TW202114659A - Combination comprising hdac inhibitor, ctla-4 inhibitor and a pd-1 inhibitor or pd-l1 inhibitor for cancer treatment - Google Patents

Abstract

The invention relates to medical uses of an HDAC inhibitor of the below general formula I, wherein R1 to R7 are as described herein, or a salt or solvate thereof in combination with CTLA-4 inhibitor and a PD-1 inhibitor or PD-L1 inhibitor for the treatment of cancer.

Description

Combinations containing HDAC inhibitors, CTLA-4 inhibitors and PD-1 inhibitors or PD-L1 inhibitors for cancer treatment

The present invention relates to the medical application of a combination of an HDAC inhibitor, a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor in the treatment of cancer.

The role of the immune system in cancer has attracted increasing interest, and treatment options that utilize the body's autoimmune system have been approved for marketing or are currently under development. Of particular interest is the treatment that eliminates tumors by activating negative regulatory pathways (also called checkpoints) related to immune homeostasis to effectively suppress the immune response or allow cancer to completely avoid the damage caused by the immune system. So far, two such checkpoints, namely cytotoxic T lymphocyte protein 4 (CTLA-4) and planned cell death protein 1 (PD-1) and its ligand (PD-L1) have received the most attention .

CTLA-4 is a negative regulator of T cells, which controls T cell activation by competing with the costimulatory molecule CD28 to bind to the common ligands CD80 (also known as B7.1) and CD86 (also known as B7.2) The role. In contrast to CD28, which delivers pro-proliferation and anti-apoptotic signals to T cells, functional linkage with CTLA-4 can limit T cell activation. Monoclonal antibodies that block CTLA-4 binding to its ligand have been shown to enhance the immune response against cancer (Pardoll, 2012, Nat Rev Cancer [Nature·Review Cancer] 2012, 10.1038/nrc3239).

The cell surface receptor PD-1 is expressed by activated T cells and binds to PD-L1. PD-L1 can be expressed on tumors and tumor-infiltrating immune cells. The combination of PD-L1 and PD-1 produces an inhibitory signal that weakens the activity of T cells. Blocking of the PD-1/PD-L1 axis by anti-PD-1/anti-PD-L1 or antibodies eliminates its inhibitory effect on T cells and restores T cells’ attack on tumors (Blank et al., Cancer Immunology, Immunotherapy [ Cancer Immunology and Immunological Therapy] 2005; Lu et al., J Oncol Pharm Pract [Journal of Cancer Drug Practice], 2015).

Histone deacetylase (HDAC) is an enzyme that catalyzes the removal of acetyl groups from specific histone sites (especially in the promoter region and enhancer region). The enzyme system regulates an essential part of cell gene transcription . HDAC also indirectly regulates gene expression by mediating the acetylation of non-histone proteins (such as DNA binding proteins, transcription factors, signal transducers, DNA repair and chaperone proteins) (Ververis K et al., Biologics: Targets). and Therapy [Biologics: Targets and Therapies] 7: 47-60, 2013; Vitt D et al., Targeting histone acetylation [Targeting histone acetylation]. In: RSC Drug Discovery Series [RSC Drug Discovery Series] No. 48 Issue: Epigenetics for Drug Discovery [Drug Discovery]. Editor: Nessa Carey. The Royal Society of Chemistry [Royal Society of Chemistry], 2016).

It has been described that HDAC inhibitors cause growth arrest and subsequently cause tumor cell differentiation or apoptosis, while normal cells are not affected. As summarized in a review article by Marks et al. (Nature Reviews Cancer, 2001, Volume 1, Pages 194-202), HDAC inhibitors cause cell cycle arrest in the G1 and/or G2 phase . In almost all transformed cell types (including cell lines derived from blood and epithelial tumors), growth inhibitory effects have been recorded in vitro. The growth inhibitory cell mechanism of HDAC inhibitors has been described as the specific induction of cell cycle inhibitor CDKN1A (p21). In addition, this review article summarizes the induction of growth arrest in tumor-bearing mice by HDAC inhibitors. The efficacy of HDAC inhibitors has been demonstrated in animal models of various cancer types, such as breast cancer, prostate cancer, lung and gastric cancer, neuroblastoma, and leukemia.

The treatment of many cancer types by HDAC inhibitors has been described in the available literature. HDAC inhibition plays a key role in many proteins in tumor-related processes (eg, HER2/neu, VEGF, raf-1, cyclin A and B, Bax, Bad, p53, c-myc, caspase 3, p21, And ERα) performance has an impact. According to a review by Villar-Garea et al. (Int. J. Cancer [International Cancer Journal]: 112, 171-178 (2004)), cancer should be considered as an epigenetic and genetic disease, and the use of HDAC inhibitors The main goal should be to restore the gene expression of those tumor suppressor genes that have been transcriptionally muted by promoter-related histone deacetylation. Drummond et al. (Annu. Rev. Pharmacol. Toxicol. [Annual Review of Pharmacology and Toxicology] 2005.45:495-528) reviewed the molecular mechanisms and results of histone and non-histone substrates in cancer cells. These groups Protein and non-histone substrates are the effectors of HDAC, but HDAC also promotes the acetylation of several key proteins besides histones. According to the review, acetylation is a key post-translational modification of many proteins responsible for regulating key intracellular pathways, and many of these substrates are tissue/development-specific (EKLF, GATA-1, ERα, MyoD) , Oncogenic (c-Myb), tumor suppressor (p53), or even ubiquitous (TFIIE, TFIIF, TCF, HNF-4) transcription factors. The adjustment of those proteins can induce cell cycle arrest, differentiation, and apoptosis, all of which are desired mechanisms for the treatment of cancer. Kelly et al. (Expert Opin Invest Drugs, 11(12), 2002) provide a further overview of HDAC inhibitors in general and their applications in cancer therapy.

The official US NIH website http://clinicaltrials.gov lists (status: February 2016) 545 clinical trials for cancer indications treated with HDAC inhibitors, especially various forms of leukemia (e.g., CML, CLL) , AML), myelodysplastic syndromes, lymphomas including non-Hodgkin’s lymphoma, multiple myeloma, plasma cell tumors, general solid tumors, small bowel cancer, mesothelioma, prostate cancer, breast cancer (male and female) , Lung cancer (including non-small cell and small cell lung cancer), neuroendocrine tumors, malignant epithelial tumors, pancreatic cancer, skin cancer (including melanoma), multiple myeloma, cervical cancer, renal cell carcinoma, head and neck cancer, Gastric cancer, ovarian cancer, liver cancer, colon cancer, rectal cancer, thymoma, fallopian tube cancer, peritoneal cancer, nasopharyngeal cancer, vestibular schwannoma, meningioma, acoustic neuroma, neurofibromatosis type 2, thyroid cancer, urothelium Carcinoma, glioma, brain cancer, esophageal cancer, astroglioma, anaplastic oligodendroglioma, giant cell glioblastoma, glioblastoma, glioma sarcoma, mixed glioma, and brain Tumor.

Domatinostat (E)-N-(2-aminophenyl)-3-(1-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonate ((Acetyl)-1H-pyrrol-3-yl)acrylamide is an oral HDAC inhibitor histone deacetylase (HDAC) inhibitor.

Domasstat has been evaluated in a phase I clinical trial (TOPAS) in 24 overpretreatment patients with different types of blood cancers. Domasstat is well tolerated, with few and/or manageable adverse events. Positive signs of anti-tumor efficacy were observed. One patient had a complete remission for 28 months, and a partial responder had remission for 8 months. The results also showed disease control in 83% of patients and long-term stability in 50% of patients.

WO 2006/097474 A1 describes certain N-sulfonylpyrrole derivatives and their medical utility.

WO 2009/112522 A1 describes the salts of certain N-sulfonylpyrrole derivatives and their medical utility.

It has been unexpectedly discovered that, compared with monotherapy and dual combination, the combination therapy using the HDAC inhibitor of the present invention, CTLA-4 inhibitor and PD-1 inhibitor or PD-L1 inhibitor shows beneficial efficacy.

