE係描述於例如Felices,
et al.,
Methods Mol Biol.(2016) 1441:333–346;Fang,
et al.,
Semin Immunol.(2017) 31:37-54。
MCL1細胞凋亡調控子,
BCL2家族成員
(MCL1)抑制劑
在一些實施例中,本文所提供之化合物係與下列之抑制劑一起投予:MCL1細胞凋亡調控子、BCL2家族成員(MCL1、TM;EAT;MCL1L;MCL1S;Mcl-1;BCL2L3;MCL1-ES;bcl2-L-3;mcl1/EAT;NCBI基因ID:4170)。MCL1抑制劑之實例包括它普克雷斯(tapotoclax) (AMG-176)、AMG-397、S-64315、AZD-5991、483-LM、A-1210477、UMI-77、JKY-5-037、PRT-1419、GS-9716、及描述於WO2018183418、WO2016033486、及WO2017147410中者。
SHP2抑制劑
在一些實施例中,本文所提供之化合物係與下列之抑制劑一起投予:蛋白酪胺酸磷酸酶非受體11型(PTPN11;BPTP3、CFC、JMML、METCDS、NS1、PTP-1D、PTP2C、SH-PTP2、SH-PTP3、SHP2;NCBI基因ID:5781)。SHP2抑制劑之實例包括TNO155 (SHP-099)、RMC-4550、JAB-3068、RMC-4630、及該些描述於WO2018172984及WO2017211303中者。
造血祖細胞激酶
1 (HPK1)抑制劑及降解劑
在一些實施例中,本文所提供之化合物係與促分裂原活化蛋白激酶激酶激酶激酶1(MAP4K1、HPK1;NCBI基因ID:11184)。造血祖細胞激酶1 (HPK1)抑制劑之實例包括但不限於描述於WO2020092621、WO2018183956、WO2018183964、WO2018167147、WO2018049152、WO2020092528、WO2016205942、WO2016090300、WO2018049214、WO2018049200、WO2018049191、WO2018102366、WO2018049152、及WO2016090300中者。
細胞凋亡信號調節激酶
(ASK)抑制劑
在一些實施例中,本文所提供之化合物係與ASK抑制劑一起投予,例如促分裂原活化蛋白激酶激酶激酶5(MAP3K5;ASK1、MAPKKK5、MEKK5;NCBI基因ID:4217)。ASK1抑制劑之實例包括描述於WO2011008709 (Gilead Sciences)及WO 2013112741 (Gilead Sciences)中者。
布魯頓氏酪胺酸激酶
(BTK)抑制劑
在一些實施例中,本文所提供之化合物係布魯頓氏酪胺酸激酶(BTK、AGMX1、AT、ATK、BPK、IGHD3、IMD1、PSCTK1、XLA;NCBI基因ID:695)。BTK抑制劑之實例包括(S)-6-胺基-9-(1-(丁-2-炔醯基)吡咯啶-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮、阿卡替尼(acalabrutinib) (ACP-196)、澤布替尼(BGB-3111)、CB988、HM71224、依魯替尼、M-2951(依伏替尼(evobrutinib))、M7583、替拉替尼(tirabrutinib) (ONO-4059)、PRN-1008、司培替尼(spebrutinib) (CC-292)、TAK-020、維卡替尼(vecabrutinib)、ARQ-531、SHR-1459、DTRMWXHS-12、PCI-32765、及TAS-5315。
週期蛋白依賴性激酶
(CDK)抑制劑
在一些實施例中,本文所提供之化合物係與下列之抑制劑一起投予:週期蛋白依賴性激酶1(CDK1、CDC2;CDC28A;P34CDC2;NCBI基因ID:983);週期蛋白依賴性激酶2(CDK2、CDKN2;p33(CDK2);NCBI基因ID:1017);週期蛋白依賴性激酶3(CDK3;NCBI基因ID:1018);週期蛋白依賴性激酶4(CDK4、CMM3;PSK-J3;NCBI基因ID:1019);週期蛋白依賴性激酶6(CDK6、MCPH12;PLSTIRE;NCBI基因ID:1021);週期蛋白依賴性激酶7(CDK7、CAK;CAK1;HCAK;MO15;STK1;CDKN7;p39MO15;NCBI基因ID:1022)、或週期蛋白依賴性激酶9(CDK9、TAK;C-2k;CTK1;CDC2L4;PITALRE;NCBI基因ID:1025)。CDK 1、2、3、4、6、7、及/或9之抑制劑包括阿貝馬昔布(abemaciclib)、阿伏西地(alvocidib)(HMR-1275、夫拉平度(flavopiridol))、AT-7519、地那昔利(dinaciclib)、艾博蘭斯(ibrance)、FLX-925、LEE001、帕博西尼(palbociclib)、山姆昔布(samuraciclib)、瑞博西尼(ribociclib)、瑞戈替布(rigosertib)、西林俄(selinexor)、UCN-01、SY1365、CT-7001、SY-1365、G1T38、米西西尼(milciclib)、曲拉西利(trilaciclib)、斯目瑟替(simurosertib)水合物(TAK931)、及TG-02。
盤基蛋白域受體
(DDR)抑制劑
在一些實施例中,本文所提供之化合物係與下列之抑制劑組合:盤基蛋白域受體酪胺酸激酶1(DDR1、CAK、CD167、DDR、EDDR1、HGK2、MCK10、NEP、NTRK4、PTK3、PTK3A、RTK6、TRKE;NCBI基因ID:780);及/或盤基蛋白域受體酪胺酸激酶2(DDR2、MIG20a、NTRKR3、TKT、TYRO10、WRCN;NCBI基因ID:4921)。DDR抑制劑之實例包括達沙替尼及揭示於WO2014/047624 (Gilead Sciences)、US 2009-0142345 (Takeda Pharmaceutical)、US 2011-0287011 (Oncomed Pharmaceuticals)、WO 2013/027802 (Chugai Pharmaceutical)、及WO2013/034933 (Imperial Innovations)中者。
靶向
E3接合酶配體接合物
在一些實施例中,本文所提供之化合物係與靶向E3接合酶配體接合物一起投予。此類接合物具有目標蛋白結合部份及E3接合酶結合部份(例如細胞凋亡蛋白抑制劑(IAP)(例如XIAP、c-IAP1、c-IAP2、NIL-IAP、Bruce、及存活)E3泛素接合酶結合部份、Von Hippel-Lindau E3泛素接合酶(VHL)結合部份、塞勒布隆E3泛素接合酶結合部份、小鼠雙微體2同源物(MDM2) E3泛素接合酶結合部份),且可例如經由泛素途徑用於促進或增加經靶向蛋白之降解。在一些實施例中,靶向E3接合酶配體接合物包含靶向或結合本文所述蛋白質之靶向或結合部份及E3接合酶配體或結合部份。在一些實施例中,靶向E3接合酶配體接合物包含靶向或結合選自下列之蛋白質之靶向或結合部份:Cbl原致癌基因B(CBLB;Cbl-b、Nbla00127、RNF56;NCBI基因ID:868)及缺氧誘導性因子1次單元α(HIF1A;NCBI基因ID:3091)。在一些實施例中,靶向E3接合酶配體接合物包含激酶抑制劑(例如BTK之例如小分子激酶抑制劑及E3接合酶配體或結合部份)。見例如WO2018098280。在一些實施例中,靶向E3接合酶配體接合物包含靶向或結合至下列之結合部份:介白素1 (IL-1)受體相關激酶4 (IRAK-4);快速加速纖維肉瘤(RAF,諸如c-RAF、A-RAF、及/或B-RAF)、c-Met/p38、或BRD蛋白之結合部份;及E3接合酶配體或結合部份。見例如WO2019099926、WO2018226542、WO2018119448、WO2018223909、WO2019079701。可共投予的額外靶向E3接合酶配體接合物係描述於例如WO2018237026、WO2019084026、WO2019084030、WO2019067733、WO2019043217、WO2019043208、及WO2018144649中。
組蛋白去乙醯酶
(HDAC)抑制劑
在一些實施例中,本文所提供之化合物係與組蛋白去乙醯酶之抑制劑一起投予,例如組蛋白去乙醯酶9(HDAC9、HD7、HD7b、HD9、HDAC、HDAC7、HDAC7B、HDAC9B、HDAC9FL、HDRP、MITR;基因ID:9734)。HDAC抑制劑之實例包括阿貝司他、ACY-241、AR-42、BEBT-908、貝林司他、CKD-581、CS-055 (HBI-8000)、CUDC-907(非米司他)、恩替諾司他、吉韋諾他、莫塞諾他、帕比司他、普拉諾他、奎西諾他(JNJ-26481585)、雷米諾他、瑞科諾他、SHP-141、丙戊酸(VAL-001)、伏立諾他、替諾斯汀、雷米斯特、及恩替諾司他。
吲哚胺
-吡咯
-2,3-二加氧酶
(IDO1)抑制劑
在一些實施例中,本文所提供之化合物係與吲哚胺2,3-二加氧酶1(IDO1;NCBI基因ID:3620)。IDO1抑制劑之實例包括BLV-0801、依波斯他(epacadostat)、啉諾朵他(linrodostat) (F-001287, BMS-986205)、GBV-1012、GBV-1028、GDC-0919、吲哚莫德(indoximod)、NKTR-218、基於NLG-919之疫苗、PF-06840003、哌喃萘醌(pyranonaphthoquinone)衍生物(SN-35837)、雷米諾他(resminostat)、SBLK-200802、及shIDO-ST、EOS-200271、KHK-2455、及LY-3381916。
Janus激酶
(JAK)抑制劑
在一些實施例中,本文所提供之化合物係與下列之抑制劑一起投予:Janus激酶1(JAK1、JAK1A、JAK1B、JTK3;NCBI基因ID:3716);Janus激酶2(JAK2、JTK10、THCYT3;NCBI基因ID:3717);及/或Janus激酶3(JAK3、JAK-3、JAK3_HUMAN、JAKL、L-JAK、LJAK;NCBI基因ID:3718)。JAK抑制劑之實例包括AT9283、AZD1480、巴瑞替尼、BMS-911543、非達替尼(fedratinib)、費戈替尼(filgotinib) (GLPG0634)、甘多替尼(gandotinib) (LY2784544)、INCB039110(伊他替尼(itacitinib))、來他替尼(lestaurtinib)、莫羅替尼(momelotinib) (CYT0387)、伊格替尼順丁烯二酸鹽(ilginatinib maleate) (NS-018)、帕瑞替尼(pacritinib) (SB1518)、皮非替尼(peficitinib) (ASP015K)、魯索替尼(ruxolitinib)、托法替尼(舊名塔索替尼(tasocitinib))、INCB052793、及XL019。
離胺醯基氧化酶樣蛋白
(LOXL)抑制劑
在一些實施例中,本文所提供之化合物係與LOXL蛋白質之抑制劑一起投予,例如LOXL1(NCBI基因ID:4016)、LOXL2(NCBI基因ID:4017)、LOXL3(NCBI基因ID:84695)、LOXL4(NCBI基因ID:84171)、及/或LOX(NCBI基因ID:4015)。LOXL2抑制劑之實例包括描述於WO 2009017833 (Arresto Biosciences)、WO 2009035791 (Arresto Biosciences)、及WO 2011097513 (Gilead Biologics)中之抗體。
基質金屬蛋白酶
(MMP)抑制劑
在一些實施例中,本文所提供之化合物係與基質金屬蛋白酶(MMP)之抑制劑一起投予,例如下列之抑制劑:MMP1(NCBI基因ID:4312)、MMP2(NCBI基因ID:4313)、MMP3(NCBI基因ID:4314)、MMP7(NCBI基因ID:4316)、MMP8(NCBI基因ID:4317)、MMP9(NCBI基因ID:4318);MMP10(NCBI基因ID:4319);MMP11(NCBI基因ID:4320);MMP12(NCBI基因ID:4321)、MMP13(NCBI基因ID:4322)、MMP14(NCBI基因ID:4323)、MMP15(NCBI基因ID:4324)、MMP16(NCBI基因ID:4325)、MMP17(NCBI基因ID:4326)、MMP19(NCBI基因ID:4327)、MMP20(NCBI基因ID:9313)、MMP21(NCBI基因ID:118856)、MMP24(NCBI基因ID:10893)、MMP25(NCBI基因ID:64386)、MMP26(NCBI基因ID:56547)、MMP27(NCBI基因ID:64066)、及/或MMP28(NCBI基因ID:79148)。MMP9抑制劑之實例包括馬立馬司他(marimastat) (BB-2516)、西馬司他(cipemastat) (Ro 32-3555)、GS-5745(安德西單抗(andecaliximab))、及描述於WO 2012027721 (Gilead Biologics)中者。
RAS及
RAS途徑抑制劑
在一些實施例中,本文所提供之化合物係與下列之抑制劑一起投予:KRAS原致癌基因,GTP酶(KRAS;又名NS;NS3;CFC2;RALD;K-Ras;KRAS1;KRAS2;RASK2;KI-RAS;C-K-RAS;K-RAS2A;K-RAS2B;K-RAS4A;K-RAS4B;c-Ki-ras2;NCBI基因ID:3845);NRAS原致癌基因(GTP酶)(NRAS;又名NS6;CMNS;NCMS;ALPS4;N-ras;NRAS1;NCBI基因ID:4893)、或HRAS原致癌基因(GTP酶)(HRAS;又名CTLO;KRAS;HAMSV;HRAS1;KRAS2;RASH1;RASK2;Ki-Ras;p21ras;C-H-RAS;c-K-ras;H-RASIDX;c-Ki-ras;C-BAS/HAS;C-HA-RAS1;NCBI基因ID:3265)。Ras抑制劑可在多核苷酸(例如轉錄抑制劑)或多肽(例如GTP酶抑制劑)層級上抑制Ras。在一些實施例中,抑制劑靶向Ras途徑中之一或多種蛋白,例如抑制EGFR、Ras、Raf (A-Raf、B-Raf、C-Raf)、MEK (MEK1、MEK2)、ERK、PI3K、AKT、及mTOR中之一或多者。可共投予的說明性K-Ras抑制劑包括索托拉西布(sotorasib) (AMG-510)、COTI-219、ARS-3248、WDB-178、BI-3406、BI-1701963、SML-8-73-1 (G12C)、達格昔布(adagrasib) (MRTX-849)、ARS-1620 (G12C)、SML-8-73-1 (G12C)、化合物3144 (G12D)、Kobe0065/2602 (Ras GTP)、RT11、MRTX-849 (G12C)、及K-Ras(G12D)-選擇性抑制肽,包括KRpep-2及KRpep-2d。說明性
KRASmRNA抑制劑包括抗KRAS U1轉接蛋白、AZD-4785、siG12D-LODER
™、及siG12D胞外體。可共投予的說明性MEK抑制劑包括畢尼替尼、考比替尼、PD-0325901、派嗎色替、RG-7304、司美替尼、曲美替尼、及描述於以下及本文中者。可共投予的說明性Raf二聚體抑制劑包括BGB-283、HM-95573、LXH-254、LY-3009120、RG7304、及TAK-580。可共投予的說明性ERK抑制劑包括LTT-462、LY-3214996、MK-8353、拉沃替尼(ravoxertinib)、及優立替尼(ulixertinib)。可共投予的說明性Ras GTP酶抑制劑包括瑞戈替布。可共投予的說明性PI3K抑制劑包括艾代拉里斯(idelalisib) (Zydelig
®)、艾培昔布(alpelisib)、布帕昔布(buparlisib)、皮克昔布(pictilisib)、英沃昔布(inavolisib) (RG6114)、ASN-003。可共投予的說明性AKT抑制劑包括卡瓦替布(capivasertib)及GSK2141795。可共投予的說明性PI3K/mTOR抑制劑包括達妥昔布(dactolisib)、奧米昔布(omipalisib)、沃塔昔布(voxtalisib)、吉達昔布(gedatolisib)、GSK2141795、GSK-2126458、英沃昔布(RG6114)、賽泮替布(sapanisertib)、ME-344、西羅莫司(口服奈米非晶配方,癌症)、拉塞米辛(racemetyrosine)(TYME-88(mTOR/細胞色素P450 3A4))、坦羅莫司(temsirolimus) (TORISEL
®, CCI-779)、CC-115、安踏瑟替(onatasertib) (CC-223)、SF-1126、及PQR-309(必米昔布(bimiralisib))。在一些實施例中,具有CDKN2A突變之Ras驅動癌症(例如NSCLC)可藉由共投予MEK抑制劑司美替尼及CDK4/6抑制劑帕博西尼來抑制。見例如Zhou,
et al.,
Cancer Lett.2017 Nov 1; 408:130-137。此外,K-RAS及突變體N-RAS可藉由不可逆ERBB1/2/4抑制劑來那替尼來減少。見例如Booth,
et al.,
Cancer Biol Ther.2018 Feb 1; 19(2):132-137。
促分裂原活化蛋白激酶
(MEK)抑制劑
在一些實施例中,本文所提供之化合物係與下列之抑制劑一起投予:促分裂原活化蛋白激酶激酶7(MAP2K7、JNKK2、MAPKK7、MEK、MEK 7、MKK7、PRKMK7、SAPKK-4、SAPKK4;NCBI基因ID:5609)。MEK抑制劑之實例包括安卓奎諾爾(antroquinonol)、畢尼替尼、考比替尼(GDC-0973, XL-518)、MT-144、司美替尼(AZD6244)、索拉非尼、曲美替尼(GSK1120212)、阿瑟替布(uprosertib) +曲美替尼、PD-0325901、皮馬瑟替、LTT462、AS703988、CC-90003、及瑞法替尼(refametinib)。
磷脂醯肌醇
3-激酶
(PI3K)抑制劑
在一些實施例中,本文所提供之化合物係與磷脂醯肌醇-4,5-雙磷酸3-激酶催化次單元之抑制劑一起投予,例如磷脂醯肌醇-4,5-雙磷酸3-激酶催化次單元α(PIK3CA、CLAPO、CLOVE、CWS5、MCAP、MCM、MCMTC、PI3K、PI3K-α、p110-α;NCBI基因ID:5290);磷脂醯肌醇-4,5-雙膦酸鹽3-激酶酶催化性次單元β(PIK3CB、P110BETA、PI3K、PI3KBETA、PIK3C1;NCBI基因ID:5291);磷脂醯肌醇-4,5-雙膦酸鹽3-激酶酶催化性次單元γ(PIK3CG、PI3CG、PI3K、PI3Kγ、PIK3、p110γ、p120-PI3K;基因ID:5494);及/或磷脂醯肌醇-4,5-雙膦酸鹽3-激酶酶催化性次單元δ(PIK3CD、APDS、IMD14、P110δ、PI3K、p110D,NCBI基因ID:5293)。在一些實施例中,PI3K抑制劑係泛PI3K抑制劑。PI3K抑制劑之實例包括ACP-319、AEZA-129、AMG-319、AS252424、AZD8186、BAY 10824391、BEZ235、布帕昔布(BKM120)、BYL719(艾培昔布)、CH5132799、考班昔布(copanlisib) (BAY 80-6946)、杜維昔布(duvelisib)、GDC-0032、GDC-0077、GDC-0941、GDC-0980、GSK2636771、GSK2269557、艾代拉里斯(Zydelig
®)、INCB50465、IPI-145、IPI-443、IPI-549、KAR4141、LY294002、LY3023414、MLN1117、OXY111A、PA799、PX-866、RG7604、瑞戈替布、RP5090、RP6530、SRX3177、泰尼昔布(taselisib)、TG100115、TGR-1202(溫布昔布(umbralisib))、TGX221、WX-037、X-339、X-414、XL147 (SAR245408)、XL499、XL756、渥曼青黴素(wortmannin)、ZSTK474、及描述於下列中之化合物:WO2005113556 (ICOS)、WO 2013/052699 (Gilead Calistoga)、WO2013116562 (Gilead Calistoga)、WO2014100765 (Gilead Calistoga)、WO2014100767 (Gilead Calistoga)、及WO2014201409 (Gilead Sciences)。
脾臟酪胺酸激酶
(SYK)抑制劑
在一些實施例中,本文所提供之化合物係與脾臟相關酪胺酸激酶(SYK、p72-Syk,NCB基因ID:6850)之抑制劑一起投予。SYK抑制劑之實例包括6-(1H-吲唑-6-基)-N-(4-
啉基苯基)咪唑并[1,2-a]吡
-8-胺、BAY-61-3606、賽度替尼(cerdulatinib) (PRT-062607)、恩妥替尼(entospletinib)、福他替尼(fostamatinib) (R788)、HMPL-523、NVP-QAB 205 AA、R112、R343、塔馬替尼(tamatinib) (R406)、古薩替尼(gusacitinib) (ASN-002)、及描述於US8450321 (Gilead Connecticut)及US20150175616中者。
類鐸受體
(TLR)促效劑
在一些實施例中,本文所提供之化合物係與類鐸受體(TLR)之促效劑一起投予,例如TLR1(NCBI基因ID:7096)、TLR2(NCBI基因ID:7097)、TLR3(NCBI基因ID:7098)、TLR4(NCBI基因ID:7099)、TLR5(NCBI基因ID:7100)、TLR6(NCBI基因ID:10333)、TLR7(NCBI基因ID:51284)、TLR8(NCBI基因ID:51311)、TLR9(NCBI基因ID:54106)、及/或TLR10(NCBI基因ID:81793)之促效劑。可共投予的例示性TLR7促效劑包括DS-0509、GS-9620(維沙莫德(vesatolimod))、維沙莫德類似物、LHC-165、TMX-101(咪喹莫特)、GSK-2245035、雷西莫特、DSR-6434、DSP-3025、IMO-4200、MCT-465、MEDI-9197、3M-051、SB-9922、3M-052、林托普(Limtop)、TMX-30X、TMX-202、RG-7863、RG-7795、BDB-001、DSP-0509、及揭示於下列中之化合物:US20100143301 (Gilead Sciences)、US20110098248 (Gilead Sciences)、及US20090047249 (Gilead Sciences)、US20140045849 (Janssen)、US20140073642 (Janssen)、WO2014056953 (Janssen)、WO2014076221 (Janssen)、WO2014128189 (Janssen)、US20140350031 (Janssen)、WO2014023813 (Janssen)、US20080234251 (Array Biopharma)、US20080306050 (Array Biopharma)、US20100029585 (Ventirx Pharma)、US20110092485 (Ventirx Pharma)、US20110118235 (Ventirx Pharma)、US20120082658 (Ventirx Pharma)、US20120219615 (Ventirx Pharma)、US20140066432 (Ventirx Pharma)、US20140088085 (Ventirx Pharma)、US20140275167 (Novira Therapeutics)、及US20130251673 (Novira Therapeutics)。可共投予的TLR7/TLR8促效劑係NKTR-262。可共投予的例示性TLR8促效劑包括E-6887、IMO-4200、IMO-8400、IMO-9200、MCT-465、MEDI-9197、莫托莫德(motolimod)、雷西莫特、GS-9688、VTX-1463、VTX-763、3M-051、3M-052、及揭示於下列中之化合物:US20140045849 (Janssen)、US20140073642 (Janssen)、WO2014/056953 (Janssen)、WO2014/076221 (Janssen)、WO2014/128189 (Janssen)、US20140350031 (Janssen)、WO2014/023813 (Janssen)、US20080234251 (Array Biopharma)、US20080306050 (Array Biopharma)、US20100029585 (Ventirx Pharma)、US20110092485 (Ventirx Pharma)、US20110118235 (Ventirx Pharma)、US20120082658 (Ventirx Pharma)、US20120219615 (Ventirx Pharma)、US20140066432 (Ventirx Pharma)、US20140088085 (Ventirx Pharma)、US20140275167 (Novira Therapeutics)、及US20130251673 (Novira Therapeutics)。可共投予的例示性TLR9促效劑包括AST-008、CMP-001、IMO-2055、IMO-2125、利騰莫特(litenimod)、MGN-1601、BB-001、BB-006、IMO-3100、IMO-8400、IR-103、IMO-9200、阿托莫特(agatolimod)、DIMS-9054、DV-1079、DV-1179、AZD-1419、勒托莫德(leftolimod) (MGN-1703)、CYT-003、CYT-003-QbG10、及PUL-042。TLR3促效劑之實例包括瑞他莫特(rintatolimod)、poly-ICLC、RIBOXXON
®、Apoxxim、RIBOXXIM
®、IPH-33、MCT-465、MCT-475、及ND-1.1。
酪胺酸激酶抑制劑
(TKI)
