TW202328133A

TW202328133A - Use of shp2 inhibitors for treating tumors containing ras pathway gene mutations

Info

Publication number: TW202328133A
Application number: TW111132352A
Authority: TW
Inventors: 田宇楠; 傅強; 林侃; 張曉靜; 張蕾; 楊昌永; 廖成; 施薇
Original assignee: 大陸商江蘇恆瑞醫藥股份有限公司; 大陸商上海盛迪醫藥有限公司
Priority date: 2021-08-27
Filing date: 2022-08-26
Publication date: 2023-07-16
Also published as: WO2023025290A1

Abstract

The present disclosure relates to the use of SHP2 inhibitors for treating tumors containing RAS pathway gene mutations. In particular, the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a tumor containing a RAS pathway gene mutation.

Description

SHP2抑制劑治療含有RAS通路基因突變的腫瘤的用途 Use of SHP2 inhibitors to treat tumors containing RAS pathway gene mutations

本揭露屬於藥學領域，SHP2抑制劑治療含有RAS通路基因突變的腫瘤的用途。 The present disclosure belongs to the field of medicine and the use of SHP2 inhibitors to treat tumors containing RAS pathway gene mutations.

MAPK信號通路的活化是腫瘤細胞中的主要促癌信號之一。RTK受體由於配體激活後，依次激活SHP2-SOS1-RAS-RAF-MEK-ERK，最終促進細胞的增殖、存活並抑制凋亡等。而在腫瘤中，該通路上的RTK、RAS、RAF等基因常在腫瘤細胞中發生擴增或活化型突變，因此增強了MAPK信號的活化並促進腫瘤的發生發展。 Activation of the MAPK signaling pathway is one of the major cancer-promoting signals in tumor cells. After RTK receptor is activated by ligand, it sequentially activates SHP2-SOS1-RAS-RAF-MEK-ERK, ultimately promoting cell proliferation, survival and inhibiting apoptosis. In tumors, genes such as RTK, RAS, and RAF in this pathway often undergo amplification or activating mutations in tumor cells, thus enhancing the activation of MAPK signaling and promoting the occurrence and development of tumors.

SHP2是由PTPN11基因編碼的非受體蛋白質酪胺酸磷酸酶，其促進多種細胞功能，包括增殖、分化、細胞週期維持和遷移。SHP2參與經由RAS-絲裂原活化蛋白激酶(MAPK)、JAK-STAT和/或磷酸肌醇3-激酶-AKT途徑進行的信號傳導。WO2018205985A公開了一種新的PD-L1/TGF-β融合蛋白，目前尚未見其藥物聯用的相關信息。WO2020259679A 公開了一種SHP2抑制劑；WO202020-0069A公開了式(II)所示化合物，其為ERK抑制劑；WO2019051084A關於一類治療癌症的SHP2抑制劑組成物和方法，為了達到更好的腫瘤治療效果的目的，更好的滿足市場需求，我們希望開發SHP2抑制劑與其他治療劑組合施用的新方法或用途，例如與ERK抑制劑組合施用治療腫瘤。 SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which promotes multiple cellular functions, including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling via the RAS-mitogen-activated protein kinase (MAPK), JAK-STAT and/or phosphoinositide 3-kinase-AKT pathways. WO2018205985A discloses a new PD-L1/TGF-β fusion protein, but there is currently no relevant information on its drug combination. WO2020259679A A SHP2 inhibitor is disclosed; WO202020-0069A discloses a compound represented by formula (II), which is an ERK inhibitor; WO2019051084A is about a type of SHP2 inhibitor composition and method for treating cancer, in order to achieve better tumor treatment effects , to better meet market demand, we hope to develop new methods or uses of SHP2 inhibitors combined with other therapeutic agents, such as combined with ERK inhibitors to treat tumors.

本揭露提供一種式(I)所示化合物或其藥學上可接受的鹽，在製備治療含有RAS通路基因突變的腫瘤的藥物中的用途， The present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in preparing a drug for treating tumors containing RAS pathway gene mutations,

其中R¹選自氫、氘、胺基、鹵素、C_1-6烷基；R²選自氘、鹵素、胺基、C_1-6烷基、C_1-6烷基取代的胺基，該C_1-6烷基、C_1-6烷基取代的胺基中C_1-6烷基視需要被氘取代； Wherein R ¹ is selected from hydrogen, deuterium, amine group, halogen, C _1-6 alkyl group; R ² is selected from deuterium, halogen, amine group, C _1-6 alkyl group, C _1-6 alkyl substituted amine group, The _C _1-6 alkyl group in the C 1-6 alkyl group or the C _1-6 alkyl substituted amino group is optionally substituted with deuterium;

X₁和X₂各自獨立的選自-CH-或氮； X ₁ and X ₂ are each independently selected from -CH- or nitrogen;

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

R⁴選自氘、鹵素、胺基、C_1-6烷基、C_1-6烷基取代的胺基； R ⁴ is selected from deuterium, halogen, amino group, C _1-6 alkyl group, C _1-6 alkyl substituted amine group;

m和n各自獨立地選自0，1，2或3； m and n are each independently selected from 0, 1, 2 or 3;

該RAS途徑基因突變選自KRAS突變、NRAS突變、HRAS突變、SOS突變、BRAF突變和NF1突變。 The RAS pathway gene mutation is selected from the group consisting of KRAS mutation, NRAS mutation, HRAS mutation, SOS mutation, BRAF mutation and NF1 mutation.

本揭露另一方面提供一種用於治療含有RAS通路基因突變的腫瘤的式(I)所示化合物或其藥學上可接受的鹽，該RAS途徑基因突變選自KRAS突變、NRAS突變、HRAS突變、SOS突變、BRAF突變和NF1突變。 Another aspect of the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treating tumors containing RAS pathway gene mutations, where the RAS pathway gene mutations are selected from KRAS mutations, NRAS mutations, HRAS mutations, SOS mutations, BRAF mutations and NF1 mutations.

一些實施方案中，該KRAS突變選自KRAS^G12A突變、KRAS^G12C突變、KRAS^G12D突變、KRAS^G12F突變、KRAS^G12I突變、KRAS^G12L突變、KRAS^G12R突變、KRAS^G12S突變、KRAS^G12V突變或KRAS^G12Y突變。 In some embodiments, the KRAS mutation is selected from the group consisting of KRAS ^G12A mutation, KRAS ^G12C mutation, KRAS ^G12D mutation, KRAS ^G12F mutation, KRAS ^G12I mutation, KRAS ^G12L mutation, KRAS ^G12R mutation, KRAS ^G12S mutation, KRAS ^G12V mutation, or KRAS ^G12Y mutation.

一些實施方案中，該RAS通路基因突變選自KRAS^G12C突變、KRAS^G12D突變或BRAF-Class3突變、編碼NF1功能喪失(NF1^LOF)變體的突變或EGFR擴增或突變。 In some embodiments, the RAS pathway gene mutation is selected from the group consisting of a KRAS ^G12C mutation, a KRAS ^G12D mutation, or a BRAF-Class3 mutation, a mutation encoding an NFl loss-of-function (NF1 ^LOF ) variant, or an EGFR amplification or mutation.

本共開另一方面提供一種式(I)所示化合物或其藥學上可接受的鹽與RAS通路抑制劑聯合在製備治療腫瘤的藥物中的用途。 Another aspect of the present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with a RAS pathway inhibitor in the preparation of a drug for treating tumors.

本揭露另一方面提供一種式(I)所示化合物或其藥學上可接受的鹽與PD-L1抗體或抗原結合片段、或含有TGF-β受體的融合蛋白聯合在製備治療腫瘤的藥物中的用途。 Another aspect of the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, combined with a PD-L1 antibody or antigen-binding fragment, or a fusion protein containing a TGF-β receptor, in the preparation of a drug for treating tumors. the use of.

一些實施方案中，本揭露中該腫瘤為RAS途徑基因突變腫瘤，該RAS途徑基因突變選自KRAS突變、NRAS突變、HRAS突變、SOS突變、BRAF突變和NF1突變。 In some embodiments, the tumor in the present disclosure is a tumor with a RAS pathway gene mutation, and the RAS pathway gene mutation is selected from the group consisting of KRAS mutation, NRAS mutation, HRAS mutation, SOS mutation, BRAF mutation and NFl mutation.

一些實施方案中，該KRAS突變選自KRAS^G12A突變、KRAS^G12C突變、KRAS^G12D突變、KRAS^G12F突變、KRAS^G12I突變、 KRAS^G12L突變、KRAS^G12R突變、KRAS^G12S突變、KRAS^G12V突變或KRAS^G12Y突變。 In some embodiments, the KRAS mutation is selected from the group consisting of a KRAS ^G12A mutation, a KRAS ^G12C mutation, a KRAS ^G12D mutation, a KRAS ^G12F mutation, a KRAS ^G12I mutation, a ^{KRAS G12L mutation, a KRAS G12R mutation, a KRAS G12S} ^mutation ^, a KRAS ^G12V mutation, or a KRAS ^G12Y mutation.

一些實施方案中，本揭露中該RAS通路抑制劑為MEK抑制劑。 In some embodiments, the RAS pathway inhibitor of the present disclosure is a MEK inhibitor.

一些實施方案中，本揭露中該RAS通路抑制劑為ERK抑制劑。 In some embodiments, the RAS pathway inhibitor of the present disclosure is an ERK inhibitor.

一些實施方案中，本揭露中該RAS通路抑制劑為EGFR抑制劑。 In some embodiments, the RAS pathway inhibitor of the present disclosure is an EGFR inhibitor.

一些實施方案中，本揭露中該EGFR擴增或突變的腫瘤選自食管癌、肝細胞癌或非小細胞肺癌。 In some embodiments, the EGFR amplified or mutated tumor of the present disclosure is selected from esophageal cancer, hepatocellular carcinoma, or non-small cell lung cancer.

些實施方案中，本揭露中該EGFR擴增或突變的腫瘤選自局部晚期或轉移性EGFR突變的非小細胞肺癌。 In some embodiments, the EGFR amplified or mutated tumor in the present disclosure is selected from locally advanced or metastatic EGFR mutated non-small cell lung cancer.

一些實施方案中，本揭露中該KRAS^G12C突變腫瘤選自非小細胞肺癌、胰腺癌、結直腸癌。 In some embodiments, the KRAS ^G12C mutant tumor in the present disclosure is selected from the group consisting of non-small cell lung cancer, pancreatic cancer, and colorectal cancer.

一些實施方案中，本揭露中該KRAS^G12D突變腫瘤選自胃癌、結腸癌、胰腺癌、結腸直腸癌、肺癌、子宮內膜癌、卵巢癌或***癌。 In some embodiments, the KRAS ^G12D mutant tumor of the present disclosure is selected from the group consisting of gastric cancer, colon cancer, pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, ovarian cancer, or prostate cancer.

一些實施方案中，本揭露中該式(I)所示化合物或其藥學上可接受的鹽選自， In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from,

一些實施方案中，本揭露中該式(I)所示化合物或其藥學上可接受的鹽為

。 In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the present disclosure is

.

一些實施方案中，本揭露中該式(I)所示化合物或其藥學上可接受的鹽給藥劑量選自0.1mg-500mg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In some embodiments, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt in the present disclosure is selected from 0.1 mg to 500 mg, and the dosage frequency is once a day, twice a day, or once every two days. , once every three days or once a week.

一些實施方案中，本揭露中該式(I)所示化合物或其藥學上可接受的鹽給藥劑量選自1mg、2mg、4mg、6mg、8mg、10mg、12mg、14mg、16mg、18mg、20mg、22mg、24mg、26mg、28mg、30mg、32mg、34mg、36mg、38mg、40mg、42mg、44mg、46mg、48mg、50mg、52mg、54mg、56mg、58mg、60mg、62mg、64mg、66mg、68mg、70mg、72mg、74mg、76mg、78mg、80mg、82mg、84mg、86mg、88mg、90mg、92mg、94mg、96mg、98mg、100mg、102mg、104mg、106mg、108mg、110mg、112mg、114mg、116mg、118mg、120mg、122mg、124mg、126mg、128mg、 130mg、132mg、134mg、136mg、138mg、140mg、142mg、144mg、146mg、148mg、150mg、152mg、154mg、156mg、158mg、160mg、162mg、164mg、166mg、168mg、170mg、172mg、174mg、176mg、178mg、180mg、182mg、184mg、186mg、188mg、190mg、192mg、194mg、196mg、198mg、200mg、202mg、204mg、206mg、208mg、210mg、212mg、214mg、216mg、218mg、220mg、222mg、224mg、226mg、228mg、230mg、232mg、234mg、236mg、238mg、240mg、242mg、244mg、246mg、248mg、250mg、252mg、254mg、256mg、258mg、260mg、262mg、264mg、266mg、268mg、270mg、272mg、274mg、276mg、278mg、280mg、282mg、284mg、286mg、288mg、290mg、292mg、294mg、296mg、298mg、300mg、302mg、304mg、306mg、308mg、310mg、312mg、314mg、316mg、318mg、320mg、322mg、324mg、326mg、328mg、330mg、332mg、334mg、336mg、338mg、340mg、342mg、344mg、346mg、348mg、350mg、352mg、354mg、356mg、358mg、360mg、362mg、364mg、366mg、368mg、370mg、372mg、374mg、376mg、378mg、380mg、382mg、384mg、386mg、388mg、390mg、392mg、394mg、396mg、398mg、400mg、402mg、404mg、406mg、408mg、410mg、412mg、414mg、416mg、418mg、420mg、422mg、424mg、426mg、428mg、430mg、432mg、434mg、436mg、438mg、440mg、442mg、444mg、446mg、448mg、450mg、452mg、454mg、456mg、458mg、460mg、462mg、464mg、466mg、468mg、470mg、472mg、474mg、476mg、478mg、480mg、482mg、484mg、486mg、488mg、490mg、492mg、494mg、496mg、498mg或500mg或者任意兩點之間的數值，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg , 22mg, 24mg, 26mg, 28mg, 30mg, 32mg, 34mg, 36mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg, 58mg, 60mg, 62mg, 64mg, 66mg, 68mg, 70mg , 72mg, 74mg, 76mg, 78mg, 80mg, 82mg, 84mg, 86mg, 88mg, 90mg, 92mg, 94mg, 96mg, 98mg, 100mg, 102mg, 104mg, 106mg, 108mg, 110mg, 112mg, 114mg, 116mg, 118mg, 120mg ,122mg, 124mg, 126mg, 128mg, 130mg, 132mg, 134mg, 136mg, 138mg, 140mg, 142mg, 144mg, 146mg, 148mg, 150mg, 152mg, 154mg, 156mg, 158mg, 160mg, 162mg, 164mg, 166mg, 168mg, 170mg, 172mg, 174mg, 176mg, 178 mg, 180mg,182mg,184mg,186mg,188mg,190mg,192mg,194mg,196mg,198mg,200mg,202mg,204mg,206mg,208mg,210mg,212mg,214mg,216mg,218mg,220mg,222mg,224mg,226mg,228 mg, 230mg, 232mg, 234mg, 236mg, 238mg, 240mg, 242mg, 244mg, 246mg, 248mg, 250mg, 252mg, 254mg, 256mg, 258mg, 260mg, 262mg, 264mg, 266mg, 268mg, 270mg, 272mg, 274mg, 276mg, 278 mg, 328 mg, 330mg, 332mg, 334mg, 336mg, 338mg, 340mg, 342mg, 344mg, 346mg, 348mg, 350mg, 352mg, 354mg, 356mg, 358mg, 360mg, 362mg, 364mg, 366mg, 368mg, 370mg, 372mg, 374mg, 376mg, 378 mg, 428 mg, 430mg, 432mg, 434mg, 436mg, 438mg, 440mg, 442mg, 444mg, 446mg, 448mg, 450mg, 452mg, 454mg, 456mg, 458mg, 460mg, 462mg, 464mg, 466mg, 468mg, 470mg, 472mg, 474mg, 476mg, 478 mg, 480mg, 482mg, 484mg, 486mg, 488mg, 490mg, 492mg, 494mg, 496mg, 498mg or 500mg or a value between any two points. The frequency of administration is once a day, twice a day, once every two days or once every three days. Or once a week.

可選的實施方案中，本揭露中該式(I)所示化合物或其藥學上可接受的鹽給藥劑量選自2mg、4mg、6mg、8mg、10mg、12mg、14mg、16mg、18mg、20mg、22mg、24mg、26mg、28mg、30mg、32mg、34mg、36mg、38mg、40mg、42mg、44mg、46mg、48mg、50mg、52mg、54mg、56mg、58mg、60mg、62mg、64mg、66mg、68mg、70mg、72mg、74mg、76mg、78mg、80mg、82mg、84mg、86mg、88mg、90mg、92mg、94mg、96mg、98mg或100mg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In an optional embodiment, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from the group consisting of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, and 20 mg. , 22mg, 24mg, 26mg, 28mg, 30mg, 32mg, 34mg, 36mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg, 58mg, 60mg, 62mg, 64mg, 66mg, 68mg, 70mg , 72mg, 74mg, 76mg, 78mg, 80mg, 82mg, 84mg, 86mg, 88mg, 90mg, 92mg, 94mg, 96mg, 98mg or 100mg. The frequency of administration is once a day, twice a day, once every two days, or three days. Once or once a week.

可選的實施方案中，本揭露該式(I)所示化合物或其藥學上可接受的鹽給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次。 In an optional embodiment, the dosage of the compound represented by formula (I) of the present disclosure or its pharmaceutically acceptable salt is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the dosage frequency is once a day.

可選的實施方案中，本揭露中該式(I)所示化合物或其藥學上可接受的鹽給藥劑量選自0.01-20mg/kg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In an optional embodiment, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt in the present disclosure is selected from 0.01-20 mg/kg, and the dosage frequency is once a day, twice a day, Once every two days, once every three days or once a week.