Certain embodiments of the invention are listed in the following entries:

其中 R1、R4和R5獨立地是氫、1-4C-烷基、鹵素、或1-4C-烷氧基， R2和R3獨立地是氫或1-4C-烷基， R6       係-T1-Q1，其中T1係鍵或1-4C-伸烷基， 或者Q1被R61和/或R62取代並且是Aa1、Hh1、Ha1、Ha2、Ha3、Ha4或Ah1，或者Q1係未取代的並且是Ha2、Ha3或Ha4， 其中 R61係1-4C-烷基、苯基-1-4C-烷基、1-4C-烷氧基、羥基、三氟甲基、氰基、鹵素、完全被氟取代的1-4C-烷氧基或其中超過一半的氫原子被氟原子替代的1-4C-烷氧基、羥基-1-4C-烷基、1-4C-烷氧基-1-4C-烷基、1-4C-烷基磺醯基胺基、甲苯基磺醯基胺基、苯基磺醯基胺基、1-4C-烷基羰基胺基、胺基甲醯基、胺磺醯基、單或二-1-4C-烷基胺基羰基、單或二-1-4C-烷基胺基磺醯基、-T2-N(R611)R612、-U-T3-N(R613)R614、-T4-Het3或-V-T5-Het4，其中 T2係鍵或1-4C-伸烷基， R611係氫、1-4C-烷基、3-7C-環烷基、3-7C-環烷基甲基、羥基-2-4C-烷基、1-4C-烷氧基-2-4C-烷基、1-4C-烷基羰基、或1-4C-烷基磺醯基， R612係氫或1-4C-烷基， 或R611和R612一起並且同時包括它們所結合的氮原子形成雜環Het1，其中Het1係𠰌啉子基（morpholino）、硫代𠰌啉子基、S-側氧基-硫代𠰌啉子基、S,S-二側氧基-硫代𠰌啉子基、哌啶子基（piperidino）、吡咯啶子基（pyrrolidino）、哌𠯤子基（piperazino）、或4N-(1-4C-烷基)-哌𠯤子基， U係-O-(氧)或-C(O)NH-， T3係2-4C-伸烷基， R613係氫、1-4C-烷基、3-7C-環烷基、3-7C-環烷基甲基、羥基-2-4C-烷基或1-4C-烷氧基-2-4C-烷基、1-4C-烷基羰基、或1-4C-烷基磺醯基 R614係氫或1-4C-烷基， 或R613和R614一起並且同時包括它們所結合的氮原子形成雜環Het2，其中 Het2係𠰌啉子基、硫代𠰌啉子基、S-側氧基-硫代𠰌啉子基、S,S-二側氧基-硫代𠰌啉子基、哌啶子基、吡咯啶子基、哌𠯤子基、或4N-(1-4C-烷基)-哌𠯤子基， T4係鍵或1-4C-伸烷基， Het3係1N-(1-4C-烷基)-哌啶基或1N-(1-4C-烷基)-吡咯啶基， V係-O-(氧)或-C(O)NH-， T5係鍵或1-4C-伸烷基， Het4係1N-(1-4C-烷基)-哌啶基或1N-(1-4C-烷基)-吡咯啶基， R62係1-4C-烷基、1-4C-烷氧基或鹵素， Aa1     係由兩個芳基基團構成的雙芳基自由基， 該等芳基基團獨立地選自由苯基和萘基組成之群組，並且 藉由單鍵連接在一起， Hh1     係由兩個雜芳基基團構成的雙雜芳基自由基， 該等雜芳基基團獨立地選自由包含一個或兩個雜原子的單環5-或6-員雜芳基自由基組成之群組，該等雜原子中的每一個選自由氮、氧和硫組成之群組，並且 該等雜芳基基團藉由單鍵連接在一起， Ah1     係由選自由苯基和萘基組成之群組的芳基基團和選自由包括一個或兩個雜原子的單環5-或6-員雜芳基自由基組成之群組的雜芳基基團構成的芳基雜芳基自由基，由此所述芳基和雜芳基基團藉由單鍵連接在一起，並且由此Ah1藉由所述雜芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha1     係由選自由包括一個或兩個雜原子的單環5-或6-員雜芳基自由基組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基自由基，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha1藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha2     係由選自由包括一個、兩個或三個雜原子的稠合雙環9-或10-員雜芳基自由基組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基自由基，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha2藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha3     係由選自由包括三個或四個雜原子的單環5-員雜芳基自由基組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基自由基，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha3藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha4     係由選自由包括不含雜原子的苯環和一個或兩個雜原子的部分飽和的稠合雙環9-或10-員雜芳基自由基組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基自由基，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha4藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， R7       係羥基、或Cyc1，其中Cyc1係式Ia的環系

其中 A和B係C（碳）， R71和R72獨立地是氫、鹵素、1-4C-烷基、或1-4C-烷氧基， M同時包括A和B係環Ar2或環Har2，其中Ar2係苯環，Har2係單環5-或6-員不飽和的雜芳環，該雜芳環包含一個至三個雜原子，該等雜原子中的每一個選自由氮、氧和硫組成之群組， 或通式III的分子：

(III) 其中： R⁰ 係鹵素； p   係0、1、或2； W 係-NHC(O)(C₁ -C₆ 烷基)或-CH₂ NH-V；並且 V  係-CO₂ -CH₂ -(雜芳基)、-C(O)-CH=CH-(雜芳基)、或視需要被1-3個雜芳基基團取代的雜芳基 或其鹽或溶劑化物。1. The use of an HDAC inhibitor in combination with a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor for the manufacture of drugs for the treatment of cancer, wherein the HDAC inhibitor is a molecule of general formula I

Wherein R1, R4 and R5 are independently hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy, R2 and R3 are independently hydrogen or 1-4C-alkyl, and R6 is -T1-Q1 , Wherein T1 is a bond or 1-4C-alkylene, or Q1 is substituted by R61 and/or R62 and is Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, or Q1 is unsubstituted and is Ha2, Ha3 Or Ha4, where R61 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkoxy, hydroxy, trifluoromethyl, cyano, halogen, 1- 4C-alkoxy or 1-4C-alkoxy in which more than half of the hydrogen atoms are replaced by fluorine atoms, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1 -4C-Alkylsulfonylamino, tosylsulfonylamino, phenylsulfonylamino, 1-4C-alkylcarbonylamino, aminomethanyl, sulfamoyl, mono-or Di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, -T2-N(R611)R612, -U-T3-N(R613)R614, -T4 -Het3 or -V-T5-Het4, where T2 is a bond or 1-4C-alkylene, R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl Group, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl, or 1-4C-alkylsulfonyl, R612 is hydrogen or 1 -4C-alkyl, or R611 and R612 together and including the nitrogen atom to which they are combined form a heterocyclic Het1, where Het1 is morpholino, thiomorpholino, S-pendant oxy-sulfur Substitution: S,S-di-side oxy-thio-thiolino, piperidino, pyrrolidino, piperazino, or 4N-( 1-4C-alkyl)-piperidino, U series -O-(oxygen) or -C(O)NH-, T3 series 2-4C-alkylene group, R613 series hydrogen, 1-4C-alkyl group , 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl , Or 1-4C-alkylsulfonyl R614 is hydrogen or 1-4C-alkyl, or R613 and R614 together and including the nitrogen atom to which they are combined form a heterocyclic Het2, where Het2 is a 𠰌olino group, sulfur Substitution, S-side oxy-thiooxy-thio, S, S-diside oxy-thiooxy, piperidino, pyrrolidino, piperidino, Or 4N-(1-4C-alkyl)-piperidinyl, T4 bond or 1-4C-alkylene, Het3 is 1N-(1-4C-alkyl)-piperidinyl or 1N -(1-4C-alkyl)-pyrrolidinyl, V series -O-(oxygen) or -C(O)NH-, T5 series bond or 1-4C-alkylene, Het4 series 1N-(1- 4C-alkyl)-piperidinyl or 1N-(1-4C-alkyl)-pyrrolidinyl, R62 is 1-4C-alkyl, 1-4C-alkoxy or halogen, Aa1 is composed of two aromatic Bisaryl radicals composed of aryl groups. These aryl groups are independently selected from the group consisting of phenyl and naphthyl and are connected by a single bond. Hh1 is composed of two heteroaryl groups. The heteroaryl radicals are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals containing one or two heteroatoms, the heteroatoms Each of them is selected from the group consisting of nitrogen, oxygen and sulfur, and these heteroaryl groups are connected together by a single bond. Ah1 is an aryl group selected from the group consisting of phenyl and naphthyl Groups and aryl heteroaryl radicals formed from heteroaryl radicals selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals including one or two heteroatoms, whereby the aromatic The group and the heteroaryl group are linked together by a single bond, and thus Ah1 is bonded to the parent molecular group through the heteroaryl moiety, and each of these heteroatoms is selected from nitrogen, oxygen and sulfur Ha1 is a heteroaryl group selected from the group consisting of monocyclic 5- or 6-membered heteroaryl radicals containing one or two heteroatoms and selected from the group consisting of phenyl and naphthyl The group of aryl groups constitutes a heteroaryl aryl radical, whereby the heteroaryl and aryl groups are connected together by a single bond, and thus Ha1 is connected to the aryl moiety through the aryl moiety. The parent molecular group is bonded, each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and Ha2 is selected from the group consisting of fused bicyclic 9- or 10 containing one, two or three heteroatoms -Heteroaryl groups consisting of heteroaryl radicals and heteroaryl aryl radicals consisting of aryl groups selected from the group consisting of phenyl and naphthyl, whereby the heteroaryl radicals The group and the aryl group are connected together by a single bond, and thus Ha2 is bonded to the parent molecular group through the aryl moiety, and each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur Group, Ha3 is a heteroaryl group selected from the group consisting of monocyclic 5-membered heteroaryl radicals including three or four heteroatoms and a group selected from the group consisting of phenyl and naphthyl A heteroaryl aryl radical constituted by an aryl group, whereby the heteroaryl and aryl groups are linked together by a single bond, and thus Ha3 is connected to the parent molecular group through the aryl moiety Bonding, each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha4 is selected from the group consisting of a benzene ring without heteroatoms and a partially saturated fused bicyclic ring containing one or two heteroatoms Heteroaryl groups consisting of 9- or 10-membered heteroaryl radicals and heteroaryl aryl radicals consisting of aryl groups selected from the group consisting of phenyl and naphthyl, consisting of The heteroaryl and aryl groups are connected together by a single bond, and thus Ha4 is bonded to the parent molecular group through the aryl moiety, and each of these heteroatoms is selected from nitrogen, The group consisting of oxygen and sulfur, R7 is a hydroxyl group, or Cyc1, where Cyc1 is the ring system of formula Ia