在一些實施例中,本文所提供之化合物係與酪胺酸激酶抑制劑(TKI)一起投予。TKI可靶向表皮生長因子受體(EGFR)及纖維母細胞生長因子(FGF)、血小板衍生性生長因子(PDGF)、及血管內皮生長因子(VEGF)之受體。TKI之實例包括但不限於阿法替尼(afatinib)、ARQ-087(德贊替尼(derazantinib))、asp5878、AZD3759、AZD4547、伯舒替尼(bosutinib)、布格替尼、卡博替尼、西地尼布、克諾拉尼(crenolanib)、達可替尼(dacomitinib)、達沙替尼、多韋替尼、E-6201、厄達替尼(erdafitinib)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、吉列替尼(ASP-2215)、FP-1039、HM61713、埃克替尼(icotinib)、伊馬替尼、KX2-391 (Src)、拉帕替尼(lapatinib)、來他替尼、樂伐替尼、米哚妥林、尼達尼布(nintedanib)、ODM-203、奧希替尼(AZD-9291)、普納替尼、波齊替尼(poziotinib)、喹雜替尼、拉多替尼(radotinib)、羅西替尼(rociletinib)、索凡替尼(sulfatinib) (HMPL-012)、舒尼替尼、法米替尼L-蘋果酸鹽、(MAC-4)、替沃尼布(tivoanib)、TH-4000、及MEDI-575(抗PDGFR抗體)。例示性EGFR靶向劑包括來那替尼、圖卡替尼(ONT-380)、特伐替尼、莫博替尼(TAK-788)、DZD-9008、瓦尼替尼(varlitinib)、艾維替尼(abivertinib) (ACEA-0010)、EGF816(那紮替尼(nazartinib))、奧莫替尼(olmutinib) (BI-1482694)、奧希替尼(AZD-9291)、AMG-596 (EGFRvIII/CD3)、力法芬尼(lifirafenib) (BGB-283)、維必施(vectibix)、拉澤替尼(lazertinib) (LECLAZA
®)、及揭示於下列中之化合物:Booth, et al., Cancer Biol Ther.2018 Feb 1; 19(2):132-137。靶向EGFR之抗體包括但不限於莫多妥昔單抗(modotuximab)、西妥昔單抗薩羅他康(cetuximab sarotalocan) (RM-1929)、塞里班土單抗、耐昔妥珠單抗、德帕妥昔珠單抗莫福汀(depatuxizumab mafodotin) (ABT-414)、托木妥昔單抗(tomuzotuximab)、德帕妥昔珠單抗(ABT-806)、及西妥昔單抗。
化學治療劑
在一些實施例中,本文所提供之化合物係與化學治療劑或抗贅瘤劑一起投予。
如本文中所使用,用語「化學治療劑(chemotherapeutic agent/chemotherapeutic)」(或在以化學治療劑治療之情況下之「化學療法(chemotherapy)」)意欲包含可用於治療癌症之任何非蛋白質(例如非肽)化學化合物。化學治療劑之實例包括但不限於:烷化劑,諸如噻替派及環磷醯胺(CYTOXAN
®);烷基磺酸酯,諸如白消安、英丙舒凡(improsulfan)、及哌泊舒凡(piposulfan);氮丙啶,諸如苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替呱(meturedepa)、及烏瑞替派(uredepa);乙烯亞胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、三乙烯三聚氰胺、三乙烯磷醯胺、三乙烯硫磷醯胺、及三羥甲基三聚氰胺;乙醯精寧(acetogenin),例如布拉他辛(bullatacin)及布拉他辛酮(bullatacinone);喜樹鹼,包括合成類似物托泊替康;苔蘚蟲素、海洋抑素(callystatin);CC-1065,包括其阿多來新(adozelesin)、卡折來新(carzelesin)、及比折來新(bizelesin)合成類似物;念珠藻素(cryptophycin),特別是念珠藻素1及念珠藻素8;海兔毒素(dolastatin);雙聯黴素,包括合成類似物KW-2189及CBI-TMI;艾榴塞洛素(eleutherobin);5-氮雜胞苷;水鬼蕉鹼(pancratistatin);沙考地汀(sarcodictyin);海綿抑素(spongistatin);氮芥,諸如氯芥苯丁酸、萘氮芥(chlornaphazine)、環磷醯胺、葡磷醯胺(glufosfamide)、伊沃醯胺(evofosfamide)、苯達莫司汀、雌二醇氮芥(estramustine)、依弗醯胺、二氯甲二乙胺(mechlorethamine)、二氯甲二乙胺氧化物鹽酸鹽、黴法蘭、新恩比興(novembichin)、芬司特瑞(phenesterine)、潑尼氮芥(prednimustine)、曲洛磷胺(trofosfamide)、及尿嘧啶氮芥;亞硝基尿素,諸如卡莫司汀、吡葡亞硝脲(chlorozotocin)、福莫司汀(foremustine)、洛莫司汀、尼氮芥(nimustine)、及雷莫司汀(ranimustine);抗生素,諸如烯二炔抗生素(例如卡利奇黴素,特別是卡利奇黴素γII及卡利奇黴素phiI1)、達內黴素(dynemicin),包括達內黴素A、雙膦酸鹽,諸如氯屈膦酸鹽(clodronate)、埃斯培拉黴素(esperamicin)、新抑癌素(neocarzinostatin)發色團及相關色素蛋白烯二炔抗生素發色團、阿克拉黴素(aclacinomycin)、放線菌素、安曲黴素(authramycin)、氮絲胺酸(azaserine)、博來黴素、放線菌素C、卡拉星(carabicin)、卡尼米辛(carrninomycin)、嗜癌素(carzinophilin)、色黴素(chromomycin)、放線菌素D、道諾黴素、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、阿黴素(包括N-
啉基-阿黴素、氰基N-
啉基-阿黴素、2-吡咯啉-阿黴素、及去氧阿黴素(deoxydoxorubicin))、泛艾黴素、依索比星(esorubicin)、艾達黴素、麻西羅黴素(marcellomycin)、絲裂黴素,諸如絲裂黴素C、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(porfiromycin)、嘌呤黴素、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈佐星、殺結核菌素(tubercidin)、鳥苯美司(ubenimex)、淨司他丁(zinostatin)、及佐柔比星(zorubicin);抗代謝物,諸如胺甲喋呤及5-氟脲嘧啶(5-FU);葉酸類似物,諸如德莫喋呤(demopterin)、甲胺喋呤、蝶羅呤(pteropterin)、及三甲喋呤;嘌呤類似物,諸如克拉屈濱、噴司他丁、氟達拉濱、6-巰嘌呤、硫咪嘌呤(thiamiprine)、及硫鳥嘌呤;嘧啶類似物,諸如安西他濱(ancitabine)、阿扎胞苷(azacitidine)、6-硫唑脲嘧啶(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷、二去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、及氟尿苷;雄性激素,諸如卡魯睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、及睪內酯(testolactone);抗腎上腺劑,諸如胺魯米特、米托坦、及曲洛司坦(trilostane);葉酸補充劑,諸如醛葉酸(frolinic acid);放射治療劑,諸如鐳-223;新月毒素(trichothecene),特別是T-2毒素、韋拉庫林A (verracurin A)、桿孢菌素A (roridin A)及安奎定(anguidine);類紫杉醇(taxoid),諸如太平洋紫杉醇(TAXOL
®)、亞柏杉(abraxane)、多西紫杉醇(TAXOTERE
®)、卡巴他賽、BIND-014、替司他賽(tesetaxel);薩必沙布林(sabizabulin) (Veru-111);鉑類似物,諸如順鉑及卡鉑、NC-6004奈鉑(nanoplatin);醋葡醛內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);赫布西爾(hestrabucil);比生群(bisantrene);依達曲沙(edatraxate);得弗伐胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);艾弗欣(elformthine);依利醋銨(elliptinium acetate);埃博黴素;依託格魯(etoglucid);硝酸鎵;羥基尿素;蘑菇多糖(lentinan);菊白葉酸(leucovorin);氯尼達明(lonidamine);類美坦素(maytansinoid)諸如美坦素及安絲菌素;米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他汀(pentostatin);凡那明(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);氟嘧啶;醛葉酸(folinic acid);鬼臼酸(podophyllinic acid);2-乙基醯肼(2-ethylhydrazide);丙卡巴肼(procarbazine);多醣-K (PSK);雷佐生(razoxane);利索新(rhizoxin);西索菲蘭(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);曲貝替定(trabectedin)、三亞胺醌(triaziquone);2,2',2''-三氯三乙胺(trichlorotriemylamine);胺甲酸酯;長春地辛(vindesine);達卡巴仁;甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);伽托辛(gacytosine);阿拉伯糖苷(「Ara-C」);環磷醯胺;賽派塔(thiopeta);氯芥苯丁酸;吉西他濱(GEMZAR
®);6-硫鳥嘌呤;巰嘌呤;甲胺喋呤;長春鹼;鉑;依託泊苷(VP-16);依弗醯胺;米托蒽醌(mitroxantrone);長春新鹼(vancristine);長春瑞濱(NAVELBINE
®);諾安托(novantrone);替尼泊苷;依達曲沙(edatrexate);道諾黴素(daunomycin);胺喋呤;希羅達(xeoloda);伊班膦酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DFMO);類視色素,諸如視黃酸;卡培他濱;NUC-1031;FOLFOX(醛葉酸、5-氟尿嘧啶、奧沙利鉑);FOLFIRI(醛葉酸、5-氟尿嘧啶、伊立替康);FOLFOXIRI(醛葉酸、5-氟尿嘧啶、奧沙利鉑、伊立替康)、FOLFIRINOX(醛葉酸、5-氟尿嘧啶、伊立替康、奧沙利鉑)、及以上任一者之醫藥上可接受之鹽、酸、或衍生物。此類藥劑可接合至本文所述之抗體或任何靶向劑上以產生抗體藥物接合物(ADC)或靶向藥物接合物。
抗荷爾蒙劑
亦包括於「化學治療劑」之定義中的是抗荷爾蒙劑,諸如抗雌激素及選擇性雌激素受體調節劑(SERM)、酶芳香酶之抑制劑、抗雄性激素、及作用為調節或抑制荷爾蒙對腫瘤作用之以上任一者之醫藥上可接受之鹽、酸、或衍生物。
抗雌激素及SERM之實例包括泰莫西芬(tamoxifen)(包括NOLVADEXTM)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羥基泰莫西芬、曲沃昔芬(trioxifene)、克沃昔芬(keoxifene)、LY117018、奧那司酮(onapristone)、及托瑞米芬(toremifene) (FARESTON
®)。
酶芳香酶之抑制劑調節腎上腺中之雌激素生產。實例包括4(5)-咪唑、胺魯米特、甲地孕酮乙酸鹽(MEGACE
®)、依西美坦、福美坦、法倔唑、伏氯唑(RIVISOR
®)、來曲唑(FEMARA
®)、及阿那曲唑(ARIMIDEX
®)。
抗雄性激素之實例包括阿帕魯醯胺(apalutamide)、阿比特龍(abiraterone)、恩雜魯胺(enzalutamide)、氟他胺(flutamide)、加利特隆(galeterone)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)、戈舍瑞林(goserelin)、ODM-201、APC-100、ODM-204、恩博沙(enobosarm) (GTX-024)、達魯胺(darolutamide)、及IONIS-AR-2.5Rx(反義)。
實例助孕素受體拮抗劑包括奧那司酮。額外黃體素靶向劑包括TRI-CYCLEN LO(炔諾酮(norethindrone) +乙炔雌二醇(ethinyl estradiol))、諾孕酯(norgestimate) +乙炔雌二醇(Tri-Cyclen)、及左炔諾孕酮(levonorgestrel)。
抗血管生成劑
在一些實施例中,本文所提供之化合物係與抗血管生成劑一起投予。可共投予的抗血管生成劑包括類視色素酸及其衍生物、2-甲氧雌二醇(methoxyestradiol)、ANGIOSTATIN
®、ENDOSTATIN
®、瑞戈非尼、尼庫拉布(necuparanib)、蘇拉明(suramin)、鯊胺(squalamine)、金屬蛋白酶組織抑制劑1、金屬蛋白酶組織抑制劑2、纖維蛋白溶酶原活化物抑制劑1、纖維蛋白溶酶原活化物抑制劑2、軟骨衍生性抑制劑、太平洋紫杉醇(白蛋白結合型太平洋紫杉醇)、血小板因子4、硫酸魚精蛋白(鯡精蛋白)、硫酸化幾丁質衍生物(自皇后蟹殼製備)、硫酸化多醣肽聚醣複合體(sp-pg)、星孢菌素(staurosporine)、基質代謝調節劑(包括脯胺酸類似物,諸如l-吖呾-2-羧酸(LACA)、順羥基脯胺酸、d,I-3,4-去氫脯胺酸、硫脯胺酸)、α,α'-二吡啶基、β-胺基丙腈反丁烯二酸鹽、4-丙基-5-(4-吡啶基)-2(3h)-
唑啉酮、胺甲喋呤、米托蒽醌、肝素、干擾素、2巨球蛋白-血清、金屬蛋白酶雞抑制劑3 (ChIMP-3)、胰凝乳蛋白酶抑制劑(chymostatin)、β-環糊精十四硫酸酯、艾尼米欣(eponemycin)、煙黴素(fumagillin)、硫蘋果酸金鈉、d-青黴胺、β-1-抗膠原蛋白酶-血清、α-2-抗血漿素、比生群、氯苯紮利二鈉(lobenzarit disodium)、n-2-羧基苯基-4-氯鄰胺苯甲酸二鈉或「CCA」、沙利度胺(thalidomide)、血管抑制性類固醇、羧基胺基咪唑、金屬蛋白酶抑制劑(諸如BB-94)、S100A9抑制劑(諸如他喹莫德)。其他抗血管生成劑包括抗體,較佳地針對這些血管生成生長因子之單株抗體:β-FGF、α-FGF、FGF-5、VEGF異構體、VEGF-C、HGF/SF、及Ang-1/Ang-2。可共投予的抗VEGFA抗體之實例包括貝伐珠單抗(bevacizumab)、凡努西珠單抗(vanucizumab)、氟西匹單抗(faricimab)、迪帕西單抗(dilpacimab) (ABT-165; DLL4/VEGF)、或納維希單抗(navicixizumab) (OMP-305B83; DLL4/VEGF)。
抗纖維化劑
在一些實施例中,本文所提供之化合物係與抗纖維化劑一起投予。可共投予的抗纖維化劑包括諸如β-胺基丙腈(BAPN)之化合物、以及揭示於US4965288中與離胺醯基氧化酶之抑制劑及其於治療與膠原蛋白異常沉積相關聯之疾病及病況之用途相關的化合物及揭示於US4997854中與抑制LOX以治療各種病理纖維化狀態之化合物相關的化合物,其以引用方式併入本文中。進一步例示性抑制劑係描述於US4943593中與諸如2-異丁基-3-氟-、氯-、或溴-烯丙胺之化合物相關、US5021456中、US5059714中、US5120764中、US5182297中、US5252608中與2-(1-萘基氧基甲基)-3-氟烯丙胺相關、及US 20040248871中,其以引用方式併入本文中。
例示性抗纖維化劑亦包括與離胺醯基氧化酶之活性部位之羰基反應的一級胺,及更具體地該些在與羰基結合後生產藉由共振穩定化之產物者,諸如下列一級胺:乙二胺(emylenemamine)、肼、苯基肼、及其衍生物;半卡肼(semicarbazide)及尿素衍生物;胺基腈,諸如BAPN或2-硝基乙胺;不飽和或飽和鹵胺,諸如2-溴-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺、及對鹵苄基胺;及硒代升半胱胺酸內酯。
其他抗纖維化劑係穿透或不穿透細胞之銅螯合劑。例示性化合物包括間接抑制劑,其阻斷源自藉由離胺醯基氧化酶對離胺醯基及羥基離胺醯基殘基之氧化去胺的醛衍生物。實例包括硫醇胺,特別是D-青黴胺及其類似物,諸如2-胺基-5-巰基-5-甲基己酸、D-2-胺基-3-甲基-3-((2-乙醯胺基乙基)二硫基)丁酸、對2-胺基-3-甲基-3-((2-胺乙基)二硫基)丁酸、鈉-4-((對1-二甲基-2-胺基-2-羧基乙基)二硫基)丁烷硫酸鹽(sulphurate)、2-乙醯胺基乙基-2-乙醯胺基乙硫醇磺酸鹽(sulphanate)、及鈉-4-巰基丁烷亞磺酸鹽(sulphinate)三水合物。
消炎劑
在一些實施例中,本文所提供之化合物係與消炎劑一起投予。實例消炎劑包括但不限於下列中之一或多者之抑制劑:精胺酸酶(ARG1(NCBI基因ID:383)、ARG2(NCBI基因ID:384))、碳酸酐酶(CA1(NCBI基因ID:759)、CA2(NCBI基因ID:760)、CA3(NCBI基因ID:761)、CA4(NCBI基因ID:762)、CA5A(NCBI基因ID:763)、CA5B(NCBI基因ID:11238)、CA6(NCBI基因ID:765)、CA7(NCBI基因ID:766)、CA8(NCBI基因ID:767)、CA9(NCBI基因ID:768)、CA10(NCBI基因ID:56934)、CA11(NCBI基因ID:770)、CA12(NCBI基因ID:771)、CA13(NCBI基因ID:377677)、CA14(NCBI基因ID:23632))、前列腺素-內過氧化物合成酶1(PTGS1、COX-1;NCBI基因ID:5742)、前列腺素-內過氧化物合成酶2(PTGS2、COX-2;NCBI基因ID:5743)、分泌磷脂酶A2、前列腺素E合成酶(PTGES、PGES;基因ID:9536)、花生四烯酸酯5-脂肪加氧酶(ALOX5、5-LOX;NCBI基因ID:240)、可溶性環氧化物水解酶2(EPHX2、SEH;NCBI基因ID:2053)、及/或促分裂原活化蛋白激酶激酶激酶8(MAP3K8、TPL2;NCBI基因ID:1326)。在一些實施例中,抑制劑係雙重抑制劑,例如COX-2/COX-1、COX-2/SEH、COX-2/CA、COX-2/5-LOX之雙重抑制劑。
可共投予的前列腺素-內過氧化物合成酶1(PTGS1、COX-1;NCBI基因ID:5742)之抑制劑之實例包括莫苯唑酸(mofezolac)、GLY-230、及TRK-700。
可共投予的前列腺素-內過氧化物合成酶2(PTGS2、COX-2;NCBI基因ID:5743)之抑制劑之實例包括雙氯芬酸(diclofenac)、美洛昔康(meloxicam)、帕瑞昔布(parecoxib)、依托昔布(etoricoxib)、AP-101、塞來昔布(celecoxib)、AXS-06、雙氯芬酸鉀、DRGT-46、AAT-076、美索舒利(meisuoshuli)、羅美昔布(lumiracoxib)、美洛昔康、伐地昔布(valdecoxib)、紮托洛芬(zaltoprofen)、尼美舒利(nimesulide)、阿尼紮芬(anitrazafen)、阿普昔布(apricoxib)、西米昔布(cimicoxib)、德拉昔布(deracoxib)、氟咪唑(flumizole)、非羅昔布(firocoxib)、馬瓦昔布(mavacoxib)、NS-398、帕米格雷(pamicogrel)、帕瑞昔布、羅苯昔布(robenacoxib)、羅非昔布(rofecoxib)、茱萸鹼(rutecarpine)、替馬昔布(tilmacoxib)、及紮托洛芬。可共投予的雙重COX1/COX2抑制劑之實例包括HP-5000、氯諾昔康(lornoxicam)、三木甲胺克妥洛(ketorolac tromethamine)、溴芬酸鈉(bromfenac sodium)、ATB-346、HP-5000。可共投予的雙重COX-2/碳酸酐酶(CA)抑制劑之實例包括帕馬考昔(polmacoxib)及艾瑞昔布(imrecoxib)。
可共投予的分泌磷脂酶A2、前列腺素E合成酶(PTGES、PGES;基因ID:9536)之抑制劑之實例包括LY3023703、GRC 27864、及描述於WO2015158204、WO2013024898、WO2006063466、WO2007059610、WO2007124589、WO2010100249、WO2010034796、WO2010034797、WO2012022793、WO2012076673、WO2012076672、WO2010034798、WO2010034799、WO2012022792、WO2009103778、WO2011048004、WO2012087771、WO2012161965、WO2013118071、WO2013072825、WO2014167444、WO2009138376、WO2011023812、WO2012110860、WO2013153535、WO2009130242、WO2009146696、WO2013186692、WO2015059618、WO2016069376、WO2016069374、WO2009117985、WO2009064250、WO2009064251、WO2009082347、WO2009117987、及WO2008071173中之化合物。進一步發現二甲雙胍阻抑COX2/PGE2/STAT3軸,且可共投予。參見例如Tong,
et al.,
Cancer Lett.(2017) 389:23-32;及Liu,
et al.,
Oncotarget.(2016) 7(19):28235-46。
可共投予的碳酸酐酶(例如CA1(NCBI基因ID:759)、CA2(NCBI基因ID:760)、CA3(NCBI基因ID:761)、CA4(NCBI基因ID:762)、CA5A(NCBI基因ID:763)、CA5B(NCBI基因ID:11238)、CA6(NCBI基因ID:765)、CA7(NCBI基因ID:766)、CA8(NCBI基因ID:767)、CA9(NCBI基因ID:768)、CA10(NCBI基因ID:56934)、CA11(NCBI基因ID:770)、CA12(NCBI基因ID:771)、CA13(NCBI基因ID:377677)、CA14(NCBI基因ID:23632)中之一或多者)之抑制劑之實例包括乙醯偶氮胺、甲唑醯胺(methazolamide)、多佐胺(dorzolamide)、唑尼沙胺(zonisamide)、布林佐胺(brinzolamide)、及雙氯非那胺(dichlorphenamide)。可共投予的雙重COX-2/CA1/CA2抑制劑包括CG100649。
可共投予的花生四烯酸酯5-脂肪加氧酶(ALOX5、5-LOX;NCBI基因ID:240)之抑制劑之實例包括美克芬那梅鈉(meclofenamate sodium)、齊留通(zileuton)。
可共投予的可溶性環氧化物水解酶2(EPHX2、SEH;NCBI基因ID:2053)之雙重抑制劑包括描述於WO2015148954中之化合物。可共投予的COX-2/SEH之雙重抑制劑包括描述於WO2012082647中之化合物。可共投予的SEH及脂肪酸醯胺水解酶(FAAH;NCBI基因ID:2166)之雙重抑制劑包括描述於WO2017160861中之化合物。
可共投予的促分裂原活化蛋白激酶激酶激酶8(MAP3K8、腫瘤進展基因座-2、TPL2;NCBI基因ID:1326)之抑制劑之實例包括GS-4875、GS-5290、BHM-078、及下列中所述者:WO2006124944、WO2006124692、WO2014064215、WO2018005435、Teli,
et al., J Enzyme Inhib Med Chem.(2012) 27(4):558-70;Gangwall,
et al., Curr Top Med Chem.(2013) 13(9):1015-35;Wu,
et al., Bioorg Med Chem Lett.(2009) 19(13):3485-8;Kaila,
et al.,
Bioorg Med Chem.(2007) 15(19):6425-42;及Hu,
et al., Bioorg Med Chem Lett.(2011) 21(16):4758-61。
腫瘤氧合劑
在一些實施例中,本文所提供之化合物係與促進或增加腫瘤氧合或再氧合、或預防或減少腫瘤缺氧之劑一起投予。可共投予的說明性藥劑包括例如缺氧誘導性因子-1α (HIF-1α)抑制劑,諸如PT-2977、PT-2385;VEGF抑制劑,諸如貝伐珠單抗(bevasizumab)、IMC-3C5、GNR-011、塔尼比單抗(tanibirumab)、LYN-00101、ABT-165;及/或氧載蛋白(例如血基質一氧化氮及/或氧結合蛋白(HNOX)),諸如描述於WO2007137767、WO2007139791、WO2014107171、及WO2016149562中之OMX-302及HNOX蛋白。
免疫治療劑
在一些實施例中,本文所提供之化合物係與免疫治療劑一起投予。在一些實施例中,免疫治療劑係抗體。可共投予之實例免疫治療劑包括阿巴伏單抗(abagovomab)、ABP308、ABP-980、阿德木單抗(adecatumumab)、阿夫妥珠單抗(afutuzumab)、阿來組單抗(alemtuzumab)、阿妥莫單抗(altumomab)、阿瑪西單抗(amatuximab)、麻安莫單抗(anatumomab)、阿西莫單抗(arcitumomab)、阿特珠單抗、巴維昔單抗(bavituximab)、貝妥莫單抗(bectumomab)、貝伐珠單抗(bevacizumab)、比伐珠單抗(bivatuzumab)、蘭妥莫單抗、布吐西單抗(brentuximab)、卡米丹單抗(camidanlumab)、坎妥珠單抗(cantuzumab)、卡托莫西單抗(catumaxomab)、CC49、西妥昔單抗(cetuximab)、西他妥珠單抗(citatuzumab)、西妥木單抗(cixutumumab)、克里伏妥珠單抗(clivatuzumab)、康納土單抗(conatumumab)、達西珠單抗(dacetuzumab)、達洛圖單抗(dalotuzumab)、達拉單抗(daratumumab)、地莫單抗(detumomab)、地努圖希單抗(dinutuximab)、多伐尼單抗(domvanalimab)、卓西單抗(drozitumab)、杜里土單抗(duligotumab)、杜西吉土單抗(dusigitumab)、依美昔單抗(ecromeximab)、埃洛妥珠單抗(elotuzumab)、艾米貝珠單抗(emibetuzumab)、恩斯土昔單抗(ensituximab)、鄂托默單抗(ertumaxomab)、埃達珠單抗(etaracizumab)、伐吐珠單抗(farletuzumab)、費拉妥珠單抗(ficlatuzumab)、非吉單抗(figitumumab)、法蘭土單抗(flanvotumab)、弗妥昔單抗(futuximab)、加尼圖單抗(ganitumab)、吉妥單抗(gemtuzumab)、吉瑞昔單抗(girentuximab)、格雷巴妥木單抗(girentuximab)、伊莫單抗(ibritumomab)、伊戈伏單抗(igovomab)、伊姆加土珠單抗(imgatuzumab)、因達西單抗(indatuximab)、英妥珠單抗(inotuzumab)、英妥木單抗(intetumumab)、伊匹單抗(ipilimumab)(YERVOY