可選的實施方案中，本揭露中該式(I)所示化合物或其藥學上可接受的鹽給藥劑量選自0.05mg/kg、0.10mg/kg、0.15mg/kg、0.20mg/kg、0.25mg/kg、0.30mg/kg、0.35mg/kg、0.40mg/kg、0.45mg/kg、0.50mg/kg、0.55mg/kg、0.60mg/kg、0.65mg/kg、0.70mg/kg、0.75mg/kg、0.80mg/kg、0.85mg/kg、0.90mg/kg、0.95mg/kg、1.00mg/kg、1.05mg/kg、1.10mg/kg、1.15mg/kg、1.20mg/kg、1.25mg/kg、1.30mg/kg、1.35mg/kg、1.40mg/kg、1.45mg/kg、1.50mg/kg、1.55mg/kg、1.60mg/kg、1.65mg/kg、1.70mg/kg、1.75mg/kg、1.80mg/kg、1.85 mg/kg、1.90mg/kg、1.95mg/kg、2.00mg/kg、2.05mg/kg、2.10mg/kg、2.15mg/kg、2.20mg/kg、2.25mg/kg、2.30mg/kg、2.35mg/kg、2.40mg/kg、2.45mg/kg、2.50mg/kg、2.55mg/kg、2.60mg/kg、2.65mg/kg、2.70mg/kg、2.75mg/kg、2.80mg/kg、2.85mg/kg、2.90mg/kg、2.95mg/kg、3.00mg/kg、3.05mg/kg、3.10mg/kg、3.15mg/kg、3.20mg/kg、3.25mg/kg、3.30mg/kg、3.35mg/kg、3.40mg/kg、3.45mg/kg、3.50mg/kg、3.55mg/kg、3.60mg/kg、3.65mg/kg、3.70mg/kg、3.75mg/kg、3.80mg/kg、3.85mg/kg、3.90mg/kg、3.95mg/kg、4.00mg/kg、4.05mg/kg、4.10mg/kg、4.15mg/kg、4.20mg/kg、4.25mg/kg、4.30mg/kg、4.35mg/kg、4.40mg/kg、4.45mg/kg、4.50mg/kg、4.55mg/kg、4.60mg/kg、4.65mg/kg、4.70mg/kg、4.75mg/kg、4.80mg/kg、4.85mg/kg、4.90mg/kg、4.95mg/kg、5.00mg/kg、5.05mg/kg、5.10mg/kg、5.15mg/kg、5.20mg/kg、5.25mg/kg、5.30mg/kg、5.35mg/kg、5.40mg/kg、5.45mg/kg、5.50mg/kg、5.55mg/kg、5.60mg/kg、5.65mg/kg、5.70mg/kg、5.75mg/kg、5.80mg/kg、5.85mg/kg、5.90mg/kg、5.95mg/kg、6.00mg/kg、6.05mg/kg、6.10mg/kg、6.15mg/kg、6.20mg/kg、6.25mg/kg、6.30mg/kg、6.35mg/kg、6.40mg/kg、6.45mg/kg、6.50mg/kg、6.55mg/kg、6.60mg/kg、6.65mg/kg、6.70mg/kg、6.75mg/kg、6.80mg/kg、6.85mg/kg、6.90mg/kg、6.95mg/kg、7.00mg/kg、7.05mg/kg、7.10mg/kg、7.15mg/kg、7.20mg/kg、7.25mg/kg、7.30mg/kg、7.35mg/kg、7.40mg/kg、7.45mg/kg、7.50mg/kg、7.55mg/kg、7.60mg/kg、7.65mg/kg、7.70mg/kg、7.75mg/kg、7.80mg/kg、7.85mg/kg、7.90 mg/kg、7.95mg/kg、8.00mg/kg、8.05mg/kg、8.10mg/kg、8.15mg/kg、8.20mg/kg、8.25mg/kg、8.30mg/kg、8.35mg/kg、8.40mg/kg、8.45mg/kg、8.50mg/kg、8.55mg/kg、8.60mg/kg、8.65mg/kg、8.70mg/kg、8.75mg/kg、8.80mg/kg、8.85mg/kg、8.90mg/kg、8.95mg/kg、9.00mg/kg、9.05mg/kg、9.10mg/kg、9.15mg/kg、9.20mg/kg、9.25mg/kg、9.30mg/kg、9.35mg/kg、9.40mg/kg、9.45mg/kg、9.50mg/kg、9.55mg/kg、9.60mg/kg、9.65mg/kg、9.70mg/kg、9.75mg/kg、9.80mg/kg、9.85mg/kg、9.90mg/kg、9.95mg/kg或10.00mg/kg或任意兩點之間的點值，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In an optional embodiment, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from the group consisting of 0.05 mg/kg, 0.10 mg/kg, 0.15 mg/kg, and 0.20 mg/kg. , 0.25mg/kg, 0.30mg/kg, 0.35mg/kg, 0.40mg/kg, 0.45mg/kg, 0.50mg/kg, 0.55mg/kg, 0.60mg/kg, 0.65mg/kg, 0.70mg/kg , 0.75mg/kg, 0.80mg/kg, 0.85mg/kg, 0.90mg/kg, 0.95mg/kg, 1.00mg/kg, 1.05mg/kg, 1.10mg/kg, 1.15mg/kg, 1.20mg/kg , 1.25mg/kg, 1.30mg/kg, 1.35mg/kg, 1.40mg/kg, 1.45mg/kg, 1.50mg/kg, 1.55mg/kg, 1.60mg/kg, 1.65mg/kg, 1.70mg/kg ,1.75mg/kg, 1.80mg/kg, 1.85 mg/kg, 1.90mg/kg, 1.95mg/kg, 2.00mg/kg, 2.05mg/kg, 2.10mg/kg, 2.15mg/kg, 2.20mg/kg, 2.25mg/kg, 2.30mg/kg, 2.35 mg/kg, 2.40mg/kg, 2.45mg/kg, 2.50mg/kg, 2.55mg/kg, 2.60mg/kg, 2.65mg/kg, 2.70mg/kg, 2.75mg/kg, 2.80mg/kg, 2.85 mg/kg, 2.90mg/kg, 2.95mg/kg, 3.00mg/kg, 3.05mg/kg, 3.10mg/kg, 3.15mg/kg, 3.20mg/kg, 3.25mg/kg, 3.30mg/kg, 3.35 mg/kg, 3.40mg/kg, 3.45mg/kg, 3.50mg/kg, 3.55mg/kg, 3.60mg/kg, 3.65mg/kg, 3.70mg/kg, 3.75mg/kg, 3.80mg/kg, 3.85 mg/kg, 3.90mg/kg, 3.95mg/kg, 4.00mg/kg, 4.05mg/kg, 4.10mg/kg, 4.15mg/kg, 4.20mg/kg, 4.25mg/kg, 4.30mg/kg, 4.35 mg/kg, 4.40mg/kg, 4.45mg/kg, 4.50mg/kg, 4.55mg/kg, 4.60mg/kg, 4.65mg/kg, 4.70mg/kg, 4.75mg/kg, 4.80mg/kg, 4.85 mg/kg, 4.90mg/kg, 4.95mg/kg, 5.00mg/kg, 5.05mg/kg, 5.10mg/kg, 5.15mg/kg, 5.20mg/kg, 5.25mg/kg, 5.30mg/kg, 5.35 mg/kg, 5.40mg/kg, 5.45mg/kg, 5.50mg/kg, 5.55mg/kg, 5.60mg/kg, 5.65mg/kg, 5.70mg/kg, 5.75mg/kg, 5.80mg/kg, 5.85 mg/kg, 5.90mg/kg, 5.95mg/kg, 6.00mg/kg, 6.05mg/kg, 6.10mg/kg, 6.15mg/kg, 6.20mg/kg, 6.25mg/kg, 6.30mg/kg, 6.35 mg/kg, 6.40mg/kg, 6.45mg/kg, 6.50mg/kg, 6.55mg/kg, 6.60mg/kg, 6.65mg/kg, 6.70mg/kg, 6.75mg/kg, 6.80mg/kg, 6.85 mg/kg, 6.90mg/kg, 6.95mg/kg, 7.00mg/kg, 7.05mg/kg, 7.10mg/kg, 7.15mg/kg, 7.20mg/kg, 7.25mg/kg, 7.30mg/kg, 7.35 mg/kg, 7.40mg/kg, 7.45mg/kg, 7.50mg/kg, 7.55mg/kg, 7.60mg/kg, 7.65mg/kg, 7.70mg/kg, 7.75mg/kg, 7.80mg/kg, 7.85 mg/kg, 7.90 mg/kg, 7.95mg/kg, 8.00mg/kg, 8.05mg/kg, 8.10mg/kg, 8.15mg/kg, 8.20mg/kg, 8.25mg/kg, 8.30mg/kg, 8.35mg/kg, 8.40 mg/kg, 8.45mg/kg, 8.50mg/kg, 8.55mg/kg, 8.60mg/kg, 8.65mg/kg, 8.70mg/kg, 8.75mg/kg, 8.80mg/kg, 8.85mg/kg, 8.90 mg/kg, 8.95mg/kg, 9.00mg/kg, 9.05mg/kg, 9.10mg/kg, 9.15mg/kg, 9.20mg/kg, 9.25mg/kg, 9.30mg/kg, 9.35mg/kg, 9.40 mg/kg, 9.45mg/kg, 9.50mg/kg, 9.55mg/kg, 9.60mg/kg, 9.65mg/kg, 9.70mg/kg, 9.75mg/kg, 9.80mg/kg, 9.85mg/kg, 9.90 mg/kg, 9.95mg/kg or 10.00mg/kg or any point value between two points. The dosing frequency is once a day, twice a day, once every two days, once every three days or once a week.

一些實施方案中，本揭露中該MEK抑制劑選自曲美替尼、司美替尼、 In some embodiments, the MEK inhibitor of the present disclosure is selected from the group consisting of trametinib, selumetinib,

考比替尼、比美替尼、皮瑪西尼(Pimasertib)、TAK733、RO4987655、CI-1040、PD-0325901、瑞美替尼、RO5126766、AZD8330、CH5126766、MAP855或GSK1120212。 Cobimetinib, bimetinib, Pimasertib, TAK733, RO4987655, CI-1040, PD-0325901, remetinib, RO5126766, AZD8330, CH5126766, MAP855, or GSK1120212.

一些實施方案中，本揭露中該MEK抑制劑為曲美替尼。 In some embodiments, the MEK inhibitor of the present disclosure is trametinib.

一些實施方案中，本揭露中該MEK抑制劑的給藥劑量選自0.1-1000mg，給藥頻次為一日一次或一日兩次。 In some embodiments, the dosage of the MEK inhibitor in the present disclosure is selected from 0.1-1000 mg, and the administration frequency is once a day or twice a day.

一些實施方案中，本揭露中該MEK抑制劑的給藥劑量選自1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、 400mg、425mg、450mg、475mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg或1000mg，給藥頻次為一日一次或一日兩次。 In some embodiments, the dosage of the MEK inhibitor in the present disclosure is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg or 1000mg. The dosage frequency is once a day or twice a day.

一些實施方案中，本揭露中該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In some embodiments, the MEK inhibitor in the present disclosure is trametinib, the dosage is 1 mg or 2 mg, and the dosage frequency is once a day.

一些實施方案中，本揭露中該ERK抑制劑選自ASTX-029、ASN-007、林內特基(rineterkib)、LY-3214996、烏利替尼(ulixertinib)、HH-2710或式(II)所示化合物或其藥學上可接受的鹽

。 In some embodiments, the ERK inhibitor of the present disclosure is selected from ASTX-029, ASN-007, rineterkib, LY-3214996, ulixertinib, HH-2710 or formula (II) The indicated compound or a pharmaceutically acceptable salt thereof

.

一些實施方案中，本揭露中該ERK抑制劑選自式(II)所示化合物或其藥學上可接受的鹽。 In some embodiments, the ERK inhibitor in the present disclosure is selected from compounds represented by formula (II) or pharmaceutically acceptable salts thereof.

一些實施方案中，本揭露中該ERK抑制劑選自式(II)所示化合物的富馬酸鹽。 In some embodiments, the ERK inhibitor in the present disclosure is selected from the fumarate salt of the compound represented by formula (II).

可選的實施方案中，本揭露中該ERK抑制劑的給藥劑量選自1mg-1000mg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In an optional embodiment, the dosage of the ERK inhibitor in the present disclosure is selected from 1 mg to 1000 mg, and the administration frequency is once a day, twice a day, once every two days, once every three days, or once a week.

可選的實施方案中，本揭露中該ERK抑制劑的給藥劑量選自5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、 195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg、605mg、610mg、615mg、620mg、625mg、630mg、635mg、640mg、645mg、650mg、655mg、660mg、665mg、670mg、675mg、680mg、685mg、690mg、695mg或700mg，或者任意兩點之間的數值，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In optional embodiments, the dosage of the ERK inhibitor in the present disclosure is selected from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315 mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440 mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565 mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690 mg, 695 mg or 700 mg, or any value between two points, and the frequency of administration is once a day, twice a day, once every two days, once every three days or once a week.

可選的實施方案中，本揭露中該ERK抑制劑的給藥劑量選自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg或700mg，給藥頻次選自一日一次或一日二次。 In optional embodiments, the dosage of the ERK inhibitor in the present disclosure is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg or 700mg. The dosage frequency is selected from once a day or twice a day.

可選的實施方案中，本揭露中該ERK抑制劑的給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the dosage of the ERK inhibitor in the present disclosure is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the administration frequency is selected from once a day or twice a day.

可選的實施方案中，本揭露中該ERK抑制劑的給藥劑量選自給藥劑量選自0.01-20mg/kg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In an optional embodiment, the dosage of the ERK inhibitor in the present disclosure is selected from the group consisting of 0.01-20 mg/kg, and the dosage frequency is once a day, twice a day, once every two days, or once every three days. Or once a week.

可選的實施方案中，本揭露中該ERK抑制劑的給藥劑量選自給藥劑量選自0.10mg/kg、0.20mg/kg、0.30mg/kg、0.40mg/kg、0.50mg/kg、0.60mg/kg、0.70mg/kg、0.80mg/kg、0.90mg/kg、1.00mg/kg、1.10mg/kg、1.20mg/kg、1.30mg/kg、1.40mg/kg、1.50mg/kg、1.60mg/kg、1.70mg/kg、1.80mg/kg、1.90mg/kg、2.00mg/kg、2.10mg/kg、2.20mg/kg、2.30mg/kg、2.40mg/kg、2.50mg/kg、2.60mg/kg、2.70mg/kg、2.80mg/kg、2.90mg/kg、3.00mg/kg、3.10mg/kg、3.20mg/kg、3.30mg/kg、3.40mg/kg、3.50mg/kg、3.60mg/kg、3.70mg/kg、3.80mg/kg、3.90mg/kg、4.00mg/kg、4.10mg/kg、4.20mg/kg、4.30mg/kg、4.40mg/kg、4.50mg/kg、4.60mg/kg、4.70mg/kg、4.80mg/kg、4.90mg/kg、5.00mg/kg、5.10mg/kg、5.20mg/kg、5.30mg/kg、5.40mg/kg、5.50mg/kg、5.60mg/kg、5.70mg/kg、5.80mg/kg、5.90mg/kg、6.00mg/kg、6.10mg/kg、6.20mg/kg、6.30mg/kg、6.40mg/kg、6.50mg/kg、6.60mg/kg、6.70mg/kg、6.80mg/kg、6.90mg/kg、7.00mg/kg、7.10mg/kg、7.20mg/kg、7.30mg/kg、7.40mg/kg、7.50mg/kg、7.60mg/kg、7.70mg/kg、7.80mg/kg、7.90mg/kg、8.00mg/kg、8.10mg/kg、8.20mg/kg、8.30mg/kg、8.40mg/kg、8.50mg/kg、8.60mg/kg、8.70mg/kg、8.80mg/kg、8.90mg/kg、9.00mg/kg、9.10mg/kg、9.20mg/kg、9.30mg/kg、9.40mg/kg、9.50mg/kg、9.60mg/kg、9.70mg/kg、9.80mg/kg、 9.90mg/kg或10.00mg/kg，或者任意兩點之間的數值，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 In an optional embodiment, the dosage of the ERK inhibitor in the present disclosure is selected from the group consisting of 0.10 mg/kg, 0.20 mg/kg, 0.30 mg/kg, 0.40 mg/kg, 0.50 mg/kg, 0.60 mg/kg, 0.70mg/kg, 0.80mg/kg, 0.90mg/kg, 1.00mg/kg, 1.10mg/kg, 1.20mg/kg, 1.30mg/kg, 1.40mg/kg, 1.50mg/kg, 1.60 mg/kg, 1.70mg/kg, 1.80mg/kg, 1.90mg/kg, 2.00mg/kg, 2.10mg/kg, 2.20mg/kg, 2.30mg/kg, 2.40mg/kg, 2.50mg/kg, 2.60 mg/kg, 2.70mg/kg, 2.80mg/kg, 2.90mg/kg, 3.00mg/kg, 3.10mg/kg, 3.20mg/kg, 3.30mg/kg, 3.40mg/kg, 3.50mg/kg, 3.60 mg/kg, 3.70mg/kg, 3.80mg/kg, 3.90mg/kg, 4.00mg/kg, 4.10mg/kg, 4.20mg/kg, 4.30mg/kg, 4.40mg/kg, 4.50mg/kg, 4.60 mg/kg, 4.70mg/kg, 4.80mg/kg, 4.90mg/kg, 5.00mg/kg, 5.10mg/kg, 5.20mg/kg, 5.30mg/kg, 5.40mg/kg, 5.50mg/kg, 5.60 mg/kg, 5.70mg/kg, 5.80mg/kg, 5.90mg/kg, 6.00mg/kg, 6.10mg/kg, 6.20mg/kg, 6.30mg/kg, 6.40mg/kg, 6.50mg/kg, 6.60 mg/kg, 6.70mg/kg, 6.80mg/kg, 6.90mg/kg, 7.00mg/kg, 7.10mg/kg, 7.20mg/kg, 7.30mg/kg, 7.40mg/kg, 7.50mg/kg, 7.60 mg/kg, 7.70mg/kg, 7.80mg/kg, 7.90mg/kg, 8.00mg/kg, 8.10mg/kg, 8.20mg/kg, 8.30mg/kg, 8.40mg/kg, 8.50mg/kg, 8.60 mg/kg, 8.70mg/kg, 8.80mg/kg, 8.90mg/kg, 9.00mg/kg, 9.10mg/kg, 9.20mg/kg, 9.30mg/kg, 9.40mg/kg, 9.50mg/kg, 9.60 mg/kg, 9.70mg/kg, 9.80mg/kg, 9.90 mg/kg or 10.00 mg/kg, or a value between any two points. The administration frequency is once a day, twice a day, once every two days, once every three days or once a week.

一些實施方案中，本揭露中該EGFR抑制劑選自奧希替尼、艾維替尼、艾氟替尼、ASK120067、BPI-7711、那札替尼(Nazartinib)、HM61713或式(III)所示的化合物或其藥學上可接受的鹽， In some embodiments, the EGFR inhibitor in the present disclosure is selected from osimertinib, avitinib, aflutinib, ASK120067, BPI-7711, Nazartinib, HM61713 or formula (III). the compound shown or a pharmaceutically acceptable salt thereof,

可選的實施方案中，本揭露中該EGFR抑制劑為式(III)所示的化合物或其藥學上可接受的鹽。 In an optional embodiment, the EGFR inhibitor in the present disclosure is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

可選的實施方案中，本揭露中該EGFR抑制劑為式(III)所示的化合物的甲磺酸鹽。 In an optional embodiment, the EGFR inhibitor in the present disclosure is the mesylate salt of the compound represented by formula (III).

可選的實施方案中，該EGFR抑制劑的給藥劑量選自1-500mg，給藥頻次為一日一次或一日二次。 In an optional embodiment, the dosage of the EGFR inhibitor is selected from 1-500 mg, and the administration frequency is once a day or twice a day.

可選的實施方案中，該EGFR抑制劑的給藥劑量選自1mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、 240mg、250mg、260mg、270mg、280mg、290mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg，給藥頻次為一日一次或一日二次。 In an optional embodiment, the dosage of the EGFR inhibitor is selected from 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg. The dosage frequency is once a day or Twice a day.

可選的實施方案中，該EGFR抑制劑的給藥劑量選自55mg、110mg、220mg或260mg，給藥頻次為一日一次。 In an optional embodiment, the dosage of the EGFR inhibitor is selected from 55 mg, 110 mg, 220 mg or 260 mg, and the dosage frequency is once a day.