Wherein A and B are C (carbon), R71 and R72 are independently hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, M includes both A and B are ring Ar2 or ring Har2, wherein Ar2 is a benzene ring, Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring, the heteroaromatic ring contains one to three heteroatoms, each of which is selected from nitrogen, oxygen and sulfur The group of, or the molecule of general formula III:

(III) Wherein: R ⁰ is halogen; p is 0, 1, or 2; W is -NHC(O) (C ₁ -C ₆ alkyl) or -CH ₂ NH-V; and V is -CO _2- CH ₂ -(heteroaryl), -C(O)-CH=CH-(heteroaryl), or a heteroaryl group substituted with 1-3 heteroaryl groups as needed, or a salt or solvate thereof.

2. The use according to item 1, wherein the HDAC inhibitor is specific for class I HDAC.

3. The use according to any one of items 1 or 2, wherein the HDAC inhibitor is (E)-N-(2-aminophenyl)-3-(1-((4-(1-methyl) -1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)acrylamide or a salt or solvate thereof.

4. The use according to any one of items 1 to 3, wherein the HDAC inhibitor is (E)-N-(2-aminophenyl)-3-(1-((4-(1-methyl) -1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)acrylamide tosylate.

5. The use according to any one of items 1 to 4, wherein the CTLA-4 inhibitor is selected from the group consisting of ipilimumab (Medarex Inc), alternative Tremelimumab (Pfizer Inc), AGEN-1884 (4-Antibody AG), AK-104 (Akeso Biopharma Inc), BMS-986218 (Bristol-Myers Squibb Co), BMS-986249 (CytomX Therapeutics Inc), KN-046 (Suzhou Alphamab Co Ltd) , ADU-1604 (Aduro BioTech Inc), AGEN-1181 (Agenus Inc), ATOR-1015 (Alligator Bioscience AB), BCD-145 (Biocad Ltd), CS-1002 (CStone Pharmaceuticals Co Ltd), FPT-155 (Five Prime Therapeutics Inc), MEDI-5752 (m Di Miuni Oncology (Medimmune Oncology Inc), MGD-019 (MacroGenics Inc), MK-1308 (Merck Sharp & Dohme Corp), PF-06753512 (Pfizer), PF-06936308 (Pfizer), REGN-4659 (Regeneron Pharmaceuticals Inc), XmAb-20717 (Xencor Inc), XmAb-22841 (Zancor)), AGEN-2041 ( Antijuns Corporation), ALPN-202 (Alpine Immune Sciences Inc), APL-509 (Crown Bioscience Inc), aptCTLA-4 (Academia Sinica) , ATOR-1144 (Alligator Biosciences Company), BA-3071 (Atala Biosciences Division (BioAtla Llc), BCD-217 (BioAtla Corporation), BPI-002 (BeyondSpring Pharmaceuticals Inc), CCC-0701 (Zenyaku Kogyo Co Ltd), CG-0161 (Cold Genesys Inc), HBM-4003-2 (Harbour BioMed), Irr-VACV-CTLA-4 (Genelux Corp), JS-007 (Shanghai Junshi Biosciences Co Ltd), KN-044 (Corning Jerry (Suzhou) Co., Ltd.), ONC-392 (OncoImmune Inc), ONCR-177 (OncoImmune Inc) Oncorus Inc., PBI-5D3H5 (Premier Biomedical Inc), PRS-300 A series (Pieris Pharmaceuticals Inc), PSB-205 (Sound Biologics)), RP-2 (Replimune Group Inc), RP-3 (Replimune Group Inc), and SN-CA21 (Synovel Sciences Inc), TBio-6517 ( Turnstone Biologics Inc (Turnstone Biologics Inc) and JHL-1155 (HumOrigin Inc).

6. The use according to any one of items 1 to 5, wherein the PD-1 inhibitor is selected from the group consisting of: pidilizumab (CT-011, CureTech), AMP -224 (MedImmune Co., Ltd. (MedImmune)), AB122 (Harbin/Wuxi/Arcus), AMP-224 (MedImmune Co., Ltd.), MEDI-5752 (m Medimmune Oncology Inc), PD1-PIK (Huashan Hospital), PF-06936308 (Pfizer Inc), RG-7769 (Hoffmann-La Roche AG) ), F-520 (Shandong New Time Pharmaceutical Co Ltd), CAB PD-1 antibody (BioAtla Llc), AK-123 (Kangfang Biopharmaceutical Company ( Akeso Biopharma Inc), MEDI-3387 (Midi Muni Co., Ltd.), MEDI-5771 (Midi Muni Co., Ltd.), 4H1128Z-E27 (Eureka Therapeutics Inc); Memorial Sloan— Kettering Cancer Center (Memorial Sloan-Kettering Cancer Center), REMD-288 (Shandong Danhong Pharmaceutical Co Ltd), SG-001 (Hangzhou Sumgen Biotechnology Co Ltd) )), BY-24.3 (Beijing Beyond Biotechnology Co Ltd; Hangzhou Shangjian Biotechnology Co., Ltd.), CB-201 (Crescendo Biologics Ltd), IBI-319 (Adimab LLC; Eli Lilly &Co; Innovent Biologics Inc), ONCR-177 (Oncorus Inc), Max-1 (Maxinovel Pharmaceuticals Inc), CS-4100 (Shenzhen Microchip Biotechnology Co., Ltd. (S henzhen Chipscreen Biosciences Ltd), JBI-426 (Jubilant Biosys Ltd), CCC-0701 (Zenyaku Kogyo Co Ltd), CCX-4503 (ChemoCentryx Inc) ), Nivolumab (BMS), Pembrolizumab (MSD), BCD-100 (Biocad), Seprolizumab (Regeneron Pharmaceuticals), Sintilizumab Anti-(IBI-308, Eli Lilly/Cinda Biopharmaceuticals), JNJ-3283 (Johnson & Johnson), Spartizumab (PDR-001, Novartis Group), Carrelizumab (SHR-1210, Incyte Corp/Jiangsu Hengrui), Tilelizumab (BeiGene Ltd), AGEN-2034 (Antigens Corp ( Agenus Inc)), MEDI-0680 (AMP-514; Amplimmune/Midimuone Co., Ltd.), Teriplimumab (JS-001, Shanghai Junshi Biomedical Technology Co., Ltd. (Shanghai Junshi Bioscience Co Ltd), Dotalizumab (TSR-042, Tesaro), ABBV-181 (AbbVie Inc), AK-104 (Kangfang Biomedicine Company), AK- 105 (Kangfang Biopharmaceutical Company), BAT-1306 (Bio-Thera Solutions Ltd), BI-754091 (Boehringer Ingelheim), CBT-501, Genozumab (CBT Pharmaceutical company (CBT Pharmaceuticals Inc/Genor), GLS-010 (Harbin Gloria/Wuxi/Axis), LZM-009 (Livzon Pharmaceutical Group Inc), MGA-012 (Insett/MacroGenics), MGD-013 (MacroGenics), PF-06801591 (Pfizer), Sym-021 (Sifogen Group), CS-1003 (Cornerstone Pharmaceuticals) Industry Co., Ltd. (CStone Pharmaceuticals Co Ltd), HLX-10 (Henlix Biotech)/Shanghai Fuhong Hanlin Biotech Co., Ltd. ( Shanghai Henlius Biotech Co Ltd), AK-103 (Kangfang Biopharmaceutical Company), AM-0001 (Amo Biosciences Company), TILT-123 (TILT Biotherapeutics Ltd), BH-2922 (Beijing Hanmi Pharmaceutical (Beijing Hanmi Pharmaceutical), BH-2941 (Beijing Hanmi Pharmaceutical), BH-2950 (Beijing Hanmi Pharmaceutical), CX-188 (CytomX Therapeutics Inc), ENUM-244C8 ( Enumeral Biomedical Holdings), ENUM-388D4 (Enumeral Biomedical Holdings), HAB-21 (Suzhou Stainwei Biotech Inc), HEISCOIII-003 ( Sichuan Haisco Pharmaceutical (Sichuan Haisco Pharmaceutical), IKT-202 (Icell Kealex Therapeutics), JS-003 (Shanghai Junshi Biomedical Technology), JTX-4014 (Johnson Medical Corporation ( Jounce Therapeutics Inc), MCLA-134 (Merus NV), MGD-019 (Macro Gene Company), MT-17000 (Molecular Templates Inc), PEGMP-7 (D5Pharma) ), PRS-332 (Pieris Pharmaceuticals Inc), RXI-762 (RXi Pharmaceuticals Corp), STI-1110 (Les Laboratoires Servier, France)/ Sorrento (Sorrento), VXM-10 (Vaximm AG), XmAb-20717 (Zanco), XmAb-23104 (Zanco), AK-112 (Kangfang Biomedical Company) ), HLX-20 (Hanlius Biotech/Shanghai Fuhong Henlius Biotechnology Co., Ltd.), SSI-361 (Lyvgen Biopharma Ltd), AT-16201 (Aim Medical Co., Ltd.) AIMM Therapeutics BV) and SNA-01 (Fountain Bioph arma Inc)).