®、MDX-010、BMS-734016、及MDX-101)、伊妥木單抗(iratumumab)、拉貝珠單抗(labetuzumab)、來沙木單抗(lexatumumab)、林妥珠單抗(lintuzumab)、洛瓦土珠單抗(lorvotuzumab)、魯卡木單抗(lucatumumab)、馬帕木單抗(mapatumumab)、馬妥珠單抗(matuzumab)、米拉珠單抗(milatuzumab)、明瑞莫單抗(minretumomab)、米妥莫單抗(mitumomab)、莫格利珠單抗(mogamulizumab)、莫昔土莫單抗(moxetumomab)、那莫單抗(naptumomab)、納納土單抗(narnatumab)、耐昔妥珠單抗(necitumumab)、尼妥珠單抗(nimotuzumab)、諾非單抗(nofetumomab)、OBI-833、阿托珠單抗(obinutuzumab)、奧卡拉珠單抗(ocaratuzumab)、歐福杜單抗(ofatumumab)、奧拉單抗(olaratumab)、奧那組單抗(onartuzumab)、奧普珠單抗(oportuzumab)、奧戈伏單抗(oregovomab)、帕尼單抗(panitumumab)、帕薩珠單抗(parsatuzumab)、帕蘇多托克斯(pasudotox)、帕特里土單抗(patritumab)、潘妥莫單抗(pemtumomab)、帕妥珠單抗(pertuzumab)、平妥單抗(pintumomab)、普托木單抗(pritumumab)、拉克莫單抗(racotumomab)、拉德瑞單抗(radretumab)、雷莫蘆單抗(ramucirumab) (Cyramza
®)、利妥木單抗(rilotumumab)、利妥昔單抗(rituximab)、羅妥木單抗(robatumumab)、薩西土珠單抗(sacituzumab)、薩馬里珠單抗(samalizumab)、沙妥莫單抗(satumomab)、西羅珠單抗(sibrotuzumab)、思圖昔單抗(siltuximab)、索利托單抗(solitomab)、辛圖珠單抗(simtuzumab)、他卡珠單抗(tacatuzumab)、他普莫單抗(taplitumomab)、泰納莫單抗(tenatumomab)、泰普洛單抗(teprotumumab)、提卡珠單抗(tigatuzumab)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、土庫珠單抗(tucotuzumab)、烏妥昔單抗(ubilituximab)、維托珠單抗(veltuzumab)、沃爾希珠單抗(vorsetuzumab)、伏妥莫單抗(votumumab)、紮魯姆單抗(zalutumumab)、賽帕利單抗、及3F8。利妥昔單抗可用於治療惰性(indolent) B細胞癌症,包括邊緣區淋巴瘤、WM、CLL、及小淋巴球性淋巴瘤。利妥昔單抗與化學治療劑之組合係特別有效的。
例示性治療性抗體可進一步用放射性同位素粒子標示或與其組合,諸如銦-111、釔-90(90Y-克里伏妥珠單抗)、或碘-131。
在一些實施例中,免疫治療劑係抗體藥物接合物(ADC)。可共投予的說明性ADC包括但不限於靶向以上及本文中列出之蛋白或抗原之藥物接合抗體、其片段、或抗體擬似物。可共投予的例示性ADC包括吉妥珠單抗、本妥昔單抗、貝蘭單抗(belantamab)(例如貝蘭單抗莫福汀(belantamab mafodotin))、卡米丹單抗(camidanlumab)(例如卡米丹單抗特西林(camidanlumab tesirine))、曲妥珠單抗(例如曲妥珠單抗德魯替康(rastuzumab deruxtecan);曲妥珠單抗(trasuzumab)恩他新)、英妥珠單抗、格雷巴妥木單抗、阿內圖單抗(anetumab)、米維妥昔單抗(mirvetuximab)(例如米維妥昔單抗索拉夫坦辛)、德帕妥昔珠單抗、伐達妥昔單抗(vadastuximab)、拉貝珠單抗、拉迪朗妥珠單抗(ladiratuzumab)(例如拉迪朗妥珠單抗維多汀)、隆卡妥昔單抗(loncastuximab)(例如隆卡妥昔單抗特西林)、薩西土珠單抗(例如薩西土珠單抗戈維特坎)、達妥伯單抗(例如達妥伯單抗德魯替康;DS-1062;Dato-DXd)、帕特里土單抗(例如帕特里土單抗德魯替康)、立伐土珠單抗(lifastuzumab)、因杜薩土單抗(indusatumab)、保納珠單抗(polatuzumab)(例如保納珠單抗維多汀)、匹納土珠單抗(pinatuzumab)、考圖昔單抗(coltuximab)、昂普菲塔單抗(upifitamab)(例如昂普菲塔單抗里索多汀(rilsodotin))、因達西單抗、米拉珠單抗、洛伐妥珠單抗(例如洛伐妥珠單抗特西林)、因福土單抗(enfortumab)(例如因福土單抗維多汀)、泰舒圖單抗(tisotumab)(例如泰舒圖單抗維多汀)、圖撒米坦單抗(tusamitamab)(例如圖撒米坦單抗拉夫坦辛(tusamitamab ravtansine))、迪西妥單抗(disitamab)(例如迪西妥單抗維多汀)、替利妥珠單抗(telisotuzumab)維多汀(ABBV-399)、AGS-16C3F、ASG-22ME、AGS67E、AMG172、AMG575、BAY1129980、BAY1187982、BAY94-9343、GSK2857916、Humax-TF-ADC、IMGN289、IMGN151、IMGN529、IMGN632、IMGN853、IMGC936、LOP628、PCA062、MDX-1203 (BMS936561)、MEDI-547、PF-06263507、PF-06647020、PF-06647263、PF-06664178、RG7450、RG7458、RG7598、SAR566658、SGN-CD19A、SGN-CD33A、SGN-CD70A、SGN-LIV1A、SYD985、DS-7300、XMT-1660、IMMU-130、及IMMU-140。可共投予的ADC係描述於例如Lambert,
et al.,
Adv Ther(2017) 34:1015–1035及de Goeij,
Current Opinion in Immunology(2016) 40:14–23。
可接合至藥物接合抗體、其片段、或抗體擬似物之說明性治療劑(例如抗癌劑或抗癌藥物)包括但不限於單甲基奧瑞他汀E (monomethyl auristatin E, MMAE)、單甲基奧瑞他汀F (MMAF)、卡奇黴素(calicheamicin)、安絲菌素(ansamitocin)、美登素(maytansine)或其類似物(例如美坦辛/恩新(mertansine/emtansine) (DM1)、雷星/索星(ravtansine/soravtansine) (DM4))、蒽環黴素(anthracyline)(例如阿黴素、道諾黴素、泛艾黴素、艾達黴素)、吡咯并苯并二氮呯(PBD) DNA交聯劑SC-DR002 (D6.5)、倍癌黴素、微管抑制劑(MTI)(例如紫杉烷、長春花生物鹼、埃博黴素(epothilone))、吡咯并苯并二氮呯(PBD)或其二聚體、倍癌黴素(A、B1、B2、C1、C2、D、SA、CC-1065)、及本文中所述之其他抗癌劑或抗癌藥物。在一些實施例中,經接合至藥物接合抗體之治療劑係拓撲異構酶I抑制劑(例如喜樹鹼類似物,諸如伊立替康或其活性代謝物SN38)。在一些實施例中,可接合至藥物接合抗體、其片段、或抗體擬似物之治療劑(例如抗癌或抗腫瘤劑)包括免疫檢查點抑制劑。在一些實施例中,經接合之免疫檢查點抑制劑係CD274 (PDL1, PD-L1)、程式性細胞死亡1 (PDCD1, PD1, PD-1)、或CTLA4之經接合之小分子抑制劑。在一些實施例中,CD274或PDCD1之經接合之小分子抑制劑係選自由GS-4224、GS-4416、INCB086550、及MAX10181所組成之群組。在一些實施例中,CTLA4之經接合之小分子抑制劑包含BPI-002。
在一些實施例中,可共投予的ADC包括靶向下列之抗體:腫瘤相關鈣信號轉導子2(TROP-2;TACSTD2;EGP-1;NCBI基因ID:4070)。說明性抗TROP-2抗體包括但不限於TROP2-XPAT (Amunix)、BAT-8003 (Bio-Thera Solutions)、TROP-2-IR700 (Chiome Bioscience)、達妥伯單抗德魯替康(Daiichi Sankyo, AstraZeneca)、GQ-1003 (Genequantum Healthcare, Samsung BioLogics)、DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences)、薩西土珠單抗戈維特坎(Gilead Sciences)、E1-3s (Immunomedics/Gilead, IBC Pharmaceuticals)、TROP2-TRACTr (Janux Therapeutics)、LIV-2008 (LivTech/Chiome, Yakult Honsha, Shanghai Henlius BioTech)、LIV-2008b (LivTech/Chiome)、抗TROP-2a (Oncoxx)、抗TROP-2b (Oncoxx)、OXG-64 (Oncoxx)、OXS-55 (Oncoxx)、人類化抗Trop2-SN38抗體接合物(Shanghai Escugen Biotechnology, TOT Biopharma)、抗Trop2抗體-CLB-SN-38接合物(Shanghai Fudan-Zhangjiang Bio-Pharmaceutical)、SKB-264 (Sichuan Kelun Pharmaceutical/Klus Pharma)、TROP2-Ab8 (Abmart)、Trop2-IgG (Nanjing Medical University (NMU))、90Y-DTPA-AF650 (Peking University First Hospital)、hRS7-CM (SynAffix)、89Zr-DFO-AF650 (University of Wisconsin-Madison)、抗Trop2抗體(Mediterranea Theranostic, LegoChem Biosciences)、KD-065 (Nanjing KAEDI Biotech)、及該些描述於WO2020016662 (Abmart)、WO2020249063 (Bio-Thera Solutions)、US20190048095 (Bio-Thera Solutions)、WO2013077458 (LivTech/Chiome)、EP20110783675 (Chiome)、WO2015098099 (Daiichi Sankyo)、WO2017002776 (Daiichi Sankyo)、WO2020130125 (Daiichi Sankyo)、WO2020240467 (Daiichi Sankyo)、US2021093730 (Daiichi Sankyo)、US9850312 (Daiichi Sankyo)、CN112321715 (Biosion)、US2006193865 (Immunomedics/Gilead)、WO2011068845 (Immunomedics/Gilead)、US2016296633 (Immunomedics/Gilead)、US2017021017 (Immunomedics/Gilead)、US2017209594 (Immunomedics/Gilead)、US2017274093 (Immunomedics/Gilead)、US2018110772 (Immunomedics/Gilead)、US2018185351 (Immunomedics/Gilead)、US2018271992 (Immunomedics/Gilead)、WO2018217227 (Immunomedics/Gilead)、US2019248917 (Immunomedics/Gilead)、CN111534585 (Immunomedics/Gilead)、US2021093730 (Immunomedics/Gilead)、US2021069343 (Immunomedics/Gilead)、US8435539 (Immunomedics/Gilead)、US8435529 (Immunomedics/Gilead)、US9492566 (Immunomedics/Gilead)、WO2003074566 (Gilead)、WO2020257648 (Gilead)、US2013039861 (Gilead)、WO2014163684 (Gilead)、US9427464 (LivTech/Chiome)、US10501555 (Abruzzo Theranostic/Oncoxx)、WO2018036428 (Sichuan Kelun Pharma)、WO2013068946 (Pfizer)、WO2007095749 (Roche)、及WO2020094670 (SynAffix)中者。在一些實施例中,抗Trop-2抗體係選自hRS7、Trop-2-XPAT、及BAT-8003。在一些實施例中,抗Trop-2抗體係hRS7。在一些實施例中,hRS7係如美國專利第7,238,785號;第7,517,964號、及第8,084,583號中所揭示,其以引用方式併入本文中。在一些實施例中,抗體藥物接合物包含抗Trop-2抗體及藉由連接子連接之抗癌劑。在一些實施例中,連接子包括揭示於USPN 7,999,083中之連接子。在一些實施例中,連接子係CL2A。在一些實施例中,抗體藥物接合物之藥物部份係化學治療劑。在一些實施例中,化學治療劑係選自阿黴素(doxorubcin) (DOX)、表柔比星(epirubicin)、N-
啉基阿黴素(morpholinodoxorubicin)(N-
啉基-DOX)、氰基N-
啉基-阿黴素(氰基N-
啉基-DOX)、2-吡咯啉-阿黴素(2-PDOX)、CPT、10-羥基喜樹鹼(camptothecin)、SN-38、托泊替康(topotecan)、勒托替康(lurtotecan)、9-胺基喜樹鹼、9-硝基喜樹鹼、紫杉烷(taxane)、膠達納黴素(geldanamycin)、安沙黴素(ansamycin)、及埃博黴素(epothilone)。在一些實施例中,化學治療劑部份係SN-38。在一些實施例中,本文所提供之化合物係與薩西土珠單抗戈維特坎(sacituzumab govitecan)一起投予。
在一些實施例中,可共投予的ADC包括靶向下列之抗體:癌胚抗原相關細胞黏附分子1(CEACAM1;CD66a;NCBI基因ID:634)。在一些實施例中,CEACAM1抗體係hMN-14(例如,如WO1996011013中所述)。在一些實施例中,CEACAM1-ADC係描述於WO2010093395中者(抗CEACAM-1-CL2A-SN38)。在一些實施例中,本文所提供之化合物係與CEACAM1-ADC IMMU-130一起投予。
在一些實施例中,可共投予的ADC包括靶向由人類白血球抗原複合體編碼之MHC第II型細胞表面受體(HLA-DR)之抗體。在一些實施例中,HLA-DR抗體係hL243(例如,如WO2006094192中所述)。在一些實施例中,HLA-DR-ADC係描述於WO2010093395中者(抗HLA-DR-CL2A-SN38)。在一些實施例中,本文所提供之化合物係與HLA-DR-ADC IMMU-140一起投予。
癌症基因療法及細胞療法
在一些實施例中,本文所提供之化合物係與癌症基因療法及細胞療法一起投予。癌症基因療法及細胞療法包括插入正常基因至癌細胞中以置換經突變或改變之基因;基因修飾以靜默經突變之基因;直接殺滅癌細胞之基因方法;包括輸注經設計以置換病患自己的大部分免疫系統之免疫細胞以增強對癌細胞的免疫反應,或活化病患自己的免疫系統(T細胞或自然殺手細胞)以殺滅癌細胞、或找到及殺滅癌細胞;修飾細胞活性之基因方法以進一步改變針對癌症之內源性免疫反應性。
細胞療法
在一些實施例中,本文所提供之化合物係與一或多種細胞療法一起投予。說明性細胞療法包括但不限於共投予自然殺手(NK)細胞群、NK-T細胞群、T細胞群、細胞介素誘導之殺手(CIK)細胞群、巨噬細胞(MAC)群、腫瘤浸潤性淋巴細胞(TIL)群、及/或樹突細胞(DC)群之一或多者。在一些實施例中,細胞療法涉及T細胞療法,例如共投α/β TCR T細胞群、γ/δ TCR T細胞群、調控子T (Treg)細胞群、及/或TRuC
™T細胞群。在一些實施例中,細胞療法涉及NK細胞療法,例如共投NK-92細胞。視情況,細胞療法可涉及共投對於對象為自體、同基因、或同種異體的細胞。
在一些實施例中,細胞療法涉及共投予包含嵌合抗原受體(CAR)之細胞。在此類療法中,免疫效應細胞群係經工程改造以表現CAR,其中CAR包含腫瘤抗原結合域。在T細胞療法中,T細胞受體(TCR)係經工程改造以靶向腫瘤細胞之表面上呈現的腫瘤衍生肽。
關於CAR之結構,在一些實施例中,CAR包含抗原結合域、跨膜域、及胞內信號傳導域。在一些實施例中,胞內域包含一級信號傳導域、共刺激域、或一級信號傳導域及共刺激域兩者。在一些實施例中,一級信號傳導域包含選自由下列所組成之群組的一或多種蛋白之功能信號傳導域:CD3 ζ、CD3 γ、CD3 δ、CD3 ε、共同FcR γ (FCERIG)、FcR β (Fc ε Rlb)、CD79a、CD79b、Fcγ RIIa、DAP10、及DAP12。
在一些實施例中,共刺激域包含選自由下列所組成之群組的一或多種蛋白之功能域:CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、CD2、CD7、LIGHT、NKG2C、B7-H3、與CD83特異性結合之配體、CDS、ICAM-1、GITR、BAFFR、HVEM (LIGHTR)、SLAMF7、NKp80 (KLRFI)、CD160、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、ITGAE、CD103、ITGAL、CD1A(NCBI基因ID:909)、CD1B(NCBI基因ID:910)、CD1C(NCBI基因ID:911)、CD1D(NCBI基因ID:912)、CD1E(NCBI基因ID:913)、ITGAM、ITGAX、ITGB1、CD29、ITGB2 (CD18, LFA-1)、ITGB7、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、NKp44、NKp30、NKp46、及NKG2D。
在一些實施例中,跨膜域包含選自由下列所組成之群組的蛋白之跨膜域:T細胞受體之α、β、或ζ鏈、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、KIRDS2、OX40、CD2、CD27、ICOS (CD278)、4-1BB(CD137)、GITR、CD40、BAFFR、HVEM (LIGHTR)、SLAMF7、NKp80 (KLRF1)、CD160、CD19、IL2Rβ、IL2Rγ、IL7R、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1A、CD1B、CD1C、CD1D、CD1E、ITGAE、CD103、ITGAL、ITGAM、ITGAX、ITGB1、CD29、ITGB2 (LFA-1、CD18)、ITGB7、TNFR2、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (TACTILE)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、PAG/Cbp、NKp44、NKp30、NKp46、NKG2D、及NKG2C。
在一些實施例中,本文所述之TCR或CAR抗原結合域或免疫治療劑(例如單特異性或多特異性抗體或其抗原結合片段或抗體擬似物)結合腫瘤相關抗原(TAA)。在一些實施例中,腫瘤相關抗原係選自由下列所組成之群組:CD19;CD123;CD22;CD30;CD171;CS-1(亦稱為CD2子集1、CRACC、SLAMF7、CD319、及19A24);C型凝集素樣分子1(CLL-1或CLECLI);CD33;表皮生長因子受體變體III (EGFRvlll);神經節苷酯G2 (GD2);神經節苷酯GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer);神經節苷酯GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer);TNF受體超家族成員17 (TNFRSF17, BCMA);Tn抗原((Tn Ag)或(GaINAcu-Ser/Thr));前列腺特異性膜抗原(PSMA);受體酪胺酸激酶樣孤兒受體1 (RORI);腫瘤相關醣蛋白72 (TAG72);CD38;CD44v6;癌胚抗原(CEA);上皮細胞黏附分子(EPCAM);B7H3 (CD276);KIT (CD117);介白素13受體次單元α-2(IL-13Ra2或CD213A2);間皮素;介白素11受體α (IL-11Ra);前列腺幹細胞抗原(PSCA);蛋白酶絲胺酸21(睪素(Testisin)或PRSS21);血管內皮生長因子受體2 (VEGFR2);Lewis(Y)抗原;CD24;血小板衍生生長因子受體β (PDGFR-β);階段特異性胚胎抗原4 (SSEA-4);CD20;δ樣3 (DLL3);葉酸受體α;受體酪胺酸蛋白激酶ERBB2 (Her2/neu);黏蛋白1,細胞表面相關(MUC1);表皮生長因子受體(EGFR);神經細胞黏附分子(NCAM);前列腺酶;前列腺酸性磷酸酶(PAP);伸長因子2突變型(ELF2M);蝶素B2;纖維母細胞活化蛋白α (FAP);胰島素樣生長因子1受體(IGF-I受體)、碳酸酐酶IX (CAIX);蛋白酶體(前體(Prosome)、巨蛋白因子(Macropain))次單元β型9 (LMP2);醣蛋白100 (gp100);由斷點簇區(BCR)及Abelson鼠白血病病毒致癌基因同源物1 (Abl)組成之致癌基因融合蛋白(bcr-abl);酪胺酸酶;蝶素A型受體2 (EphA2);岩藻醣基GM1;唾液酸基Lewis黏附分子(sLe);轉麩醯胺酸酶5 (TGS5);高分子量黑色素瘤相關抗原(HMWMAA);o-乙醯基-GD2神經節苷酯(OAcGD2);葉酸受體β;腫瘤內皮標記1 (TEM1/CD248);腫瘤內皮標記7相關(TEM7R);前列腺I之六跨膜上皮抗原(STEAP1);密連蛋白6 (CLDN6);促甲狀腺荷爾蒙受體(TSHR);G蛋白偶合受體C型5組成員D (GPRCSD);染色體X開讀框61 (CXORF61);CD97;CD179a;退行性淋巴瘤激酶(ALK);聚唾液酸;胎盤特異性1 (PLAC1);globoH糖基神經醯胺之六醣部分(GloboH);乳腺分化抗原(NY-BR-1);尿溶蛋白2 (UPK2);A型肝炎病毒細胞性受體1 (HAVCR1);腎上腺素受體β3 (ADRB3);泛連接蛋白(pannexin) 3 (PANX3);G蛋白質偶合受體20 (GPR20);淋巴細胞抗原6複合體,基因座K9 (LY6K);嗅覺受體51E2 (ORS IE2);TCRγ交替讀框蛋白(TARP);Wilms腫瘤蛋白(WT1);癌症/睪丸抗原1 (NY-ESO-1);癌症/睪丸抗原2 (LAGE-la);黑色素瘤相關抗原1 (MAGE-A1);ETS轉位變體基因6,位於染色體12p上(ETV6-AML);精子蛋白17 (SPA17);X抗原家族成員1A (XAGE1);促血管生成素結合細胞表面受體2 (Tie 2);黑色素瘤癌症睪丸抗原1 (MADCT-1);黑色素瘤癌症睪丸抗原2 (MAD-CT-2);fos相關抗原1;腫瘤蛋白p53 (p53);p53突變體;前列腺蛋白(prostein);生存素(Survivin);端粒酶;前列腺癌腫瘤抗原1(PCTA-1或半乳糖凝集素8),由T細胞辨識之黑色素瘤抗原1(MelanA或MARTI);大鼠肉瘤(Ras)突變體;人類端粒酶反轉錄酶(hTERT);肉瘤轉位斷點;黑色素瘤細胞凋亡抑制子(ML-IAP);ERG(跨膜蛋白酶,絲胺酸2 (TMPRSS2) ETS融合基因);N-乙醯基葡萄糖胺基轉移酶V (NA17);成對盒蛋白Pax-3 (PAX3);雄性激素受體;週期蛋白B1;v-myc禽骨髓細胞過多症病毒致癌基因神經胚細胞瘤衍生性同源物(MYCN);Ras同源物家族成員C (RhoC);酪胺酸酶相關蛋白2 (TRP-2);細胞色素P450 1B1 (CYP IBI);CCCTC結合因子(鋅指蛋白)樣(BORIS或印記位點、調控物兄弟)、T細胞辨識之鱗狀細胞癌抗原3 (SART3);成對盒蛋白Pax-5 (PAX5);原精帽粒蛋白(proacrosin)結合蛋白sp32 (OY-TES I);淋巴細胞特異性蛋白酪胺酸激酶(LCK);A激酶錨定蛋白4 (AKAP-4);滑膜肉瘤,X斷點2 (SSX2);晚期糖化終產物受體(RAGE-I);腎遍在1 (RUI);腎遍在2 (RU2);天冬胺酸內肽酶(legumain);人類乳突瘤病毒E6 (HPV E6);人類乳突瘤病毒E7 (HPV E7);腸羧基酯酶;熱休克蛋白70-2突變型(mut hsp70-2);CD79a;CD79b;CD72;白血球相關免疫球蛋白樣受體1 (LAIRI);IgA受體之Fc片段(FCAR或CD89);白血球免疫球蛋白樣受體亞家族A成員2 (LILRA2);CD300分子樣家族成員f (CD300LF);C型凝集素域家族12成員A (CLEC12A);骨髓基質細胞抗原2 (BST2);含EGF樣模組黏液素樣荷爾蒙受體樣2 (EMR2);淋巴細胞抗原75 (LY75);磷脂肌醇聚糖3 (GPC3);Fc受體樣5 (FCRL5);及免疫球蛋白λ樣多肽1 (IGLL1)。在一些實施例中,目標係MHC呈現之腫瘤相關抗原的表位。
在一些實施例中,腫瘤抗原係選自CD150、5T4、ActRIIA、B7、TNF受體超家族成員17 (TNFRSF17、BCMA)、CA-125、CCNA1、CD123、CD126、CD138、CD14、CD148、CD15、CD19、CD20、CD200、CD21、CD22、CD23、CD24、CD25、CD26、CD261、CD262、CD30、CD33、CD362、CD37、CD38、CD4、CD40、CD40L、CD44、CD46、CD5、CD52、CD53、CD54、CD56、CD66a-d、CD74、CD8、CD80、CD92、CE7、CS-1、CSPG4、ED-B纖維黏連蛋白、EGFR、EGFRvIII、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、FBP、組合的HER1-HER2、組合的HER2-HER3、HERV-K、HIV-1封套糖蛋白gp120、HIV-1封套糖蛋白gp41、HLA-DR、HM1.24、HMW-MAA、Her2、Her2/neu、IGF-1R、IL-11Rα、IL-13R-α2、IL-2、IL-22R-α、IL-6、IL-6R、Ia、Ii、L1-CAM、L1-細胞黏附分子、Lewis Y、Ll-CAM、MAGE A3、MAGE-A1、MART-1、MUC1、NKG2C配體、NKG2D配體、NYESO-1、OEPHa2、PIGF、PSCA、PSMA、ROR1、T101、TAC、TAG72、TIM-3、TRAIL-R1、TRAIL-R1 (DR4)、TRAIL-R2 (DR5)、VEGF、VEGFR2、WT-I、G蛋白偶合受體、α-胎兒蛋白(AFP)、血管生成因子、外源性同源結合分子(ExoCBM)、致癌基因產物、抗葉酸受體、c-Met、癌胚抗原(CEA)、週期蛋白(D 1)、蝶素B2、上皮腫瘤抗原、雌激素受體、胎兒乙醯膽鹼e受體、葉酸結合蛋白、gp100、B型肝炎表面抗原、κ鏈、κ輕鏈、kdr、λ鏈、活素(livin)、黑色素瘤相關抗原、間皮素、小鼠雙微體2同源物(MDM2)、黏液素16 (MUC16)、經突變之p53、經突變之ras、壞死抗原、致癌胎兒抗原、ROR2、助孕素受體、前列腺特異性抗原、tEGFR、腱生蛋白、P2-微球蛋白、Fc受體樣5 (FcRL5)。