一些實施方案中，該PD-L1抗體或抗原結合片段任意1個選自以下的CDR區序列或其突變序列：抗體重鏈可變區HCDR區序列：SEQ ID NO：1-3；和抗體輕鏈可變區LCDR區序列：SEQ ID NO：4-6；具體如下： In some embodiments, any one of the PD-L1 antibodies or antigen-binding fragments is selected from the following CDR region sequences or mutant sequences thereof: antibody heavy chain variable region HCDR region sequence: SEQ ID NO: 1-3; and antibody light chain sequence Chain variable region LCDR region sequence: SEQ ID NO: 4-6; details are as follows:

HCDR1選自： HCDR1 is selected from:

SYWMH SEQ ID NO：1 SYWMH SEQ ID NO: 1

HCDR2選自： HCDR2 is selected from:

RIX₁PNSGX₂TSYNEKFKN SEQ ID NO：2 RIX ₁ PNSGX ₂ TSYNEKFKN SEQ ID NO: 2

HCDR3選自： HCDR3 is selected from:

GGSSYDYFDY SEQ ID NO：3 GGSSYDYFDY SEQ ID NO: 3

LCDR1選自： LCDR1 is selected from:

RASESVSIHGTHLMH SEQ ID NO：4 RASESVSIHGTHLMH SEQ ID NO: 4

LCDR2選自： LCDR2 selected from:

AASNLES SEQ ID NO：5 AASNLES SEQ ID NO: 5

LCDR3選自： LCDR3 selected from:

QQSFEDPLT SEQ ID NO：6； QQSFEDPLT SEQ ID NO: 6;

其中X₁選自H或G，X₂選自G或F。 Where X ₁ is selected from H or G, and X ₂ is selected from G or F.

可選的實施方案中X₁為G；X₂為F。 In optional embodiments, X ₁ is G; X ₂ is F.

可選的實施方案中，該PD-L1抗體或抗原結合片段的重鏈可變區序列為SEQ ID NO：7，輕鏈可變區序列為SEQ ID NO：8。 In an optional embodiment, the heavy chain variable region sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 7, and the light chain variable region sequence is SEQ ID NO: 8.

SEQ ID NO：7 SEQ ID NO: 7

SEQ ID NO：8 SEQ ID NO: 8

註：序列中斜體為FR序列；下劃線為CDR序列。 Note: The italics in the sequence are FR sequences; the underlined ones are CDR sequences.

在某些實施方式中，該PD-L1抗體或抗原結合片段可選自鼠源抗體、嵌合抗體、人源化抗體，人抗體。 In certain embodiments, the PD-L1 antibody or antigen-binding fragment can be selected from the group consisting of murine antibodies, chimeric antibodies, humanized antibodies, and human antibodies.

在某些實施方式中，該PD-L1抗體或抗原結合片段為人源化抗體。 In certain embodiments, the PD-L1 antibody or antigen-binding fragment is a humanized antibody.

可選的實施方案中，該PD-L1抗體或抗原結合片段進一步包含人源IgG1、IgG2、IgG3或IgG4或其變體的重鏈恆定區。 In an optional embodiment, the PD-L1 antibody or antigen-binding fragment further comprises the heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof.

可選的實施方案中，該PD-L1抗體或抗原結合片段進一步包含人源IgG2或IgG4重鏈恆定區或其變體的重鏈恆定區。 In an optional embodiment, the PD-L1 antibody or antigen-binding fragment further comprises a human IgG2 or IgG4 heavy chain constant region or a heavy chain constant region of a variant thereof.

可選的實施方案中，該PD-L1抗體或抗原結合片段進一步包含引入F234A和L235A突變的IgG4重鏈恆定區；該人源化抗體輕鏈進一步包含人源κ、λ鏈或其變體的恆定區。 In an optional embodiment, the PD-L1 antibody or antigen-binding fragment further comprises an IgG4 heavy chain constant region incorporating F234A and L235A mutations; the humanized antibody light chain further comprises human kappa, lambda chains or variants thereof constant region.

可選的實施方案中，該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11。 In an optional embodiment, the heavy chain sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11.

重鏈序列 heavy chain sequence

SEQ ID NO：9 SEQ ID NO: 9

重鏈序列編碼基因序列 Heavy chain sequence encoding gene sequence

SEQ ID NO：10 SEQ ID NO: 10

輕鏈序列 light chain sequence

SEQ ID NO：11 SEQ ID NO: 11

輕鏈序列編碼基因序列： Light chain sequence encoding gene sequence:

SEQ ID NO：12 SEQ ID NO: 12

可選的實施方案中，該PD-L1抗體或抗原結合片段劑量選自1-200mg/kg，給藥頻次為一週一次、一週兩次、兩週一次、三週一次或四週一次。 In an optional embodiment, the dose of the PD-L1 antibody or antigen-binding fragment is selected from 1-200 mg/kg, and the administration frequency is once a week, twice a week, once every two weeks, once every three weeks, or once every four weeks.

可選的實施方案中，該PD-L1抗體或抗原結合片段劑量選自1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、55mg/kg、60mg/kg、65mg/kg、70mg/kg、75mg/kg、80mg/kg、85mg/kg、90mg/kg、95mg/kg、100mg/kg、105mg/kg、110mg/kg、115mg/kg、120mg/kg、125mg/kg、130mg/kg、135mg/kg、140mg/kg、145mg/kg、150mg/kg、155mg/kg、160mg/kg、165mg/kg、170mg/kg、175mg/kg、180mg/kg、185mg/kg、190mg/kg、195mg/kg或200mg/kg，給藥頻次為兩週一次或三週一次。 In an optional embodiment, the dose of the PD-L1 antibody or antigen-binding fragment is selected from 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg , 40mg/kg, 45mg/kg, 50mg/kg, 55mg/kg, 60mg/kg, 65mg/kg, 70mg/kg, 75mg/kg, 80mg/kg, 85mg/kg, 90mg/kg, 95mg/kg, 100mg /kg, 105mg/kg, 110mg/kg, 115mg/kg, 120mg/kg, 125mg/kg, 130mg/kg, 135mg/kg, 140mg/kg, 145mg/kg, 150mg/kg, 155mg/kg, 160mg/kg , 165mg/kg, 170mg/kg, 175mg/kg, 180mg/kg, 185mg/kg, 190mg/kg, 195mg/kg or 200mg/kg. The dosage frequency is once every two weeks or once every three weeks.

可選的實施方案中，該PD-L1抗體或抗原結合片段劑量選自10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg或50mg/kg，給藥頻次為兩週一次或三週一次。 In an optional embodiment, the dose of the PD-L1 antibody or antigen-binding fragment is selected from the group consisting of 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, and 45 mg/kg. Or 50mg/kg, the administration frequency is once every two weeks or once every three weeks.

可選的實施方案中該PD-L1抗體或抗原結合片段劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the dose of the PD-L1 antibody or antigen-binding fragment is 20 mg/kg, and the administration frequency is once every three weeks.

一些實施方案中，該含有TGF-β受體的融合蛋白包含PD-L1抗體或其抗原結合片段和TGF-β受體，其中TGF-β受體部分為TGF-βRII胞外區的N端截短形式。 In some embodiments, the TGF-β receptor-containing fusion protein comprises a PD-L1 antibody or an antigen-binding fragment thereof and a TGF-β receptor, wherein the TGF-β receptor portion is an N-terminal truncation of the extracellular domain of TGF-βRII. Short form.

在某些實施方式中，該TGF-β受體融合蛋白如通式(IV)所示： In certain embodiments, the TGF-β receptor fusion protein is represented by general formula (IV):

Ab-L-TGF-βRII ECD (IV) Ab-L-TGF-βRII ECD (IV)

其中TGF-βRII ECD為TGF-βRII胞外區的截短形式； Among them, TGF-βRII ECD is a truncated form of the extracellular domain of TGF-βRII;

Ab為PD-L1抗體或其抗原結合片段； Ab is PD-L1 antibody or its antigen-binding fragment;

L為連接序列。 L is the connection sequence.

在某些實施方式中，該連接序列為(G₄S)xG，其中x選自3-6。 In certain embodiments, the linking sequence is (G ₄ S)xG, where x is selected from 3-6.

在某些實施方式中，該連接序列為(G₄S)xG，其中x為4。 In certain embodiments, the linker sequence is (G ₄ S)xG, where x is 4.

在某些實施方式中，該PD-L1抗體或其抗原結合片段包含：分別如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3，和分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3，其中，前面所述的各CDR序列如下所示： In certain embodiments, the PD-L1 antibody or antigen-binding fragment thereof comprises: HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, wherein the previously mentioned CDR sequences are as follows:

HCDR1：SYWMH SEQ ID NO：1 HCDR1：SYWMH SEQ ID NO：1

HCDR2：RIX₁PNSGX₂TSYNEKFKN SEQ ID NO：2 HCDR2: RIX ₁ PNSGX ₂ TSYNEKFKN SEQ ID NO: 2

HCDR3：GGSSYDYFDY SEQ ID NO：3 HCDR3：GGSSYDYFDY SEQ ID NO：3

LCDR1：RASESVSIHGTHLMH SEQ ID NO：4 LCDR1:RASESVSIHGTHLMH SEQ ID NO:4

LCDR2：AASNLES SEQ ID NO：5 LCDR2：AASNLES SEQ ID NO：5

LCDR3：QQSFEDPLT SEQ ID NO：6 LCDR3: QQSFEDPLT SEQ ID NO: 6

其中X₁為G，X₂為F。 Where X ₁ is G and X ₂ is F.

在某些實施方式中，該PD-L1抗體或其抗原結合片段謂嵌合抗體或其功能片段、人源化抗體或其功能片段或人抗體或其功能片段。 In certain embodiments, the PD-L1 antibody or antigen-binding fragment thereof is a chimeric antibody or functional fragment thereof, a humanized antibody or functional fragment thereof, or a human antibody or functional fragment thereof.

在某些實施方式中，該人源化PD-L1抗體重、輕鏈的序列如下所示： In certain embodiments, the sequences of the heavy and light chains of the humanized PD-L1 antibody are as follows:

PD-L1抗體重鏈可變區： PD-L1 antibody heavy chain variable region:

SEQ ID NO：7 SEQ ID NO: 7

PD-L1抗體輕鏈可變區： PD-L1 antibody light chain variable region:

SEQ ID NO：8 SEQ ID NO: 8

註：順序為FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4，序列中斜體為FR序列；下劃線為CDR序列，其中雙下劃線的位點為親和力成熟篩選後得到的位點。 Note: The sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, the italics in the sequence are the FR sequences; the underlined are the CDR sequences, and the double-underlined sites are sites obtained after affinity maturation screening.

在某些實施方案中，該PD-L1抗體或其抗原結合片段的重鏈胺基酸序列如SEQ ID NO：13所示或與SEQ ID NO：13所示的序列具有至少85%，86%，87%，88%，89%，90%，91%，92%，93%，94%，95%，96%，97%，98%，99%或100%的序列同一性，該PD-L1抗體或其抗原結合片段的輕鏈胺基酸序列如SEQ ID NO：14所示或與SEQ ID NO：14所示的序列具有至少85%，86%，87%，88%，89%，90%，91%，92%，93%，94%，95%，96%，97%，98%，99%或100%的序列同一性，其中 In certain embodiments, the heavy chain amino acid sequence of the PD-L1 antibody or antigen-binding fragment thereof is as set forth in SEQ ID NO: 13 or is at least 85%, 86% identical to the sequence set forth in SEQ ID NO: 13 , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, the PD- The light chain amino acid sequence of the L1 antibody or its antigen-binding fragment is as shown in SEQ ID NO: 14 or has at least 85%, 86%, 87%, 88%, 89% with the sequence shown in SEQ ID NO: 14. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, where

PD-L1抗體重鏈序列：Ig G4(AA)(S228P) PD-L1 antibody heavy chain sequence: IgG4(AA)(S228P)

SEQ ID NO：13 SEQ ID NO: 13

PD-L1抗體輕鏈序列： PD-L1 antibody light chain sequence:

SEQ ID NO：14 SEQ ID NO: 14

本揭露中TGF-βRII胞外結構域及其截短形式的非限制性實施例序列如下： Non-limiting example sequences of the TGF-βRII extracellular domain and its truncated forms in the present disclosure are as follows:

TGF-βRII胞外結構域序列：ECD(1-136) TGF-βRII extracellular domain sequence: ECD(1-136)

SEQ ID NO：15 SEQ ID NO: 15

TGF-βRII胞外結構域序列在N端有19個胺基酸的截短或缺失：ECD(20-136) The TGF-βRII extracellular domain sequence has 19 amino acids truncated or deleted at the N-terminus: ECD (20-136)

SEQ ID NO：16 SEQ ID NO: 16

TGF-βRII胞外結構域序列在N端有21個胺基酸的截短或缺失：ECD(22-136) The TGF-βRII extracellular domain sequence has 21 amino acids truncated or deleted at the N terminus: ECD (22-136)

SEQ ID NO：17 SEQ ID NO: 17

TGF-βRII胞外結構域序列在N端有14個胺基酸的截短或缺失：ECD(15-136) The TGF-βRII extracellular domain sequence has 14 amino acid truncations or deletions at the N-terminus: ECD (15-136)

SEQ ID NO：18 SEQ ID NO: 18

利用同源重組技術將PD-L1抗體的重鏈C末端胺基酸藉由(G₄S)_xG連接不同長度TGF-βRII胞外區，與輕鏈一起，藉由293表達系統進行常規表達，得到如表1所示的融合蛋白： Using homologous recombination technology, the C-terminal amino acid of the heavy chain of the PD-L1 antibody is connected to the TGF-βRII extracellular region of different lengths through (G ₄ S) _x G, and together with the light chain, it is conventionally expressed through the 293 expression system , to obtain the fusion protein shown in Table 1:

表1. PD-L1抗體/TGF-βRII胞外區融合蛋白

Table 1. PD-L1 antibody/TGF-βRII extracellular domain fusion protein

可選的實施方案中，該含有TGF-β受體的融合蛋白的給藥劑量選自1-200mg/kg，給藥頻次為一週一次、一週兩次、兩週一次、三週一次或四一次。 In an optional embodiment, the dosage of the fusion protein containing TGF-β receptor is selected from 1-200 mg/kg, and the frequency of administration is once a week, twice a week, once every two weeks, once every three weeks or once every four weeks. Second-rate.

可選的實施方案中，該含有TGF-β受體的融合蛋白的給藥劑量選自1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、55mg/kg、60mg/kg、65mg/kg、70mg/kg、75mg/kg、80mg/kg、85mg/kg、90mg/kg、95mg/kg、100mg/kg、105mg/kg、110mg/kg、115mg/kg、120mg/kg、125mg/kg、130mg/kg、135mg/kg、140mg/kg、145mg/kg、150mg/kg、155mg/kg、160mg/kg、165mg/kg、170mg/kg、175mg/kg、180mg/kg、185mg/kg、190mg/kg、195mg/kg或200mg/kg，給藥頻次為兩週一次或三週一次。 In an optional embodiment, the dosage of the fusion protein containing TGF-β receptor is selected from the group consisting of 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, and 30 mg/kg. , 35mg/kg, 40mg/kg, 45mg/kg, 50mg/kg, 55mg/kg, 60mg/kg, 65mg/kg, 70mg/kg, 75mg/kg, 80mg/kg, 85mg/kg, 90mg/kg, 95mg /kg, 100mg/kg, 105mg/kg, 110mg/kg, 115mg/kg, 120mg/kg, 125mg/kg, 130mg/kg, 135mg/kg, 140mg/kg, 145mg/kg, 150mg/kg, 155mg/kg , 160mg/kg, 165mg/kg, 170mg/kg, 175mg/kg, 180mg/kg, 185mg/kg, 190mg/kg, 195mg/kg or 200mg/kg. The dosage frequency is once every two weeks or once every three weeks.

可選的實施方案中，該含有TGF-β受體的融合蛋白的給藥劑量選自10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg或60mg/kg，給藥頻次為兩週一次或三週一次。 In an optional embodiment, the dosage of the fusion protein containing TGF-β receptor is selected from the group consisting of 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, and 40 mg/kg. , 45mg/kg, 50mg/kg or 60mg/kg, the dosage frequency is once every two weeks or once every three weeks.

可選的實施方案中，該含有TGF-β受體的融合蛋白的給藥劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the dosage of the fusion protein containing TGF-β receptor is 30 mg/kg, and the frequency of administration is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day.

可選的實施方案中，該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the MEK inhibitor is trametinib, the dosage is 1 mg or 2 mg, and the dosage frequency is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為10mg，給藥頻次為一日一次；該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 10 mg, and the dosage frequency is once a day; the MEK inhibitor is trametid Ni, the dosage is 1 mg or 2 mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為20mg，給藥頻次為一日一次；該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 20 mg, and the dosage frequency is once a day; the MEK inhibitor is trametid Ni, the dosage is 1 mg or 2 mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為30mg，給藥頻次為一日一次；該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 30 mg, and the dosage frequency is once a day; the MEK inhibitor is trametid Ni, the dosage is 1 mg or 2 mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為40mg，給藥頻次為一日一次；該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 40 mg, and the dosage frequency is once a day; the MEK inhibitor is trametid Ni, the dosage is 1 mg or 2 mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為50mg，給藥頻次為一日一次；該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 50 mg, and the dosage frequency is once a day; the MEK inhibitor is trametid Ni, the dosage is 1 mg or 2 mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為60mg，給藥頻次為一日一次；該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 60 mg, and the dosage frequency is once a day; the MEK inhibitor is trametid Ni, the dosage is 1 mg or 2 mg, and the frequency of administration is once a day.

可選的實施方案中，該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽； In an optional embodiment, the ERK inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof;

可選的實施方案中，該ERK抑制劑為式(II)所示化合物的富馬酸鹽。 In an optional embodiment, the ERK inhibitor is the fumarate salt of the compound represented by formula (II).

可選的實施方案中，該ERK抑制劑的給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the dosage of the ERK inhibitor is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from once a day or twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為10mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽；給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 10 mg, and the frequency of administration is once a day; the ERK inhibitor is formula (II) ) or a pharmaceutically acceptable salt thereof; the dosage is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from once a day or twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為20mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽；給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 20 mg, and the frequency of administration is once a day; the ERK inhibitor is formula (II) ) or a pharmaceutically acceptable salt thereof; the dosage is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from once a day or twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為30mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽；給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 30 mg, and the frequency of administration is once a day; the ERK inhibitor is formula (II) ) or a pharmaceutically acceptable salt thereof; the dosage is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from once a day or twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為40mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽；給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 40 mg, and the frequency of administration is once a day; the ERK inhibitor is formula (II) ) or a pharmaceutically acceptable salt thereof; the dosage is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from once a day or twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為50mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽；給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 50 mg, and the frequency of administration is once a day; the ERK inhibitor is formula (II) ) or a pharmaceutically acceptable salt thereof; the dosage is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from once a day or twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為60mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽；給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 60 mg, and the frequency of administration is once a day; the ERK inhibition The agent is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof; the dosage is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from once a day or twice a day.

可選的實施方案中，該EGFR抑制劑為式(III)所示化合物或其藥學上可接受的鹽。 In an optional embodiment, the EGFR inhibitor is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

可選的實施方案中，該EGFR抑制劑為式(III)所示化合物甲磺酸鹽。 In an optional embodiment, the EGFR inhibitor is mesylate, a compound represented by formula (III).