7. The use according to any one of items 1 to 6, wherein the PD-L1 inhibitor is selected from the group consisting of: BCD-135 (Biocard), APL-502 (CBT-402 or TQB2450, Innovative Biopharmaceutical Company (Apollomics)), MDX-1105 (BMS-936559, Bristol-Myers Squibb), IMC-001 (ImmuneOncia Medical Company; Sorrento Medical Company (Sorrento Therapeutics Inc)), KD-045 (Nanjing) Nanjing Kaedi Biotech Inc), INBRX-105 (Elpiscience Biopharmaceuticals Inc; INHIBRx LLC), KN-046 (Corning Jerry (Suzhou) ) Co. Ltd. (Suzhou Alphamab Co Ltd), INCB-086550 (Insett), IMC-2102 (ImmuneOncia Medical), IMC-2101 (ImmuneOncia Medical), anti-PDL1-TGFbRIIecd (Johns Hopkins University (Johns Hopkins University); Y-Trap Inc (Y-Trap Inc), KD-005 (Nanjing Kaidi Biotechnology Company), PM-PDL-GEX (Glycotope GmbH) , IMM-2502 (ImmuneOnco Biopharm Co Ltd), 89Zr-CX-072 (Xitomax Medical Company; University Medical Center Groningen), KY-1055 (Kay Microlab Ltd. (Kymab Ltd), MEDI-1109 (Midi Miuni Co., Ltd.), MT-5594 (Molecular Template Company), 89Zr-DFO-6E11 (Minerva Imaging); Thermo Fisher Technology company (Thermo Fisher Scientific Inc), SL-279252 (Shattuck Labs Inc; Takeda Pharmaceutical Co Ltd), DSP-106 (KAHR Medical Ltd) ; Groningen University Medical Center), Gensci-047 (GeneScience Pharmaceut icals Co Ltd), REMD-290 (Shandong Danhong Pharmaceutical Co., Ltd.), N-809 (NantKwest Inc; National Cancer Institute), PRS-344 (Pieris Pharmaceuticals; Servier), FS-222 (F-star Biotechnologische Forschungs-und Entwicklungs GmbH), GEN-1046 (BioNTech SE; Genmab Holding BV), BH-29xx (Beijing Hanmi Pharmaceutical Co., Ltd.), Atezolizumab (Genentech Inc), Avirulumab (Merck Group/Pfizer), Duvaluzumab (Astertec Pharmaceuticals) Company (AstraZeneca Pharmaceuticals LP)/Midi Muuni Co., Ltd., BGB-A333 (BeiGene Co., Ltd.), CX-072 (Xitomax Medical Corporation), GNS-1480 (Yuhan Corp)/Keno Cisco (Genosco), AMP-224 (Midi Muuni Co., Ltd.), CA-170 (Aurigene Discovery Technologies Ltd), CK-301 (Checkpoint Therapeutics)/TG Medical), CS-1001 (Corner Stone Pharmaceutical Co., Ltd.), FAZ-053 (Novartis Group), Ivaflizumab (ASC22 or KN-035; Corning Jerry (Suzhou)/Side Di (3DMed)), LY -3300054 (Eli Lilly and Company), M-7824 (Merck Group), HTI-1088 (HTI-131, SHR-1316; Atridia and Jiangsu Hengrui Pharmaceutical Company), MSB-2311 (Med MabSpace Biosciences (Suzhou) Co Ltd), STI-A1014 (Lee's Pharmaceutical/Sorrento), AK-106 (Kangfang Biomedicine Company), AVA-004 (Avicta Life Sciences Co., Ltd.), BBI-801 (Boston Biomedical Inc), CA-327 (Aurigene/Curis), CBA- 0710 (Sorrento Medical Company), CBT-502 (CBT Pharmaceuticals/Chia Tai Tianqing Pharmac eutical)), FPT-155 (Five Prime Therapeutics Inc), FS-118 (F-Star Biotechnology Co., Ltd.), IKT-201 (Isaier Kelex Medical), IKT-703 ( Iserkelex Medical), IO-103 (IO Biotech ApS), JS-003 (Shanghai Junshi Biomedical Technology), KD-033 (Kadmon Corp)/Essence Pharmaceutical (Jinghua Pharmaceutical), KY-1003 (Kamaibo Co., Ltd.), MCLA-145 (Merus Group/Insett), MT-5050 (Molecular Template Company), and SNA-02 (Quansheng Biopharmaceutical the company).

8. The use according to any one of items 1 to 7, wherein the cancer is selected from the group consisting of melanoma (especially ocular and uveal melanoma, but also skin melanoma) ; Head and neck cancer; Kidney cancer; Non-small cell lung cancer (NSCLC); Microsatellite unstable cancer (Lynch syndrome, especially gastroesophageal cancer and colorectal cancer); Urothelial cancer, including bladder cancer; Merkel cell Carcinoma; Hodgkin's lymphoma; gastric cancer; gastrointestinal cancer (microsatellite stable and unstable), including colorectal cancer (CRC); hepatocellular carcinoma (HCC); renal cell carcinoma (RCC); nasopharyngeal carcinoma; basal Cell carcinoma; cervical cancer; anogenital cancer; Kaposi’s sarcoma; adult T-cell leukemia; primary exudative lymphoma; and Casterman’s disease, or selected from the group consisting of: breast cancer, especially Triple negative breast cancer; esophageal cancer; non-Hodgkin’s lymphoma; small cell lung cancer (SCLC); osteosarcoma; mesothelioma; glioblastoma; microsatellite stable cancers (especially gastroesophageal cancer and colorectal cancer) ; Pancreatic cancer; prostate cancer; skin T-cell lymphoma (CTCL); and squamous cell carcinoma.

In certain embodiments, (E)-N-(2-aminophenyl)-3-(1-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfon (((Acetyl)-1H-pyrrol-3-yl)) acrylamide is administered at a dosage of 80 mg/day to 120 mg/day, particularly 90 mg/day to 110 mg/day, more particularly 95 mg/day To 105 mg/day, even more particularly about 100 mg/day, or alternatively twice any of the above-mentioned doses, or alternatively 4 times any of the above-mentioned doses, wherein any of the daily doses are as required Administer in two parts (each half of the above-mentioned amount) twice daily, especially once in the morning and once in the evening (wherein especially the evening dose is 10 hours to 14 hours after the morning dose, more particularly 11 hours to 13 hours , And even more specifically about 12 hours of administration).