在一些實施例中,抗原結合域結合至主要組織相容性複合體(MHC)分子呈現之目標或腫瘤相關抗原(TAA)的表位。在一些實施例中,TAA係癌症睪丸抗原。在一些實施例中,癌症睪丸抗原係選自由下列所組成之群組:精帽粒蛋白結合蛋白(ACRBP;CT23、OY-TES-1、SP32;NCBI基因ID:84519)、α胎兒蛋白(AFP;AFPD、FETA、HPAFP;NCBI基因ID:174);A激酶錨定蛋白4(AKAP4;AKAP 82、AKAP-4、AKAP82、CT99、FSC1、HI、PRKA4、hAKAP82、p82;NCBI基因ID:8852)、含ATP酶家族AAA域2(ATAD2;ANCCA、CT137、PRO2000;NCBI基因ID:29028)、著絲點支架1(KNL1;AF15Q14、CASC5、CT29、D40、MCPH4、PPP1R55、Spc7、hKNL-1、hSpc105;NCBI基因ID:57082)、中心體蛋白55(CEP55;C10orf3、CT111、MARCH、URCC6;NCBI基因ID:55165)、癌症/睪丸抗原1A(CTAG1A;ESO1;CT6.1;LAGE-2;LAGE2A;NY-ESO-1;NCBI基因ID:246100)、癌症/睪丸抗原1B(CTAG1B;CT6.1、CTAG、CTAG1、ESO1、LAGE-2、LAGE2B、NY-ESO-1;NCBI基因ID:1485)、癌症/睪丸抗原2(CTAG2;CAMEL、CT2、CT6.2、CT6.2a、CT6.2b、ESO2、LAGE-1、LAGE2B;NCBI基因ID:30848)、類CCCTC結合因子(CTCFL;BORIS、CT27、CTCF-T、HMGB1L1、dJ579F20.2;NCBI基因ID:140690)、連環蛋白α2(CTNNA2;CAP-R、CAPR、CDCBM9、CT114、CTNR;NCBI基因ID:1496)、癌症/睪丸抗原83(CT83;CXorf61、KK-LC-1、KKLC1;NCBI基因ID:203413)、週期蛋白A1(CCNA1;CT146;NCBI基因ID:8900)、死亡盒解螺旋酶43(DDX43;CT13、HAGE;NCBI基因ID:55510)、發育多能性相關2(DPPA2;CT100、ECAT15-2、PESCRG1;NCBI基因ID:151871)、胎兒及成人睪丸表現1(FATE1;CT43、FATE;NCBI基因ID:89885)、FMR1鄰居(FMR1NB;CT37、NY-SAR-35、NYSAR35;NCBI基因ID:158521)、含HORMA域1(HORMAD1;CT46、NOHMA;NCBI基因ID:84072)、類胰島素生長因子2 mRNA結合蛋白3(IGF2BP3;CT98、IMP-3、IMP3、KOC、KOC1、VICKZ3;NCBI基因ID:10643)、白胺酸拉鍊蛋白4(LUZP4;CT-28、CT-8、CT28、HOM-TES-85;NCBI基因ID:51213)、淋巴細胞抗原6家族成員K(LY6K;CT97、HSJ001348、URLC10、ly-6K;NCBI基因ID:54742)、大漩渦生精轉位子靜默子(MAEL;CT128、SPATA35;NCBI基因ID:84944)、MAGE家族成員A1(MAGEA1;CT1.1、MAGE1;NCBI基因ID:4100);MAGE家族成員A3(MAGEA3;CT1.3、HIP8、HYPD、MAGE3、MAGEA6;NCBI基因ID:4102);MAGE家族成員A4(MAGEA4;CT1.4、MAGE-41、MAGE-X2、MAGE4、MAGE4A、MAGE4B;NCBI基因ID:4103);MAGE家族成員A11(MAGEA11;CT1.11、MAGE-11、MAGE11、MAGEA-11;NCBI基因ID:4110);MAGE家族成員C1(MAGEC1;CT7、CT7.1;NCBI基因ID:9947);MAGE家族成員C2(MAGEC2;CT10、HCA587、MAGEE1;NCBI基因ID:51438);MAGE家族成員D1(MAGED1;DLXIN-1、NRAGE;NCBI基因ID:9500);MAGE家族成員D2(MAGED2;11B6、BARTS5、BCG-1、BCG1、HCA10、MAGE-D2;NCBI基因ID:10916)、驅動蛋白家族成員20B(KIF20B;CT90、KRMP1、MPHOSPH1、MPP-1、MPP1;NCBI基因ID:9585)、NDC80著絲點複合體NUF2組分(NUF2;CDCA1、CT106、NUF2R;NCBI基因ID:83540)、核RNA輸出因子2(NXF2;CT39、TAPL-2、TCP11X2;NCBI基因ID:56001)、含PAS域阻抑子1(PASD1;CT63、CT64、OXTES1;NCBI基因ID:139135)、PDZ結合激酶(PBK;CT84、HEL164、Nori-3、SPK、TOPK;NCBI基因ID:55872)、類piwiRNA介導之基因靜默2(PIWIL2;CT80、HILI、PIWIL1L、mili;NCBI基因ID:55124)、黑色素瘤優先表現抗原(PRAME;CT130、MAPE、OIP-4、OIP4;NCBI基因ID:23532)、精子相關抗原9(SPAG9;CT89、HLC-6、HLC4、HLC6、JIP-4、JIP4、JLP、PHET、PIG6;NCBI基因ID:9043)、X性聯核相關聯精子蛋白家族成員A1(SPANXA1;CT11.1、CT11.3、NAP-X、SPAN-X、SPAN-Xa、SPAN-Xb、SPANX、SPANX-A;NCBI基因ID:30014)、SPANX家族成員A2(SPANXA2;CT11.1、CT11.3、SPANX、SPANX-A、SPANX-C、SPANXA、SPANXC;NCBI基因ID:728712)、SPANX家族成員C(SPANXC;CT11.3、CTp11、SPANX-C、SPANX-E、SPANXE;NCBI基因ID:64663)、SPANX家族成員D(SPANXD;CT11.3、CT11.4、SPANX-C、SPANX-D、SPANX-E、SPANXC、SPANXE、dJ171K16.1;NCBI基因ID:64648)、SSX家族成員1(SSX1;CT5.1、SSRC;NCBI基因ID:6756)、SSX家族成員2(SSX2;CT5.2、CT5.2A、HD21、HOM-MEL-40、SSX;NCBI基因ID:6757)、聯會複合體蛋白3(SYCP3;COR1、RPRGL4、SCP3、SPGF4;NCBI基因ID:50511)、細胞間橋形成因子睪丸表現14(TEX14;CT113、SPGF23;NCBI基因ID:56155)、轉錄因子Dp家族成員3(TFDP3;CT30、DP4、HCA661;NCBI基因ID:51270)、絲胺酸蛋白酶50(PRSS50;CT20、TSP50;NCBI基因ID:29122)、TTK蛋白激酶(TTK;CT96、ESK、MPH1、MPS1、MPS1L1、PYT;NCBI基因ID:7272)、及鋅指蛋白165(ZNF165;CT53、LD65、ZSCAN7;NCBI基因ID:7718)。結合至主要組織相容性複合體(MHC)分子呈現之癌症睪丸抗原的表位之T細胞受體(TCR)及類TCR抗體係所屬技術領域中已知且可用於本文所述之異二聚體。與腫瘤相關聯之癌症睪丸抗原係總結於例如Gibbs,
et al., Trends Cancer2018 Oct; 4(10):701-712及CT資料庫網站cta.lncc.br/index.php。結合至MHC呈現之NY-ESO-1的表位之說明性TCR及類TCR抗體係描述於例如Stewart-Jones,
et al.,
Proc Natl Acad Sci USA.2009 Apr 7; 106(14):5784-8;WO2005113595、WO2006031221、WO2010106431、WO2016177339、WO2016210365、WO2017044661、WO2017076308、WO2017109496、WO2018132739、WO2019084538、WO2019162043、WO2020086158、及WO2020086647。結合至MHC呈現之PRAME的表位之說明性TCR及類TCR抗體係描述於例如WO2011062634、WO2016142783、WO2016191246、WO2018172533、WO2018234319、及WO2019109821。結合至MHC呈現之MAGE變體的表位之說明性TCR及類TCR抗體係描述於例如WO2007032255、WO2012054825、WO2013039889、WO2013041865、WO2014118236、WO2016055785、WO2017174822、WO2017174823、WO2017174824、WO2017175006、WO2018097951、WO2018170338、WO2018225732、及WO2019204683。結合至MHC呈現之α胎兒蛋白(AFP)的表位之說明性TCR及類TCR抗體係描述於例如WO2015011450。結合至MHC呈現之SSX2的表位之說明性TCR及類TCR抗體係描述於例如WO2020063488。結合至MHC呈現之KK-LC-1 (CT83)的表位之說明性TCR及類TCR抗體係描述於例如WO2017189254。
細胞療法之實例包括:艾普塞爾-L (Algenpantucel-L)、西普魯塞-T (Sipuleucel-T)、(BPX-501)瑞沃賽爾(rivogenlecleucel) US9089520、WO2016100236、AU-105、ACTR-087、活化同種異體自然殺手細胞CNDO-109-AANK、MG-4101、AU-101、BPX-601、FATE-NK100、LFU-835造血幹細胞、伊米塞爾-T (Imilecleucel-T)、巴塔塞爾-T (baltaleucel-T)、PNK-007、UCARTCS1、ET-1504、ET-1501、ET-1502、ET-190、CD19-ARTEMIS、ProHema、FT-1050治療之骨髓幹細胞療法、CD4CARNK-92細胞、CryoStim、AlloStim、慢病毒轉導之huCART-間皮細胞、CART-22細胞、EGFRt/19-28z/4-1BBL CAR T細胞、自體4H11-28z/fIL-12/EFGRt T細胞、CCR5-SBC-728-HSPC、CAR4-1BBZ、CH-296、dnTGFbRII-NY-ESOc259T、Ad-RTS-IL-12、IMA-101、IMA-201、CARMA-0508、TT-18、CMD-501、CMD-503、CMD-504、CMD-502、CMD-601、CMD-602、及CSG-005。
在一些實施例中,一或多種額外共投予治療劑可依其作用機制分類為例如下列群組:
• 靶向腺苷去胺酶之劑,諸如噴司他丁(pentostatin)或克拉屈濱(cladribine);
• 靶向ATM之劑,諸如AZD1390;
• 靶向MET之劑,諸如薩沃替尼(savolitinib)、卡馬替尼(capmatinib)、特潑替尼(tepotinib)、ABT-700、AG213、JNJ-38877618 (OMO-1)、默萊替尼(merestinib)、HQP-8361、BMS-817378、或TAS-115;
• 靶向致裂物質活化蛋白激酶之藥劑,諸如安奎諾爾、畢尼替尼(binimetinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、阿普色替(uprosertib)、米達替尼(mirdametinib) (PD-0325901)、派嗎色替(pimasertib)、瑞法替尼(refametinib)、或揭示於下列中之化合物:WO2011008709、WO2013112741、WO2006124944、WO2006124692、WO2014064215、WO2018005435、Zhou, et al., Cancer Lett.2017 Nov 1, 408:130-137、Teli, et al., J Enzyme Inhib Med Chem.(2012) 27(4):558-70;Gangwall, et al., Curr Top Med Chem.(2013) 13(9):1015-35;Wu, et al., Bioorg Med Chem Lett.(2009) 19(13):3485-8;Kaila, et al., Bioorg Med Chem.(2007) 15(19):6425-42、或Hu, et al., Bioorg Med Chem Lett.(2011) 21(16):4758-61;
• 靶向胸苷激酶之劑,諸如阿格維克(aglatimagene besadenovec)(ProstAtak、PancAtak、GliAtak、GMCI、或AdV-tk);
• 靶向靶向介白素路徑之劑,諸如培吉介白素(pegilodecakin) (AM-0010)(聚乙二醇化IL10)、CA-4948(IRAK4抑制劑);
• 靶向細胞色素P450家族成員之劑,諸如來曲唑(letrozole)、阿那曲唑(anastrozole)、胺魯米特(aminoglutethimide)、甲地孕酮乙酸鹽(megestrol acetate) (MEGACE
®)、依西美坦(exemestane)、福美坦(formestane)、法倔唑(fadrozole)、伏氯唑(vorozole) (RIVISOR
®)、來曲唑(FEMARA
®)、或阿那曲唑(ARIMIDEX
®);
• 靶向CD73之劑,諸如CD73抑制劑(例如,奎立克魯司他(quemliclustat) (AB680))或抗CD73抗體(例如奧勒魯單抗);
• 靶向DKK3之劑,諸如MTG-201;
• 靶向EEF1A2之劑,諸如普利肽新(plitidepsin);
• 靶向EIF4A1之藥劑,諸如羅西替布(rohinitib);
• 靶向內皮糖蛋白之劑,諸如TRC105(卡妥昔單抗(carotuximab));
• 靶向外輸蛋白1之劑,諸如艾塔尼西(eltanexor);
• 靶向脂肪酸醯胺水解酶之劑,諸如揭示於WO2017160861中之化合物;
• 靶向熱休克蛋白90β家族成員1之劑,諸如安羅替尼(anlotinib);
• 靶向乳轉鐵蛋白之劑,諸如乳特米德(ruxotemitide) (LTX-315);
• 靶向離胺醯基氧化酶之劑,諸如揭示於US4965288、US4997854、US4943593、US5021456、US5059714、US5120764、US5182297、US5252608、或US20040248871中之化合物;
• 靶向MAGE家族成員之劑,諸如KITE-718、MAGE-A10C796T、或MAGE-A10 TCR;
• 靶向MDM2之劑,諸如ALRN-6924、CMG-097、米拉美坦單甲苯磺酸鹽單水合物(milademetan monotosylate monohydrate) (DS-3032b)、或AMG-232;
• 靶向MDM4之劑,諸如ALRN-6924;
• 靶向melan-A之劑,諸如MART-1 F5 TCR工程改造之PBMC;
• 靶向間皮素之劑,諸如CSG-MESO、或TC-210;
• 靶向METAP2之劑,諸如M8891、或APL-1202;
• 靶向NLRP3之劑,諸如BMS-986299;
• 靶向側氧戊二酸去氫酶之劑,諸如得維米司他(devimistat) (CPI-613);
• 靶向胎盤生長因子之劑,諸如阿柏西普(aflibercept);
• 靶向SLC10A3之劑,諸如揭示於WO2015148954、WO2012082647、或WO2017160861中之化合物;
• 靶向轉形生長因子α (TGFa)之劑,諸如揭示於WO2019103203中之化合物;
• 靶向腫瘤蛋白p53之劑,諸如克維林(kevetrin)(刺激劑);
• 靶向血管內皮生長因子A之劑,諸如阿柏西普;
• 靶向血管內皮生長因子受體之劑,諸如呋喹替尼(fruquintinib)、或MP0250;
• 靶向VISTA之劑,諸如CA-170、或HMBD-002;
• 靶向WEE1之劑,諸如阿達替布(adavosertib) (AZD-1775);
• 靶向ABL1之小分子抑制劑,諸如伊馬替尼、瑞巴替尼、阿西尼布(asciminib)、或普納替尼(ICLUSIG
®);
• 靶向腺苷受體之小分子拮抗劑,諸如CPI-444、AZD-4635、普雷迪南(preladenant)、艾魯美冷(etrumadenant) (AB928)、或PBF-509;
• 靶向花生四烯酸酯5-脂肪加氧酶之小分子抑制劑,諸如甲氯芬那酸鈉或齊留通;
• 靶向ATR絲胺酸/蘇胺酸激酶之小分子抑制劑,諸如BAY-937、塞拉賽替(ceralasertib) (AZD6738)、AZD6783、VX-803、或VX-970(貝佐替布(berzosertib));
• 靶向AXL受體酪胺酸激酶之小分子抑制劑,諸如貝西替尼(bemcentinib) (BGB-324)、SLC-0211、或吉列替尼(gilteritinib) (Axl/Flt3);
• 靶向布魯頓氏酪胺酸激酶(BTK)之小分子抑制劑,諸如(S)-6-胺基-9-(1-(丁-2-炔醯基)吡咯啶-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮、阿卡替尼(ACP-196)、贊布替尼(BGB-3111)、CB988、普瑟替尼(poseltinib) (HM71224)、依魯替尼(依布魯維卡(Imbruvica))、M-2951(伊沃替尼(evobrutinib))、替拉替尼(ONO-4059)、瑞薩布替尼(rilzabrutinib) (PRN-1008)、司培替尼(CC-292)、維卡替尼、ARQ-531 (MK-1026)、SHR-1459、DTRMWXHS-12、或TAS-5315;
• 靶向神經滋養受體酪胺酸激酶之小分子抑制劑,諸如拉羅替尼、恩曲替尼(entrectinib)、或色力替尼(selitrectinib) (LOXO-195);
• 靶向ROS原致癌基因1,受體酪胺酸激酶之小分子抑制劑,諸如恩曲替尼、瑞普替尼(repotrectinib) (TPX-0005)、或洛拉替尼(lorlatinib);
• 靶向SRC原致癌基因,非受體酪胺酸激酶之小分子抑制劑,諸如VAL-201、曲班布林(tirbanibulin) (KX2-391)、或伊格替尼順丁烯二酸鹽(NS-018);
• 靶向B細胞淋巴瘤2之小分子抑制劑,諸如納維托克(navitoclax) (ABT-263)、維奈托克(venetoclax) (ABT-199, RG-7601)、或AT-101(棉酚);
• 靶向含溴域及外域(BET)溴域之蛋白質之小分子抑制劑,諸如ABBV-744、INCB-054329、INCB057643、AZD-5153、ABT-767、BMS-986158、CC-90010、NHWD-870、ODM-207、ZBC246、ZEN3694、CC-95775 (FT-1101)、米韋西布(mivebresib)、BI-894999、PLX-2853、PLX-51107、CPI-0610、或GS-5829;
• 靶向碳水化合物磺基轉移酶15之小分子抑制劑,諸如STNM-01;
• 靶向碳酸酐酶之小分子抑制劑,諸如波馬昔布、乙醯唑胺、或醋甲唑胺;
• 靶向連環蛋白β1之小分子抑制劑,諸如CWP-291、或PRI-724;
• 靶向C-C模體趨化因子受體之小分子拮抗劑,諸如CCX-872、BMS-813160 (CCR2/CCR5)、或MK-7690(維克維若(vicriviroc));
• 靶向C-X-C模體趨化因子受體(例如,CXCR4)之小分子拮抗劑,波立沙福泰(blixafortide);
• 靶向塞勒布隆(cereblon)之小分子抑制劑,諸如阿多米德(avadomide) (CC-122)、CC-92480、CC-90009、或伊柏米特(iberdomide);
• 靶向檢查點激酶1之小分子抑制劑,諸如SRA737;
• 靶向補體組分之小分子抑制劑,諸如因普拉姆PGG (Imprime PGG) (Biothera Pharmaceuticals);
• 靶向C-X-C模體趨化因子配體(例如,CXCL12)之小分子抑制劑,諸如聚乙二醇化奧拉希德(olaptesed pegol) (NOX-A12);
• 靶向細胞色素P450家族之小分子抑制劑,諸如ODM-209、LAE-201、西維諾尼(seviteronel) (VT-464)、CFG920、阿比特龍、或阿比特龍乙酸鹽;
• 靶向死亡盒解螺旋酶5之小分子抑制劑,諸如蘇平辛(supinoxin) (RX-5902);
• 靶向DGKa之小分子抑制劑,例如諸如描述於WO2021130638中者;
• 靶向diablo IAP結合粒線體蛋白之小分子抑制劑,諸如BI-891065;
• 靶向二氫葉酸還原酶之小分子抑制劑,諸如普拉曲沙(pralatrexate)或培美曲塞二鈉(pemetrexed disodium);
• 靶向DNA依賴性蛋白激酶之小分子抑制劑,諸如MSC2490484A(尼瑟替布(nedisertib))、VX-984、AsiDNA (DT-01)、LXS-196、或索塔妥林(sotrastaurin);
• 靶向MARCKS之小分子抑制劑,諸如BIO-11006;
• 靶向RIPK1之小分子抑制劑,諸如GSK-3145094;
• 靶向含Rho相關捲曲螺旋蛋白激酶之小分子抑制劑,諸如AT13148、或KD025;
• 靶向DNA拓撲異構酶之小分子抑制劑,諸如伊立替康(irinotecan)、聚乙二醇化非特坎(firtecan pegol)、或胺柔比星(amrubicin);
• 靶向多巴胺受體D2之小分子抑制劑,諸如ONC-201;
• 靶向DOT1樣組蛋白離胺酸甲基轉移酶之小分子抑制劑,諸如皮諾斯塔(pinometostat) (EPZ-5676);
• 靶向EZH2之小分子抑制劑,諸如塔澤斯塔(tazemetostat)、CPI-1205、或PF-06821497;
• 靶向脂肪酸合成酶之小分子抑制劑,諸如TVB-2640 (Sagimet Biosciences);
• 靶向纖維母細胞生長因子受體2 (FGFR2)之小分子抑制劑,諸如貝馬圖單抗(bemarituzumab) (FPA144);
• 靶向黏著斑激酶(FAK, PTK2)之小分子抑制劑,諸如VS-4718、迪法替尼(defactinib)、或GSK2256098;
• 靶向葉酸受體1之小分子抑制劑,諸如普拉曲沙;
• 靶向FOXM1之小分子抑制劑,諸如硫鏈絲菌肽(thiostrepton);
• 靶向半乳糖凝集素3 (galectin 3)之小分子抑制劑,諸如貝拉培汀(belapectin) (GR-MD-02);
• 靶向葡萄糖皮質素受體之小分子拮抗劑,諸如瑞拉蘭特(relacorilant) (CORT-125134);
• 靶向麩醯胺酸酶之小分子抑制劑,包括但不限於CB-839(泰萊司他(telaglenastat))、或雙-2-(5-苯基乙醯胺基-1,3,4-噻二唑-2-基)乙基硫醚(BPTES);
• 靶向GNRHR之小分子抑制劑,諸如惡拉戈利(elagolix)、瑞拉戈利(relugolix)、或地加瑞克(degarelix);
• 靶向EPAS1之小分子抑制劑,諸如貝珠替凡(belzutifan) (PT-2977 (Merck & Co.));
• 靶向異檸檬酸去氫酶(NADP(+))之小分子抑制劑,諸如限制性艾伏尼布(ivosidenib) (Ag-120)、沃拉得尼(vorasidenib) (AG-881)(DH1及IDH2)、IDH-305、或艾那尼布(enasidenib) (AG-221);
• 靶向離胺酸去甲基酶1A之小分子抑制劑,諸如CC-90011;
• 靶向MAPK交互作用型絲胺酸/蘇胺酸激酶之小分子抑制劑,諸如妥米瑟替(tomivosertib) (eFT-508);
• 靶向notch受體之小分子抑制劑,諸如AL-101 (BMS-906024);
• 靶向polo樣激酶1 (PLK1)之小分子抑制劑,諸如沃納瑟替(volasertib)或安凡瑟替(onvansertib);
• 靶向聚(ADP-核糖)聚合酶(PARP)之小分子抑制劑,諸如奧拉帕尼(olaparib) (MK7339)、盧卡帕瑞(rucaparib)、維利帕尼(veliparib)、他拉帕瑞(talazoparib)、ABT-767、帕米帕里(pamiparib) (BGB-290)、氟唑帕力(fluazolepali) (SHR-3162)、尼拉帕瑞(niraparib) (JNJ-64091742)、斯坦帕瑞(stenoparib) (2X-121 (e-7499))、斯密帕尼(simmiparib)、IMP-4297、SC-10914、IDX-1197、HWH-340、CEP 9722、CEP-8983、E7016、3-胺基苯甲醯胺、或CK-102;
• 靶向多梳蛋白EED之小分子抑制劑,諸如MAK683;
• 靶向豪豬O-醯基轉移酶之小分子抑制劑,諸如WNT-974;
• 靶向前列腺素-內過氧化物合成酶之小分子抑制劑,諸如HP-5000、氯諾昔康、酮咯酸緩血酸胺、溴芬酸鈉、奧坦普羅(otenaproxesul) (ATB-346)、莫苯唑酸(mofezolac)、GLY-230、TRK-700、雙氯芬酸(diclofenac)、美洛昔康、帕瑞昔布、依托昔布、塞來昔布、AXS-06、雙氯芬酸鉀、經再調配之塞來昔布(DRGT-46)、AAT-076、美索舒利、羅美昔布、美洛昔康、伐地昔布(valdecoxib)、紮托洛芬、尼美舒利、阿尼紮芬、阿普昔布、西米昔布、德拉昔布、氟咪唑、非羅昔布、馬瓦昔布、帕米格雷、帕瑞昔布、羅苯昔布、羅非昔布、茱萸鹼、替馬昔布、紮托洛芬、或艾瑞昔布;
• 靶向蛋白精胺酸N甲基轉移酶之小分子抑制劑,諸如MS203、PF-06939999、GSK3368715、或GSK3326595;
• 靶向PTPN11之小分子抑制劑,諸如TNO155 (SHP-099)、RMC-4550、JAB-3068、RMC-4630 (SAR442720)、或揭示於WO2018172984或WO2017211303中之化合物;
• 靶向視黃酸受體之小分子拮抗劑,諸如他米巴羅汀(tamibarotene)(SY-1425);