可選的實施方案中，該PD-L1抗體或抗原結合片段劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the dose of the PD-L1 antibody or antigen-binding fragment is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，該含有TGF-β受體的融合蛋白為融合蛋白9，劑量選自10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg或60mg/kg，給藥頻次為兩週一次或三週一次。 In an optional embodiment, the fusion protein containing TGF-β receptor is fusion protein 9, and the dosage is selected from 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, and 40 mg. /kg, 45mg/kg, 50mg/kg or 60mg/kg, the dosage frequency is once every two weeks or once every three weeks.

可選的實施方案中，該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the fusion protein containing TGF-β receptor is fusion protein 9, the dosage is 30 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或 60mg，給藥頻次為一日一次；該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), and the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, the dosage frequency is once a day; the MEK inhibitor is trametinib, the dosage is 1 mg or 2 mg, the dosage frequency is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽；該ERK抑制劑的給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day; the ERK inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof; the dosage of the ERK inhibitor is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the frequency of administration is selected from one Once a day or twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次；該ERK抑制劑為式(II)所示化合物的富馬酸鹽；該ERK抑制劑的給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day; the ERK inhibitor is the fumarate salt of the compound represented by formula (II); the dosage of the ERK inhibitor is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the administration frequency is selected from once a day or Twice a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次；該EGFR抑制劑的給藥劑量選自55mg、110mg、220mg或260mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day; the dosage of the EGFR inhibitor is selected from 55 mg, 110 mg, 220 mg or 260 mg, and the administration frequency is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為10mg，給藥頻次為一日一次；該EGFR抑制劑的給藥劑量選自55mg、110mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), and the dosage is 10 mg, and the dosage frequency is once a day; the dosage of the EGFR inhibitor is Choose from 55mg and 110mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為20mg，給藥頻次為一日一次；該EGFR抑制劑的給藥劑量選自55mg、110mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), and the dosage is 20 mg, and the dosage frequency is once a day; the dosage of the EGFR inhibitor is Choose from 55mg and 110mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為30mg，給藥頻次為一日一次；該EGFR抑制劑的給藥劑量選自55mg、110mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), and the dosage is 30 mg, and the dosage frequency is once a day; the dosage of the EGFR inhibitor is Choose from 55mg and 110mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為40mg，給藥頻次為一日一次；該EGFR抑制劑的給藥劑量選自55mg、110mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), and the dosage is 40 mg, and the dosage frequency is once a day; the dosage of the EGFR inhibitor is Choose from 55mg and 110mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為50mg，給藥頻次為一日一次；該EGFR抑制劑的給藥劑量選自55mg、110mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), and the dosage is 50 mg, and the dosage frequency is once a day; the dosage of the EGFR inhibitor is Choose from 55mg and 110mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為60mg，給藥頻次為一日一次；該EGFR抑制劑的給藥劑量選自55mg、110mg，給藥頻次為一日一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), and the dosage is 60 mg, and the dosage frequency is once a day; the dosage of the EGFR inhibitor is Choose from 55mg and 110mg, and the frequency of administration is once a day.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量選自10mg/kg、15mg/kg、 20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg或50mg/kg，給藥頻次為兩週一次或三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day; the heavy chain sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 9, the light chain sequence is SEQ ID NO: 11, and the dose is selected from 10 mg/kg, 15 mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg/kg or 50mg/kg, the dosage frequency is once every two weeks or once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day; the heavy chain sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11. The dose is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為10mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 10 mg, and the frequency of administration is once a day; the PD-L1 antibody or antigen-binding The heavy chain sequence of the fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11. The dosage is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為20mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 20 mg, and the frequency of administration is once a day; the PD-L1 antibody or antigen-binding The heavy chain sequence of the fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11. The dosage is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為30mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 30 mg, and the frequency of administration is once a day; the PD-L1 antibody or antigen-binding The heavy chain sequence of the fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11. The dosage is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為40mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 40 mg, and the frequency of administration is once a day; the PD-L1 antibody or antigen-binding The heavy chain sequence of the fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11. The dosage is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為50mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 50 mg, and the frequency of administration is once a day; the PD-L1 antibody or antigen-binding The heavy chain sequence of the fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11. The dosage is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為60mg，給藥頻次為一日一次；該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11，劑量為20mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 60 mg, and the frequency of administration is once a day; the PD-L1 antibody or antigen-binding The heavy chain sequence of the fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11. The dosage is 20 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量選自10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg或60mg/kg，給藥頻次為兩週一次或三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day; the fusion protein containing TGF-β receptor is fusion protein 9, and the dose is selected from 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg /kg, 50mg/kg or 60mg/kg, the dosage frequency is once every two weeks or once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg, and the frequency of administration is one. Once a day; the fusion protein containing TGF-β receptor is fusion protein 9, the dose is 30 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為10mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 10 mg, and the frequency of administration is once a day; the TGF-β receptor-containing The fusion protein is fusion protein 9, the dosage is 30 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為20mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 20 mg, and the frequency of administration is once a day; the TGF-β receptor-containing The fusion protein is fusion protein 9, the dosage is 30 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為30mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 30 mg, and the frequency of administration is once a day; the TGF-β receptor-containing The fusion protein is fusion protein 9, the dosage is 30 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為40mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 40 mg, and the frequency of administration is once a day; the TGF-β receptor-containing The fusion protein is fusion protein 9, the dosage is 30 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為50mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 50 mg, and the frequency of administration is once a day; the TGF-β receptor-containing The fusion protein is fusion protein 9, the dosage is 30 mg/kg, and the administration frequency is once every three weeks.

可選的實施方案中，式(I)所示化合物或其藥學上可接受的鹽為化合物(5)，給藥劑量為60mg，給藥頻次為一日一次；該含有TGF-β受體的融合蛋白為融合蛋白9，劑量為30mg/kg，給藥頻次為三週一次。 In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is compound (5), the dosage is 60 mg, and the frequency of administration is once a day; the TGF-β receptor-containing The fusion protein is fusion protein 9, the dosage is 30 mg/kg, and the administration frequency is once every three weeks.

本揭露中該腫瘤可選自黑色素瘤、皮膚癌、腎細胞癌、肝細胞癌、胃癌、乳腺癌、胰腺結直腸癌、膠質母細胞瘤、卵巢癌、***癌、血液系統癌症、尿路上皮癌、膀胱癌、非小細胞肺癌、食道癌、頭頸癌或胃腸道間質瘤。 In this disclosure, the tumor may be selected from the group consisting of melanoma, skin cancer, renal cell carcinoma, hepatocellular carcinoma, gastric cancer, breast cancer, pancreatic colorectal cancer, glioblastoma, ovarian cancer, prostate cancer, hematological cancer, urothelial cancer cancer, bladder cancer, non-small cell lung cancer, esophageal cancer, head and neck cancer, or gastrointestinal stromal tumor.

本揭露另一方面提供一種治療腫瘤的式(I)所示化合物或其藥學上可接受的鹽，其與選自MEK抑制劑、ERK抑制劑、EGFR抑制劑、PD-L1抗體或其抗原結合片段、含有TGF-β受體的融合蛋白中的至少一種聯用，該MEK抑制劑、ERK抑制劑、EGFR抑制劑、PD-L1抗體或其抗原結合片段、含有TGF-β受體的融合蛋白如前所述。 Another aspect of the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treating tumors, which is combined with a compound selected from the group consisting of MEK inhibitors, ERK inhibitors, EGFR inhibitors, PD-L1 antibodies or antigens thereof. At least one of fragments and fusion proteins containing TGF-β receptors In combination, the MEK inhibitor, ERK inhibitor, EGFR inhibitor, PD-L1 antibody or antigen-binding fragment thereof, and fusion protein containing TGF-β receptor are as described above.

本揭露另一方面提供一種治療腫瘤的MEK抑制劑，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用，該MEK抑制劑如前所述。 Another aspect of the present disclosure provides a MEK inhibitor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The MEK inhibitor is as described above.

本揭露另一方面提供一種治療腫瘤的ERK抑制劑，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用，該ERK抑制劑如前所述。 Another aspect of the present disclosure provides an ERK inhibitor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The ERK inhibitor is as described above.

本揭露另一方面提供一種治療腫瘤的EGFR抑制劑，其與式(I)所示化合物或其藥學上接受的鹽聯合使用，該EGFR抑制劑如前所述。 Another aspect of the present disclosure provides an EGFR inhibitor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The EGFR inhibitor is as described above.

本揭露另一方面提供一種治療腫瘤的PD-L1或抗原結合片段，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用，該PD-L1或抗原結合片段如前所述。 Another aspect of the present disclosure provides a PD-L1 or antigen-binding fragment for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The PD-L1 or antigen-binding fragment is as described above. .

本揭露一種治療腫瘤的含有TGF-β受體的融合蛋白，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用，該含有TGF-β受體的融合蛋白如前所述。 The present disclosure discloses a fusion protein containing TGF-β receptor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The fusion protein containing TGF-β receptor is as described above. .

本揭露另一方面提供一種治療含有RAS通路基因突變的腫瘤的方法，給與受試者治療有效量的式(I)所示化合物或其藥學上可接受的鹽。 Another aspect of the present disclosure provides a method of treating tumors containing RAS pathway gene mutations, which involves administering to a subject a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

本揭露另一方面提供一種治療癌症的方法，給與受試者治療有效量的式(I)所示化合物或其藥學上可接受的鹽，和治療有效量的上述MEK抑制劑。 Another aspect of the present disclosure provides a method for treating cancer, which involves administering to a subject a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the above-mentioned MEK inhibitor.

本揭露另一方面提供一種治療癌症的方法，給與受試者治療有效量的式(I)所示化合物或其藥學上可接受的鹽，和治療有效量的上述ERK抑制劑。 Another aspect of the present disclosure provides a method for treating cancer, which involves administering to a subject a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the above-mentioned ERK inhibitor.

本揭露另一方面提供一種治療癌症的方法，給與受試者治療有效量的式(I)所示化合物或其藥學上可接受的鹽，和治療有效量的上述EGFR抑制劑。 Another aspect of the present disclosure provides a method for treating cancer, which involves administering to a subject a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the above-mentioned EGFR inhibitor.

本揭露另一方面提供一種治療癌症的方法，給與受試者治療有效量的式(I)所示化合物或其藥學上可接受的鹽，和治療有效量的上述PD-L1或抗原結合片段。 Another aspect of the present disclosure provides a method for treating cancer, which involves administering to a subject a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the above-mentioned PD-L1 or antigen-binding fragment. .

本揭露另一方面提供一種治療癌症的方法，給與受試者治療有效量的式(I)所示化合物或其藥學上可接受的鹽，和治療有效量的上述含有TGF-β受體的融合蛋白。 Another aspect of the present disclosure provides a method for treating cancer, which involves administering to a subject a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the above-mentioned TGF-β receptor-containing compound. fusion protein.

本揭露中該藥學上可接受的鹽可以是鹽酸鹽、磷酸鹽、磷酸氫鹽、硫酸鹽、硫酸氫鹽、亞硫酸鹽、乙酸鹽、草酸鹽、丙二酸鹽、戊酸鹽、谷胺酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、硼酸鹽、對甲苯磺酸鹽、甲磺酸鹽、羥乙基磺酸鹽、馬來酸鹽、蘋果酸鹽、酒石酸鹽、苯甲酸鹽、雙羥萘酸鹽、水楊酸鹽、香草酸鹽、扁桃酸鹽、琥珀酸鹽、葡萄糖酸鹽、乳糖酸鹽或月桂基磺酸鹽等。 The pharmaceutically acceptable salt in the present disclosure can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, Glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malic acid Salt, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonate, etc.

本揭露另一方面提供提供一種包含上述式(I)所示化合物或其藥學上可接受的鹽和視需要自MEK抑制劑、ERK抑制劑、EGFR中至少一種的醫藥組成物，該醫藥組成物進一步包含一種或多種可藥用的賦型劑。 Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, and optionally at least one of MEK inhibitors, ERK inhibitors, and EGFR. The pharmaceutical composition One or more pharmaceutically acceptable excipients are further included.

本揭露中該醫藥組成物可以製備為片劑、膠囊劑、丸劑、顆粒劑、溶液劑、混懸劑、糖漿劑、注射劑、栓劑、吸入劑或噴霧劑等。 In the present disclosure, the pharmaceutical composition can be prepared as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays, etc.

本揭露該聯合的給藥方式選自同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。 The combined administration mode of the present disclosure is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and administered sequentially.

本揭露該聯合的給藥途徑選自經口給藥、胃腸外給藥、經皮給藥，該胃腸外給藥包括但不限於靜脈注射、皮下注射、肌肉注射。 The combined administration route of the present disclosure is selected from oral administration, parenteral administration, and transdermal administration. The parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

本共開中該受試者，可以為哺乳動物，具體可以是健康的人類或患者。 The subject in this invention may be a mammal, specifically a healthy human or a patient.

術語說明 Terminology

除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

術語“烷基”指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子的烷基，更佳為含有1至6個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3- 二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳獨立地視需要選自D原子、鹵素、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g. 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl base, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl base, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Pentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent is preferably independently selected from the group consisting of D atom, halogen, alkoxy, halogen. Alkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents.

本揭露的化合物包含其同位素衍生物。術語“同位素衍生物”指結構不同僅在於存在一種或多種同位素富集原子的化合物。例如，具有本揭露的結構，用“氘”或“氚”代替氫，或者用¹⁸F-氟標記(¹⁸F同位素)代替氟，或者用¹¹C-，¹³C-，或者¹⁴C-富集的碳(¹¹C-，¹³C-，或者¹⁴C-碳標記；¹¹C-，¹³C-，或者¹⁴C-同位素)代替碳原子的化合物處於本揭露的範圍內。這樣的化合物可用作例如生物學測定中的分析工具或探針，或者可以用作疾病的體內診斷成像示蹤劑，或者作為藥效學、藥動學或受體研究的示蹤劑。本揭露的各種氘化形式的化合物是指與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。所屬技術領域具有通常知識者能夠參考相關文獻合成氘化形式的化合物。在製備氘代形式的化合物時可使用市售的氘代起始物質，或它們可使用常規技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留與未氘代的化合物相當的活性，並且當氘代在某些特定位點時可以取得更好的代謝穩定性，從而獲得某些治療優勢。 The compounds of the present disclosure include isotopic derivatives thereof. The term "isotope derivative" refers to compounds that differ structurally only in the presence of one or more isotopically enriched atoms. For example, with a structure of the present disclosure, "deuterium" or "tritium" is used instead of hydrogen, or ^18F -fluorine labeling ( ^18F isotope) is used instead of fluorine, or ^11C- , ^13C- , or ^14C -enrichment Compounds in which a carbon atom is replaced by a carbon ( ^11C- , ^13C- , or ^14C -carbon label; ^11C- , ^13C- , or ^14C -isotope) are within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. A person of ordinary skill in the art can synthesize the deuterated form of the compound with reference to the relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran. , Deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds often retain comparable activity to non-deuterated compounds, and when deuterated at certain sites, better metabolic stability can be achieved, resulting in certain therapeutic advantages.

“取代的”指基團中的一個或多個氫原子，較佳為1~5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。所屬技術領域具有通常知識者能夠在不付出過多努力的情況下(藉由實驗或理論)確定可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" means that one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. A person of ordinary skill in the art can determine possible or impossible substitutions without undue effort (by experiment or theory). For example, an amine or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, olefinic) bond.

本揭露中該“聯合”是一種給藥方式，以式(I)所示化合物或其藥學上可接受的鹽聯合ERK抑制劑為例，是指在一定時間期限內給予至少一種劑量的式(I)所示化合物或其藥學上可接受的鹽和ERK抑制劑，其中兩種藥物都顯示藥理學作用。該時間期限可以是一個給藥週期內，較佳4週內、3週內、2週內、1週內、或24小時以內。可以同時或依次給予式(I)所示化合物或其藥學上可接受的鹽或其藥學上可接受的鹽和ERK抑制劑。這種期限包括這樣的治療，其中藉由相同給藥途徑或不同給藥途徑給予給予式(I)所示化合物或其藥學上可接受的鹽或其藥學上可接受的鹽和ERK抑制劑。本申請所述聯合的給藥方式選自同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。 In this disclosure, the "combination" refers to a method of administration. Taking the compound represented by formula (I) or its pharmaceutically acceptable salt combined with an ERK inhibitor as an example, it refers to administering at least one dose of formula (I) within a certain period of time. I) The compound or a pharmaceutically acceptable salt thereof and an ERK inhibitor, wherein both drugs exhibit pharmacological effects. The time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof and an ERK inhibitor can be administered simultaneously or sequentially. Preparations. This term includes treatments in which a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof and an ERK inhibitor are administered by the same route of administration or by different routes of administration. The administration mode of the combination described in this application is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and administered sequentially.

本揭露中該“有效量”或“有效治療量”包含足以改善或預防醫學病症的症狀或病症的量。有效量還意指足以允許或促進診斷的量。用於特定患者或獸醫學受試者的有效量可依據以下因素而變化：如待治療的病症、患者的總體健康情況、給藥的方法途徑和劑量以及副作用嚴重性。有效量可以是避免顯著副作用或毒性作用的最大劑量或給藥方案。 In this disclosure, an "effective amount" or a "therapeutically effective amount" includes an amount sufficient to ameliorate or prevent symptoms or symptoms of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of the side effects. An effective amount may be the maximum dosage or dosage regimen that avoids significant side effects or toxic effects.

本揭露所用胺基酸三字母代碼和單字母代碼如J.biol.chem,243,p3558(1968)中所述。 The amino acid three-letter codes and single-letter codes used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

本揭露所述的“抗體”指免疫球蛋白，是由兩條相同的重鏈和兩條相同的輕鏈藉由鏈間二硫鍵連接而成的四肽鏈結構。免疫球蛋白重鏈恆定區的胺基酸組成和排列順序不同，故其抗原性也不同。據此，可將免疫球蛋白分為五類，或稱為免疫球蛋白的同種型，即IgM、IgD、IgG、IgA和IgE，其相應的重鏈分別為μ鏈、δ鏈、γ鏈、α鏈、和ε鏈。同一類Ig根據其鉸鏈區胺基酸組成和重鏈二硫鍵的數目和位置的差別，又可分為不同的亞類，如IgG可分為IgG1、IgG2、IgG3、IgG4。輕鏈藉由恆定區的不同分為κ鏈或λ鏈。五類Ig中每類Ig都可以有κ鏈或λ鏈。 The "antibody" mentioned in this disclosure refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by inter-chain disulfide bonds. The amino acid composition and sequence of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different. Accordingly, immunoglobulins can be divided into five categories, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE. Their corresponding heavy chains are μ chain, δ chain, γ chain, α chain, and ε chain. The same type of Ig can be divided into different subclasses based on differences in the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are divided into kappa or lambda chains based on differences in constant regions. Each of the five types of Ig can have either a kappa chain or a lambda chain.

在本揭露中，本揭露所述的抗體輕鏈可進一步包含輕鏈恆定區，該輕鏈恆定區包含人源或鼠源的κ、λ鏈或其變體。 In the present disclosure, the antibody light chain described in the present disclosure may further comprise a light chain constant region, which includes a human or murine kappa, lambda chain or a variant thereof.