In some embodiments, the CTLA-4 inhibitor and/or PD-1 inhibitor and/or PD-L1 inhibitor can be selected from the group consisting of: antibodies (for example, monoclonal or bispecific monoclonal antibodies) , Fusion proteins, recombinant proteins, or aptamers, oncolytic viruses, antisense RNAi oligonucleotides, vaccines; especially antibodies (such as monoclonal or bispecific monoclonal antibodies), fusion proteins, recombinant proteins, or aptamers ; More particularly antibodies, such as monoclonal or bispecific monoclonal antibodies; and in certain embodiments, the aforementioned biological analogs of antibodies, in particular, are encompassed in the present invention.

CTLA-4 inhibitors and/or PD-1 inhibitors and/or PD-L1 inhibitors may be specific to the corresponding targets, or they may act on two or more targets, which may include acting on PD-1 and CTLA-4 or PD-L1 and CTLA-4 (in this case, a single molecule (such as a bispecific antibody) is enough to be a series of "CTLA-4 inhibitors and PD-1 inhibitors or PD- "L1 inhibitor"), or in addition to the activity against PD-1, PD-L1 or CTLA-4, it may also include activity against one or more additional targets.

In a specific embodiment, the CTLA-4 inhibitor is selected from the group consisting of: ipilimumab (Medarex Inc), tremelimumab (Pfizer ( Pfizer Inc), AGEN-1884 (4-Antibody AG), AK-104 (Akeso Biopharma Inc), BMS-986218 (Bristol-Myers Squibb Co)), BMS-986249 (CytomX Therapeutics Inc), KN-046 (Suzhou Alphamab Co Ltd), ADU-1604 (Aduro Biotech (Aduro BioTech Inc), AGEN-1181 (Agenus Inc), ATOR-1015 (Alligator Bioscience AB), BCD-145 (Biocad Ltd) , CS-1002 (CStone Pharmaceuticals Co Ltd), FPT-155 (Five Prime Therapeutics Inc), MEDI-5752 (Medimmune Oncology Inc) ), MGD-019 (MacroGenics Inc), MK-1308 (Merck Sharp & Dohme Corp), PF-06753512 (Pfizer), PF-06936308 (Pfizer), REGN-4659 (Regeneron Pharmaceuticals Inc), XmAb-20717 (Xencor Inc), XmAb-22841 (Zancor)), AGEN-2041 (An Dijunsi company), ALPN-202 (Alpine Alpine Immune Sciences Inc), APL-509 (Crown Bioscience Inc), aptCTLA-4 (Academia Sinica), ATOR-1144 (Crocodile Biosciences), BA-3071 (BioAtla Llc), BCD-217 (Biocard), BPI-002 (BeyondSpring Pharmaceuticals Inc), CCC-0701 (Zenyaku Kogyo Co Ltd), CG-0161 (Kogyo Co Ltd) (Cold Genesys Inc), HBM-4003-2 (Harbour BioMed), Irr-VACV-CTLA-4 (Genelux Corp), JS-007 (Shanghai Junshi Biotechnology Co., Ltd.) Company (Shanghai Junshi Biosciences Co Ltd), KN-044 (Corning Jerry (Suzhou) Co., Ltd.), ONC-392 (OncoImmune Inc), ONCR-177 (Oncorus Inc) ), PBI-5D3H5 (Premier Biomedical Inc), PRS-300 A series (Pieris Pharmaceuticals Inc), PSB-205 (Sound Biologics), RP-2 (Replimune Group Inc), RP-3 (Replimune Group Inc), and SN-CA21 (Synovel Sciences Inc), TBio-6517 (Ternstone Biological Products Company) (Turnstone Biologics Inc)), JHL-1155 (HumOrigin Inc); more particularly selected from the group consisting of: Ipilimumab, Tecilimumab, AGEN-1884, AK-104, BMS-986218, BMS-986249, KN-046, ADU-1604, AGEN-1181, ATOR-1015, BCD-145, CS-1002, FPT-155, MEDI-5752, MGD-019, MK-1308, PF- 06753512, PF-06936308, REGN-4659, XmAb-20717 and XmAb-22841; even more particularly selected from the group consisting of: Ipilimumab, Tecilimumab, AGEN-1884, AK-104, BMS -986218, BMS-986249 and KN-046; even more particularly selected from the group consisting of: Ipilimumab and Tecilimumab.

In a specific embodiment, the PD-1 inhibitor is selected from the group consisting of: pinclizumab (CT-011, CureTech), AMP-224 (MedImmune Co., Ltd. (MedImmune) )), AB122 (Harbin/Wuxi/Arcus), AMP-224 (Medimuni Co., Ltd.), MEDI-5752 (Medimmune Oncology Inc) ), PD1-PIK (Huashan Hospital), PF-06936308 (Pfizer Inc), RG-7769 (Hoffmann-La Roche AG), F-520 (Shandong New Times Pharmaceutical Co., Ltd. (Shandong New Time Pharmaceutical Co Ltd), CAB PD-1 antibody (BioAtla Llc), AK-123 (Akeso Biopharma Inc), MEDI-3387 (m Di Miuni Co., Ltd., MEDI-5771 (Medi Miuni Co., Ltd.), 4H1128Z-E27 (Eureka Therapeutics Inc); Memorial Sloan-Kettering Cancer Center )), REMD-288 (Shandong Danhong Pharmaceutical Co Ltd), SG-001 (Hangzhou Sumgen Biotechnology Co Ltd), BY-24.3 (Beijing Biyang Biotechnology Co., Ltd.) Technology Co., Ltd. (Beijing Beyond Biotechnology Co Ltd); Hangzhou Shangjian Biotechnology Co., Ltd.), CB-201 (Crescendo Biologics Ltd), IBI-319 (Adimab Co., Ltd.) LLC); Eli Lilly &Co; Innovent Biologics Inc), ONCR-177 (Oncorus Inc), Max-1 (Zaiji Pharmaceutical Technology Co., Ltd. ( Maxinovel Pharmaceuticals Inc), CS-4100 (Shenzhen Chipscre Biotechnology Co., Ltd.) en Biosciences Ltd), JBI-426 (Jubilant Biosys Ltd), CCC-0701 (Zenyaku Kogyo Co Ltd), CCX-4503 (ChemoCentryx Inc) , Nivolumab (BMS), Pembrolizumab (MSD), BCD-100 (Biocad), Seprolizumab (Regeneron Pharmaceuticals), Sintilizumab (IBI-308, Eli Lilly/Cinda Biopharmaceuticals), JNJ-3283 (Johnson & Johnson), Spartizumab (PDR-001, Novartis Group), Carrelizumab ( SHR-1210, Incyte Corp/Jiangsu Hengrui), Tilelizumab (BeiGene Ltd), AGEN-2034 (Agenus Inc)), MEDI-0680 (AMP-514; Amplimmune/Midimuuni Co., Ltd.), Teriplimumab (JS-001, Shanghai Junshi Biomedical Technology Co., Ltd.) Bioscience Co Ltd), Dotalizumab (TSR-042, Tesaro), ABBV-181 (AbbVie Inc), AK-104 (Kangfang Biomedicine Company), AK-105 (Kangfang Biopharmaceutical Company), BAT-1306 (Bio-Thera Solutions Ltd), BI-754091 (Boehringer Ingelheim), CBT-501, Genozumab (CBT Pharmaceuticals) Company (CBT Pharmaceuticals Inc/Genor), GLS-010 (Harbin Gloria/Wuxi/Akesi), LZM-009 (Livzon Pharmaceutical Group Inc), MGA -012 (Insett/MacroGenics), MGD-013 (MacroGenics), PF-06801591 (Pfizer), Sym-021 (Sifogen Group), CS-1003 (Cornerstone Pharmaceuticals) Co Ltd (CStone Pharmaceuticals Co Ltd), HLX-10 (Henlix Biotech)/Shanghai Henlius Biotech Co., Ltd. (Shanghai Henlius Biotech Co Ltd), AK-103 (Kangfang Biomedicine Company), AM-0001 (Amo Biosciences Company), TILT-123 (TILT Biotherapeutics Ltd), BH-2922 (Beijing Hanmei Pharmaceuticals (Beijing Hanmi Pharmaceutical), BH-2941 (Beijing Hanmi Pharmaceutical), BH-2950 (Beijing Hanmi Pharmaceutical), CX-188 (CytomX Therapeutics Inc), ENUM-244C8 (An Youmei) Enumeral Biomedical Holdings), ENUM-388D4 (Enumeral Biomedical Holdings), HAB-21 (Suzhou Stainwei Biotech Inc), HEISCOIII-003 (Sichuan Hai Cisco Pharmaceutical (Sichuan Haisco Pharmaceutical), IKT-202 (Icell Kealex Therapeutics), JS-003 (Shanghai Junshi Biomedical Technology), JTX-4014 (Jounce Therapeutics) Inc)), MCLA-134 (Merus NV), MGD-019 (Macro Gene Company), MT-17000 (Molecular Templates Inc), PEGMP-7 (D5Pharma), PRS-332 (Pieris Pharmaceuticals Inc), RXI-762 (RXi Pharmaceuticals Corp), STI-1110 (Les Laboratoires Servier, France)/Sauron (Sorrento), VXM-10 (Vaximm AG), XmAb-20717 (Zanke), XmAb-23104 (Zanke), AK-112 (Kangfang Biomedicine Company), HLX-20 (Hanlius Biotechnology/Shanghai Fuhong Henlius Biotechnology Co., Ltd.), SSI-361 (Lyvgen Biopharma Ltd), AT-16201 (AIMM Therapeutics) BV)) and SNA-01 (Fountain Biopharma Inc); more specifically Sintilizumab, Spartizumab, Carrelizumab, Teriplizumab, Pedelizumab, AMP-224, AB122, AMP-224, Dotalizumab, MEDI -5752, PD1-PIK, PF-06936308, RG-7769, nivolumab, pembrolizumab, BCD-100, seprolizumab, IBI-308, JNJ-3283, PDR-001, SHR- 1210, Tilelizumab, AGEN-2034, MEDI-0680, JS-001, TSR-042, ABBV-181, AK-104, AK-105, BAT-1306, BI-754091, CBT-501, Jie Nozumab, GLS-010, LZM-009, MGA-012, MGD-013, PF-06801591, Sym-021, CS-1003, and HLX-10; even more particularly Sintilizumab, Sparta Daclizumab, karelizumab, teriplizumab, pidilizumab, AMP-224, AB122, AMP-224, dotalizumab, MEDI-5752, PD1-PIK, PF -06936308, RG-7769, nivolumab, pembrolizumab, BCD-100, seprolizumab, IBI-308, JNJ-3283, PDR-001, SHR-1210, tislelizumab , AGEN-2034, MEDI-0680, JS-001, and TSR-042, and even more specifically Sintilizumab, Spartizumab, Carrelizumab, Teriplizumab, Pidirizumab, dotalizumab, nivolumab, pembrolizumab, BCD-100, seprolizumab, IBI-308, JNJ-3283, PDR-001, SHR-1210, and Tilelizumab; even more specifically nivolumab and pembrolizumab.