• 靶向核糖體蛋白S6激酶B1之小分子抑制劑,諸如MSC2363318A;
• 靶向S100鈣結合蛋白A9之小分子抑制劑,諸如他喹莫德;
• 靶向選擇素E之小分子抑制劑,諸如普羅色蘭鈉(uproleselan sodium) (GMI-1271);
• 靶向SF3B1之小分子抑制劑,諸如H3B-8800;
• 靶向長壽蛋白-3之小分子抑制劑,諸如YC8-02;
• 靶向SMO之小分子抑制劑,諸如索尼得吉(sonidegib)(Odomzo
®,舊名LDE-225)、維莫德吉(vismodegib) (GDC-0449)、格拉斯代吉(glasdegib) (PF-04449913)、艾妥可那唑(itraconazole)、或帕替吉伯(patidegib)、塔拉吉伯(taladegib);
• 靶向體抑素受體之小分子拮抗劑,諸如OPS-201;
• 靶向神經鞘胺醇激酶2之小分子抑制劑,諸如奧帕尼布(opaganib) (Yeliva
®, ABC294640);
• 靶向STAT3之小分子抑制劑,諸如那帕布新(napabucasin) (BBI-608);
• 靶向端錨聚合酶之小分子抑制劑,諸如G007-LK、或斯坦帕瑞(2X-121 (e-7499));
• 靶向TFGBR1之小分子抑制劑,諸如高倫替布(galunisertib)、PF-06952229;
• 靶向胸苷酸合成酶之小分子抑制劑,諸如得曲賽(idetrexed) (ONX-0801);
• 靶向腫瘤蛋白p53之小分子抑制劑,諸如CMG-097;
• 靶向含纈酪胺酸蛋白之小分子抑制劑,諸如CB-5083;
• 靶向WT1之小分子抑制劑,諸如安比派目(ombipepimut-S) (DSP-7888);
• 靶向腺苷受體之小分子促效劑,諸如那末德松(namodenoson) (CF102);
• 靶向天冬醯胺酶之(多種)小分子促效劑,諸如克立他酶(crisantaspase) (Erwinase
®)、GRASPA (ERY-001, ERY-ASP)、聚乙二醇化卡拉斯酶(calaspargase pegol)、或培門冬酶(pegaspargase);
• 靶向CCAAT增強子結合蛋白α之小分子促效劑,諸如MTL-501;
• 靶向細胞色素P450家族之小分子促效劑,諸如米托坦(mitotane);
• 靶向DExD/H盒解螺旋酶58之小分子促效劑,諸如RGT-100;
• 靶向GNRHR之小分子促效劑,諸如亮丙瑞林乙酸鹽(leuprorelin acetate)、亮丙瑞林乙酸鹽持續釋放貯劑(ATRIGEL)、曲普瑞林雙羥萘酸鹽(triptorelin pamoate)、或戈舍瑞林乙酸鹽(goserelin acetate);
• 靶向GRB2之小分子促效劑,諸如普瑞博森(prexigebersen) (BP1001);
• 靶向NFE2L2之小分子促效劑,諸如奧馬索龍(omaveloxolone) (RTA-408);
• 靶向NOD2之小分子促效劑,諸如米法莫肽(mifamurtide)(脂質體);
• 靶向RAR相關孤兒受體γ之小分子促效劑,諸如辛特奧汞(cintirorgon) (LYC-55716);
• 靶向視黃酸受體(RAR)之小分子促效劑,諸如維甲酸(tretinoin);
• 靶向STING1之小分子促效劑,諸如ADU-S100 (MIW-815)、SB-11285、MK-1454、SR-8291、AdVCA0848、GSK-532、SYN-STING、MSA-1、SR-8291、環狀-GAMP (cGAMP)、或環狀-二-AMP;
• 靶向甲狀腺荷爾蒙受體β之小分子促效劑,諸如左旋甲狀腺素鈉;
• 靶向腫瘤壞死因子之小分子促效劑,諸如他索納明(tasonermin);
• 靶向含桿狀病毒IAP重複5之反義劑,諸如EZN-3042;
• 靶向GRB2之反義劑,諸如普瑞博森;
• 靶向熱休克蛋白27之反義劑,諸如阿帕托森(apatorsen);
• 靶向STAT3之反義劑,諸如丹伐特生(danvatirsen) (IONIS-STAT3-2.5Rx);
• 靶向C-C模體趨化因子受體之基因療法,諸如SB-728-T;
• 靶向介白素之基因療法,諸如EGENE-001、特它奇基(tavokinogene telseplasmid)、諾格介白素α (nogapendekin alfa) (ALT-803)、NKTR-255、NIZ-985 (hetIL-15)、SAR441000、或MDNA-55;
• 靶向密連蛋白18之抗體,諸如克勞迪單抗(claudiximab);
• 靶向群集素之抗體,諸如AB-16B5;
• 靶向補體組分之抗體,諸如拉夫珠單抗(ravulizumab) (ALXN-1210);
• 靶向C-X-C模體趨化因子配體之抗體,諸如BMS-986253 (HuMax-Inflam);
• 靶向δ樣典型Notch配體4 (DLL4)之抗體,諸如登西珠單抗(demcizumab)、納維希單抗(DLL4/VEGF);
• 靶向EPH受體A3之抗體,諸如非巴珠單抗(KB-004);
• 靶向上皮細胞黏附分子之抗體,諸如奧普珠單抗莫那毒素(oportuzumab monatox) (VB4-845);
• 靶向纖維母細胞生長因子之抗體,諸如GAL-F2、B-701(沃法單抗(vofatamab));
• 靶向肝細胞生長因子之抗體,諸如MP-0250;
• 靶向介白素之抗體,諸如卡那單抗(canakinumab) (ACZ885)、介維單抗(gevokizumab) (VPM087)、CJM-112、鼓賽庫單抗(guselkumab)、塔拉考單抗(talacotuzumab) (JNJ-56022473)、思圖昔單抗、或托珠單抗(tocilizumab);
• 靶向LRRC15之抗體,諸如ABBV-085、或庫薩珠單抗(cusatuzumab) (ARGX-110);
• 靶向間皮素之抗體,諸如BMS-986148、SEL-403、或抗MSLN-MMAE;
• 靶向肌肉生成抑制素之抗體,諸如蘭多單抗(landogrozumab);
• 靶向notch受體之抗體,諸如他瑞妥單抗(tarextumab);
• 靶向TGFB1 (TGFb1)之抗體,諸如SAR439459、ABBV-151、NIS793、SRK-181、XOMA089、或揭示於WO2019103203中之化合物;
• 靶向fms相關受體酪胺酸激酶之疫苗,諸如HLA-A2402/HLA-A0201限制表位肽疫苗;
• 靶向熱休克蛋白27之疫苗,諸如PSV-AML (PhosphoSynVax);
• 靶向PD-L1之疫苗,諸如IO-120 + IO-103(PD-L1/PD-L2疫苗)、或IO-103;
• 靶向腫瘤蛋白p53之疫苗,諸如MVA-p53;
• 靶向WT1之疫苗,諸如WT-1類似物肽疫苗(WT1-CTL);
• 靶向含桿狀病毒IAP重複5之細胞療法,諸如裝載腫瘤溶解物/MUC1/生存素PepTivator之樹突細胞疫苗;
• 靶向碳酸酐酶之細胞療法,諸如DC-Ad-GMCAIX;
• 靶向C-C模體趨化因子受體之細胞療法,諸如CCR5-SBC-728-HSPC;
• 靶向葉酸水解酶1之細胞療法,諸如CIK-CAR.PSMA、或CART-PSMA-TGFβRDN;
• 靶向GSTP1之細胞療法,諸如CPG3-CAR (GLYCAR);
• 靶向HLA-A之細胞療法,諸如FH-MCVA2TCR、或NeoTCR-P1;
• 靶向介白素之細胞療法,諸如CST-101;
• 靶向KRAS之細胞療法,諸如抗KRAS G12D mTCR PBL;
• 靶向MET之細胞療法,諸如抗cMet RNA CAR T;
• 靶向MUC16之細胞療法,諸如JCAR-020;
• 靶向PD-1之細胞療法,諸如PD-1基因剔除T細胞療法(食道癌/NSCLC);
• 靶向PRAME之細胞療法,諸如BPX-701;
• 靶向轉形蛋白E7之細胞療法,諸如KITE-439;
• 靶向WT1之細胞療法,諸如WT1-CTL、ASP-7517、或JTCR-016。
例示性組合療法淋巴瘤或白血病組合療法
一些化學療法劑適用於治療淋巴瘤或白血病。此等藥劑包括阿地介白素、阿伏西地、胺磷汀三水合物、胺基喜樹鹼、抗新普拉通(antineoplaston) A10、抗新普拉通AS2-1、抗胸腺細胞球蛋白、三氧化二砷、Bcl-2家族蛋白抑制劑ABT-263、β阿立辛(alethine)、BMS-345541、硼替佐米(VELCADE
®)、硼替佐米(VELCADE
®, PS-341)、苔蘚蟲素1、白消安(bulsulfan)、坎帕斯(campath)-1H、卡鉑、卡非佐米(Kyprolis
®)、卡莫司汀、卡泊芬淨(caspofungin)乙酸酯、CC-5103、氯芥苯丁酸、CHOP(環磷醯胺、阿黴素、長春新鹼、及潑尼松)、順鉑、克拉屈濱、氯法拉濱、薑黃素、CVP(環磷醯胺、長春新鹼、及潑尼松)、環磷醯胺、環孢素、阿糖胞苷、地尼白介素-毒素連接物、地塞米松、多西紫杉醇、海兔毒素10、阿黴素、阿黴素鹽酸鹽、DT-PACE(地塞米松、沙利度胺、順鉑、阿黴素、環磷醯胺、及依託泊苷)、恩紮妥林、阿法依伯汀、依託泊苷、依維莫司(RAD001)、FCM(氟達拉濱、環磷醯胺、及米托蒽醌)、FCR(氟達拉濱、環磷醯胺、及利妥昔單抗)、芬維A胺、非格司亭、夫拉平度、氟達拉濱、FR(氟達拉濱及利妥昔單抗)、膠達納黴素(17 AAG)、hyperCVAD(高分餾環磷醯胺、長春新鹼、阿黴素、地塞米松、胺甲喋呤、及阿糖胞苷)、ICE(異環磷醯胺、卡鉑、及依託泊苷)、異環磷醯胺、伊立替康鹽酸鹽、干擾素α-2b、伊沙匹隆、來那度胺(REVLIMID
®, CC-5013)、淋巴激素活化殺手細胞、MCP(米托蒽醌、氯芥苯丁酸、及潑尼松龍)、美法侖、美司鈉、胺甲喋呤、米托蒽醌鹽酸鹽、莫特沙芬釓、黴酚酸酯、奈拉濱、奧巴克拉(GX15-070)、奧利默森(oblimersen)、奧曲肽乙酸酯、Ω-3脂肪酸、Omr-IgG-am (WNIG, Omrix)、奧沙利鉑、太平洋紫杉醇、帕博西尼(PD0332991)、培非司亭、聚乙二醇化微脂體阿黴素鹽酸鹽、派瑞弗辛(perifosin)、潑尼松龍、潑尼松、重組flt3配體、重組人類血小板生成素、重組干擾素α、重組介白素11、重組介白素12、利妥昔單抗、R-CHOP(利妥昔單抗及CHOP)、R-CVP(利妥昔單抗及CVP)、R-FCM(利妥昔單抗及FCM)、R-ICE(利妥昔單抗及ICE)、及R MCP(利妥昔單抗及MCP)、R-羅可威汀(roscovitine)(塞利昔布(seliciclib)、CYC202)、沙格司亭、西地那非檸檬酸鹽、辛伐他汀、西羅莫司、苯乙烯基碸、他克莫司、坦螺旋黴素(tanespimycin)、替西羅莫司(CCl-779)、沙利度胺、治療性同種異體淋巴球、噻替派、替吡法尼(tipifarnib)、長春新鹼、長春新鹼硫酸鹽、長春瑞濱二酒石酸鹽、SAHA(辛二醯苯胺羥肟酸、或辛二醯基、苯胺、及羥肟酸)、維羅非尼(vemurafenib) (Zelboraf
®)、維奈托克(ABT-199)。
一種改良方法係放射免疫療法,其中單株抗體係與放射性同位素粒子諸如銦-111、釔-90、及碘-131組合。組合療法之實例包括但不限於碘-131托西莫單抗(BEXXAR
®)、釔-90替伊莫單抗(ibritumomab tiuxetan) (ZEVALIN
®)、及BEXXAR
®與CHOP。
上述療法可補充或組合幹細胞移植或治療。治療性程序包括周邊血液幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身照射、輸注幹細胞、在幹細胞支持下之骨髓剝蝕、活體外處理周邊血液幹細胞移植、臍帶血移植、免疫酶技術、低LET鈷-60 γ射線療法、博來黴素、習知手術、放射療法、及非骨髓清除式同種異體造血幹細胞移植。
非霍奇金氏淋巴瘤組合療法
非霍奇金氏淋巴瘤(NHL)(特別是B細胞來源者)之治療包括使用單株抗體、標準化學療法方法(例如CHOP(環磷醯胺、阿黴素、長春新鹼、及潑尼松)、CVP(環磷醯胺、長春新鹼、及潑尼松)、FCM(氟達拉濱、環磷醯胺、及米托蒽醌)、MCP(米托蒽醌、氯芥苯丁酸、潑尼松龍),全部可選地包括利妥昔單抗(R)及類似者)、放射免疫療法、及其組合,特別是整合抗體療法與化學療法。
用於治療NHL/B細胞癌症之未接合單株抗體之實例包括利妥昔單抗、阿侖單抗、人類或人源化抗CD20抗體、盧米西單抗(lumiliximab)、抗TNF相關細胞凋亡誘導配體(抗TRAIL)、貝伐珠單抗、加利昔單抗(galiximab)、依帕珠單抗、SGN-40、及抗CD74。
用於治療NHL/B細胞癌症之實驗抗體劑之實例包括奧法木單抗、ha20、PRO131921、阿侖單抗、加利昔單抗、SGN-40、CHIR-12.12、依帕珠單抗、盧米西單抗、阿泊珠單抗(apolizumab)、米拉珠單抗、及貝伐珠單抗。
用於NHL/B細胞癌症之化學療法的標準方案之實例包括CHOP、FCM、CVP、MCP、R-CHOP(利妥昔單抗、環磷醯胺、阿黴素、長春新鹼、及潑尼松)、R-FCM、R-CVP、及R MCP。
用於NHL/B細胞癌症之放射免疫療法之實例包括釔-90替伊莫單抗(ZEVALIN
®)及碘-131托西莫單抗(BEXXAR
®)。
外套細胞淋巴瘤組合療法
用於外套細胞淋巴瘤(MCL)之治療性治療包括組合化學療法,諸如CHOP、hyperCVAD、及FCM。這些方案亦可補充單株抗體利妥昔單抗以形成組合療法R-CHOP、hyperCVAD-R、及R-FCM。上述療法之任一者可與幹細胞移植或ICE組合以治療MCL。
治療MCL之替代方法係免疫療法。一種免疫療法使用單株抗體像是利妥昔單抗。另一種使用癌症疫苗,諸如GTOP-99,其係基於個別病患之腫瘤的基因組成。
治療MCL之改良方法係放射免疫療法,其中單株抗體係與放射性同位素粒子組合,諸如碘-131妥司莫單抗(BEXXAR
®)及釔-90替伊莫單抗(ZEVALIN
®)。在另一實例中,BEXXAR
®係與CHOP用於系列性治療(sequential treatment)。
其他治療MCL之方法包括結合高劑量化學療法之自體幹細胞移植、投予蛋白酶體抑制劑諸如硼替佐米(VELCADE
®或PS-341)、或投予抗血管生成劑諸如沙利度胺,特別是與利妥昔單抗組合。
另一種治療方法係投予導致Bcl-2蛋白降解及增加癌細胞對化學療法敏感度之藥物,諸如奧利默森,與其他化學治療劑之組合。
進一步治療方法包括投予mTOR抑制劑,其可導致抑制細胞生長及甚至細胞死亡。非限制性實例係西羅莫司、坦羅莫司(TORISEL
®, CCI-779)、CC-115、CC-223、SF-1126、PQR-309(必米昔布)、沃塔昔布、GSK-2126458、及坦羅莫司與RITUXAN
®、VELCADE
®、或其他化學治療劑之組合。
其他用於MCL之新近療法已經揭示。此類實例包括夫拉平度、帕博西尼(PD0332991)、R-羅可威汀(塞利昔布(selicicilib)、CYC202)、苯乙烯基碸、奧巴克拉(GX15-070)、TRAIL、抗TRAIL死亡受體DR4及DR5抗體、坦羅莫司(TORISEL
®, CCl-779)、依維莫司(RAD001)、BMS-345541、薑黃素、SAHA、沙利度胺、來那度胺(REVLIMID
®, CC-5013)、及膠達納黴素(17 AAG)。
Waldenstrom氏巨球蛋白血症組合療法
用於治療Waldenstrom氏巨球蛋白血症(WM)之治療劑包括阿地介白素、阿侖單抗、阿伏西地、胺磷汀三水合物、胺基喜樹鹼、抗新普拉通A10、抗新普拉通AS2-1、抗胸腺細胞球蛋白、三氧化二砷、自體人類腫瘤衍生性HSPPC-96、Bcl-2家族蛋白抑制劑ABT-263、β阿立辛、硼替佐米(VELCADE
®)、苔蘚蟲素1、白消安、坎帕斯-1H、卡鉑、卡莫司汀、卡泊芬淨乙酸鹽、CC-5103、順鉑、氯法拉濱、環磷醯胺、環孢素、阿糖胞苷、地尼白介素-毒素連接物、地塞米松、多西紫杉醇、海兔毒素10、阿黴素鹽酸鹽、DT-PACE、恩紮妥林、阿法依伯汀、依帕珠單抗(hLL2-抗CD22人源化抗體)、依託泊苷、依維莫司、芬維A胺、非格司亭、氟達拉濱、依魯替尼、依弗醯胺、銦-111單株抗體MN-14、碘-131托西莫單抗、伊立替康鹽酸鹽、伊莎匹龍、淋巴激素活化殺手細胞、黴法蘭、美司鈉、甲胺喋呤、米托蒽醌鹽酸鹽、單株抗體CD19(諸如替薩金魯-T、CART-19、CTL-019)、單株抗體CD20、莫特沙芬釓、黴酚酸酯、奈拉濱、奧利默森、奧曲肽乙酸鹽、Ω-3脂肪酸、奧沙利鉑、太平洋紫杉醇、培非司亭、聚乙二醇化脂質體阿黴素鹽酸鹽、噴司他丁、哌立福新、潑尼松、重組flt3配體、重組人類血小板生成素、重組干擾素α、重組介白素11、重組介白素12、利妥昔單抗、沙格司亭、西地那非檸檬酸鹽(VIAGRA
®)、辛伐他汀、西羅莫司、他克莫司、坦螺旋黴素、沙利度胺、治療性同種異體淋巴細胞、噻替派、替吡法尼、托西莫單抗、尤洛庫單抗(ulocuplumab)、維托珠單抗、長春新鹼硫酸鹽、長春瑞濱二酒石酸鹽、伏立諾他、WT1 126-134肽疫苗、WT-1類似物肽疫苗、釔-90替伊莫單抗、釔-90人源化依帕珠單抗、及其任何組合。
用於治療WM之治療性程序之實例包括周邊血液幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身照射、輸注幹細胞、在幹細胞支持下之骨髓剝蝕、活體外處理周邊血液幹細胞移植、臍帶血移植、免疫酶技術、低LET鈷-60 γ射線療法、博來黴素、習知手術、放射療法、及非骨髓清除式同種異體造血幹細胞移植。
瀰漫性大
B細胞淋巴瘤
(DLBCL)組合療法
用於治療瀰漫性大B細胞淋巴瘤(DLBCL)之治療劑包括環磷醯胺、阿黴素、長春新鹼、潑尼松、抗CD20單株抗體、依託泊苷、博來黴素、所列之用於WM之許多藥劑、及其任何組合,諸如ICE及RICE。在一些實施例中,用於治療DLBCL之治療劑包括利妥昔單抗(Rituxan
®)、環磷醯胺、多柔比星鹽酸鹽(羥基道諾黴素)、長春新鹼硫酸鹽(Oncovin
®)、潑尼松、苯達莫司汀、依弗醯胺、卡鉑、依託泊苷、依魯替尼、保納珠單抗維多汀piiq、苯達莫司汀、考班昔布(copanlisib)、來那度胺(Revlimid
®)、地塞米松、阿糖胞苷、順鉑、Yescarta
®、Kymriah
®、Polivy
®(保納珠單抗維多汀)、BR(苯達莫司汀(Treanda
®)、吉西他濱、奧西鉑(oxiplatin)、奧沙利鉑、他法替他單抗、保納珠單抗、環磷醯胺、或其組合。在一些實施例中,用於治療DLBCL之治療劑包括R-CHOP(利妥昔單抗+環磷醯胺+多柔比星鹽酸鹽(羥基道諾黴素)+長春新鹼硫酸鹽(Oncovin
®)+潑尼松)、利妥昔單抗+苯達莫司汀、R-ICE(利妥昔單抗+依弗醯胺+卡鉑+依託泊苷)、利妥昔單抗+來那洛胺(lenalomide)、R-DHAP(利妥昔單抗+地塞米松+高劑量阿糖胞苷(Ara C)+順鉑)、Polivy
®(保納珠單抗維多汀)+BR(苯達莫司汀(Treanda
®)及利妥昔單抗(Rituxan
®)、R-GemOx(吉西他濱+奧沙利鉑+利妥昔單抗)、Tafa-Len(他法替他單抗+來那度胺)、他法替他單抗+Revlimid
®、保納珠單抗+苯達莫司汀、吉西他濱+奧沙利鉑、R-EPOCH(利妥昔單抗+依託泊苷磷酸鹽+潑尼松+長春新鹼硫酸鹽(Oncovin
®)+環磷醯胺+多柔比星鹽酸鹽(羥基道諾黴素))、或CHOP(環磷醯胺+多柔比星鹽酸鹽(羥基道諾黴素)+長春新鹼硫酸鹽(Oncovin
®)+潑尼松)。在一些實施例中,用於治療DLBCL之治療劑包括他法替他單抗、格菲妥單抗(glofitamab)、依可利單抗(epcoritamab)、Lonca-T(隆卡妥昔單抗特西林(loncastuximab tesirine))、Debio-1562、保納珠單抗polatuzumab、Yescarta、JCAR017、ADCT-402、本妥昔單抗維多汀、MT-3724、奧卓尼單抗(odronextamab)、Auto-03、Allo-501A、或TAK-007。
慢性淋巴球性白血病組合療法
用於治療慢性淋巴球性白血病(CLL)之治療劑包括氯芥苯丁酸、環磷醯胺、氟達拉濱、噴司他丁、克拉屈濱、阿黴素、長春新鹼、潑尼松、潑尼松龍、阿侖單抗、許多針對WM所列之藥劑、及化學療法及化學免疫療法之組合,包括下列常見組合方案:CVP、R-CVP、ICE、R-ICE、FCR、及FR。
高風險骨髓發育不良症候群
(HR MDS)組合療法
用於治療HR MDS之治療劑包括阿扎胞苷(Vidaza
®)、地西他濱(Dacogen
®)、來那度胺(Revlimid
®)、阿糖胞苷、伊達比星、道諾黴素、及其組合。在一些實施例中,組合包括阿糖胞苷+道諾黴素及阿糖胞苷+伊達比星。在一些實施例中,用於治療HR MDS之治療劑包括佩沃塔特(pevonedistat)、維奈托克、薩巴托利單抗(sabatolimab)、瓜達西他濱(guadecitabine)、瑞戈替布、艾伏尼布、艾那尼布、西林俄、BGB324、DSP-7888、或SNS-301。
低風險骨髓發育不良症候群
(LR MDS)組合療法
用於治療LR MDS之治療劑包括來那度胺、氮雜胞苷、及其組合。在一些實施例中,用於治療LR MDS之治療劑包括洛達司他(roxadustat)、盧帕西普(luspatercept)、依美德史塔(imetelstat)、LB-100、或瑞戈替布。
急性骨髓樣白血病
(AML)組合療法
用於治療AML之治療劑包括阿糖胞苷、伊達比星、道諾黴素、米哚妥林(Rydapt
®)、維奈托克、阿扎胞苷、艾伐尼布(ivasidenib)、吉列替尼、艾那尼布、低劑量阿糖胞苷(LoDAC)、米托蒽醌、氟達拉濱、顆粒球群落刺激因子、伊達比星、吉列替尼(Xospata
®)、艾那尼布(Idhifa
®)、艾伏尼布(Tibsovo
®)、地西他濱(Dacogen
®)、米托蒽醌、依託泊苷、吉妥珠單抗奧唑米星(Mylotarg
®)、格拉斯代吉(Daurismo
®)、及其組合。在一些實施例中,用於治療AML之治療劑包括FLAG- Ida(氟達拉濱、阿糖胞苷(Ara-C)、顆粒球-群落刺激因子(G-CSF)、及伊達比星)、阿糖胞苷+伊達比星、阿糖胞苷+道諾黴素+米哚妥林、維奈托克+阿扎胞苷、阿糖胞苷+道諾黴素、或MEC(米托蒽醌、依託泊苷、及阿糖胞苷)。在一些實施例中,用於治療AML之治療劑包括佩沃塔特、維奈托克、薩巴托利單抗、普恩塔泊(eprenetapopt)、或利佐帕單抗。
多發性骨髓瘤
(MM)組合療法
用於治療MM之治療劑包括來那度胺、硼替佐米、地塞米松、達拉單抗(Darzalex
®)、泊瑪度胺、環磷醯胺、卡非佐米(Kyprolis
®)、埃洛妥珠單抗(Empliciti)、及其組合。在一些實施例中,用於治療MM包括RVS(來那度胺+硼替佐米+地塞米松)、RevDex(來那度胺加上地塞米松)、CYBORD(環磷醯胺+硼替佐米+地塞米松)、Vel/Dex(硼替佐米加上地塞米松)、或PomDex(泊瑪度胺+低劑量地塞米松)。在一些實施例中,用於治療MM之治療劑包括JCARH125、TAK-573、貝蘭單抗-m、ide-cel (CAR-T)。
乳癌組合療法
用於治療乳癌之治療劑包括白蛋白結合型太平洋紫杉醇、阿那曲唑、阿特珠單抗、卡培他濱、卡鉑、順鉑、環磷醯胺、多西紫杉醇、阿黴素、泛艾黴素、依維莫司、依西美坦、氟尿嘧啶、氟維司群、吉西他濱、伊沙匹隆、拉帕替尼、來曲唑、胺甲喋呤、米托蒽醌、太平洋紫杉醇、聚乙二醇化微脂體阿黴素、帕妥珠單抗、泰莫西芬、托瑞米芬、曲妥珠單抗、長春瑞濱、及其任何組合。在一些實施例中,用於治療乳癌(例如HR+/-/HER2 +/-)之治療劑包括曲妥珠單抗(Herceptin
®)、帕妥珠單抗(Perjeta
®)、多西紫杉醇、卡鉑、帕博西尼(Ibrance
®)、來曲唑、曲妥珠單抗恩他新(trastuzumab emtansine) (Kadcyla
®)、氟維司群(Faslodex
®)、奧拉帕尼(Lynparza
®)、艾日布林、圖卡替尼、卡培他濱、拉帕替尼、依維莫司(Afinitor
®)、依西美坦、艾日布林甲磺酸酯(Halaven
®)、及其組合。在一些實施例中,用於治療乳癌之治療劑包括曲妥珠單抗+帕妥珠單抗+多西紫杉醇、曲妥珠單抗+帕妥珠單抗+多西紫杉醇+卡鉑、帕博西尼+來曲唑、圖卡替尼+卡培他濱、拉帕替尼+卡培他濱、帕博西尼+氟維司群、或依維莫司+依西美坦。在一些實施例中,用於治療乳癌之治療劑包括曲妥珠單抗德魯替康(Enhertu
®)、達妥伯單抗德魯替康(DS-1062)、因福土單抗維多汀(Padcev
®)、巴沙福泰(balixafortide)、艾拉司群、或其組合。在一些實施例中,用於治療乳癌之治療劑包括巴沙福泰+艾日布林。
三陰性乳癌
(TNBC)組合療法
用於治療TNBC之治療劑包括阿特珠單抗、環磷醯胺、多西紫杉醇、阿黴素、泛艾黴素、氟尿嘧啶、太平洋紫杉醇、及其組合。在一些實施例中,用於治療TNBC之治療劑包括奧拉帕尼(Lynparza
®)、阿特珠單抗(Tecentriq
®)、太平洋紫杉醇(Abraxane
®)、艾日布林、貝伐珠單抗(Avastin
®)、卡鉑、吉西他濱、艾日布林甲磺酸酯(Halaven
®)、薩西土珠單抗戈維特坎(Trodelvy
®)、派姆單抗(Keytruda
®)、順鉑、阿黴素、泛艾黴素、或其組合。在一些實施例中,治療TNBC之治療劑包括阿特珠單抗+太平洋紫杉醇、貝伐珠單抗+太平洋紫杉醇、卡鉑+太平洋紫杉醇、卡鉑+吉西他濱、或太平洋紫杉醇+吉西他濱。在一些實施例中,用於治療TNBC之治療劑包括艾利亞斯酶(eryaspase)、卡瓦替布、艾培昔布、盧卡帕瑞+尼沃魯單抗、阿索盧單抗(atezolumab) +太平洋紫杉醇+吉西他濱+卡培他濱+卡鉑、伊帕他色替+太平洋紫杉醇、拉迪朗妥珠單抗維多汀+派伯利單抗(pembrolimab)、德瓦魯單抗+ DS-8201a、曲拉西利+吉西他濱+卡鉑。在一些實施例中,用於治療TNBC之治療劑包括曲妥珠單抗德魯替康(Enhertu
®)、達妥伯單抗德魯替康(DS-1062)、因福土單抗維多汀(Padcev
®)、巴沙福泰、阿達洛德西莫林(adagloxad simolenin)、萊尼哌嗎-s (NeuVax
®)、尼沃魯單抗(Opdivo
®)、盧卡帕瑞、特瑞普利單抗(Tuoyi
®)、卡瑞利珠單抗、卡瓦替布、德瓦魯單抗(Imfinzi
®)、及其組合。在一些實施例中,用於治療TNBC之治療劑包括尼沃魯單抗+盧卡帕瑞、貝伐珠單抗(Avastin
®) +化學療法、特瑞普利單抗+太平洋紫杉醇、特瑞普利單抗+白蛋白結合型太平洋紫杉醇、卡瑞利珠單抗+化學療法、派姆單抗+化學療法、巴沙福泰+艾日布林、德瓦魯單抗+曲妥珠單抗德魯替康、德瓦魯單抗+太平洋紫杉醇、或卡瓦替布+太平洋紫杉醇。
膀胱癌組合療法
用於治療膀胱癌之治療劑包括達妥伯單抗德魯替康(datopotamab deruxtecan) (DS-1062)、曲妥珠單抗德魯替康(trastuzumab deruxtecan) (Enhertu
®)、厄達替尼、依格利昔(eganelisib)、樂伐替尼、貝加德盧金(bempegaldesleukin) (NKTR-214)、或其組合。在一些實施例中,用於治療膀胱癌之治療劑包括依格利昔(eganelisib) +尼沃魯單抗、派姆單抗(Keytruda
®) +因福土單抗維多汀(Padcev
®)、尼沃魯單抗+伊匹單抗、度伐魯單抗(duravalumab) +曲美木單抗、樂伐替尼+派姆單抗、因福土單抗維多汀(Padcev
®) +派姆單抗、及貝加德盧金+尼沃魯單抗。
結直腸癌
(CRC)組合療法
用於治療CRC之治療劑,包括貝伐珠單抗、卡培他濱、西妥昔單抗、氟尿嘧啶、伊立替康、菊白葉酸、奧沙利鉑、帕尼單抗、ziv-阿柏西普、及其任何組合。在一些實施例中,用於治療CRC之治療劑包括貝伐珠單抗(Avastin