在本揭露中，本揭露所述的抗體重鏈可進一步包含重鏈恆定區，該重鏈恆定區包含人源或鼠源的IgG1、IgG2、IgG3、IgG4或其變體。抗體重鏈和輕鏈靠近N端的約110個胺基酸的序列變化很大，為可變區(Fv區)；靠近C端的其餘胺基酸序列相對穩定，為恆定區。可變區包括3個高變區(HVR)和4個序列相對保守的骨架區(FR)。3個高變區決定抗體的特異性，又稱為互補性決定區(CDR)。每條輕鏈可變區(LCVR)和重鏈可變區(HCVR)由3個CDR區4個FR區組成，從胺基端到羧基端依次排列的順序為：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。輕鏈的3個CDR區指LCDR1、LCDR2、和LCDR3；重鏈的3個CDR區指HCDR1、HCDR2和HCDR3。本揭露所述的抗體或抗原結合片段的LCVR區和HCVR區的CDR胺基酸殘基在數量和位置符合已知的Kabat編號規則。 In the present disclosure, the antibody heavy chain described in the present disclosure may further comprise a heavy chain constant region comprising human or murine IgG1, IgG2, IgG3, IgG4 or variants thereof. The sequence of about 110 amino acids near the N-terminus of the antibody heavy chain and light chain varies greatly and is the variable region (Fv region); the remaining amino acid sequences near the C-terminus are relatively stable and are the constant region. The variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conserved sequences. Three hypervariable regions determine the specificity of the antibody, also known as complementarity determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of 3 CDR regions and 4 FR regions. The order from the amino end to the carboxyl end is: FR1, CDR1, FR2, CDR2 , FR3, CDR3, FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3. The number and position of the CDR amino acid residues of the LCVR region and HCVR region of the antibody or antigen-binding fragment described in the present disclosure conform to the known Kabat numbering rule.

本揭露的抗體包括鼠源抗體、嵌合抗體、人源化抗體，較佳人源化抗體。術語“人源化抗體(humanized antibody)”，也稱為CDR移植抗體(CDR-grafted antibody)，是指將小鼠的CDR序列移植到人的抗體可變區框架，即不同類型的人種系抗體構架序列中產生的抗體。可以克服嵌合抗體由於攜帶大量小鼠蛋白成分，從而誘導的強烈的抗體可變抗體反應。此類構架序列可以從包括種系抗體基因序列的公共DNA數據庫或公開的參考文獻獲得。如人重鏈和輕鏈可變區基因的種系DNA序列可以在“VBase”人種系序列數據庫(在因特網www.mrccpe.com.ac.uk/vbase可獲得)，以及在Kabat，E.A.等人，1991 Sequences of Proteins of Immunological Interest，第5版中找到。為避免免疫原性下降的同時，引起的活性下降，可對該人抗體可變區框架序列進行最少反向突變或回復突變，以保持活性。本揭露的人源化抗體也包括進一步由噬菌體展示對CDR進行親和力成熟後的人源化抗體。 The antibodies of the present disclosure include murine antibodies, chimeric antibodies, and humanized antibodies, preferably humanized antibodies. The term "humanized antibody", also known as CDR-grafted antibody, refers to transplanting the mouse CDR sequence into the human antibody variable region framework, that is, different types of human germline Antibodies produced from antibody framework sequences. It can overcome the strong antibody variable antibody response induced by chimeric antibodies carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes are available in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), and in Kabat, E.A. et al. Found in Man, 1991 Sequences of Proteins of Immunological Interest, 5th ed. In order to avoid a decrease in immunogenicity, the If the activity decreases, the human antibody variable region framework sequence can be subjected to minimal reverse mutation or back mutation to maintain activity. The humanized antibodies of the present disclosure also include humanized antibodies that further undergo affinity maturation of CDRs by phage display.

本揭露中該“抗原結合片段”，指具有抗原結合活性的Fab片段，Fab‘片段，F(ab’)2片段，以及與人PD-L1結合的Fv片段ScFv片段；其包含本揭露所述抗體的選自SEQ ID NO：1至SEQ ID NO：12中的一個或多個CDR區。Fv片段含有抗體重鏈可變區和輕鏈可變區，但沒有恆定區，並具有全部抗原結合位點的最小抗體片段。一般地，Fv抗體還包含在VH和VL結構域之間的多肽接頭，且能夠形成抗原結合所需的結構。也可以用不同的連接物將兩個抗體可變區連接成一條多肽鏈，稱為單鏈抗體(single chain antibody)或單鏈Ev(sFv)。本揭露的術語“與PD-L1結合”，指能與人PD-L1相互作用。本揭露的術語“抗原結合位點”指抗原上不連續的，由本揭露抗體或抗原結合片段識別的三維空間位點。 In this disclosure, the "antigen-binding fragment" refers to Fab fragments, Fab' fragments, F(ab')2 fragments with antigen-binding activity, and Fv fragments ScFv fragments that bind to human PD-L1; which include those described in this disclosure. The antibody has one or more CDR regions selected from SEQ ID NO: 1 to SEQ ID NO: 12. The Fv fragment is the smallest antibody fragment that contains the variable region of the heavy chain and the variable region of the light chain of an antibody, but no constant region, and has all the antigen-binding sites. Typically, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding. Different linkers can also be used to connect the variable regions of two antibodies into a polypeptide chain, called a single chain antibody or single chain Ev (sFv). The term "binding to PD-L1" in this disclosure refers to the ability to interact with human PD-L1. The term "antigen binding site" of the present disclosure refers to a discontinuous three-dimensional site on the antigen recognized by the antibody or antigen-binding fragment of the present disclosure.

本揭露所述的“蛋白複合物”或“複合蛋白”是指兩個不同的單體蛋白質結合而成的蛋白。本揭露中組成蛋白複合物的“單體蛋白質”(即可溶性融合蛋白(I)、可溶性融合蛋白(Π))可以是融合蛋白或非融合蛋白。 The "protein complex" or "complex protein" used in this disclosure refers to a protein formed by combining two different monomeric proteins. The "monomeric protein" constituting the protein complex in the present disclosure (i.e., soluble fusion protein (I), soluble fusion protein (II)) may be a fusion protein or a non-fusion protein.

本揭露所述的“融合蛋白”是指，藉由用基因重組方法、化學方法或其它適當方法將兩個或多個基因的編碼區連接，在同一調控序列控制下表達基因重組所得的蛋白質產物。在本揭露的一些實施方案中，可溶性融合蛋白(I)為IL-15或其變體與生物活性多肽如Fc片段融合或非融合表達得到的單體蛋白質；可溶性融合蛋白(Π)為IL-15Rα或其變體與生物活性多肽如Fc片段融合或非融合表達得到的單體蛋白質。本揭露的融合蛋白中，兩個或多個基因的編碼區之間可由編碼肽接頭的序列於一個或數個位置融合。肽接頭也可用於構建本揭露的融合蛋白。 The "fusion protein" mentioned in this disclosure refers to a protein product obtained by gene recombination by connecting the coding regions of two or more genes using genetic recombination methods, chemical methods, or other appropriate methods, and expressing them under the control of the same regulatory sequence. . In some embodiments of the present disclosure, the soluble fusion protein (I) is a monomeric protein obtained by fusion or non-fusion expression of IL-15 or a variant thereof and a biologically active polypeptide such as an Fc fragment; the soluble fusion protein (II) is IL-15 15Rα or its variants are associated with Biologically active polypeptides such as monomeric proteins obtained by fusion or non-fusion expression of Fc fragments. In the fusion protein of the present disclosure, the coding regions of two or more genes can be fused at one or several positions by a sequence encoding a peptide linker. Peptide linkers can also be used to construct the fusion proteins of the present disclosure.

“給予”和“處理”當應用於動物、人、實驗受試者、細胞、組織、器官或生物流體時，是指外源性藥物、治療劑、診斷劑或組成物與動物、人、受試者、細胞、組織、器官或生物流體的接觸。“給予”和“處理”可以指例如治療、藥物代謝動力學、診斷、研究和實驗方法。細胞的處理包括試劑與細胞的接觸，以及試劑與流體的接觸，其中該流體與細胞接觸。“給予”和“處理”還意指藉由試劑、診斷、結合組成物或藉由另一種細胞體外和離體處理例如細胞。“處理”當應用於人、獸醫學或研究受試者時，是指治療處理、預防或預防性措施，研究和診斷應用。 "Administer" and "treat" when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, means the administration of exogenous drugs, therapeutics, diagnostics, or compositions to animals, humans, subjects, Contact with subjects, cells, tissues, organs or biological fluids. "Administration" and "treatment" may refer to, for example, treatment, pharmacokinetics, diagnostics, research and experimental procedures. Treatment of cells includes contact of reagents with the cells, and contact of the reagents with a fluid, where the fluid is in contact with the cells. "Administration" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by a reagent, a diagnostic, a binding composition or by another cell. "Treatment" when applied to human, veterinary medicine or research subjects means therapeutic treatment, prophylactic or prophylactic measures, research and diagnostic applications.

“治療”意指給予患者內用或外用治療劑，例如包含本揭露的任一種結合化合物的組成物，該患者具有一種或多種疾病症狀，而已知該治療劑對這些症狀具有治療作用。通常，在受治療患者或群體中以有效緩解一種或多種疾病症狀的量給予治療劑，以誘導這類症狀退化或抑制這類症狀發展到任何臨床右測量的程度。有效緩解任何具體疾病症狀的治療劑的量(也稱作“治療有效量”)可根據多種因素變化，例如患者的疾病狀態、年齡和體重，以及藥物在患者產生需要療效的能力。藉由醫生或其它專業衛生保健人士通常用於評價該症狀的嚴重性或進展狀況的任何臨床檢測方法，可評價疾病症狀是否已被減輕。儘管本揭露的實施方案(例如治療方法或製品)在緩解每個目標疾病症狀方面可能無效，但是根據本領域已知的任何統計學檢驗方法如Student t檢驗、卡方檢驗、依據Mann和Whitney 的U檢驗、Kruskal-Wallis檢驗(H檢驗)、Jonckheere-Terpstra檢驗和Wilcoxon檢驗確定，其在統計學顯著數目的患者中應當減輕目標疾病症狀。 "Treat" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more disease symptoms for which the therapeutic agent is known to have a therapeutic effect. Generally, a therapeutic agent is administered to a subject or population in an amount effective to alleviate one or more disease symptoms, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable extent. The amount of therapeutic agent effective to alleviate the symptoms of any particular disease (also referred to as a "therapeutically effective amount") can vary depending on a variety of factors, such as the patient's disease state, age and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether disease symptoms have been alleviated can be assessed by any of the clinical tests commonly used by physicians or other health care professionals to evaluate the severity or progression of symptoms. Although embodiments of the present disclosure (e.g., treatments or articles of manufacture) may not be effective in alleviating each target disease symptom, the results may be determined by any statistical test known in the art, such as the Student's t-test, Chi-square test, Mann and Whitney The U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test and Wilcoxon test determined that it should alleviate the symptoms of the target disease in a statistically significant number of patients.

本揭露所述的“抗體”指免疫球蛋白，是由兩條相同的重鏈和兩條相同的輕鏈藉由鏈間二硫鍵連接而成的四肽鏈結構。 The "antibody" mentioned in this disclosure refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by inter-chain disulfide bonds.

在本揭露中，本揭露所述的抗體重鏈可進一步包含重鏈恆定區，該重鏈恆定區包含人源或鼠源的IgG1、IgG2、IgG3、IgG4或其變體。 In the present disclosure, the antibody heavy chain described in the present disclosure may further comprise a heavy chain constant region comprising human or murine IgG1, IgG2, IgG3, IgG4 or variants thereof.

抗體重鏈和輕鏈靠近N端的約110個胺基酸的序列變化很大，為可變區(Fv區)；靠近C端的其餘胺基酸序列相對穩定，為恆定區。可變區包括3個高變區(HVR)和4個序列相對保守的骨架區(FR)。3個高變區決定抗體的特異性，又稱為互補性決定區(CDR)。每條輕鏈可變區(LCVR)和重鏈可變區(HCVR)由3個CDR區4個FR區組成，從胺基端到羧基端依次排列的順序為：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。輕鏈的3個CDR區指LCDR1、LCDR2、和LCDR3；重鏈的3個CDR區指HCDR1、HCDR2和HCDR3。本揭露該抗體或抗原結合片段的LCVR區和HCVR區的CDR胺基酸殘基在數量和位置符合已知的Kabat編號規則(LCDR1-3，HCDE2-3)，或者符合kabat和chothia的編號規則(HCDR1)。 The sequence of about 110 amino acids near the N-terminus of the antibody heavy chain and light chain varies greatly and is the variable region (Fv region); the remaining amino acid sequences near the C-terminus are relatively stable and are the constant region. The variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conserved sequences. Three hypervariable regions determine the specificity of the antibody, also known as complementarity determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of 3 CDR regions and 4 FR regions. The order from the amino end to the carboxyl end is: FR1, CDR1, FR2, CDR2 , FR3, CDR3, FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3. The number and position of the CDR amino acid residues in the LCVR region and HCVR region of the antibody or antigen-binding fragment disclosed herein conform to the known Kabat numbering rules (LCDR1-3, HCDE2-3), or conform to the numbering rules of kabat and chothia. (HCDR1).

本揭露的抗體包括鼠源抗體、嵌合抗體、人源化抗體，較佳人源化抗體。 The antibodies of the present disclosure include murine antibodies, chimeric antibodies, and humanized antibodies, preferably humanized antibodies.

本揭露中該“抗體或其抗原結合”或“功能片段”，指具有抗原結合活性的Fab片段，Fab’片段，F(ab’)2片段，以及與抗體結合的Fv片段ScFv片段。Fv片段含有抗體重鏈可變區和輕鏈可變區，但沒有恆定區，並具有全部抗原結合位點的最小抗體片段。一般地，Fv抗體還包含在VH和VL結構域之間的多肽接頭，且能夠形成抗原結合所需的結構。也可以用不同的連接物將兩個抗體可變區連接成一條多肽鏈，稱為單鏈抗體(single chain antibody)或單鏈Fv(sFv)。本揭露的術語“與PD-L1結合”，指能與人PD-L1相互作用。本揭露的術語“抗原結合位點”指抗原上不連續的，由本揭露抗體或抗原結合片段識別的三維空間位點。 In this disclosure, the "antibody or its antigen-binding" or "functional fragment" refers to Fab fragments, Fab' fragments, F(ab')2 fragments with antigen-binding activity, and Fv fragments ScFv fragments that bind to antibodies. The Fv fragment is the smallest antibody fragment that contains the variable region of the heavy chain and the variable region of the light chain of an antibody, but no constant region, and has all the antigen-binding sites. Typically, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding. Different linkers can also be used to connect the variable regions of two antibodies into a polypeptide chain, called a single chain antibody or single chain Fv (sFv). The term "binding to PD-L1" in this disclosure refers to the ability to interact with human PD-L1. The term "antigen binding site" of the present disclosure refers to a discontinuous three-dimensional site on the antigen recognized by the antibody or antigen-binding fragment of the present disclosure.

術語“鼠源抗體”在本揭露中為根據本領域知識和技能製備的對人PD-L1的單株抗體。製備時用PD-L1抗原注射試驗對象，然後分離表達具有所需序列或功能特性的抗體的融合瘤。 The term "murine antibody" in this disclosure refers to a monoclonal antibody to human PD-L1 prepared according to the knowledge and skill in the art. During preparation, test subjects are injected with PD-L1 antigen, and then fusion tumors expressing antibodies with desired sequence or functional properties are isolated.

術語“嵌合抗體(chimeric antibody)”，是將鼠源性抗體的可變區與人抗體的恆定區融合而成的抗體，可以減輕鼠源性抗體誘發的免疫應答反應。建立嵌合抗體，要先建立分泌鼠源性特異性單抗的融合瘤，然後從小鼠融合瘤細胞中選殖可變區基因，再根據需要選殖人抗體的恆定區基因，將小鼠可變區基因與人恆定區基因連接成嵌合基因後***人載體中，最後在真核工業系統或原核工業系統中表達嵌合抗體分子。在本揭露一個較佳的實施方案中，該PCSK-9嵌合抗體的抗體輕鏈進一步包含人源κ、λ鏈或其變體的輕鏈恆定區。該PCSK-9嵌合抗體的抗體重鏈進一步包含人源IgG1、IgG2、IgG3、IgG4或其變體的重鏈恆定區。人抗體的恆定區可選自人源IgG1、IgG2、IgG3或IgG4或其變體的重鏈恆定區，較佳包含人源IgG2或IgG4重鏈恆定區，或者使用胺基酸突變後無ADCC(antibody-dependent cell-mediated cytotoxicity，抗體依賴的細胞介導的細胞毒作用) 毒性的IgG4。 The term "chimeric antibody" refers to an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody. It can reduce the immune response induced by the murine antibody. To establish a chimeric antibody, you must first establish a fusion tumor that secretes mouse-derived specific monoclonal antibodies, then select and clone the variable region genes from the mouse fusion tumor cells, and then select and clone the constant region genes of the human antibody as needed. The mouse can be The variable region gene and the human constant region gene are connected to form a chimeric gene and then inserted into a human vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic industrial system or a prokaryotic industrial system. In a preferred embodiment of the present disclosure, the antibody light chain of the PCSK-9 chimeric antibody further comprises the light chain constant region of human kappa, lambda chains or variants thereof. The antibody heavy chain of the PCSK-9 chimeric antibody further includes the heavy chain constant region of human IgG1, IgG2, IgG3, IgG4 or variants thereof. The constant region of the human antibody can be selected from the heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof, preferably comprising a human IgG2 or IgG4 heavy chain constant region, or using amino acid mutations without ADCC ( antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity) Toxic IgG4.

術語“人源化抗體(humanized antibody)”，也稱為CDR移植抗體(CDR-grafted antibody)，是指將小鼠的CDR序列移植到人的抗體可變區框架，即不同類型的人種系抗體構架序列中產生的抗體。可以克服嵌合抗體由於攜帶大量小鼠蛋白成分，從而誘導的強烈的抗體可變抗體反應。此類構架序列可以從包括種系抗體基因序列的公共DNA數據庫或公開的參考文獻獲得。如人重鏈和輕鏈可變區基因的種系DNA序列可以在“VBase”人種系序列數據庫(在因特網www.mrccpe.com.ac.uk/vbase可獲得)，以及在Kabat，E.A.等人，1991 Sequences of Proteins of Immunological Interest，第5版中找到。為避免免疫原性下降的同時，引起的活性下降，可對該人抗體可變區框架序列進行最少反向突變或回復突變，以保持活性。本揭露的人源化抗體也包括進一步由噬菌體展示對CDR進行親和力成熟後的人源化抗體。 The term "humanized antibody", also known as CDR-grafted antibody, refers to transplanting the mouse CDR sequence into the human antibody variable region framework, that is, different types of human germline Antibodies produced from antibody framework sequences. It can overcome the strong antibody variable antibody response induced by chimeric antibodies carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes are available in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), and in Kabat, E.A. et al. Found in Man, 1991 Sequences of Proteins of Immunological Interest, 5th ed. In order to avoid a decrease in activity caused by a decrease in immunogenicity, a minimum of reverse mutation or back mutation can be performed on the framework sequence of the variable region of the human antibody to maintain activity. The humanized antibodies of the present disclosure also include humanized antibodies that further undergo affinity maturation of CDRs by phage display.