In a specific embodiment, the PD-L1 inhibitor is selected from the group consisting of: BCD-135 (Biocard), APL-502 (CBT-402 or TQB2450, Innovative Biopharmaceutical Company), MDX-1105 ( BMS-936559, Bristol-Myers Squibb), IMC-001 (ImmuneOncia Medical Company; Sorrento Medical Company), KD-045 (Nanjing Kaidi Biotechnology Company), INBRX-105 (Kewang Biomedical Company; INHIBRx Company) , KN-046 (Corning Jerry (Suzhou) Co., Ltd.), INCB-086550 (Insett), IMC-2102 (ImmuneOncia Medical), IMC-2101 (ImmuneOncia Medical), anti-PDL1-TGFbRIIecd (John · Hopkins University; Y-Trapp Company), KD-005 (Nanjing Kaidi Biotechnology Company), PM-PDL-GEX (Glactop Company), IMM-2502 (Immuno-Oncology Biopharmaceutical Co., Ltd.) ), 89Zr-CX-072 (Sitomax Medical Company; University of Groningen Medical Center, KY-1055 (Kamai Bo Co., Ltd., MEDI-1109 (Midi Muuni Co., Ltd.), MT-5594 (Molecular Template Company) , 89Zr-DFO-6E11 (Minerva imaging; Thermo Fisher Scientific), SL-279252 (Saudi Crabs; Takeda Pharmaceutical Co., Ltd.), DSP-106 (KAHR Medical Co., Ltd.; University of Groningen Medical Center ), Gensci-047 (Jinsai Pharmaceutical Co., Ltd.), REMD-290 (Shandong Danhong Pharmaceutical Co., Ltd.), N-809 (Nant West Company; National Cancer Institute), PRS-344 (Peet Reese Pharmaceutical Company; Servier), FS-222 (F-Star Biotechnology Co., Ltd.), GEN-1046 (BioNTech SE; Genmab Holding Company), BH-29xx (Beijing Hanmi Pharmaceutical Co., Ltd.), Atez Monoclonal antibody (Genentech), Avirulumab (Merck Group/Pfizer), Duvaluzumab (AstraZeneca/Midimuuni Co., Ltd.), BGB-A333 (BeiGene) China Co., Ltd.), CX-072 (Xitomax Medical Co., Ltd.), GNS-1480 (Yue Yuen Company/Kino Cisco), AMP-224 (Midi Muuni Co., Ltd.), CA-170 (Origini Discovery Technology Co., Ltd.) Company), CK-301 (Checkpoint Medical/TG Medical), CS-1001 (Cornerstone Pharmaceutical Co., Ltd.), FAZ-053 (Novartis Group), Ivaflizumab (ASC22 or KN-035; Corning Jerry (Suzhou)/Side Di), LY-3300054 (Eli Lilly), M-7824 (Merck Group), HTI-1088 (HTI -131, SHR-1316; Atelidia and Jiangsu Hengrui Pharmaceutical Company), MSB-2311 (Maebs Biosciences (Suzhou) Co., Ltd.), STI-A1014 (Li's Pharmaceutical Factory/Sorrento) , AK-106 (Kangfang Biomedicine Company), AVA-004 (Avicota Life Science Co., Ltd.), BBI-801 (Boston Biomedical Company), CA-327 (Ore Gene/Curie Company), CBA -0710 (Sorrento Medical Company), CBT-502 (CBT Pharmaceuticals/Zhengda Tianqing Pharmaceutical), FPT-155 (Five Prime Medical Company), FS-118 (F-Star Biotechnology Co., Ltd.), IKT-201 (Isaier Kelex Medical), IKT-703 (Iser Kelex Medical), IO-103 (IO Biotechnology Company), JS-003 (Shanghai Junshi Biomedical Technology), KD-033 (Kay Deman/Essence Pharmaceuticals), KY-1003 (Kamaibo Co., Ltd.), MCLA-145 (Merus Group/Insett), MT-5050 (Molecular Template Company), and SNA-02 (Quan Sheng Bio Pharmaceutical companies); more specifically BCD-135, APL-502, MDX-1105, IMC-001, KD-045, INBRX-105, KN-046, INCB-086550, Ivaflizumab, Atez Mab, Aviruzumab, Duvaluzumab, BGB-A333, CX-072, GNS-1480, AMP-224, CA-170, CK-301, CS-1001, FAZ-053, KN-035 , LY-3300054, M-7824, SHR-1316, MSB-2311, and STI-A1014; even more specifically Ivaflizumab, Atezolizumab, Aviruzumab, Duvaluzumab Antibodies, BGB-A333, CX-072, and GNS-1480; even more specifically atezolizumab, aviruzumab, and duvaluzumab.