®)、亞葉酸、5-FU、奧沙利鉑(FOLFOX)、派姆單抗(Keytruda
®)、FOLFIRI、瑞戈非尼(Stivarga
®)、阿柏西普(Zaltrap
®)、西妥昔單抗(Erbitux
®)、朗斯弗(Lonsurf) (Orcantas
®)、XELOX、FOLFOXIRI、或其組合。在一些實施例中,用於治療CRC之治療劑包括貝伐珠單抗+菊白葉酸+ 5-FU +奧沙利鉑(FOLFOX)、貝伐珠單抗+ FOLFIRI、貝伐珠單抗+ FOLFOX、阿柏西普+ FOLFIRI、西妥昔單抗+ FOLFIRI、貝伐珠單抗+ XELOX、及貝伐珠單抗+ FOLFOXIRI。在一些實施例中,用於治療CRC之治療劑包括畢尼替尼+恩考非尼+西妥昔單抗、曲美替尼+達拉菲尼+帕尼單抗、曲妥珠單抗+帕妥珠單抗、那帕布新+ FOLFIRI +貝伐珠單抗、尼沃魯單抗+伊匹單抗。
食道癌及食道胃接合處癌組合療法
用於治療食道癌及食道胃接合處癌之治療劑包括卡培他濱、卡鉑、順鉑、多西紫杉醇、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、菊白葉酸、奧沙利鉑、太平洋紫杉醇、雷莫蘆單抗、曲妥珠單抗、及其任何組合。在一些實施例中,用於治療胃食道接合處癌(GEJ)之治療劑包括賀癌平(herceptin)、順鉑、5-FU、拉米庫單抗(ramicurimab)、或太平洋紫杉醇。在一些實施例中,用於治療GEJ癌症之治療劑包括ALX-148、AO-176、或IBI-188。
胃癌組合療法
用於治療胃癌之治療劑包括卡培他濱、卡鉑、順鉑、多西紫杉醇、泛艾黴素、氟嘧啶、氟尿嘧啶、伊立替康、亞葉酸、絲裂黴素、奧沙利鉑、太平洋紫杉醇、雷莫蘆單抗、曲妥珠單抗、及其任何組合。
頭頸癌組合療法
用於治療頭頸癌之治療劑包括阿法替尼、博來黴素、卡培他濱、卡鉑、西妥昔單抗、順鉑、多西紫杉醇、氟尿嘧啶、吉西他濱、羥基尿素、甲胺喋呤、尼沃魯單抗、太平洋紫杉醇、派姆單抗、長春瑞濱、及其任何組合。
用於治療頭頸鱗狀細胞癌(HNSCC)之治療劑包括派姆單抗、卡鉑、5-FU、多西紫杉醇、西妥昔單抗(Erbitux
®)、順鉑、尼沃魯單抗(Opdivo
®)、及其組合。在一些實施例中,用於治療HNSCC之治療劑包括派姆單抗+卡鉑+ 5-FU、西妥昔單抗+順鉑+ 5-FU、西妥昔單抗+卡鉑+ 5-FU、順鉑+ 5-FU、及卡鉑+ 5-FU。在一些實施例中,用於治療HNSCC之治療劑包括德瓦魯單抗、德瓦魯單抗+曲美木單抗、尼沃魯單抗+伊匹單抗、羅伐盧賽爾(rovaluecel)、派姆單抗、派姆單抗+依波斯他、GSK3359609 +派姆單抗、樂伐替尼+派姆單抗、瑞弗利單抗、瑞弗利單抗+恩諾必單抗(enobituzumab)、ADU-S100 +派姆單抗、依波斯他+尼沃魯單抗+伊匹單抗/立魯單抗。
非小細胞肺癌組合療法
用於治療非小細胞肺癌(NSCLC)之治療劑包括阿法替尼、白蛋白結合型太平洋紫杉醇、艾樂替尼、阿特珠單抗、貝伐珠單抗、貝伐珠單抗、卡博替尼、卡鉑、順鉑、克唑替尼(crizotinib)、達拉菲尼、多西紫杉醇、埃羅替尼、依託泊苷、吉西他濱、納武單抗、太平洋紫杉醇、派姆單抗、培美曲塞、雷莫蘆單抗、曲美替尼、曲妥珠單抗、凡德他尼、維羅非尼、長春鹼、長春瑞濱、及其任何組合。在一些實施例中,用於治療NSCLC之治療劑包括艾樂替尼(Alecensa
®)、達拉菲尼(Tafinlar
®)、曲美替尼(Mekinist
®)、奧希替尼(Tagrisso
®)、恩曲替尼(Tarceva
®)、克唑替尼(Xalkori
®)、派姆單抗(Keytruda
®)、卡鉑、培美曲塞(Alimta
®)、白蛋白結合型太平洋紫杉醇(Abraxane
®)、雷莫蘆單抗(Cyramza
®)、多西紫杉醇、貝伐珠單抗(Avastin
®)、布格替尼、吉西他濱、順鉑、阿法替尼(Gilotrif
®)、尼沃魯單抗(Opdivo
®)、吉非替尼(Iressa
®)、及其組合。在一些實施例中,用於治療NSCLC之治療劑包括達拉菲尼+曲美替尼、派姆單抗+卡鉑+培美曲塞、派姆單抗+卡鉑+白蛋白結合型太平洋紫杉醇、雷莫蘆單抗+多西紫杉醇、貝伐珠單抗+卡鉑+培美曲塞、派姆單抗+培美曲塞+卡鉑、順鉑+培美曲塞、貝伐珠單抗+卡鉑+白蛋白結合型太平洋紫杉醇、順鉑+吉西他濱、尼沃魯單抗+多西紫杉醇、卡鉑+培美曲塞、卡鉑+白蛋白結合型太平洋紫杉醇、或培美曲塞+順鉑+卡鉑。在一些實施例中,用於NSCLC之治療劑包括達妥伯單抗德魯替康(DS-1062)、曲妥珠單抗德魯替康(Enhertu
®)、因福土單抗維多汀(Padcev
®)、德瓦魯單抗、卡那單抗、賽米單抗、諾格介白素α、艾維路單抗、替瑞利尤單抗、多伐尼單抗、維博利單抗、奧西伯利單抗、或其組合。在一些實施例中,用於治療NSCLC之治療劑包括達妥伯單抗德魯替康+派姆單抗、達妥伯單抗德魯替康+德瓦魯單抗、德瓦魯單抗+曲美木單抗、派姆單抗+樂伐替尼+培美曲塞、派姆單抗+奧拉帕尼、諾格介白素α (N-803) +派姆單抗、替瑞利尤單抗+阿特珠單抗、維博利單抗+派姆單抗、或奧西伯利單抗+替雷利珠單抗。
小細胞肺癌組合療法
用於治療小細胞肺癌(SCLC)之治療劑包括苯達莫司汀(bendamustime)、卡鉑、順鉑、環磷醯胺、多西紫杉醇、多柔比星、依託泊苷、吉西他濱、伊匹單抗(ipillimumab)、伊立替康、尼沃魯單抗、太平洋紫杉醇、替莫唑胺、托泊替康、長春新鹼、長春瑞濱、及其任何組合。在一些實施例中,用於治療SCLC之治療劑包括阿特珠單抗、卡鉑、順鉑、依託泊苷、太平洋紫杉醇、拓撲替康、尼沃魯單抗、德瓦魯單抗、曲拉西利、或其組合。在一些實施例中,用於治療SCLC之治療劑包括阿特珠單抗+卡鉑+依託泊苷、阿特珠單抗+卡鉑、阿特珠單抗+依託泊苷、或卡鉑+太平洋紫杉醇。
卵巢癌組合療法
用於治療卵巢癌之治療劑包括5-氟尿嘧啶、白蛋白結合型太平洋紫杉醇、六甲蜜胺、阿那曲唑、貝伐珠單抗、卡培他濱、卡鉑、順鉑、環磷醯胺、多西紫杉醇、阿黴素、依託泊苷、依西美坦、吉西他濱、異環磷醯胺、伊立替康、來曲唑、亮丙瑞林乙酸酯、微脂體阿黴素、甲地孕酮乙酸酯、美法侖、奧拉帕尼、奧沙利鉑、太平洋紫杉醇、帕唑帕尼、培美曲塞、泰莫西芬、拓撲替康、長春瑞濱、及其任何組合。
胰臟癌組合療法
用於治療胰臟癌之治療劑包括5-FU、菊白葉酸、奧沙利鉑、伊立替康、吉西他濱、白蛋白結合型太平洋紫杉醇(Abraxane
®)、FOLFIRINOX、及其組合。在一些實施例中,用於治療胰臟癌之治療劑包括5-FU +菊白葉酸+奧沙利鉑+伊立替康、5-FU +奈米脂質體伊立替康、菊白葉酸+奈米脂質體伊立替康、及吉西他濱+白蛋白結合型太平洋紫杉醇。
前列腺癌組合療法
用於治療前列腺癌之治療劑包括恩雜魯胺(Xtandi
®)、亮丙瑞林、曲氟尿苷、替吡嘧啶(朗斯弗)、卡巴他賽、潑尼松、阿比特龍(Zytiga
®)、多西紫杉醇、米托蒽醌、比卡魯胺、LHRH、氟他胺、ADT、薩必沙布林(Veru-111)、及其組合。在一些實施例中,用於治療前列腺癌之治療劑包括恩雜魯胺+亮丙瑞林、曲氟尿苷+替吡嘧啶(隆瑟夫)、卡巴他賽+潑尼松、阿比特龍+潑尼松、多西紫杉醇+潑尼松、米托蒽醌+潑尼松、比卡魯胺+ LHRH、氟他胺+ LHRH、亮丙瑞林+氟他胺、及阿比特龍+潑尼松+ ADT。
額外例示性組合療法
在一些實施例中,本文所提供之化合物係與選自下列之一或多種治療劑一起投予:PI3K抑制劑、Trop-2結合劑、CD47拮抗劑、SIRPα拮抗劑、FLT3R促效劑、PD-1拮抗劑、PD-L1拮抗劑、MCL1抑制劑、CCR8結合劑、HPK1拮抗劑、DGKa抑制劑、CISH抑制劑、PARP-7抑制劑、Cbl-b抑制劑、KRAS抑制劑(例如,KRAS G12C、或G12D抑制劑)、KRAS降解劑、β-連環蛋白降解劑、helios降解劑、CD73抑制劑、腺苷受體拮抗劑、TIGIT拮抗劑、TREM1結合劑、TREM2結合劑、CD137促效劑、GITR結合劑、OX40結合劑、及CAR-T細胞療法。
在一些實施例中,本文所提供之化合物係與選自下列之一或多種治療劑一起投予:PI3Kd抑制劑(例如,依地利司(idealisib))、抗Trop-2抗體藥物接合物(例如,薩西土珠單抗戈維特坎、達妥伯單抗德魯替康(DS-1062))、抗CD47抗體或CD47阻斷劑(例如,馬格羅單抗、DSP-107、AO-176、ALX-148、勒塔普利單抗(IBI-188)、利佐帕單抗、TTI-621、TTI-622)、抗SIRPα抗體(例如,GS-0189)、FLT3L-Fc融合蛋白(例如,GS-3583)、抗PD-1抗體(派姆單抗、尼沃魯單抗、賽帕利單抗)、小分子PD-L1抑制劑(例如,GS-4224)、抗PD-L1抗體(例如,阿特珠單抗、艾維路單抗)、小分子MCL1抑制劑(例如,GS-9716)、小分子HPK1抑制劑(例如,GS-6451)、HPK1降解劑(PROTAC;例如,ARV-766)、小分子DGKa抑制劑、小分子CD73抑制劑(例如,奎立克魯司他(AB680))、抗CD73抗體(例如奧勒魯單抗)、雙重A
2a/A
2b腺苷受體拮抗劑(例如,艾魯美冷(etrumadenant) (AB928))、抗TIGIT抗體(例如,替瑞利尤單抗、維博利單抗、多伐尼單抗、AB308)、抗TREM1抗體(例如,PY159)、抗TREM2抗體(例如,PY314)、CD137促效劑(例如,AGEN-2373)、GITR/OX40結合劑(例如,AGEN-1223)、及CAR-T細胞療法(例如,西卡思羅、布萊奧妥(brexucabtagene autoleucel)、替薩金魯)。
在一些實施例中,本文所提供之化合物係與選自下列之一或多種治療劑一起投予:依地利司、薩西土珠單抗戈維特坎、馬格羅單抗、GS-0189、GS-3583、賽帕利單抗、GS-4224、GS-9716、GS-6451、奎立克魯司他(AB680)、艾魯美冷(AB928)、多伐尼單抗、AB308、PY159、PY314、AGEN-1223、AGEN-2373、西卡思羅、及布萊奧妥。
VI. 實例 縮寫
在描述實驗細節中使用某些縮寫及頭字語。雖然所屬技術領域中具有通常知識者會理解此等中之大多數者,但表1含有許多此等縮寫及頭字語之清單。
表1 :縮寫及頭字語之清單
表2 :化合物
通用程序1 : 製備二- 三級丁基((5-(8-(3,3- 二氟-4,4- 二甲基吡咯啶-1- 基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基) 磷酸酯:
縮寫 | 定義 |
Ac | 乙酸鹽 |
Ar | 氬 |
ACN | 乙腈 |
cat | 催化劑 |
DCM | 二氯甲烷 |
DIPEA | N,N-二異丙基乙基胺 |
DMSO | 二甲基亞碸 |
DMF | 二甲基甲醯胺 |
ES/MS | 電子噴灑質譜法 |
Et | 乙基 |
EtOAc | 乙酸乙酯 |
HPLC | 高效液相層析法 |
LC | 液相層析法 |
Me | 甲基 |
MeCN | 乙腈 |
m/z | 質荷比 |
NMP | N-甲基-2-吡咯啶酮 |
NMR | 核磁共振 |
Ph | 苯基 |
Pd(dppf)Cl 2或PdCl 2(dppf) | [1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) |
Pr | 丙基 |
RP | 逆相 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TBHP | 三級丁基過氧化氫 |
δ | 參考殘留非氘化溶劑峰的百萬分點 |
結構 | 實例編號 | IUPAC名稱 |
實例1 | (5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒 -6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 | |
實例2 | (2,4-二側氧基-5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒 -6-基)-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 | |
實例3 | (5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒 -6-基)-2,4-二側氧基嘧啶-1,3(2H,4H)-二基)雙(亞甲基)雙(二氫磷酸酯) | |
實例4 | (5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒 -6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 | |
實例5 | (5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒 -6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 | |
實例6 | (2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 | |
實例7 | (2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-1,3(2H,4H)-二基)雙(亞甲基)雙(二氫磷酸酯) | |
實例8 | (S)-5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-2,4(1H,3H)-二酮 | |
實例9 | (S)-(5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 | |
實例10 | (S)-(5-(8-(3,3-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)吡咯啶-1-基)-3-氟咪唑并[1,2-b]嗒 -6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 | |
實例11 | (S)-(5-(8-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)咪唑并[1,2-b]嗒 -6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯 |
向5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮(500 mg,1.38 mmol,1當量)及三乙胺(0.67 mL,4.83 mmol,3.5當量)於DMF (16 mL)中之溶液中添加(氯甲基)磷酸二-三級丁酯(1.07 g,4.14 mmol,3當量)。將反應混合物加熱至60℃並攪拌16小時。添加另一等分試樣的(氯甲基)磷酸二-三級丁酯(1.07 g,4.14 mmol,3當量)及三乙胺(0.67 mL,4.83 mmol,3.5當量)並將反應再攪拌16小時。隨後將反應混合物用EtOAc/水稀釋,用EtOAc萃取兩次。將合併之有機層以MgSO4乾燥,過濾並在真空中濃縮。將粗製產物藉由矽膠層析法(100% EtOAc)純化,以提供二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯。
實例1 製備(5-(8-(3,3- 二氟-4,4- 二甲基吡咯啶-1- 基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基二氫磷酸酯
向二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯(671 mg,1.15 mmol,1當量)於DCM (15 mL)中之溶液中添加TFA (5 mL)。將反應混合物在室溫下攪拌15分鐘,之後在真空中濃縮並藉由HPLC(10至80% MeCN/水(含TFA))純化。LC-MS m/z: 473.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.25 (s, 1H), 8.08 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 6.54 (s, 1H), 5.53 (d, J = 10.7 Hz, 2H), 4.41 (s, 2H), 3.86 (s, 2H), 1.21 (s, 6H)。19F NMR (376 MHz, DMSO-d6) δ -115.33 (m, 2F)。31P NMR (162 MHz, DMSO-d6) δ -2.24 (t, J = 10.6 Hz, 1P)。
下列化合物係以類似於(5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯之方式,使用以下所列之修改製備:
實例2
二-三級丁基((2,4-二側氧基-5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯係使用5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽代替5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮製備
5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1-H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮係使用二-三級丁基((2,4-二側氧基-5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯代替二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 578.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.33 (s, 1H), 8.28 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.77 – 7.66 (m, 3H), 7.49 (s, 1H), 7.13 (dd, J = 8.6, 1.2 Hz, 1H), 5.56 (d, J = 10.8 Hz, 2H), 5.41 (q, J = 9.1 Hz, 2H), 3.09 – 3.00 (m, 1H), 2.81 (dt, J = 9.6, 5.2 Hz, 1H), 2.19 (dt, J = 9.4, 5.1 Hz, 1H), 1.89 (dt, J = 9.4, 5.3 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -70.08 (t, J = 9.1 Hz, 3F)。31P NMR (162 MHz, DMSO-d6) δ -2.22 (t, J = 11.0 Hz, 1P)。
實例3
四-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)係使用5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮代替5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮製備。
(5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基嘧啶-1,3(2H,4H)-二基)雙(亞甲基)雙(二氫磷酸酯)係使用四-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)代替二-三級丁基((5-(8-(3,3-二氟-4,4-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 706.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 7.1 Hz, 1H), 7.43 (s, 1H), 7.13 (dd, J = 8.4, 1.4 Hz, 1H), 5.69 (d, J = 6.5 Hz, 2H), 5.64 (d, J = 10.8 Hz, 2H), 5.41 (q, J = 9.2 Hz, 2H), 3.02 (ddd, J = 8.9, 6.3, 4.3 Hz, 1H), 2.83 (ddd, J = 8.8, 5.9, 4.3 Hz, 1H), 2.21 – 2.09 (m, 1H), 1.91 (dt, J = 8.7, 5.5 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -70.08 (t, J = 9.1 Hz, 3F), -155.02 (d, J = 7.2 Hz, 1F)。31P NMR (162 MHz, DMSO-d6) δ -2.18 (t, J = 11.0 Hz, 1P), -3.44 (t, J = 6.5 Hz, 1P)。
通用程序2 :
製備二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯
向5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽(100 mg,0.192 mmol,1當量)於DMAc (1 mL)中之溶液中添加KHCO
3(48 mg,0.479 mmol,2.5當量)及(氯甲基)磷酸二-三級丁酯(59.5 mg,0.23 mmol,1.2當量)。將反應混合物加熱至60℃並攪拌16小時。隨後將反應混合物用EtOAc/水稀釋,用EtOAc萃取兩次。將合併之有機層以MgSO4乾燥,過濾並在真空中濃縮。將粗製產物藉由矽膠層析法(100% EtOAc)純化,以提供二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯。
實例4
製備(5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯。
向二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯
(90 mg,0.127 mmol,1當量)於DCM (2.5 mL)中之溶液中添加TFA (0.25 mL)。將反應混合物在室溫下攪拌15分鐘,之後在真空中濃縮並藉由HPLC(10至80% MeCN/水(含TFA))純化。LC-MS m/z: 596.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.78 – 7.68 (m, 2H), 7.58 (d, J = 7.0 Hz, 1H), 7.49 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.57 (d, J = 10.8 Hz, 2H), 5.40 (q, J = 9.1 Hz, 2H), 3.04 (ddd, J = 9.3, 6.3, 4.4 Hz, 1H), 2.79 (dt, J = 9.4, 5.2 Hz, 1H), 2.18 (dt, J = 8.8, 5.2 Hz, 1H), 1.90 (dt, J = 8.6, 5.2 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -70.08 (t, J = 9.2 Hz, 3F), -155.18 (d, J = 7.0 Hz, 1F)。
下列化合物係以類似於(5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯之方式,使用以下所列之修改製備:
實例5
二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯係使用5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮代替5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽製備。
(5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯係使用二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯代替二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 597.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.1 Hz, 1H), 7.51 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 5.57 (d, J = 10.8 Hz, 2H), 5.34 (tt, J = 9.3, 4.8 Hz, 2H), 3.24 (ddd, J = 8.6, 5.9, 4.1 Hz, 2H), 3.07 (ddd, J = 8.9, 6.1, 4.0 Hz, 1H), 2.22 (ddd, J = 8.6, 6.2, 3.9 Hz, 1H), 2.06 (ddd, J = 9.4, 5.8, 3.9 Hz, 1H)。19F NMR (376 MHz, DMSO-d6) δ -69.89 (t, J = 9.1 Hz, 3F), -155.18 (d, J = 7.1 Hz, 1F)。31P NMR (162 MHz, DMSO-d6) δ -2.18 (t, J = 10.8 Hz, 1P)。
實例6 及7
二-三級丁基(2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯及四-三級丁基((2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)係使用5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-2,4(1H,3H)-二酮;三氟乙酸代替5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮;鹽酸鹽製備。
及
(2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯係使用二-三級丁基((2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯代替二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 578.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.68 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.20 (dd, J = 8.4, 1.3 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 5.61 (d, J = 11.1 Hz, 2H), 5.42 (q, J = 9.1 Hz, 2H), 3.17 (ddd, J = 8.5, 6.4, 4.4 Hz, 1H), 2.82 (td, J = 7.1, 4.5 Hz, 1H), 1.97 (t, J = 8.2 Hz, 2H)。19F NMR (376 MHz, DMSO-d6) δ -70.06 (t, J = 9.1 Hz, 3F)。31P NMR (162 MHz, DMSO-d6) δ -2.17 (t, J = 11.1 Hz, 1P)。