本揭露中該“同一性”是指兩個多核苷酸序列之間或兩個多肽之間的序列相似性。本揭露中的序列同一性可以至少為85%、90%或95%，較佳至少為95%。非限制性實施例包括85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、100%。兩個序列之間的序列比較和同一性百分比測定可以藉由National Center For Biotechnology Institute網站上可得的BLASTN/BLASTP算法的默認設置來進行。 In this disclosure, "identity" refers to sequence similarity between two polynucleotide sequences or between two polypeptides. The sequence identity in the present disclosure can be at least 85%, 90% or 95%, preferably at least 95%. Non-limiting examples include 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% , 100%. Sequence comparison and determination of percent identity between two sequences can be performed with the default settings of the BLASTN/BLASTP algorithm available on the National Center For Biotechnology Institute website.

術語“TGF-β受體II”或“TGFβRII”或“轉化生長因子β受體II”是指結合配體(包括但不限於TGFβ1、TGFβ2和TGFβ3)、並且由此引發細胞內的信號轉導途徑的細胞表面受體。 The term "TGF-β receptor II" or "TGFβRII" or "transforming growth factor β receptor II" refers to the binding of a ligand (including, but not limited to, TGFβ1, TGFβ2, and TGFβ3), and thereby initiating intracellular signal transduction. cell surface receptors of the pathway.

術語“PD-L1”是指程序性死亡配體1，也稱為CD274和 B7H1。PD-L1是具有胞外IgV樣和IgC樣結構域(全長PD-L1的胺基酸19-239)、跨膜結構域和約30個胺基酸的胞內結構域的290個胺基酸的蛋白質。PD-L1在許多細胞例如抗原呈遞細胞(例如，樹突細胞、巨噬細胞和B細胞)上以及造血細胞和非造血細胞(例如，血管內皮細胞、胰島、和免疫赦免部位)上組成型表達。PD-L1也在多種腫瘤和病毒感染的細胞上表達，並且是免疫抑制環境(immunosuppressive milieu)的組成(Ribas 2012，NEJM 366：2517-2519)。PD-L1與兩種T細胞共抑制劑PD-1和B7-1之一結合。 The term "PD-L1" refers to programmed death ligand 1, also known as CD274 and B7H1. PD-L1 is a 290-amino-acid protein with extracellular IgV-like and IgC-like domains (amino acids 19-239 of full-length PD-L1), a transmembrane domain, and an intracellular domain of approximately 30 amino acids. of protein. PD-L1 is constitutively expressed on many cells such as antigen-presenting cells (e.g., dendritic cells, macrophages, and B cells) as well as on hematopoietic and non-hematopoietic cells (e.g., vascular endothelial cells, pancreatic islets, and immune-privileged sites) . PD-L1 is also expressed on a variety of tumors and virus-infected cells and is a component of the immunosuppressive milieu (Ribas 2012, NEJM 366: 2517-2519). PD-L1 binds to one of two T cell co-inhibitors, PD-1 and B7-1.

客觀緩解率(ORR)是指最佳總體療效為CR或PR的受試者人數占可評價受試者的比例。可評價受試者的定義：符合以下標準的所有受試者，即基線期CT/MRI檢查存在至少一個可測量病灶(依據RECIST 1.1標準)，接受至少1次研究治療，且在開始研究治療後接受過至少1次CT/MRI檢查。若療效達CR、PR，受試者須在首次評價4週後進行複查確認。 Objective response rate (ORR) refers to the proportion of subjects whose best overall response is CR or PR to evaluable subjects. The definition of evaluable subjects: all subjects who meet the following criteria, that is, have at least one measurable lesion on baseline CT/MRI examination (according to RECIST 1.1 criteria), receive at least 1 study treatment, and after starting study treatment Have received at least 1 CT/MRI examination. If the efficacy reaches CR or PR, the subject must be re-examined and confirmed 4 weeks after the first evaluation.

客緩解持續時間(DoR)是指首次CR或PR出現日期至首次PD日期(根據RECIST v1.1)或任何原因導致的死亡日期的時間。 Duration of response (DoR) is the time from the date of first CR or PR to the date of first PD (according to RECIST v1.1) or the date of death from any cause.

疾病控制率(DCR)是指經治療後CR、PR及SD的受試者人數占可評價受試者的比例。 Disease control rate (DCR) refers to the proportion of subjects with CR, PR and SD after treatment to the evaluable subjects.

無進展生存期(PFS)是指從首次用藥開始到發生影像學疾病進展(以影像學檢查日期為准)或任何原因導致的死亡的時間，按照先發生的時間計算。 Progression-free survival (PFS) refers to the time from the first dose to the occurrence of imaging disease progression (based on the date of imaging examination) or death due to any cause, and is calculated according to the time that occurs first.

圖1為藥物A影響p-MEK、p-ERK的Western blot結果； Figure 1 shows the Western blot results of drug A affecting p-MEK and p-ERK;

圖2為藥物A能夠在KYSE-520細胞中誘導G0/G1期阻滯； Figure 2 shows that drug A can induce G0/G1 phase arrest in KYSE-520 cells;

圖3為藥物A在KYSE-520移植瘤模型中的抑瘤作用； Figure 3 shows the tumor inhibitory effect of drug A in the KYSE-520 transplanted tumor model;

圖4為藥物A在KYSE-520移植瘤模型中對動物體重的影響； Figure 4 shows the effect of drug A on animal body weight in the KYSE-520 transplanted tumor model;

圖5為藥物A在KRAS^G12C突變的PDX移植瘤模型中的抑瘤作用； Figure 5 shows the tumor inhibitory effect of drug A in the PDX xenograft tumor model with KRAS ^G12C mutation;

圖6為藥物A在KRAS^G12C突變的PDX移植瘤模型中對動物體重的影響； Figure 6 shows the effect of drug A on animal body weight in the PDX xenograft tumor model with KRAS ^G12C mutation;

圖7為藥物A與藥物B聯合用藥對人肺癌NCI-H358裸小鼠移植瘤的抑瘤作用； Figure 7 shows the tumor inhibitory effect of drug A and drug B combined on human lung cancer NCI-H358 nude mouse transplanted tumors;

圖8為藥物A與藥物B聯合用藥對人肺癌NCI-H358裸小鼠移植瘤模型中對動物體重的影響； Figure 8 shows the effect of drug A and drug B combined on animal body weight in the human lung cancer NCI-H358 nude mouse transplant tumor model;

圖9為藥物A與阿美替尼聯合用藥對人肺腺癌NCI-H1975裸小鼠移植瘤的抑瘤作用； Figure 9 shows the tumor inhibitory effect of drug A combined with ametinib on human lung adenocarcinoma NCI-H1975 nude mouse transplanted tumors;

圖10為藥物A與阿美替尼聯合用藥對人肺腺癌NCI-H1975裸小鼠移植瘤模型中對動物體重的影響； Figure 10 shows the effect of drug A combined with ametinib on animal body weight in the human lung adenocarcinoma NCI-H1975 nude mouse transplant tumor model;

圖11為藥物A與曲美替尼聯合用藥對人結腸癌SW620裸小鼠移植瘤的抑瘤作用； Figure 11 shows the tumor inhibitory effect of drug A combined with trametinib on transplanted tumors of human colon cancer SW620 nude mice;

圖12為藥物A與曲美替尼聯合用藥對人結腸癌SW620裸小鼠移植瘤的模型中對動物體重的影響； Figure 12 shows the effect of drug A combined with trametinib on animal body weight in the human colon cancer SW620 nude mouse transplanted tumor model;

圖13為藥物A與藥物C聯合用藥在小鼠MC38模型中的抑瘤作用； Figure 13 shows the tumor inhibitory effect of drug A and drug C combined in the mouse MC38 model;

圖14為藥物A與藥物C聯合用藥在小鼠MC38模型中對動物體重的影響； Figure 14 shows the effect of drug A and drug C combined on animal body weight in the mouse MC38 model;

圖15為藥物A與藥物D聯合用藥在小鼠MC38模型中的抑瘤作用； Figure 15 shows the tumor inhibitory effect of drug A and drug D combined in the mouse MC38 model;

圖16為藥物A與藥物D聯合用藥在小鼠MC38模型中對動物體重的影響。 Figure 16 shows the effect of drug A and drug D combined on animal body weight in the mouse MC38 model.

以下結合實施例用於進一步描述本揭露，但這些實施例並非限制本揭露的範圍。 The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

實驗材料：SHP2抑制劑，WO2020259679A公開了化合物5(藥物A)；ERK抑制劑(藥物B)，式(II)所示化合物富馬酸鹽，WO2020200069A公開了式(II)所示化合物；藥物C，PD-L1抗體：其重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11；藥物D，TGF-β受體融合蛋白：融合蛋白9。RMC-4550結構為， Experimental materials: SHP2 inhibitor, WO2020259679A discloses compound 5 (drug A); ERK inhibitor (drug B), a compound represented by formula (II) fumarate, WO2020200069A discloses a compound represented by formula (II); drug C , PD-L1 antibody: its heavy chain sequence is SEQ ID NO: 9, and its light chain sequence is SEQ ID NO: 11; Drug D, TGF-β receptor fusion protein: fusion protein 9. The structure of RMC-4550 is,

實施例1、SHP2抑制劑(藥物A)對p-MEK、p-ERK的影響Example 1. Effect of SHP2 inhibitor (drug A) on p-MEK and p-ERK

採用Western blot法對藥物A、RMC-4550是否影響p-MEK、p-ERK水平進行檢測。結果顯示，藥物A、RMC-4550均能夠在KYSE-520細胞中顯著降低MEK和ERK蛋白的磷酸化水平(圖1)。 Western blot method was used to detect whether drug A and RMC-4550 affected the levels of p-MEK and p-ERK. The results showed that both Drug A and RMC-4550 could significantly reduce the phosphorylation levels of MEK and ERK proteins in KYSE-520 cells (Figure 1).

1.1 藥物A抑制p-ERK的活性 1.1 Drug A inhibits the activity of p-ERK

採用Alphalisa法對藥物A、RMC-4550抑制p-ERK水平的活性進行檢測。結果顯示，藥物A抑制p-ERK的IC₅₀值為1.20±0.18nM，參比化合物RMC-4550抑制p-ERK的IC₅₀值為3.93±0.63nM。藥物A的p-ERK抑制作用強於RMC-4550(表1)。 Alphalisa method was used to detect the activity of drug A and RMC-4550 in inhibiting p-ERK levels. The results showed that the IC ₅₀ value of Drug A for inhibiting p-ERK was 1.20±0.18nM, and the IC ₅₀ value of reference compound RMC-4550 for inhibiting p-ERK was 3.93±0.63nM. The p-ERK inhibitory effect of Drug A is stronger than that of RMC-4550 (Table 1).

1.2 藥物A對KYSE-520細胞細胞週期的調控 1.2 Regulation of cell cycle of KYSE-520 cells by drug A

藥物A分別作用於KYSE-520細胞24h、48h後採用流式細胞術對藥物A調控細胞週期的作用進行檢測。結果顯示，藥物A能夠濃度依賴性地誘導KYSE-520細胞發生G0/G1期阻滯，其作用與RMC-4550相當(圖2)。 Drug A acted on KYSE-520 cells for 24h and 48h respectively, and then flow cytometry was used to detect the effect of drug A in regulating the cell cycle. The results showed that drug A could induce G0/G1 phase arrest in KYSE-520 cells in a concentration-dependent manner, and its effect was equivalent to that of RMC-4550 (Figure 2).

1.3 藥物A對不同突變腫瘤細胞的增殖抑制作用 1.3 The inhibitory effect of drug A on the proliferation of tumor cells with different mutations

藥物A作用不同MAPK通路突變腫瘤細胞120h後採用3D CellTiter Glo法對藥物A抑制腫瘤細胞增殖的作用進行檢測。結果顯示，藥物A對EGFR、KRAS G12C、NF1 lof突變的腫瘤細胞株具有較強增殖抑制活性，IC₅₀值為0.70-25.64nM，其活性強於RMC-4550，藥物A和RMC-4550對KRAS G13D突變的腫瘤細胞株HCT116增殖抑制活性較弱，IC₅₀值大於10μM(表3)。 The 3D CellTiter Glo method was used to detect the effect of Drug A on inhibiting tumor cell proliferation 120 hours after drug A acted on tumor cells with different MAPK pathway mutations. The results show that Drug A has strong proliferation inhibitory activity against tumor cell lines with EGFR, KRAS G12C, and NF1 lof mutations, with an IC ₅₀ value of 0.70-25.64nM. Its activity is stronger than RMC-4550. Drug A and RMC-4550 have a strong inhibitory effect on KRAS. The proliferation inhibitory activity of the G13D mutated tumor cell line HCT116 was weak, with an IC ₅₀ value greater than 10 μM (Table 3).

實施例2、體內藥效及聯用研究Example 2. In vivo drug efficacy and combined use studies

2.1 藥物A在EGFR amp突變的人食管癌KYSE-520移植瘤模型中的抗腫瘤作用研究 2.1 Study on the anti-tumor effect of Drug A in the EGFR amp mutated human esophageal cancer KYSE-520 xenograft tumor model

Balb/c裸鼠於皮下接種人食管癌KYSE-520細胞，待瘤體積大小為100mm³左右時隨機分為5組，除溶劑對照組為12隻外，其餘各 Balb/c nude mice were ^{subcutaneously} inoculated with human esophageal cancer KYSE-520 cells. When the tumor size reached about 100 mm, they were randomly divided into 5 groups. Except for the solvent control group, which consisted of 12 mice, the remaining mice were

組均為6隻，分別灌胃給予溶媒對照品(0.5% HPMC+0.1%吐溫80水溶液)、30mg/kg RMC-4550、1、3、10mg/kg藥物A，每天1次，連續給藥39天。結果顯示，藥物A 1-10mg/kg灌胃給藥能劑量依賴性地抑制人食管癌KYSE-520裸小鼠移植瘤的生長，給藥過程中未發現體重明顯下降(圖3、圖4)。藥物A 10mg/kg的抑瘤作用與RMC-4550 30mg/kg相當(表4)。 There were 6 rats in each group, and the vehicle control substance (0.5% HPMC + 0.1% Tween 80 aqueous solution), 30 mg/kg RMC-4550, 1, 3, and 10 mg/kg drug A were administered by gavage respectively, once a day, continuously. 39 days. The results showed that intragastric administration of Drug A at 1-10 mg/kg could dose-dependently inhibit the growth of transplanted tumors of human esophageal cancer KYSE-520 nude mice, and no significant decrease in body weight was found during the administration (Figure 3, Figure 4) . The tumor inhibitory effect of Drug A 10mg/kg is equivalent to that of RMC-4550 30mg/kg (Table 4).

與Control組相比，^*：P<0.05；^**：P<0.01；^***：P<0.001 Compared with Control group, ^* : P <0.05; ^** : P <0.01; ^*** : P <0.001

2.2 藥物A在KRAS G12C突變的PDX移植瘤模型中的抗腫瘤作用研究 2.2 Study on the anti-tumor effect of drug A in the PDX xenograft tumor model with KRAS G12C mutation

Balb/c裸鼠於皮下接種KRAS G12C突變的腸癌PDX種鼠模型瘤塊，待瘤體積大小為100mm³左右時隨機分為5組，除溶劑對照組為12隻外，其餘各組均為6隻，分別灌胃給予溶媒對照品(0.5% HP.1%吐溫80水溶液)、30mg/kg RMC-4550、1、3、10mg/kg藥物A，每天1次，連續給藥21天。結果顯示，藥物A 1-10mg/kg灌胃給藥能劑量依賴性地抑制KRAS G12C突變的PDX模型裸小鼠移植瘤的生長，且未見明顯毒性(圖5、圖6、表5)。 Balb/c nude mice were subcutaneously inoculated with tumors of the KRAS G12C mutated intestinal cancer PDX mouse model. When the tumor size reached about 100 mm, they were ^randomly divided into 5 groups. Except for the solvent control group, which consisted of 12 mice, the other groups were all 6 animals were given vehicle reference substance (0.5% HP.1% Tween 80 aqueous solution), 30 mg/kg RMC-4550, 1, 3, and 10 mg/kg drug A by gavage respectively, once a day for 21 consecutive days. The results showed that intragastric administration of Drug A at 1-10 mg/kg dose-dependently inhibited the growth of transplanted tumors in nude mice with KRAS G12C mutation in the PDX model, without obvious toxicity (Figure 5, Figure 6, Table 5).

2.3 藥物A在KRAS G12C突變的NCI-H358移植瘤模型中聯用ERK抑制劑藥物B的抗腫瘤作用研究 2.3 Study on the anti-tumor effect of drug A combined with ERK inhibitor drug B in the NCI-H358 transplanted tumor model with KRAS G12C mutation

Balb/c裸鼠於皮下接種人肺癌NCI-H358細胞，待腫瘤生長至平均體積150mm³左右時，將動物隨機分為4組，分別為溶劑對照組(Vehicle)、藥物A 1mg/kg單藥組、藥物B 25mg/kg單藥組、藥物A(1mg/kg)+藥物B(25mg/kg)聯用組，每組8隻小鼠。各組灌胃給予相應濃度的受試物，每天1次，給藥週期21天，結果顯示，藥物A與藥物B聯合用藥在人肺癌NCI-H358裸小鼠移植瘤中具有顯著協同抗腫瘤活性，且未見明顯毒性(圖7、圖8、表6)。 Balb/c nude mice were subcutaneously inoculated with human lung cancer NCI-H358 cells. When the tumors grew to an average volume of ^about 150mm, the animals were randomly divided into 4 groups, namely vehicle control group (Vehicle) and drug A 1mg/kg single drug. Group, drug B 25mg/kg single drug group, drug A (1mg/kg) + drug B (25mg/kg) combined group, 8 mice in each group. Each group was intragastrically administered test substances of corresponding concentrations once a day for 21 days. The results showed that the combination of Drug A and Drug B had significant synergistic anti-tumor activity in human lung cancer NCI-H358 nude mouse transplanted tumors. , and no obvious toxicity was found (Figure 7, Figure 8, Table 6).