In another embodiment, the PD-1 or PD-L1 inhibitor is a monoclonal antibody or an antigen-binding fragment thereof, which comprises the complementarity determining region (CDR) or variable region defined sequence of the heavy chain and the light chain, as follows Those listed. Use abYsis integrated database and analysis suite (version 3.1.0) and Kabat numbering system for sequence annotation. Area sequence Anti-PD-1 antibody 1 CDRL1 RASKGVSTSGYSYLH (SEQ ID NO: 1) CDRL2 LASYLES (SEQ ID NO: 2) CDRL3 QHSRDLPLT (SEQ ID NO: 3) CDRH1 NYYMY (SEQ ID NO: 4) CDRH2 GINPSNGGTNFNEKFKN (SEQ ID NO: 5) CDRH3 RDYRFDMGFDY (SEQ ID NO: 6) LCVR EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK (SEQ ID NO: 7) HCVR QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS (SEQ ID NO: 8) LC EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVQWKESVDNALQDSKANSTK VTSKID HC QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 10) Anti-PD-1 antibody 2 CDRL1 RASQSVSSYLAW (SEQ ID NO: 11) CDRL2 DASNRAT (SEQ ID NO: 12) CDRL3 QQSSNWPRT (SEQ ID NO: 13) CDRH1 SNSGMH (SEQ ID NO: 14) CDRH2 VIWYDGSKRYYADSVKG (SEQ ID NO: 15) CDRH3 NDDY (SEQ ID NO: 16) LCVR EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK (SEQ ID NO: 17) HCVR QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS (SEQ ID NO: 18) LC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPTKPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGSSDYSGSLACE SGSL SNRRACE HYPREAKVQWKVDNALQSGNSKESVTEVTETLSID HC QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 20) Anti-PD-1 antibody 3 CDRL1 RASLSINTFLN (SEQ ID NO: 21) CDRL2 AASSLHG (SEQ ID NO: 22) CDRL3 QQSSNTPFT (SEQ ID NO: 23) CDRH1 NFGMT (SEQ ID NO: 24) CDRH2 GISGGGRDTYFADSVKG (SEQ ID NO: 25) CDRH3 WGNIYFDY (SEQ ID NO: 26) LCVR DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFR (SEQ ID NO: 27) HCVR EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSS (SEQ ID NO: 28) LC DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPPSTKDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSKDSQESVTEQSLACE SFYPREAKVQWKVDNALQSGNSKDSHQVQVTEQVTACE IDG HC EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 30) Anti-PD-L1 antibody 1 CDRL1 RASQDVSTAVA (SEQ ID NO: 31) CDRL2 SASFLYS (SEQ ID NO: 32) CDRL3 QQYLYHPAT (SEQ ID NO: 33) CDRH1 DSWIH (SEQ ID NO: 34) CDRH2 WISPYGGSTYYADSVKG (SEQ ID NO: 35) CDRH3 RHWPGGFDY (SEQ ID NO: 36) LCVR DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIK (SEQ ID NO: 37) HCVR EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 38) LC DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFITKPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQDSGETLS VTNRACESNFYPREAKVQWKVDNALQDSGETLSIDSLQDSKESVQESV HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 40) Anti-PD-L1 antibody 2 CDRL1 TGTSSDVGGYNYVS (SEQ ID NO: 41) CDRL2 DVSNRPS (SEQ ID NO: 42) CDRL3 SSYTSSSTRV (SEQ ID NO: 43) CDRH1 SYIMM (SEQ ID NO: 44) CDRH2 SIYPSGGITFYADTVKG (SEQ ID NO: 45) CDRH3 IKLGTVTTVDY (SEQ ID NO: 46) LCVR QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL (SEQ ID NO: 47) HCVR EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS (SEQ ID NO: 48) LC QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVSETTVKASDGSPVKAVKAVYAGSequences 49CTSVKANKKSSYSELQANKATLVCLISDFYPGAVTS HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 50) Anti-PD-L1 antibody 3 CDRL1 RASQRVSSSYLA (SEQ ID NO: 51) CDRL2 DASSRAT (SEQ ID NO: 52) CDRL3 QQYGSLPWT (SEQ ID NO: 53) CDRH1 RYWMS (SEQ ID NO: 54) CDRH2 NIKQDGSEKYYVDSVKG (SEQ ID NO: 55) CDRH3 EGGWFGELAFDY (SEQ ID NO: 56) LCVR EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO: 57) HCVR EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS (SEQ ID NO: 58) LC EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFITKPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALSSTLACEPVSLQDSKESVQESVQESVQESVQESVQSQESVQSLGESVVFITKPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQDSKESV HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 60)

For example, in some embodiments, the anti-PD-1 monoclonal antibody or PD-1 binding fragment thereof comprises (i) the light chain CDR sequence of SEQ ID NO: 1-3 and the heavy chain CDR sequence of SEQ ID NO: 4-6 Sequence, or (ii) the light chain variable region sequence of SEQ ID NO: 7 and the heavy chain variable region sequence of SEQ ID NO: 8. In some embodiments, the anti-PD-1 monoclonal antibody comprises the light chain sequence of SEQ ID NO: 9 and the heavy chain sequence of SEQ ID NO: 10. In other embodiments, the anti-PD-1 monoclonal antibody or PD-1 binding fragment thereof comprises (i) the light chain CDR sequence of SEQ ID NO: 11-13 and the heavy chain CDR sequence of SEQ ID NO: 14-16, Or (ii) the light chain variable region sequence of SEQ ID NO: 17 and the heavy chain variable region sequence of SEQ ID NO: 18. In some embodiments, the anti-PD-1 monoclonal antibody comprises the light chain sequence of SEQ ID NO: 19 and the heavy chain sequence of SEQ ID NO: 20. In other embodiments, the anti-PD-1 monoclonal antibody or PD-1 binding fragment thereof comprises (i) the light chain CDR sequence of SEQ ID NO: 21-23 and the heavy chain CDR sequence of SEQ ID NO: 24-26, Or (ii) the light chain variable region sequence of SEQ ID NO: 27 and the heavy chain variable region sequence of SEQ ID NO: 28. In some embodiments, the anti-PD-1 monoclonal antibody comprises the light chain sequence of SEQ ID NO: 29 and the heavy chain sequence of SEQ ID NO: 30. In other embodiments, the anti-PD-L1 monoclonal antibody or PD-L1 binding fragment thereof comprises (i) the light chain CDR sequence of SEQ ID NO: 31-33 and the heavy chain CDR sequence of SEQ ID NO: 34-36, Or (ii) the light chain variable region sequence of SEQ ID NO: 37 and the heavy chain variable region sequence of SEQ ID NO: 38. In some embodiments, the anti-PD-L1 monoclonal antibody comprises the light chain sequence of SEQ ID NO: 39 and the heavy chain sequence of SEQ ID NO: 40. In other embodiments, the anti-PD-L1 monoclonal antibody or PD-L1 binding fragment thereof comprises (i) the light chain CDR sequence of SEQ ID NO: 41-43 and the heavy chain CDR sequence of SEQ ID NO: 44-46, Or (ii) the light chain variable region sequence of SEQ ID NO: 47 and the heavy chain variable region sequence of SEQ ID NO: 48. In some embodiments, the anti-PD-L1 monoclonal antibody comprises the light chain sequence of SEQ ID NO: 49 and the heavy chain sequence of SEQ ID NO: 50. In other embodiments, the anti-PD-L1 monoclonal antibody or PD-L1 binding fragment thereof comprises (i) the light chain CDR sequence of SEQ ID NO: 51-53 and the heavy chain CDR sequence of SEQ ID NO: 54-56, Or (ii) the light chain variable region sequence of SEQ ID NO: 57 and the heavy chain variable region sequence of SEQ ID NO: 58. In some embodiments, the anti-PD-L1 monoclonal antibody comprises the light chain sequence of SEQ ID NO: 59 and the heavy chain sequence of SEQ ID NO: 60.

In other embodiments, the anti-PD-1 monoclonal antibody comprises the CDR of one of the following light chain and heavy chain sequence pairs identified using the abYsis integrated database and analysis suite (version 3.1.0) and the Clothia numbering system Sequence: (i) SEQ ID NO: 9 and SEQ ID NO: 10; (ii) SEQ ID NO: 19 and SEQ ID NO: 20; or (iii) SEQ ID NO: 29 and SEQ ID NO: 30. In another embodiment, the anti-PD-L1 monoclonal antibody comprises the CDR sequence of one of the following light chain and heavy chain sequence pairs identified using the abYsis integrated database and analysis suite (version 3.1.0) and the Josia numbering system: (i) SEQ ID NO: 39 and SEQ ID NO: 40; (ii) SEQ ID NO: 49 and SEQ ID NO: 50; or (iii) SEQ ID NO: 59 and SEQ ID NO: 60.