(2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-1,3(2H,4H)-二基)雙(亞甲基)雙(二氫磷酸酯)係使用四-三級丁基((2,4-二側氧基-5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-1,3(2H,4H)-二基)雙(亞甲基))雙(磷酸酯)代替二-三級丁基((5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 688.1 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 7.79 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.21 (dd, J = 8.4, 1.3 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.73 (d, J = 6.3 Hz, 2H), 5.69 (d, J = 11.1 Hz, 2H), 5.42 (q, J = 9.1 Hz, 2H), 3.21 (td, J = 7.4, 4.5 Hz, 3H), 2.83 (td, J = 7.8, 4.5 Hz, 1H), 2.00 (t, J = 7.6 Hz, 2H)。19F NMR (376 MHz, DMSO-d6) δ -70.06 (t, J = 9.1 Hz, 3F)。31P NMR (162 MHz, DMSO-d6) δ -2.15 (t, J = 11.1 Hz), -3.45 (t, J = 6.5 Hz)。
實例8 製備(S)-6-((1-(5-(2,4- 二甲氧基嘧啶-5- 基) 吡唑并[1,5-a] 嘧啶-7- 基)-4,4- 二氟吡咯啶-3- 基) 氧基)-1-(2,2,2- 三氟乙基)-1H- 吡唑并[4,3-c] 吡啶
向密封容器中之(S)-1-(5-(2,4-二甲氧基嘧啶-5-基)吡唑并[1,5-a]嘧啶-7-基)-4,4-二氟吡咯啶-3-醇(99 mg, 0.26 mmol)、6-溴-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶(82 mg, 0.29 mmol)、碘化銅(I) (28 mg, 0.15 mmol)、3,4,7,8-四甲基-1,10-啡啉(13 mg, 0.06 mmol)、及碳酸銫(132 mg, 0.41 mmol)中添加甲苯(2.6 mL)。將混合物加熱至110℃維持14小時,然後加熱至135℃維持24小時。然後將碘化銅(I) (25 mg, 0.13 mmol)、3,4,7,8-四甲基-1,10-啡啉(12 mg, 0.05 mmol)、碳酸銫(131 mg, 0.4 mmol)、及甲苯(0.5 mL)添加至混合物中並在135℃下持續攪拌。在24小時之後,將混合物冷卻至環境溫度並通過矽藻土過濾。將餅用EtOAc潤洗並將合併之濾液在真空中濃縮。藉由管柱層析法(EtOAc/己烷)純化,得到(S)-6-((1-(5-(2,4-二甲氧基嘧啶-5-基)吡唑并[1,5-a]嘧啶-7-基)-4,4-二氟吡咯啶-3-基)氧基)-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶。
LC-MS m/z: 578.1 (M+1)。
製備(S)-5-(7-(3,3- 二氟-4-((1-(2,2,2- 三氟乙基)-1H- 吡唑并[4,3-c] 吡啶-6- 基) 氧基) 吡咯啶-1- 基) 吡唑并[1,5-a] 嘧啶-5- 基) 嘧啶-2,4(1H,3H)- 二酮
向(S)-6-((1-(5-(2,4-二甲氧基嘧啶-5-基)吡唑并[1,5-a]嘧啶-7-基)-4,4-二氟吡咯啶-3-基)氧基)-1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶(104 mg, 0.18 mmol)添加MeOH (1 mL)及1 M HCl(aq) (1 mL)。將混合物加熱至70℃維持5小時。藉由製備型HPLC(水/MeCN(含0.1% TFA))純化,得到(S)-5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-2,4(1H,3H)-二酮(92 mg, 77%),其呈TFA鹽之形式。
LC-MS m/z: 550.0 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.75 (d, J = 3.7 Hz, 1H), 11.59 (s, 1H), 8.88 (d, J = 1.0 Hz, 1H), 8.43 (d, J = 6.1 Hz, 1H), 8.40 (d, J = 0.9 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.36 (s, 1H), 7.04 (s, 1H), 6.48 (d, J = 2.2 Hz, 1H), 6.03 (dq, J = 9.3, 4.7 Hz, 1H), 5.41 (qd, J = 9.2, 2.5 Hz, 2H), 4.79 – 4.58 (m, 3H), 4.29 (d, J = 12.5 Hz, 1H)。19F NMR (377 MHz, DMSO-d6) δ -70.16 (t, J = 9.2 Hz), -75.26, -108.37 (d, J = 238.3 Hz), -119.70 (d, J = 237.7 Hz)。
實例9 製備(S)- 二- 三級丁基((5-(7-(3,3- 二氟-4-((1-(2,2,2- 三氟乙基)-1H- 吡唑并[4,3-c] 吡啶-6- 基) 氧基) 吡咯啶-1- 基) 吡唑并[1,5-a] 嘧啶-5- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基) 磷酸酯
將於EtOAc (30 mL)中之(S)-5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-2,4(1H,3H)-二酮2,2,2-三氟乙酸酯(60 mg, 0.09 mmol)用飽和NaHCO3(aq) (20 mL)洗滌。將有機物以Na2SO4乾燥,在真空中濃縮,且無需進一步純化即可使用。向粗製材料中添加KHCO
3(14 mg,0.14 mmol,1.5當量)及DMAc (0.35 mL),接著添加於DMAc (0.2 mL)中之(氯甲基)磷酸二-三級丁酯(30 mg,0.11 mmol,1.2當量)。將反應混合物加熱至60℃並攪拌17小時。隨後將反應混合物用EtOAc (30 mL)稀釋,用鹽水(25 mL)洗滌。將有機層以Na2SO4乾燥,過濾,並在真空中濃縮,以提供粗製(S)-二-三級丁基((5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯,其無需進一步純化即可使用。
LC-MS m/z: 716.0 (M-[t-Bu]+2)。
製備(S)-(5-(7-(3,3- 二氟-4-((1-(2,2,2- 三氟乙基)-1H- 吡唑并[4,3-c] 吡啶-6- 基) 氧基) 吡咯啶-1- 基) 吡唑并[1,5-a] 嘧啶-5- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基二氫磷酸酯
向於DCM (1 mL)中之粗製(S)-二-三級丁基((5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯中添加TFA (0.1 mL)。在30分鐘之後,添加更多的TFA (0.4 mL)。在30分鐘之後,將混合物在真空中濃縮。藉由製備型HPLC(水/MeCN(含0.1% TFA))純化,得到(S)-(5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯(39 mg,56%總體),其呈TFA鹽之形式。
LC-MS m/z: 660.0 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.87 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.36 (s, 1H), 7.10 (s, 1H), 6.46 (d, J = 2.3 Hz, 1H), 6.02 (h, J = 4.7 Hz, 1H), 5.57 (d, J = 10.9 Hz, 2H), 5.40 (q, J = 8.8 Hz, 2H), 4.78 – 4.54 (m, 3H), 4.23 (d, J = 12.2 Hz, 1H)。19F NMR (377 MHz, DMSO-d6) δ -70.17 (t, J = 9.1 Hz), -75.37, -108.21 (d, J = 237.8 Hz), -119.50 (d, J = 237.6 Hz)。31P NMR (162 MHz, DMSO-d6) δ -2.27 (t, J = 10.9 Hz)。
實例10 製備(S)- 二- 三級丁基((5-(8-(3,3- 二氟-4-((2-( 三氟甲基) 吡啶-4- 基) 氧基) 吡咯啶-1- 基)-3- 氟咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基) 磷酸酯
將於EtOAc (60 mL)中之(S)-(-5-(8-(3,3-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)吡咯啶-1-基)-3-氟咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮; TFA鹽(81 mg, 0.13 mmol)用飽和NaHCO3(aq) (20 mL)洗滌。將有機物在真空中濃縮,且無需進一步純化即可使用。向粗製材料中添加KHCO
3(20 mg,0.19 mmol,1.5當量)及DMAc (0.75 mL),接著添加於DMAc (0.25 mL)中之(氯甲基)磷酸二-三級丁酯(41 mg,0.16 mmol,1.2當量)。將反應混合物加熱至60℃並攪拌17小時。隨後將反應混合物用EtOAc (30 mL)稀釋,用鹽水(2 x 20 mL)洗滌。將有機層以Na2SO4乾燥,過濾,並在真空中濃縮,以提供粗製(S)-二-三級丁基((5-(8-(3,3-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)吡咯啶-1-基)-3-氟咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯,其無需進一步純化即可使用。
LC-MS m/z: 736.08 (M+1)。
製備(S)-(5-(8-(3,3- 二氟-4-((2-( 三氟甲基) 吡啶-4- 基) 氧基) 吡咯啶-1- 基)-3- 氟咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基二氫磷酸酯
向於DCM (1 mL)中之粗製(S)-二-三級丁基((5-(8-(3,3-二氟-4-((2-三氟甲基)吡啶-4-基)氧基)吡咯啶-1-基)-3-氟咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯中添加TFA (0.5 mL)。在1小時之後,添加更多的TFA (0.5 mL)。在30分鐘之後,將混合物在真空中濃縮。藉由製備型HPLC(水/MeCN(含0.1% TFA))純化,得到(S)-(5-(8-(3,3-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)吡咯啶-1-基)-3-氟咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯(42 mg,63%總體),其呈TFA鹽之形式。
LC-MS m/z: 624.0 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.66 (d, J = 5.7 Hz, 1H), 8.28 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 5.8, 2.4 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 6.62 (s, 1H), 5.86 – 5.78 (m, 1H), 5.55 (d, J = 10.8 Hz, 2H), 4.70 – 4.53 (m, 1H), 4.53 – 4.34 (m, 2H), 4.34 – 4.15 (m, 1H)。19F NMR (377 MHz, DMSO-d6) δ -67.17, -75.35, -106.97 (d, J = 242.2 Hz), -120.71 (d, J = 240.3 Hz), -154.97 (d, J = 7.1 Hz)。31P NMR (162 MHz, DMSO-d6) δ -2.20 (t, J = 10.6 Hz)。
實例11 製備(S)- 二- 三級丁基((5-(8-(3,3- 二氟-4-((1-(2,2,2- 三氟乙基)-1H- 吡唑并[4,3-c] 吡啶-6- 基) 氧基) 吡咯啶-1- 基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基) 磷酸酯
向於NMP (0.5 mL)中之(S)-5-(8-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮; TFA鹽(52 mg, 0.078 mmol)中添加咪唑(14 mg, 0.206 mmol)。將混合物攪拌3小時,之後添加水(5 mL)。將所得白色沈澱物藉由過濾單離,用水洗滌兩次,並乾燥整夜,以得到(S)-5-(8-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮。
然後(S)-二-三級丁基((5-(8-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯係以(S)-二-三級丁基((5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯所述之方式,使用(S)-5-(8-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮代替(S)-5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-2,4(1H,3H)-二酮製備。LC-MS m/z: 771.6 (M+1)。
製備(S)-(5-(8-(3,3- 二氟-4-((1-(2,2,2- 三氟乙基)-1H- 吡唑并[4,3-c] 吡啶-6- 基) 氧基) 吡咯啶-1- 基) 咪唑并[1,2-b] 嗒 -6- 基)-2,4- 二側氧基-3,4- 二氫嘧啶-1(2H)- 基) 甲基二氫磷酸酯
(S)-(5-(8-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯係以(S)-(5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)吡唑并[1,5-a]嘧啶-5-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基二氫磷酸酯所述之方式,使用(S)-二-三級丁基((5-(8-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯代替(S)-二-三級丁基((5-(7-(3,3-二氟-4-((1-(2,2,2-三氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)氧基)吡咯啶-1-yl)吡唑并[1,5-a]嘧啶-5-基)-2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲基)磷酸酯製備。
LC-MS m/z: 659.6 (M+1)。1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.88 (d, J = 1.1 Hz, 1H), 8.40 (d, J = 1.0 Hz, 1H), 8.25 (s, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.35 (s, 1H), 6.61 (s, 1H), 6.00 (s, 1H), 5.53 (d, J = 10.7 Hz, 2H), 5.39 (q, J = 9.0 Hz, 2H), 4.71 – 4.38 (m, 3H), 4.20 (s, 1H)。19F NMR (376 MHz, DMSO-d6) δ -70.15 (t, J = 9.1 Hz), -108.33 (d, J = 242.5 Hz), -119.76 (d, J = 237.7 Hz)。31P NMR (162 MHz, DMSO-d6) δ -2.25 (t, J = 10.9 Hz)。
生物數據 比較例
比較例可見於2021年4月29日申請之美國專利申請案序號17/243,911中,其內容以全文引用方式併入本文中。
簡言之,化合物可以以下方式合成:
方案1 :
代表性合成方案1顯示本揭露之化合物的一般合成。該方法與各式各樣的官能性相容。在代表性合成1中,將經合適取代之氯咪唑嗒
(或對應的溴-或碘-化合物)與(2,4-二甲氧基嘧啶-5-基)硼酸於合適的溶劑系統(例如水+二
烷、THF、DME、甲苯等)中在鈀催化劑(例如Pd(dppf)Cl
2、Pd(PPh
3)
4等)及鹼(例如Cs
2CO
3、K
2CO
3、K
3PO
4等)存在下在高溫(例如,在約80至120℃之範圍內)下組合,其可例如在微波反應器中或以習知加熱進行。隨後,所得經合適取代之2,4-二甲氧基嘧啶可用酸(例如鹽酸)於合適的溶劑系統(例如水+甲醇、乙醇等)中在高溫(例如,在約50至80℃之範圍內)下處理。
方案2 :
代表性合成方案2顯示實施例之化合物的一般合成。該方法與各式各樣的官能性相容。在代表性合成方案2中,將經合適取代之溴咪唑嗒
(或對應的氯-或碘-化合物)與烷基硼酸或硼酸衍生物(例如硼酸酯、或三氟硼酸鹽)於合適的溶劑系統(例如水+二
烷、THF、DME、甲苯等)中在鈀催化劑(例如Pd(dppf)Cl
2、cataCXium-A-Pd G3等)及鹼(例如Cs
2CO
3、K
2CO
3、K
3PO
4等)存在下在高溫(例如,在約90至150℃之範圍內)下組合,其可在微波反應器中或以習知加熱進行)。
方案3 :
代表性合成方案3顯示實施例之化合物的一般合成。該方法與各式各樣的官能性相容。在代表性合成方案3中,將經合適取代之溴咪唑嗒
(或對應的氯-或氟-化合物)與親核劑(例如胺、醇、雜環等)於合適的溶劑系統(例如乙腈、EtOH、THF、NMP等)中在鹼(例如Cs
2CO
3、K
2CO
3、三乙胺、DIPEA、NaH等)存在下在環境溫度或高溫(例如,約20至90℃之範圍內)下組合。
方案4 :
代表性合成方案4顯示實施例之化合物的一般合成。該方法與各式各樣的官能性相容。在代表性合成方案4中,將經合適取代之氯咪唑嗒
與自由基前驅物(諸如烷基亞磺酸鈉或烷基亞磺酸鋅)於合適的溶劑系統(例如DMSO/H
2O、DCE/H
2O等)中在氧化劑(例如TBHP)存在下在環境溫度或高溫(例如,在約20至60℃之範圍內)下組合。可使用各種自由基前驅物及反應條件以生成適當的烷基自由基中間物,包括Minisci條件(即烷基羧酸、(NH
4)
2S
2O
9、AgNO
3、TFA)。
方案5 :
代表性合成方案5顯示實施例之化合物的一般合成。該方法與各式各樣的官能性相容。在代表性合成方案5中,將經合適取代之芳基或雜芳基鹵化物與乙烯三氟硼酸鉀(或類似的-Bpin、-BMIDA、或-B(OH)
2試劑)於合適的溶劑系統(例如水+ THF、二
烷、DME、甲苯等)中在鈀催化劑(例如Pd(dppf)Cl
2、Pd(PPh
3)
4等)及鹼(例如K
2CO
3 、Cs
2CO
3、K
3PO
4等)存在下在高溫(例如,在約80至120℃之範圍內)下組合,其可在微波反應器中或以習知加熱進行。隨後,將經合適取代之烯烴於合適的溶劑系統(例如DCM)中用肆(乙腈)[2-[(4
R)-4,5-二氫-4-苯基-2-
唑基-
N]苯基]釕(II)六氟磷酸鹽(或另一合適的過渡金屬催化劑)及1,3-二側氧基異吲哚啉-2-基2-重氮乙酸酯在低溫(例如,在約-20℃至5℃之範圍內)下處理。將所得經合適取代之N-羥基酞醯亞胺酯(N-hydroxyphthalimide ester)與異菸鹼酸甲酯(或另一合適的異菸鹼酸酯衍生物,例如異菸鹼酸三級丁酯等)及雙(頻哪醇根基)二硼(bis(pinacolato)diboron)於合適的溶劑(例如EtOAc、CF
3Ph等異菸鹼酸三級丁酯)中在高溫(例如,在約60至100℃之範圍內)下組合。替代地,硼化反應可藉由在藍色LED燈下將經合適取代之N-羥基酞醯亞胺酯與雙(兒茶酚)二硼(bis(catecholato)diboron)於合適的溶劑系統(例如DMF)中組合,並將所得硼酸酯與頻哪醇(pinacol)及三乙胺組合。
替代地,此反應序列可藉由將經合適取代之烯烴與重氮乙酸乙酯於合適的溶劑系統(亦即甲苯)中在高溫(例如在約80至120℃之範圍內)下組合來提供化合物之外消旋混合物。隨後,乙酯可在鹼性水性條件(例如LiOH、或NaOMe)下水解,且所得酸可與N-羥基酞醯亞胺及合適的偶合試劑(例如DIC、EDC)組合。最終的硼化步驟可如上述進行。
比較例A :5-(8-((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吲唑-5- 基) 環丙基) 咪唑并[1,2-b] 嗒 -6- 基) 嘧啶-2,4(1H,3H)- 二酮。 中間物A :6-(2,4- 二甲氧基嘧啶-5- 基)-8-((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吲唑-5- 基) 環丙基) 咪唑并[1,2-b] 嗒 。
6-(2,4-二甲氧基嘧啶-5-基)-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
係如下製備:8-環丙基-6-(2,4-二甲氧基嘧啶-5-基)-2-甲基-咪唑并[1,2-b]嗒
係如下製備:將微波小瓶裝入(2,4-二甲氧基嘧啶-5-基)硼酸(59.4 mg、0.323 mmol、1.0當量)、Pd(dppf)Cl
2-CH
2Cl
2(23.6 mg, 0.032 mmol, 10 mol%)、Cs
2CO
3(210 mg、0.645 mmol、2當量)、及6-氯-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
(1當量)。將反應混合物溶解於3:1的二
烷/H
2O (4 mL)中,用氬氣吹掃,並在80℃下攪拌5小時。將反應混合物藉由矽膠層析法(0至15% MeOH/CH
2Cl
2)直接純化。將化合物藉由SiO
2層析法(0至100% EtOAc/己烷)再次純化,得到8-環丙基-6-(2,4-二甲氧基嘧啶-5-基)-2-甲基-咪唑并[1,2-b]嗒
。ES/MS m/z: 496.05 [M+H]。
三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
(1當量)。將反應混合物溶解於3:1的二
烷/H
2O (4 mL)中,用氬氣吹掃,並在80℃下攪拌5小時。將反應混合物藉由矽膠層析法(0至15% MeOH/CH
2Cl
2)直接純化。將化合物藉由SiO
2層析法(0至100% EtOAc/己烷)再次純化,得到8-環丙基-6-(2,4-二甲氧基嘧啶-5-基)-2-甲基-咪唑并[1,2-b]嗒
。ES/MS m/z: 312.20 [M+H]。
5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮係如下製備:向6-(2,4-二甲氧基嘧啶-5-基)-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
於MeOH (1.5 mL)中之溶液中添加1.5 M HCl
(aq)溶液(1 mL)。將反應容器加熱至80℃維持6小時。過濾分離之固體,用水洗滌並乾燥,得到5-(8-環丙基-2-甲基-咪唑并[1,2-b]嗒
-6-基)-1H-嘧啶-2,4-二酮且藉由過濾單離成HCl鹽。ES/MS m/z: 468.00 [M+H]。
1H NMR (400 MHz, DMSO-d6) δ 11.62 – 11.48 (m, 2H), 8.35 (s, 1H), 8.14 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.39 (dd, J = 8.8, 1.6 Hz, 1H), 5.44 (q, J = 9.2 Hz, 2H), 2.96 – 2.89 (m, 1H), 2.81 – 2.74 (m, 1H), 2.04 (dt, J = 10.0, 5.3 Hz, 1H), 1.85 (dt, J = 8.6, 5.4 Hz, 1H)。
19F NMR (376 MHz, DMSO-d6) δ -70.15 (t, J = 9.1 Hz)。
比較例B :5-[8-(3,3- 二氟-4,4- 二甲基- 吡咯啶-1- 基) 咪唑并[1,2-b] 嗒 -6- 基]-1H- 嘧啶-2,4- 二酮 中間物B. 6- 氯-8-(3,3- 二氟-4,4- 二甲基- 吡咯啶-1- 基) 咪唑并[1,2-b] 嗒
6-氯-8-(3,3-二氟-4,4-二甲基-吡咯啶-1-基)咪唑并[1,2-b]嗒
係以6-氯-8-(3,3-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
所述之方式,但以3,3-二氟-4,4-二甲基-吡咯啶鹽酸鹽取代3,3-二甲基吡咯啶鹽酸鹽製備。
將微波小瓶裝入8-溴-6-氯咪唑并[1,2-b]嗒
(250 mg,1.08 mmol、3,3-二氟-4,4-二甲基-吡咯啶鹽酸鹽,1.1當量)、DIPEA(0.481 mL,2.69 mmol,2.5當量)、及MeCN (5 mL)。將反應混合物加熱至85℃。在24小時後,將反應混合物濃縮。將獲得之殘餘物用水研製,將所得固體過濾,用水洗滌,並乾燥,得到6-氯-8-(3,3-二甲基吡咯啶-1-基)咪唑并[1,2-b]嗒
。ES/MS m/z: 287.10 [M+H]。