2.4 藥物A在EGFR T790M突變的NCI-H1975移植瘤模型中聯用EGFR抑制劑阿美替尼的抗腫瘤作用研究 2.4 Study on the anti-tumor effect of drug A combined with the EGFR inhibitor ametinib in the NCI-H1975 transplanted tumor model with EGFR T790M mutation

將1×10⁷個人肺腺癌NCI-H1975細胞注射入裸小鼠腋下，傳三代後，剖取NCI-H1975種鼠瘤塊，放入盛有生理鹽水的玻璃皿內，剝棄表面血管，切開去除壞死區域後，將瘤塊切至1-2mm³，用套管針接種於裸小鼠左腋下。待腫瘤生長至平均體積100mm³左右時，將裸小鼠按瘤體積隨機分為4組，除溶劑對照組(Control)為12隻外，其餘各組均為6隻，分別灌胃給予溶媒對照品(0.5% HPMC+0.1%吐溫80水溶液)、3mg/kg藥物A、5mg/kg阿美替尼、3mg/kg藥物A+5mg/kg阿美替尼，每天1次，給藥21天後，停藥觀察。結果顯示，藥物A與阿美替尼聯合用藥在人肺腺癌細胞NCI-H1975裸小鼠移植瘤中具有協同抗腫瘤活性，且未見明顯毒性。停藥後仍能持續發揮一定的抗腫瘤作用(圖9、圖10、表7)。 1× ¹⁰⁷ human lung adenocarcinoma NCI-H1975 cells were injected into the armpits of nude mice. After three generations, the NCI-H1975 mouse tumor pieces were dissected and placed in a glass dish filled with physiological saline, and the surface blood vessels were peeled off. , after incision and removal of necrotic areas, cut the tumor mass to 1-2 mm ³ and inoculate it into the left armpit of nude mice with a trocar. When the tumor grew to an average volume of ^about 100 mm, the nude mice were randomly divided into 4 groups according to the tumor volume. Except for the solvent control group (Control), which had 12 mice, the other groups had 6 mice. The mice were given the vehicle control by gavage. product (0.5% HPMC + 0.1% Tween 80 aqueous solution), 3 mg/kg drug A, 5 mg/kg ametinib, 3 mg/kg drug A + 5 mg/kg ametinib, once a day, after 21 days of administration, Stop medication and observe. The results showed that the combination of drug A and ametinib had synergistic anti-tumor activity in nude mouse transplanted tumors of human lung adenocarcinoma cell NCI-H1975, without obvious toxicity. It can still continue to exert a certain anti-tumor effect after stopping the drug (Figure 9, Figure 10, Table 7).

與Control組相比，^***：P<0.001；與藥物A組相比，^###：P<0.001；與阿美替尼組相比，^△：P<0.05。 Compared with the Control group, ^*** : P <0.001; compared with the drug group A, ^### : P <0.001; compared with the ametinib group, ^△ : P <0.05.

2.5 藥物A在KRAS G12V突變的SW620移植瘤模型中聯用MEK抑制劑曲美替尼的抗腫瘤作用研究 2.5 Study on the anti-tumor effect of drug A combined with the MEK inhibitor trametinib in the SW620 transplanted tumor model with KRAS G12V mutation

將1×10⁷個人結腸癌細胞SW620注射入裸小鼠腋下，傳三代後，剖取SW620種鼠瘤塊，放入盛有生理鹽水的玻璃皿內，剝棄表面血管，切開去除壞死區域後，將瘤塊切至1-2mm³，用套管針接種於裸小鼠左腋下。待腫瘤生長至平均體積100mm³左右時，將裸小鼠按瘤體積隨機分為4組，除溶劑對照組(Control)為12隻外，其餘各組均為6隻，分別灌胃給予溶媒對照品(0.5% HPMC+0.1%吐溫80水溶液)、1.5/5mg/kg藥物A、0.1/0.3mg/kg曲美替尼、1.5/5mg/kg藥物A+0.1/0.3mg/kg曲美替尼，每天1次，連續給藥28天。給藥11天後，藥物A劑量由1.5mg/kg調整為5mg/kg，曲美替尼劑量由0.1mg/kg調整為0.3mg/kg。結果顯示，藥物A與曲美替尼聯合用藥在人結腸癌SW620裸小鼠移植瘤中具有協同抗腫瘤活性。實驗結束時，與Control組相比，各組裸小鼠體重無明顯下降(圖11、圖12、表8)。 1×10 ⁷ human colon cancer cells SW620 were injected into the armpits of nude mice. After three passages, the SW620 mouse tumor was dissected and placed in a glass dish filled with physiological saline. Surface blood vessels were peeled off and the necrotic area was removed by incision. Afterwards, the tumor was cut into 1-2 mm ³ and inoculated into the left armpit of nude mice using a trocar. When the tumor grew to an average volume of ^about 100 mm, the nude mice were randomly divided into 4 groups according to the tumor volume. Except for the solvent control group (Control), which had 12 mice, the other groups had 6 mice. The mice were given the vehicle control by gavage. Product (0.5% HPMC+0.1% Tween 80 aqueous solution), 1.5/5mg/kg drug A, 0.1/0.3mg/kg trametinib, 1.5/5mg/kg drug A+0.1/0.3mg/kg trametinib Ni, once a day, for 28 consecutive days. After 11 days of administration, the dose of drug A was adjusted from 1.5 mg/kg to 5 mg/kg, and the dose of trametinib was adjusted from 0.1 mg/kg to 0.3 mg/kg. The results showed that the combination of drug A and trametinib had synergistic anti-tumor activity in human colon cancer SW620 nude mouse transplant tumors. At the end of the experiment, compared with the Control group, the body weight of nude mice in each group did not decrease significantly (Figure 11, Figure 12, Table 8).

2.6 藥物A在小鼠MC38模型中聯用PD-L1單抗(藥物C)或重組的抗PD-L1/TGF-βRII雙功能融合蛋白(藥物D)的抗腫瘤作用研究 2.6 Study on the anti-tumor effect of drug A combined with PD-L1 monoclonal antibody (drug C) or recombinant anti-PD-L1/TGF-βRII bifunctional fusion protein (drug D) in mouse MC38 model

將小鼠MC38細胞按1×10⁶/隻接種於小鼠腹背部皮下，待腫瘤生長至平均體積80mm³左右時，將動物隨機分為6組，分別為溶劑對照組(Vehicle)、藥物A 10或5mg/kg單藥組、藥物C 3mg/kg單藥組、藥物D 3mg/kg單藥組、藥物A(10mg/kg)+藥物C(3mg/kg)聯用組、藥物A(5mg/kg)+藥物D(3mg/kg)聯用組，每組7隻小鼠。各組分別給予相應受試物，藥物A每天1次，灌胃給藥；藥物C或藥物D每週2次，腹腔注射給藥，給藥週期17或14天。結果顯示，藥物A與藥物C或藥物D聯合用藥在鼠腸癌MC38小鼠移植瘤中具有顯著協同抗腫瘤活性，且未見明顯毒性(圖13、圖14、圖15、圖16、表9、表10)。 Mouse MC38 cells were inoculated subcutaneously on the abdomen and back of mice at 1×10 ⁶ /mouse. When the tumors grew to an average volume of about 80 mm ³ , the animals were randomly divided into 6 groups, namely vehicle control group (Vehicle) and drug A. 10 or 5mg/kg single drug group, drug C 3mg/kg single drug group, drug D 3mg/kg single drug group, drug A (10mg/kg) + drug C (3mg/kg) combination group, drug A (5mg /kg) + drug D (3mg/kg) combined group, 7 mice in each group. Each group was given corresponding test substances respectively. Drug A was administered by intragastric administration once a day; Drug C or Drug D was administered by intraperitoneal injection twice a week, with a administration period of 17 or 14 days. The results showed that drug A combined with drug C or drug D had significant synergistic anti-tumor activity in mouse intestinal cancer MC38 mouse transplant tumors, and no obvious toxicity was found (Figure 13, Figure 14, Figure 15, Figure 16, Table 9 , Table 10).

表9. 藥物A與藥物C聯合用藥在小鼠MC38模型中的抑瘤作用

Table 9. Antitumor effect of drug A and drug C combined in mouse MC38 model

實施例3、藥物A單藥及分別聯合藥物C、藥物D、曲美替尼和阿美替尼在晚期惡性腫瘤患者中的劑量遞增和劑量拓展的多中心、開放的I期臨床研究Example 3. A multi-center, open phase I clinical study of dose escalation and dose expansion of drug A alone and in combination with drug C, drug D, trametinib and ametinib in patients with advanced malignant tumors.

1、主要目的 1. Main purpose

‧評價藥物A單藥在晚期惡性腫瘤患者中的安全性和耐受性； ‧Evaluate the safety and tolerability of Drug A alone in patients with advanced malignant tumors;

‧評價藥物A聯合用藥(分別聯合藥物C、藥物D、曲美替尼、阿美替尼)在晚期惡性腫瘤患者中的安全性和耐受性； ‧Evaluate the safety and tolerability of the combination of drug A (combined with drug C, drug D, trametinib, and ametinib respectively) in patients with advanced malignant tumors;

‧確定藥物A單藥及聯合用藥的最大耐受劑量(MTD)及II期臨床研究推薦劑量(RP2D)。 ‧Determine the maximum tolerated dose (MTD) and recommended dose (RP2D) of Phase II clinical studies of Drug A as a single agent and combination.

2、研究方案 2. Research plan

分為藥物A單藥劑量遞增、藥物A單藥劑量拓展、藥物A分別聯 It is divided into drug A single drug dose escalation, drug A single drug dose expansion, and drug A separate combination.

藥物C、藥物D、曲美替尼、阿美替尼劑量遞增和聯合劑量拓展四個階段 Four stages of drug C, drug D, trametinib, and ametinib dose escalation and combined dose expansion

第一階段：藥物A單藥劑量遞增 Phase 1: Drug A single dose escalation

本階段擬入組晚期惡性腫瘤患者。 Patients with advanced malignant tumors are planned to be enrolled at this stage.

藥物A在本階段預設5個遞增劑量組：10mg、20mg、40mg、50mg和60mg，QD給藥。 Drug A is preset into 5 ascending dose groups at this stage: 10 mg, 20 mg, 40 mg, 50 mg and 60 mg, administered QD.

第二階段：藥物A單藥劑量拓展 Phase II: Single drug dose expansion of Drug A

本階段擬入組晚期惡性腫瘤患者。依據藥物A劑量遞增階段各劑量組的安全性/耐受性、PK、PD及有效性數據，選擇2~3個劑量組進行藥物A單藥劑量拓展。每個劑量組拓展至10~20例受試者。 Patients with advanced malignant tumors are planned to be enrolled at this stage. Based on the safety/tolerability, PK, PD and effectiveness data of each dose group during the dose escalation phase of Drug A, 2 to 3 dose groups were selected to expand the single dose of Drug A. Each dose group was expanded to 10 to 20 subjects.

第三階段：聯合劑量遞增 Phase III: Combination dose escalation

擬開展的聯合劑量遞增研究包括： The proposed combination dose escalation studies include:

(1)藥物A+藥物C(PD-L1單抗) (1) Drug A + Drug C (PD-L1 monoclonal antibody)

(2)藥物A+藥物D(PD-L1和TGFβ雙抗) (2) Drug A + Drug D (PD-L1 and TGFβ dual antibodies)

(3)藥物A+曲美替尼(MEK抑制劑) (3) Drug A + trametinib (MEK inhibitor)

(4)藥物A+阿美替尼(EGFR抑制劑) (4) Drug A + Amitinib (EGFR inhibitor)

本階段擬入組晚期惡性腫瘤患者，採用“3+3”原則進行聯合劑量爬坡試驗。 At this stage, patients with advanced malignant tumors are planned to be enrolled, and a combination dose escalation trial will be conducted using the "3+3" principle.

1)藥物A聯合藥物C/藥物D： 1) Drug A combined with drug C/drug D:

藥物C/藥物D採用III期臨床劑量，藥物C為20mg/kg，每三週給藥一次(Q3W)，藥物D為30mg/kg，每三週給藥一次(Q3W)；藥物A首先採用RP2D前一個劑量(RP2D-1)分別聯合藥物C和藥物D，若該組合給藥方案下，耐受性/安全性可接受，藥物A可採用RP2D分別聯合藥物C和藥物D進一步進行聯合劑量探索。 Drug C/Drug D adopt phase III clinical dosage, drug C is 20mg/kg, administered once every three weeks (Q3W), drug D is 30mg/kg, administered once every three weeks (Q3W); drug A first adopts the previous one of RP2D The dosage (RP2D-1) is combined with drug C and drug D respectively. If the tolerability/safety is acceptable under this combination dosage regimen, drug A can be combined with drug C and drug D respectively using RP2D to further explore the combined dosage.

2)藥物A聯合曲美替尼/阿美替尼： 2) Drug A combined with trametinib/ametinib:

藥物A預設RP2D-1和RP2D兩個劑量，曲美替尼預設1mg QD和2mg QD(III期臨床劑量)兩個劑量組，阿美替尼預設55mg QD和110mg QD(III期臨床劑量)兩個劑量組。 Drug A has two preset doses of RP2D-1 and RP2D, trametinib has two preset dose groups of 1mg QD and 2mg QD (Phase III clinical dose), and ametinib has preset 55mg QD and 110mg QD (Phase III clinical dose). ) two dose groups.

第四階段：聯合劑量拓展 Phase 4: Combination dose expansion

根據第三階段的爬坡結果，綜合安全性和有效性數據，選擇藥物A分別與藥物C、藥物D、曲美替尼、阿美替尼聯用的1-2個組合給藥方案進行劑量拓展，每個劑量組拓展至20-30例受試者。 Based on the ramp-up results of the third phase and comprehensive safety and effectiveness data, 1-2 combination dosage regimens of drug A, drug C, drug D, trametinib, and ametinib were selected for dose expansion. , each dose group was expanded to 20-30 subjects.

3、入組標準 3. Entry criteria

標準治療無效、不耐受標準治療或經研究者判定不適合接受標準治療的病理學確診的晚期實體瘤患者(除外肝細胞癌和軟骨肉瘤)，同時在以下階段患者需要另外滿足如下條件： Patients with pathologically confirmed advanced solid tumors (excluding hepatocellular carcinoma and chondrosarcoma) who are ineffective, intolerant to standard treatment, or judged by the investigator to be unsuitable for standard treatment. Patients at the following stages need to meet the following additional conditions:

‧單藥劑量拓展階段：患者需要攜帶有以下至少一種突變：KRAS突變或擴增，BRAF class3突變或NF1 LOF； ‧Single drug dose expansion phase: patients need to carry at least one of the following mutations: KRAS mutation or amplification, BRAF class3 mutation or NF1 LOF;

‧聯合曲美替尼劑量遞增及拓展階段：患者需要攜帶有以下至少一種突變：KRAS突變或擴增，BRAF突變，或NF1 LOF； ‧Combined with trametinib dose escalation and expansion phase: patients need to carry at least one of the following mutations: KRAS mutation or amplification, BRAF mutation, or NF1 LOF;

‧聯合阿美替尼劑量遞增及拓展階段：局部晚期或轉移性EGFR突變的肺腺癌，既往EGFR-TKI藥物治療失敗； ‧Dose escalation and expansion phase of combination with ametinib: locally advanced or metastatic EGFR-mutated lung adenocarcinoma, previous EGFR-TKI drug treatment failure;

‧聯合藥物C、藥物D階段，入組肺癌受試者時，需排除EGFR和ALK陽性的受試者 ‧In combination drug C and drug D phases, when enrolling lung cancer subjects, EGFR and ALK positive subjects need to be excluded

4、療效評價根據RECIST1.1標準 4. The efficacy evaluation is based on RECIST1.1 standard

客觀緩解率(ORR)、緩解持續時間(DoR)、疾病控制率(DCR)、無進展生存期(PFS)、總生存期(OS) Objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS)

TW202328133A_111132352_SEQL.xmlTW202328133A_111132352_SEQL.xml

Claims

一種式(I)所示化合物或其藥學上可接受的鹽在製備治療含有RAS通路基因突變的腫瘤的藥物中的用途， The use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in preparing a drug for treating tumors containing RAS pathway gene mutations,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

該RAS途徑基因突變選自KRAS突變、NRAS突變、HRAS突變、SOS突變、BRAF突變和NF1突變；較佳地，該KRAS突變選自KRAS^G12A突變、KRAS^G12C突變、KRAS^G12D突變、KRAS^G12F突變、KRAS^G12I突變、KRAS^G12L突變、KRAS^G12R突變、KRAS^G12S突變、KRAS^G12V突變或KRAS^G12Y突變；最佳地，該RAS通路基因突變選自KRAS^G12C突變、KRAS^G12D突變或BRAF-Class3突變、編碼NF1功能喪失(NF1^LOF)變體的突變或EGFR擴增或突變。 The RAS pathway gene mutation is selected from the group consisting of KRAS mutation, NRAS mutation, HRAS mutation, SOS mutation, BRAF mutation and NF1 mutation; preferably, the KRAS mutation is selected from the group consisting of KRAS ^G12A mutation, KRAS ^G12C mutation, KRAS ^G12D mutation, KRAS ^G12F mutation, KRAS ^G12I mutation, KRAS ^G12L mutation, KRAS ^G12R mutation, KRAS ^G12S mutation, KRAS ^G12V mutation or KRAS ^G12Y mutation; optimally, the RAS pathway gene mutation is selected from KRAS ^G12C mutation, KRAS ^G12D mutation or BRAF-Class3 mutation, encoding NF1 Mutation of loss-of-function (NF1 ^LOF ) variants or EGFR amplification or mutation.

一種式(I)所示化合物或其藥學上可接受的鹽與RAS通路抑制劑聯合 A compound represented by formula (I) or a pharmaceutically acceptable salt thereof combined with a RAS pathway inhibitor

在製備治療腫瘤的藥物中的用途， Use in the preparation of drugs for treating tumors,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

m和n各自獨立地選自0，1，2或3。 m and n are each independently selected from 0, 1, 2 or 3.

一種式(I)所示化合物或其藥學上可接受的鹽與PD-L1抗體或抗原結合片段、或含有TGF-β受體的融合蛋白聯合在製備治療腫瘤的藥物中的用途， The use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with a PD-L1 antibody or antigen-binding fragment, or a fusion protein containing a TGF-β receptor, in the preparation of a drug for treating tumors,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

如請求項2或3所述的用途，其中該腫瘤為 The use as described in claim 2 or 3, wherein the tumor is

RAS途徑基因突變腫瘤，該RAS途徑基因突變選自KRAS突變、NRAS突變、HRAS突變、SOS突變、BRAF突變和NF1突變；較佳地，該KRAS突變選自KRAS^G12A突變、KRAS^G12C突變、KRAS^G12D突變、KRAS^G12F突變、KRAS^G12I突變、KRAS^G12L突變、KRAS^G12R突變、KRAS^G12S突變、KRAS^G12V突變或KRAS^G12Y突變；最佳地，該RAS通路基因突變選自KRAS^G12C突變、KRAS^G12D突變或BRAF-Class3突變、編碼NF1功能喪失(NF1^LOF)變體的突變或EGFR擴增或突變。 RAS pathway gene mutation tumors, the RAS pathway gene mutation is selected from KRAS mutation, NRAS mutation, HRAS mutation, SOS mutation, BRAF mutation and NF1 mutation; preferably, the KRAS mutation is selected from KRAS ^G12A mutation, KRAS ^G12C mutation, KRAS ^G12D mutation, KRAS ^G12F mutation, KRAS ^G12I mutation, KRAS ^G12L mutation, KRAS ^G12R mutation, KRAS ^G12S mutation, KRAS ^G12V mutation or KRAS ^G12Y mutation; optimally, the RAS pathway gene mutation is selected from KRAS ^G12C mutation, KRAS ^G12D mutation or BRAF -Class3 mutations, mutations encoding NF1 loss-of-function (NF1 ^LOF ) variants, or EGFR amplification or mutations.

如請求項2或4所述的用途，其中該RAS通路抑制劑為MEK抑制劑。 The use as described in claim 2 or 4, wherein the RAS pathway inhibitor is a MEK inhibitor.