5-[8-(3,3-二氟-4,4-二甲基-吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基]-1H-嘧啶-2,4-二酮係如下製備:向8-(3,3-二氟-4,4-二甲基-吡咯啶-1-基)-6-(2,4-二甲氧基嘧啶-5-基)咪唑并[1,2-b]嗒
於MeOH (2.5 mL)中之溶液中添加1 M HCl(aq)溶液(1.5 mL)。將反應容器加熱至80℃維持6小時。過濾分離之固體,用水洗滌並乾燥,得到5-[8-(3,3-二氟-4,4-二甲基-吡咯啶-1-基)咪唑并[1,2-b]嗒
-6-基]-1H-嘧啶-2,4-二酮,其呈HCl鹽之形式。ES/MS:363.10 [M+1]。
1H NMR (400 MHz, DMSO-d6) δ 11.58 – 11.46 (m, 2H), 8.23 – 8.22 (m, 1H), 8.01 – 7.97 (m, 1H), 7.81 – 7.80 (m, 1H), 6.81 (s, 1H), 4.47 – 4.41(m, 2H), 3.83 – 3.82 (m, 2H), 1.22 – 1.20 (m, 6H)。
19F NMR (377 MHz, DMSO-d6) δ -115.19 (m, 2F)。
比較例C : 中間物709. 三氟((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吲唑-6- 基) 環丙基) 硼酸鉀
將6-((1S,2S)-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)環丙基)-1-(2,2,2-三氟乙基)-1H-吲唑(209 mg, 0.57 mmol)及KHF2 (312 g, 4.0 mmol)秤入小瓶中,並添加MeOH (2.5 mL)、及水(0.5 mL)。將混合物在室溫下攪拌整夜,然後在真空中移除溶劑。將所得殘餘物溶解於MeCN中,並過濾以移除固體,用MeCN洗滌。將濾液於真空中濃縮,然後將固體用二乙基醚洗滌並乾燥,以得到三氟((1S,2S)-2-(4-(三氟甲基)苯基)環丙基)硼酸鉀。
1H NMR (400 MHz,丙酮-d6) δ 7.92 (d, J = 1.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 6.87 (dd, J = 8.4, 1.3 Hz, 1H), 5.21 (q, J = 9.0 Hz, 2H), 1.80 – 1.72 (m, 1H), 0.85 (td, J = 7.4, 2.6 Hz, 1H), 0.52 (d, J = 10.2 Hz, 1H), 0.09 – -0.02 (m, 1H)。
19F NMR (376 MHz,丙酮-d6) δ -71.97 (t, J = 9.0 Hz), -145.46 (d, J = 77.9 Hz)。
中間物710. 5- 溴-7-((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吲唑-6- 基) 環丙基) 吡唑并[1,5-a] 嘧啶
5-溴-7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶係如下製備:向5,7-二氯吡唑并[1,5-a]嘧啶(0.500 g, 2.66 mmol)於MeCN (13 mL)中之溶液中添加溴三甲基矽烷(1.75 mL, 13.3 mmol)。將混合物在60℃下攪拌3小時。將懸浮液過濾,用MeCN洗滌,並將固體在真空下乾燥,以得到5,7-二溴吡唑并[1,5-a]嘧啶。ES/MS m/z: 276.0 [M+H]。
將微波小瓶裝入5,7-二溴吡唑并[1,5-a]嘧啶(354 mg, 1.28 mmol)、三氟((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)硼酸鉀(295 mg, 0.852 mmol)、碳酸銫(833 mg, 2.56 mmol)、及Pd(PPh
3)
4(49 mg, 0.043 mmol)。將固體溶解於甲苯(5 mL)及H
2O (1 mL),並將混合物用N
2除氣。將小瓶密封並加熱至100℃維持5小時。然後將反應混合物冷卻並通過矽藻土過濾,用EtOAc洗滌。將濾液在真空中濃縮,並將所得殘餘物藉由矽膠層析法(0至100% EtOAc/己烷)純化,得到5-溴-7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶。ES/MS m/z: 436.1 [M+H]。
實例456 5-(7-((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吲唑-6- 基) 環丙基) 吡唑并[1,5-a] 嘧啶-5- 基) 嘧啶-2,4(1H,3H)- 二酮
5-(7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶-5-基)嘧啶-2,4(1H,3H)-二酮係如下製備:將5-溴-7-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)環丙基)吡唑并[1,5-a]嘧啶(120 mg, 0.275 mmol)、(2,4-二三級丁氧基嘧啶-5-基)硼酸(88.5 mg, 0.330 mmol)、碳酸銫(269 mg, 0.825 mmol)、及Pd(dppf)Cl
2-CH
2Cl
2(22.5 mg, 0.0275 mmol)秤入微波小瓶中,並添加二
烷(2 mL)及水(0.5 mL)。將混合物用N
2除氣,並將小瓶密封並且加熱至80℃維持16小時。然後將混合物冷卻至室溫,並緩慢添加TFA (1 mL)。將混合物在室溫下再攪拌20分鐘,然後濃縮並藉由RP-HPLC(10至90% MeCN/H
2O(含TFA改質劑),Gemini管柱)純化。ES/MS m/z: 468.1 [M+H]。
1H NMR (400 MHz, DMSO-d6) δ 11.62 (dd, J = 6.4, 2.0 Hz, 1H), 11.52 (d, J = 1.9 Hz, 1H), 8.35 (d, J = 6.3 Hz, 1H), 8.19 – 8.07 (m, 2H), 7.80 – 7.65 (m, 3H), 7.18 (dd, J = 8.4, 1.4 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 5.41 (q, J = 9.1 Hz, 2H), 3.15 (ddd, J = 8.3, 6.6, 4.5 Hz, 1H), 2.84 – 2.74 (m, 1H), 1.95 (ddd, J = 8.3, 6.6, 1.5 Hz, 2H)。
19F NMR (376 MHz, DMSO-d6) δ -70.08 (t, J = 9.0 Hz), -75.62。
比較例D: 中間物798. 6-((1S,2S)-2-(4,4,5,5- 四甲基-1,3,2- 二氧雜硼雜環戊-2- 基) 環丙基)-1-(2,2,2- 三氟乙基)-1H- 吡唑并[3,4-b] 吡啶
步驟1 :向1-(2,2,2-三氟乙基)-6-乙烯基-1H-吡唑并[3,4-b]吡啶(600 mg,2.64 mmol,1當量)於甲苯(6 mL)中之溶液中添加重氮乙酸乙酯(0.42 mL,3.96 mmol,1當量)。將反應混合物加熱至80℃。在24小時之後,將反應混合物用MeOH (5 mL)稀釋並濃縮至~5 mL。藉由SiO
2層析法(0至100% EtOAc/Hex)完成純化,得到外消旋乙基(1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙烷-1-羧酸酯。
步驟2 :向外消旋乙基(1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙烷-1-羧酸酯(882 mg,2.82 mmol,1當量)於5:1 THF:H
2O (5 mL)中之溶液中添加LiOH-H
2O(591 mg,14.1 mmol,5當量)。將反應混合物加熱至45C並攪拌20小時。將反應混合物在0℃下用2M HCl中和,然後用EtOAc徹底萃取。將合併之有機層以Na
2SO
4乾燥,過濾,並濃縮,以得到外消旋(1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙烷-1-羧酸。ES/MS m/z: 286.10 [M+H]。
步驟3 :向外消旋(1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙烷-1-羧酸(1000 mg,3.51 mmol,1當量)於CH
2Cl
2(30 mL)中之溶液中添加二異丙基甲烷二亞胺(0.60 mL,3.86 mmol,1.1當量)、DMAP (42.8 mg, 10 mol%)、及2-羥基異吲哚啉-1,3-二酮(629 mg,3.86 mmol,1.1當量)。在5小時之後,將反應混合物過濾,用CH
2Cl
2洗滌並濃縮。將殘餘物藉由SiO
2層析法(0至100% EtOAc/Hex)純化,得到外消旋1,3-二側氧基異吲哚啉-2-基(1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙烷-1-羧酸酯。
步驟4 :向外消旋1,3-二側氧基異吲哚啉-2-基(1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙烷-1-羧酸酯(1071 mg,2.49 mmol,1當量)於EtOAc (12 mL)中之溶液中添加B
2Pin
2(1264 mg,4.98 mmol,2當量)、及異菸鹼酸甲酯(0.147 mL,1.24 mmol,0.5當量)。將所得混合物在氬氣氣氛下加熱至80℃。在12小時之後,將反應混合物過濾,濃縮,並藉由SiO
2層析法(0至20% EtOAc/Hex)純化,得到外消旋6-((1S,2S)-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)環丙基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶。ES/MS m/z: 368.20 [M+H]。
中間物838. 6-((1S,2S)-2-(6- 氯-3- 氟咪唑并[1,2-b] 嗒 -8- 基) 環丙基)-1-(2,2,2- 三氟乙基)-1H- 吡唑并[3,4-b] 吡啶
將8-溴-6-氯-3-氟-咪唑并[1,2-b]嗒
(426 mg, 1.7 mmol)、6-((1S,2S)-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)環丙基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶(外消旋混合物)(650 mg, 1.42 mmol)、cataCXium A Pd G3 (103 mg, 0.142 mmol)、及磷酸三鉀(potassium phosphate tribasic) (902 mg, 4.25 mmol)秤入微波小瓶中,然後將其抽空並用N
2回填3次。添加經預先除氣之二
烷(6.7 mL)及水(1.3 mL),並將小瓶密封並且加熱至100℃維持10小時。然後將混合通過矽藻土過濾,用EtOAc洗滌。將濾液在真空中濃縮並藉由矽膠層析法(0至100% EtOAc於己烷中)純化,得到4-((1S,2S)-2-(6-氯咪唑并[1,2-b]嗒
-8-基)環丙基)-2-(三氟甲基)苯甲腈(外消旋混合物)。ES/MS m/z: 411.10 [M+H]。
中間物839. 6-((1S,2S)-2-(6- 氯-3- 氟咪唑并[1,2-b] 嗒 -8- 基) 環丙基)-1-(2,2,2- 三氟乙基)-1H- 吡唑并[3,4-b] 吡啶
6-((1S,2S)-2-(6-氯-3-氟咪唑并[1,2-b]嗒
-8-基)環丙基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶係藉由SFC OJ-H管柱(15% EtOH)自外消旋中間物838中掌性分離。
中間物911. 6-((1S,2S)-2-(6-(2,4- 二甲氧基嘧啶-5- 基)-3- 氟咪唑并[1,2-b] 嗒 -8- 基) 環丙基)-1-(2,2,2- 三氟乙基)-1H- 吡唑并[3,4-b] 吡啶
6-((1S,2S)-2-(6-(2,4-二甲氧基嘧啶-5-基)-3-氟咪唑并[1,2-b]嗒
-8-基)環丙基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶係以中間物A所述之方式,但用6-((1S,2S)-2-(6-氯-3-氟咪唑并[1,2-b]嗒
-8-基)環丙基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶取代6-氯-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
製備。ES/MS m/z: 515.10 [M+H]。
實例610. 5-(3- 氟-8-((1S,2S)-2-(1-(2,2,2- 三氟乙基)-1H- 吡唑并[3,4-b] 吡啶-6- 基) 環丙基) 咪唑并[1,2-b] 嗒 -6- 基) 嘧啶-2,4(1H,3H)- 二酮
5-(3-氟-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮係以5-(8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
-6-基)嘧啶-2,4(1H,3H)-二酮所述之方式,但用6-((1S,2S)-2-(6-(2,4-二甲氧基嘧啶-5-基)-3-氟咪唑并[1,2-b]嗒
-8-基)環丙基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-b]吡啶取代6-(2,4-二甲氧基嘧啶-5-基)-8-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-5-基)環丙基)咪唑并[1,2-b]嗒
製備。ES/MS m/z: 487.10 [M+H]。
1H NMR (400 MHz,甲醇-
d 4) δ 8.20 (s, 1H), 8.12 (s, 1H), 8.12 (d,
J= 8.2 Hz, 1H), 7.67 (s, 1H), 7.43 (d,
J= 6.7 Hz, 1H), 7.33 (d,
J= 8.2 Hz, 1H), 5.35 – 5.07 (m, 2H), 3.26 – 3.20 (m, 1H), 3.11 – 3.04 (m, 1H), 2.20 – 2.11 (m, 1H), 2.07 – 1.98 (m, 1H)。
生物數據
下列生物活性數據證明本發明之一些實施例的一些特性。
在FASSIF 及FESSIF 中之熱力學溶解度。
評估化合物在20小時之時間內的水溶解度(aqueous solubility)。溶解度係於使用BioRelevant Simulated Intestinal Fluid (SIF)粉末之內部製備之緩衝禁食狀態模擬腸液(fasted-state simulated intestinal fluid) (FaSSIF, pH 6.5)及緩衝餵食狀態模擬腸液(fed-state simulated intestinal fluid) (FeSSIF, pH 5.0)中於環境溫度下判定。將固體添加至於1.5-mL艾本德管(Eppendorf tube)中之FaSSIF或FeSSIF中,渦旋1分鐘,然後在Eppendorf ThermoMixer C中攪拌20小時。為了判定溶液中之濃度,將懸浮液以14,800 rpm離心10分鐘並用1:1 v/v乙腈:水將上清液稀釋成1 mL之體積。藉由UPLC(使用具有PDA UV偵測器之Waters Acquity UPLC)分析所有經稀釋之上清液。結果如表3中所示。
在pH 1 及7 下之動力學溶解度
藉由使用Hamilton Starlet液體處理系統(Hamilton Starlet liquid handling)將3 µL的DMSO儲備液(stock)與297 µL的適當介質於具有0.45 µM聚碳酸酯過濾膜之Millipore溶解度濾板中組合來製備各化合物之100倍稀釋液作為DMSO儲備溶液(stock solution)。最終DMSO濃度係1.0%且最大理論化合物濃度係100 µM(假設儲備液濃度為10 mM)。將濾板密封。在環境溫度(22.2至23.6℃)下培育24小時之後,將樣本真空過濾,並在96孔聚丙烯板中收集濾液以進行分析。密封收集板以進行分析。將濾液注入氮偵測器中以進行定量。使用跨越0.08至4500 µg/ml氮之儀器動態範圍的標準品來校準偵測器之等莫耳氮反應。對於此校準曲線定量濾液。所計算之溶解度值針對存在於DMSO中之背景氮及用於製備樣本之介質進行校正。
表3 :
鹼性磷酸酶穩定性檢定
結構 | 化合物編號 | FaSSIF (pH 6.5) (ug/mL) | FeSSIF (pH 5.0) (ug/mL) | 動力學溶解度 pH 1 (uM) | 動力學溶解度 pH 7 (uM) |
A | 0.7 | 12.4 | 72 | 10 | |
B | 12 | 33 | 95 | 5 | |
C | 0.5 | 11.1 | 65 | 7 | |
D | 9 | 6 | |||
E | 94 | 8 | |||
實例1 | >1000 | >1000 | >100 | >100 | |
實例2 | 3 | 89 | |||
實例3 | 91 | >100 | |||
實例4 | 1100 | >5400 | 96 | >100 | |
實例5 | 79 | 86 | |||
實例6 | 10 | 85 | |||
實例7 | 89 | >100 |
鹼性磷酸酶穩定性檢定係使用純化之牛小腸鹼性磷酸酶(Bovine intestinal alkaline phosphatas)執行。用TECAN液體處理器進行重複組。檢定受質濃度係2 µM。純化之牛小腸鹼性磷酸酶係以凍乾粉末之形式透過MilliPore Sigma獲得。反應混合物係藉由在有或沒有100 ng/mL純化之牛小腸鹼性磷酸酶之情況下,將2 µL化合物(於DMSO中之400 µM儲備溶液)添加至含有396 µL Tris緩衝液(100 mM,pH 7.8,1 mM MgCl
2及1 mM ZnCl
2)之96孔板之孔中來製備。樣本係在3、30、60、120、180、及240分鐘之時間點進行評估。在每個時間點,將25 µL的反應混合物添加至含有225 µL的淬熄溶液(99%乙腈與1%甲酸及作為內部標準品之100 nM Labetalol)之96孔板中。然後將含有該淬熄樣本之板以1100 RPM渦旋10分鐘並以4500 RPM離心20分鐘。將150 µ L的所得上清液轉移至含有150 µL的水之96孔板中並以1100 RPM渦旋3分鐘以混合。
用Leap HTC Autosampler及Dionex UltiMate 3000 HPLC系統分析樣本,該系統介接至以正離子電灑模式操作之Thermo Q-Exactive質譜儀。使用Thermo Scientific Hypersil GOLD(粒徑1.9 µM,50 × 2.1 mm)HPLC管柱且移動相係以0.5 mL/min泵送。分析物之洗提係藉由在含有0.1% (v/v)甲酸之乙腈於水中之一系列線性梯度來達成。藉由分析物/內部標準品峰面積比(peak area ratio, PAR)來進行定量。
表4 :
體內食蟹獼猴(CYNO) 藥物動力學實驗
結構 | 實例編號 | ALP半衰期(分鐘) | 檢定緩衝液半衰期(分鐘) |
實例2 | 11 | >1584 | |
實例4 | 4 | >1584 | |
實例2 | 10 | >1584 | |
實例6 | 8 | >1584 | |
實例5 | 14 | >1584 |
化合物比較組B及實例1之體內食蟹獼猴藥物動力學實驗評定如下。
實例1 比較組B
化合物比較組B鹽酸鹽係使用下列配方以30 mg/kg懸浮液給藥至食蟹獼猴(N=3):0.5% Methocel E4M Premium、0.1% Tween-80、99.4%水。化合物比較組B游離鹼係使用下列配方以12.5 mg/kg(固定50 mg)懸浮液分別給藥至食蟹獼猴(N=3):0.5% Methocel E4M Premium、0.1% Tween-80、99.4%水。化合物實例1係使用下列配方以12.5 mg/kg(固定50 mg)懸浮液分別給藥至食蟹獼猴(N=3):0.5% Methocel E4M Premium、0.1% Tween-80、99.4%水。針對實例1及比較組B之存在來評定樣本。圖2顯示在用使用前述懸浮液配方之比較組B或實例1給藥之後,在24小時時間期間化合物比較組B之血漿濃度(nM)。如表4中所示,在用實例1給藥之後,比較組B在血漿中測得之AUC 0-24h比在用同等劑量的比較組B給藥之後測得之值更高。
表5 :
體內大鼠藥物動力學實驗
結構 | 化合物 | 劑量 | 比較組B AUC 0-24 h (nM·h) |
實例1 | 固定50 mg (12.5 mg/kg) | 98467 | |
比較組B HCl鹽 | 固定120 mg (30 mg/kg) | 33167 | |
比較組B 游離鹼 | 固定50 mg | 6063 |
化合物比較組C及實例4之體內威-漢大鼠(Wister Han rat)藥物動力學實驗評定如下。
實例4 比較組C
化合物比較組C係使用下列配方以100 mg/kg懸浮液給藥至威-漢大鼠(N=3):30% captisol、5% soluplus、65% pH 2水。化合物實例1170997係使用下列配方以100 mg-eq/kg(123 mg/kg)溶液分別給藥至威-漢大鼠(N=3):0.5% Methocel E4M Premium、0.1% Tween-80、99.4%水。針對比較組C之存在來評定樣本。
比較組C及實例4。圖2顯示在用使用前述溶液配方之比較組C或實例4給藥之後,在24小時時間期間比較組C之血漿濃度(nM)。如表4中所示,在用實例4給藥之後,比較組C在血漿中測得之AUC 0-24h比在用同等劑量的比較組C給藥之後測得之值更高。
結構 | 化合物 | 劑量 | 比較組C AUC 0-24 h (nM·h) |
實例4 | 100 mg-eq/kg | 32800 | |
比較組C HCl鹽 | 100 mg/kg | 11200 |
無
[
圖1]顯示在用比較組B或實例1給藥之後,化合物比較組B在24小時時間期間之血漿濃度(nM)。
[
圖2]顯示在用比較組C或實例4給藥之後,比較組C在24小時時間期間之血漿濃度(nM)。
Claims (27)
- 一種式I之化合物或其醫藥上可接受之鹽、立體異構物或水合物,
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R1係H。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R1係CH2OP(O)(OH)2。
- 如請求項1或2之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R2係經一或多個R4取代之C3-6環烷基。
- 如請求項1或2之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R2係經一或多個R4取代之3至8員雜環基。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R2係經一或多個R4取代之環丙基。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係可選地經一或多個R6取代之4至10員雜芳基。
- 如請求項7之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係經一或多個R6取代之4至10員雜芳基。
- 如請求項8之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係經一或多個C1-5烷基取代之4至10員雜芳基,該C1-5烷基可選地經鹵基取代。
- 如請求項9之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係經一或多個C1-5烷基取代之4至10員雜芳基,該C1-5烷基經一或多個鹵基取代。
- 如請求項10之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係經一或多個C1-5烷基取代之4至10員雜芳基,該C1-5烷基經一或多個氟基取代。
- 如請求項10之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係經一或多個C1-5烷基取代之吲唑,該C1-5烷基經一或多個氟基取代。
- 如請求項12之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係經一個C1-5烷基取代之吲唑,該C1-5烷基經一或多個氟基取代。
- 如請求項13之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R4係經三氟乙基取代之吲唑。
- 如請求項14之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R3係H。
- 如請求項14之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R3係鹵基。
- 如請求項16之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R3係F。
- 如請求項1之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R2係3至8員雜環基;其中該雜環基係經一或多個R4取代。
- 如請求項19之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R2係經一或多個R4取代之吡咯啶基。
- 如請求項20之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中該吡咯啶基係經二個氟基及-OR5取代。
- 如請求項21之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中R5係4至10員雜芳基且係可選地經一或多個R6及鹵基取代。
- 如請求項20之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中該吡咯啶基係獨立地經四個R4取代。
- 如請求項23之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中該吡咯啶基係經二個甲基及二個氟基取代。
- 如請求項24之化合物或其醫藥上可接受之鹽、立體異構物或水合物,其中該吡咯啶基係偕二甲基取代。
- 一種醫藥組成物,其包含如請求項1至26中任一項之化合物或其醫藥上可接受之鹽、立體異構物或水合物,及醫藥上可接受之載劑。
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