如請求項2或4所述的用途，其中該RAS通路抑制劑為ERK抑制劑。 The use as described in claim 2 or 4, wherein the RAS pathway inhibitor is an ERK inhibitor.

如請求項2或4所述的用途，其中該RAS通路抑制劑為EGFR抑制劑。 The use as described in claim 2 or 4, wherein the RAS pathway inhibitor is an EGFR inhibitor.

如請求項1、4至7中任一項所述的用途，其中該EGFR擴增或突變的腫瘤選自食管癌、肝細胞癌或非小細胞肺癌，較佳局部晚期或轉移性EGFR突變的非小細胞肺癌。 The use as described in any one of claims 1, 4 to 7, wherein the EGFR amplified or mutated tumor is selected from esophageal cancer, hepatocellular carcinoma or non-small cell lung cancer, preferably locally advanced or metastatic EGFR mutated tumors. Non-small cell lung cancer.

如請求項1、4至7中任一項所述的用途，其中該KRAS^G12C突變腫瘤選自非小細胞肺癌、胰腺癌、結直腸癌。 The use as described in any one of claims 1, 4 to 7, wherein the KRAS ^G12C mutant tumor is selected from the group consisting of non-small cell lung cancer, pancreatic cancer, and colorectal cancer.

如請求項1、4至7中任一項所述的用途，其中該KRAS^G12D突變腫瘤選自胃癌、結腸癌、胰腺癌、結腸直腸癌、肺癌、子宮內膜癌、卵巢癌或***癌。 The use according to any one of claims 1, 4 to 7, wherein the KRAS ^G12D mutant tumor is selected from gastric cancer, colon cancer, pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, ovarian cancer or prostate cancer.

如請求項1至10中任一項所述的用途，其中該式(I)所示化合物或其藥學上可接受的鹽選自 The use as described in any one of claims 1 to 10, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from

，較佳

。

, better

.

如請求項1至11中任一項所述的用途，其中該式(I)所示化合物或其藥學上可接受的鹽的給藥劑量選自0.1mg-500mg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次，較佳的，式(I)所示化合物或其藥學上可接受的鹽的給藥劑量選自10mg、20mg、30mg、40mg、50mg或60mg，給藥頻次為一日一次。 The use as described in any one of claims 1 to 11, wherein the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 0.1 mg to 500 mg, and the dosage frequency is once a day. , twice a day, once every two days, once every three days or once a week. Preferably, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50mg or 60mg, the frequency of administration is once a day.

如請求項1至11中任一項所述的用途，其中該式(I)所示化合物或其藥學上可接受的鹽的給藥劑量選自0.01-20mg/kg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 The use as described in any one of claims 1 to 11, wherein the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 0.01-20 mg/kg, and the dosage frequency is one day Once, twice a day, once every two days, once every three days or once a week.

如請求項5、8至13中任一項所述的用途，其中該MEK抑制劑選自曲美替尼、司美替尼、考比替尼、比美替尼、皮瑪西替(Pimasertib)、TAK733、RO4987655、CI-1040、PD-0325901、瑞美替尼、RO5126766、AZD8330、CH5126766、MAP855或GSK1120212，較佳曲美替尼。 The use as described in any one of claims 5, 8 to 13, wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, bimetinib, and pimasertib , TAK733, RO4987655, CI-1040, PD-0325901, remetinib, RO5126766, AZD8330, CH5126766, MAP855 or GSK1120212, preferably trametinib.

如請求項14所述的用途，其中該MEK抑制劑的給藥劑量選自0.1-1000mg，給藥頻次為一日一次或一日兩次。 The use as described in claim 14, wherein the dosage of the MEK inhibitor is selected from 0.1-1000 mg, and the dosage frequency is once a day or twice a day.

如請求項14所述的用途，其中該MEK抑制劑為曲美替尼，給藥劑量為1mg或2mg，給藥頻次為一日一次。 The use as described in claim 14, wherein the MEK inhibitor is trametinib, the dosage is 1 mg or 2 mg, and the dosage frequency is once a day.

如請求項6、8至13中任一項所述的用途，其中該ERK抑制劑選自ASTX-029、ASN-007、林內特基(rineterkib)、LY-3214996、烏利替尼(ulixertinib)、HH-2710或式(II)所示化合物或其藥學上可接受的鹽

； The use as described in any one of claims 6, 8 to 13, wherein the ERK inhibitor is selected from ASTX-029, ASN-007, rineterkib, LY-3214996, ulixertinib ), HH-2710 or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof

;

較佳地，該ERK抑制劑為式(II)所示化合物或其藥學上可接受的鹽； Preferably, the ERK inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof;

最佳，該ERK抑制劑式(II)所示化合物的富馬酸鹽。 Most preferably, the ERK inhibitor is the fumarate salt of the compound represented by formula (II).

如請求項17所述的用途，其中該ERK抑制劑的給藥劑量選自1mg-1000mg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次，較佳的，該ERK抑制劑的給藥劑量選自25mg、75mg、150mg、300mg或450mg，給藥頻次選自一日一次或一日二次。 The use as described in claim 17, wherein the dosage of the ERK inhibitor is selected from 1 mg to 1000 mg, and the frequency of administration is once a day, twice a day, once every two days, once every three days or once a week, preferably , the dosage of the ERK inhibitor is selected from 25 mg, 75 mg, 150 mg, 300 mg or 450 mg, and the dosage frequency is selected from once a day or twice a day.

如請求項17所述的用途，其中該ERK抑制劑的給藥劑量選自0.01-20mg/kg，給藥頻次為一日一次、一日二次、二日一次、三日一次或一週一次。 The use as described in claim 17, wherein the dosage of the ERK inhibitor is selected from 0.01-20 mg/kg, and the dosage frequency is once a day, twice a day, once every two days, once every three days or once a week.

如請求項7至13中任一項所述的用途，其中該EGFR抑制劑選自奧希替尼、艾維替尼、艾氟替尼、ASK120067、BPI-7711、那札替尼(Nazartinib)、HM61713或式(III)所示的化合物或其藥學上可接受的鹽， The use as described in any one of claims 7 to 13, wherein the EGFR inhibitor is selected from the group consisting of osimertinib, avitinib, aflutinib, ASK120067, BPI-7711, and Nazartinib , HM61713 or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

較佳地，該EGFR抑制劑為式(III)所示的化合物或其藥學上可接受的鹽； Preferably, the EGFR inhibitor is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof;

最佳地，該EGFR抑制劑為式(III)所示的化合物的甲磺酸鹽。 Optimally, the EGFR inhibitor is the mesylate salt of the compound represented by formula (III).

如請求項20所述的用途，其中該EGFR抑制劑的給藥劑量選自1-500mg，給藥頻次為一日一次或一日二次，較佳地，該EGFR抑制劑的給藥劑量選自55mg、110mg、220mg或260mg，給藥頻次為一日一次。 The use as described in claim 20, wherein the dosage of the EGFR inhibitor is selected from 1-500 mg, and the dosage frequency is once a day or twice a day. Preferably, the dosage of the EGFR inhibitor is selected from From 55mg, 110mg, 220mg or 260mg, the dosing frequency is once a day.

如請求項3所述的用途，其中該PD-L1抗體或抗原結合片段任意1個選自以下的CDR區序列或其突變序列：抗體重鏈可變區HCDR 區序列：SEQ ID NO：1-3；和抗體輕鏈可變區LCDR區序列：SEQ ID NO：4-6；具體如下： The use as described in claim 3, wherein any one of the PD-L1 antibodies or antigen-binding fragments is selected from the following CDR region sequences or their mutant sequences: Antibody heavy chain variable region HCDR Region sequence: SEQ ID NO: 1-3; and antibody light chain variable region LCDR region sequence: SEQ ID NO: 4-6; details are as follows:

HCDR1選自： HCDR1 is selected from:

SYWMH SEQ ID NO：1 SYWMH SEQ ID NO: 1

HCDR2選自： HCDR2 is selected from:

RI X₁PNSG X₂TSYNEKFKN SEQ ID NO：2 RI X ₁ PNSG X ₂ TSYNEKFKN SEQ ID NO: 2

HCDR3選自： HCDR3 is selected from:

GGSSYDYFDY SEQ ID NO：3 GGSSYDYFDY SEQ ID NO: 3

LCDR1選自： LCDR1 is selected from:

RASESVSIHGTHLMH SEQ ID NO：4 RASESVSIHGTHLMH SEQ ID NO: 4

LCDR2選自： LCDR2 selected from:

AASNLES SEQ ID NO：5 AASNLES SEQ ID NO: 5

LCDR3選自： LCDR3 selected from:

QQSFEDPLT SEQ ID NO：6； QQSFEDPLT SEQ ID NO: 6;

其中X₁選自H或G，較佳G；X₂選自G或F，較佳F。 Among them, X ₁ is selected from H or G, preferably G; X ₂ is selected from G or F, preferably F.

如請求項3所述的用途，其中該PD-L1抗體或抗原結合片段的重鏈可變區序列為SEQ ID NO：7，輕鏈可變區序列為SEQ ID NO：8。 The use as described in claim 3, wherein the heavy chain variable region sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 7, and the light chain variable region sequence is SEQ ID NO: 8.

如請求項22或23所述的用途，其中該PD-L1抗體或抗原結合片段選自鼠源抗體、嵌合抗體、人源化抗體、人抗體，較佳人源化抗體。 The use as described in claim 22 or 23, wherein the PD-L1 antibody or antigen-binding fragment is selected from the group consisting of murine antibodies, chimeric antibodies, humanized antibodies, and human antibodies, preferably humanized antibodies.

如請求項23所述的用途，其中該PD-L1抗體或抗原結合片段進一步包含人源IgG1、IgG2、IgG3或IgG4或其變體的重鏈恆定區，較佳包含人源IgG2或IgG4重鏈恆定區，更佳包含引入F234A和L235A 突變的IgG4重鏈恆定區；該人源化抗體輕鏈進一步包含人源κ、λ鏈或其變體的恆定區。 The use as described in claim 23, wherein the PD-L1 antibody or antigen-binding fragment further comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof, preferably comprising a human IgG2 or IgG4 heavy chain Constant region, preferably including introduction of F234A and L235A Mutated IgG4 heavy chain constant region; the humanized antibody light chain further comprises the constant region of human kappa, lambda chains or variants thereof.

如請求項25所述的用途，其中該PD-L1抗體或抗原結合片段的重鏈序列為SEQ ID NO：9，輕鏈序列為SEQ ID NO：11。 The use as described in claim 25, wherein the heavy chain sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 11.

如請求項3至4、8-13、22至26中任一項所述的用途，其中該PD-L1抗體或抗原結合片段劑量選自1-200mg/kg，給藥頻次為一週一次、一週兩次、兩週一次、三週一次或四週一次；較佳地，該PD-L1抗體或抗原結合片段劑量選自10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg或50mg/kg，給藥頻次為兩週一次或三週一次，最佳地，該PD-L1抗體或抗原結合片段劑量為20mg/kg，給藥頻次為三週一次。 The use as described in any one of claims 3 to 4, 8 to 13, and 22 to 26, wherein the dose of the PD-L1 antibody or antigen-binding fragment is selected from 1-200 mg/kg, and the administration frequency is once a week, once a week Twice, once every two weeks, once every three weeks or once every four weeks; preferably, the dose of the PD-L1 antibody or antigen-binding fragment is selected from 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35mg/kg, 40mg/kg, 45mg/kg or 50mg/kg, and the administration frequency is once every two weeks or once every three weeks. Optimally, the dose of the PD-L1 antibody or antigen-binding fragment is 20mg/kg, and the administration frequency is Once every three weeks.

如請求項3所述的用途，其中該含有TGF-β受體的融合蛋白包含PD-L1抗體或其抗原結合片段和TGF-β受體，其中TGF-β受體部分為TGF-βRII胞外區的N端截短形式。 The use as described in claim 3, wherein the fusion protein containing TGF-β receptor includes a PD-L1 antibody or an antigen-binding fragment thereof and a TGF-β receptor, wherein the TGF-β receptor part is TGF-βRII extracellular N-terminally truncated form of the region.

如請求項28所述的用途，其中該TGF-β受體融合蛋白如通式(IV)所示： The use as described in claim 28, wherein the TGF-β receptor fusion protein is represented by general formula (IV):

Ab-L-TGF-βRII ECD (IV) Ab-L-TGF-βRII ECD (IV)

L為連接序列。 L is the connection sequence.

如請求項29所述的用途，其中該連接序列為(G4S)xG，其中x為3-6，較佳為4。 The use as described in claim 29, wherein the connection sequence is (G4S)xG, where x is 3-6, preferably 4.

如請求項29所述的用途，其中該TGF-βRII胞外區的序列如SEQ ID NO：15、16、17和18所示；較佳包含SEQ ID NO：16所示的序列。 The use as described in claim 29, wherein the sequences of the TGF-βRII extracellular region are shown in SEQ ID NO: 15, 16, 17 and 18; preferably, the sequence shown in SEQ ID NO: 16 is included.

如請求項29所述的用途，其中該PD-L1抗體或其抗原結合片段包含： The use as described in claim 29, wherein the PD-L1 antibody or antigen-binding fragment thereof contains:

分別如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3，和分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3。 HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively, and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively LCDR1, LCDR2 and LCDR3.

如請求項29至32中任一項所述的用途，其中該PD-L1抗體或其抗原結合片段謂嵌合抗體或其功能片段、人源化抗體或其功能片段或人抗體或其功能片段。 The use as described in any one of claims 29 to 32, wherein the PD-L1 antibody or antigen-binding fragment thereof is a chimeric antibody or functional fragment thereof, a humanized antibody or functional fragment thereof, or a human antibody or functional fragment thereof .

如請求項33所述的用途，其中該PD-L1抗體或其抗原結合片段包含包含如SEQ ID NO：7所示的重鏈可變區，和如SEQ ID NO：8所示的輕鏈可變區。 The use as described in claim 33, wherein the PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 7, and a light chain variable region as shown in SEQ ID NO: 8. Change area.

如請求項29至34中任一項所述的用途，其中該PD-L1抗體或其抗原結合片段的重鏈胺基酸序列如SEQ ID NO：13所示或與SEQ ID NO：13所示的胺基酸序列具有至少95%的同一性，該PD-L1抗體或其抗原結合片段的輕鏈胺基酸序列如SEQ ID NO：14所示或與SEQ ID NO：14所示胺基酸序列具有至少95%的同一性。 The use as described in any one of claims 29 to 34, wherein the heavy chain amino acid sequence of the PD-L1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 13 or is the same as that shown in SEQ ID NO: 13 The amino acid sequence has at least 95% identity, and the light chain amino acid sequence of the PD-L1 antibody or its antigen-binding fragment is as shown in SEQ ID NO: 14 or is identical to the amino acid sequence as shown in SEQ ID NO: 14 Sequences have at least 95% identity.

如請求項3、4、8至13、28至35中任一項所述的用途，其中該含有TGF-β受體的融合蛋白的給藥劑量選自1-200mg/kg，給藥頻次為一週一次、一週兩次、兩週一次、三週一次或四週一次；較佳地，該含有TGF-β受體的融合蛋白劑量選自10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg或60mg/kg，給藥頻次為兩週一次或三週一次，最佳地，該含有TGF-β受體的融合蛋白劑量為30mg/kg，給藥頻次為三週一次。 The use as described in any one of claims 3, 4, 8 to 13, 28 to 35, wherein the dosage of the fusion protein containing TGF-β receptor is selected from 1-200 mg/kg, and the frequency of administration is Once a week, twice a week, once every two weeks, once every three weeks or once every four weeks; preferably, the The dosage of the fusion protein containing TGF-β receptor is selected from 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg or 60 mg/kg. kg, and the administration frequency is once every two weeks or once every three weeks. Optimally, the dose of the fusion protein containing TGF-β receptor is 30 mg/kg, and the administration frequency is once every three weeks.

如請求項2至36中任一項所述的用途，其中該腫瘤選自黑色素瘤、皮膚癌、腎細胞癌、肝細胞癌、胃癌、乳腺癌、胰腺結直腸癌、膠質母細胞瘤、卵巢癌、***癌、血液系統癌症、尿路上皮癌、膀胱癌、非小細胞肺癌、食道癌、頭頸癌或胃腸道間質瘤。 The use according to any one of claims 2 to 36, wherein the tumor is selected from the group consisting of melanoma, skin cancer, renal cell carcinoma, hepatocellular carcinoma, gastric cancer, breast cancer, pancreatic colorectal cancer, glioblastoma, ovarian cancer cancer, prostate cancer, hematologic cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, esophageal cancer, head and neck cancer, or gastrointestinal stromal tumor.

一種治療腫瘤的式(I)所示化合物或其藥學上可接受的鹽，其與選自MEK抑制劑、ERK抑制劑、EGFR抑制劑、PD-L1抗體或其抗原結合片段、含有TGF-β受體的融合蛋白中的至少一種聯用，該MEK抑制劑、ERK抑制劑、EGFR抑制劑、PD-L1抗體或其抗原結合片段、含有TGF-β受體的融合蛋白如請求項4至37中任一項所述； A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treating tumors, which is combined with a compound selected from the group consisting of MEK inhibitors, ERK inhibitors, EGFR inhibitors, PD-L1 antibodies or antigen-binding fragments thereof, and containing TGF-β Combination of at least one of the fusion proteins of the receptor, the MEK inhibitor, ERK inhibitor, EGFR inhibitor, PD-L1 antibody or antigen-binding fragment thereof, fusion protein containing TGF-β receptor, as in claims 4 to 37 any of the above;

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

一種治療腫瘤的MEK抑制劑，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用， A MEK inhibitor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

該MEK抑制劑如請求項5、8至16、37中任一項所述。 The MEK inhibitor is as described in any one of claims 5, 8 to 16, and 37.

一種治療腫瘤的ERK抑制劑，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用， An ERK inhibitor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

該ERK抑制劑如請求項6、8至13、17至19、37中任一項所述。 The ERK inhibitor is as described in any one of claims 6, 8 to 13, 17 to 19, and 37.

一種治療腫瘤的EGFR抑制劑，其與式(I)所示化合物或其藥學上接受的鹽聯合使用， An EGFR inhibitor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

該EGFR抑制劑如請求項7至13、20、21、37中任一項所述。 The EGFR inhibitor is as described in any one of claims 7 to 13, 20, 21, and 37.

一種治療腫瘤的PD-L1或抗原結合片段，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用， A PD-L1 or antigen-binding fragment for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

該PD-L1或抗原結合片段如請求項3、4、8至13、22至27、37中任一項所述。 The PD-L1 or antigen-binding fragment is as described in any one of claims 3, 4, 8 to 13, 22 to 27, and 37.

一種治療腫瘤的含有TGF-β受體的融合蛋白，其與式(I)所示化合物或其藥學上可接受的鹽聯合使用， A fusion protein containing TGF-β receptor for treating tumors, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

R³選自氫或胺基； R ³ is selected from hydrogen or amine group;

該含有TGF-β受體的融合蛋白如請求項3、4、8至13、28至37中任一項所述。 The fusion protein containing TGF-β receptor is as described in any one of claims 3, 4, 8 to 13, 28 to 37.