In other embodiments, when the immune checkpoint inhibitor is a monoclonal antibody, the monoclonal antibody may be a variant comprising heavy chain and light chain sequences that are compatible with the anti-PD-1 or anti-PD-1 specified in the preceding paragraph. One of the PD-1L monoclonal antibodies (reference monoclonal antibodies) is the same. This variant is the same as the reference monoclonal antibody, except that it has three, two or one conservative amino acid substitutions at positions other than the light chain complementarity determining region (CDR) and six other than the heavy chain CDR. , Five, four, three, two or one conservative amino acid substitution (for example, the position of the variant is in the framework region or constant region). In other words, the reference monoclonal antibody and the variant monoclonal antibody contain the same CDR sequence, but because they have conservative amino acid substitutions at no more than three or six other positions in their full-length light chain and heavy chain sequences, respectively And different from each other. With respect to the following characteristics, the variant monoclonal antibody is basically the same as the reference monoclonal antibody: binding affinity to its target molecule and the ability to block the binding of the target molecule to the ligand.

For the sake of brevity, in the following description of certain embodiments, CTLA-4, PD-1 and PD-L1 are generally referred to as "present immune checkpoints of the present invention" in several cases, and therefore, The corresponding inhibitor is generally referred to as the "immune checkpoint inhibitor of the present invention". This should normally be understood as involving one, two or all three of CTLA-4, PD-1 and PD-L1 (inhibitors) (as the case may be), unless explicitly stated to the contrary, and regardless of these terms Is it used in the singular or plural form.

In some embodiments, the immune checkpoint inhibitors of the present invention are molecules that bind to CTLA-4, PD-1 or PD-L1 (as the case may be), which can be determined in an ELISA assay, for example, anti- CTLA-4 antibody, anti-PD-1 antibody or PD-L1 antibody, specifically having an EC ₅₀ of 250 nM or lower, more specifically 100 nM or lower, even more specifically 75 nM or lower . The specific ELISA that can be used in this context, specifically for biological preparations, and more specifically for antibodies, can be the following assays: Materials and methods: ● The immune checkpoint inhibitor of the present invention (anti-CTLA-4 or anti-PD- 1. Or anti-PD-L1) ● Recombined immune checkpoint of the present invention, extracellular part of immune checkpoint of the present invention, or chimeric protein containing the extracellular part of immune checkpoint of the present invention (especially human) ● Immunity to the present invention Checkpoint inhibitor has a specific antibody, coupled with horseradish peroxidase (HRP) ● ELISA plate 96-well high binding (Greiner#655061) ● PBS (such as Gibco#21300-058) ● BSA (such as Sigma (Sigma)#A3733) ● Tween20 (for example, Sigma Company#P1379) ● TMB (3,3',5,5'-tetramethylbenzidine) ELISA substrate (for example, Thermo#34029's 1-Step™ Ultra TMB- ELISA substrate solution) ● Blocking solution: 1% BSA in PBS ● Washing solution: PBS with 0.05% Tween ● Stop solution: 250 mM sulfuric acid The extracellular part of the immune checkpoint of the invention or the chimeric protein containing the extracellular part of the immune checkpoint of the invention is dissolved in PBS, 100 µL of the solution is added to each well of the ELISA 96-well plate, and the plate is placed at 4°C Incubate for 12 to 24 hours (coating the wells with the immune checkpoint of the present invention) 2. Then, remove the solution and wash each well with 200 µL of washing solution twice 3. Then add 200 µL of blocking solution to each well and place it in the chamber Incubate for 1 hour at warm (approximately 22°C) 4. Then, remove the blocking solution and wash each well with 1 × 200 µL of washing solution. 5. Then, add 100 µL of the immune checkpoint inhibitor of the present invention to the corresponding well. Serial dilutions in PBS with 1% BSA (particularly suitable ranges for serial dilutions can include 1 µM, 0.5 µM, 0.25 µM, 0.125 µM, 0.06 µM, 0.03 µM, 0.015 µM, 8 nM, 4 nM, 2 nM, 1 nM, 0.3 nM, 0.1 nM, 0.03 nM, 0.01 nM, 0.003 nM, and 0.001 nM), incubate at room temperature for 1 hour 6. Subsequently, remove the supernatant and wash each with 4 × 200 µL washing solution Well 7. Then, add 100 µL of capture antibody solution in PBS with 1% BSA to each well (eg goat anti-human IgG-HRP, 50 ng/ml to 5 µg/ml, usually determined by titration), Incubate at room temperature for 45 min. 8. Then, remove the supernatant and use 6 × 200 µL washing solution to wash each well 9. Subsequently, 100 µL of TMB substrate is added to each well 10. When the reaction is sufficiently complete (when a color gradient can be seen between the different dilutions of the immune checkpoint inhibitor of the present invention, Usually 5 to 20 minutes after the substrate is added), add 100 µL of 250 mM sulfuric acid per well (to stop the reaction) 11. Then, measure the absorbance at 450 nm in a suitable plate reader (such as Tecan Sunrise) 12 . Plot the data as the relative absorbance at 450 nm relative to the concentration of the immune checkpoint inhibitor of the present invention, and use a suitable software (such as Graphpad Prism) to use a suitable curve for a suitable pharmacological model (such as an Emax model) Calculate the EC ₅₀ value together.

For example, the recombinant immune checkpoint protein can be human CTLA-4/CD152 protein, human PD-1/PDCD1 protein (Acro Biosystems, PD-1-H52221, Newark, USA), or human PD-L1/B7-H1 Protein (Acro Biosystems, PD-1-C52H4, Newark, USA). In a specific form of assay, the anti-immune checkpoint antibody of the present invention can be: goat anti-human IgG (H + L) affinity purified antibody (R&D System, G-101-C-ABS, Minneapolis, USA) USA)).

Alternatively, for example, a biotin (type B) conjugate kit (Abcam, ab102867) can be used to biotinylate the immune checkpoint inhibitor of the present invention according to the manufacturer’s instructions and use streptavidin-HRP conjugate Such as streptavidin (HRP) (Abcam, ab7403).

Alternative competition format: The above assay procedure can be performed in a competitive format, for example, suitable for determining the binding of the immune checkpoint inhibitor of the present invention for small molecules.

In step 5, add serial dilutions of the immune checkpoint inhibitor of the present invention (particularly suitable ranges for serial dilutions can include 1 µM, 0.5 µM, 0.25 µM, 0.125 µM, 0.06 µM, 0.03 µM, 0.015 µM, 8 nM, 4 nM, 2 nM, 1 nM, 0.3 nM, 0.1 nM, 0.03 nM, 0.01 nM, 0.003 nM and 0.001 nM) and add a recombinant immune checkpoint ligand of the present invention (for example, relative to the immune checkpoint of the present invention The serial dilutions of the inhibitor are in a matrix pattern serial dilutions to determine the appropriate concentration of the immune checkpoint ligand of the present invention, and the appropriate concentration may be in a range similar to the aforementioned dilutions). In step 7, the capture antibody has specificity for the recombinant immune checkpoint ligand of the present invention. Suitable IC ₅₀ value of 100 nM or less, in particular 75 nM or less, more especially 50 nM or less.

The ability of immune checkpoint inhibitors as biological agents to bind to their corresponding targets (such as PD-1, PD-L1, or CTLA-4) can be achieved by using target proteins or purified domains of cells, using ELISA or flow cytometry methods Use a variety of assays (such as ELISA assays as described herein) to be assessed by in vitro/in vivo and/or cell-based assays. Similarly, the ability of an antibody to block interaction with its corresponding ligand or the ability to generate a biological response in general can be performed in a similar manner (in vitro and/or cell-based) using a designated ligand/receptor binding system or bioassay Evaluation. Exemplary methods for the in vitro characterization of immune checkpoint modulators are described in: Cancer Immunol Res. [Cancer Immunol Research] September 2014; 2(9): 846-56 and [Cancer Immunol Research] September 2015; 3(9): 1052-62.

Several specific immune checkpoint inhibitors of the present invention described herein are commercially available and their preparation methods can be obtained from relevant literature.

The immune checkpoint inhibitor of the present invention can be a small molecule (having a molecular weight of about 600 or less, particularly 500 or less, more particularly 400 or less) or a biological agent (as used herein, such as antibodies, modified antibodies) , Antibody fragments and other proteins).

In a specific embodiment, the immune checkpoint inhibitors of the present invention, more specifically all immune checkpoint inhibitors of the present invention are antibodies, more specifically human antibodies or humanized antibodies.

The immune checkpoint inhibitor of the present invention may be administered in a fixed dose, which means a dose that is equally administered to each patient regardless of the weight of the corresponding patient, especially in the case of biomolecules such as antibodies.

The immune checkpoint inhibitor of the present invention will be administered in a dose that doctors usually use for the corresponding immune checkpoint inhibitor of the present invention, especially the dose approved by the corresponding government agency. In some embodiments, the immune checkpoint inhibitors of the present invention (such as antibodies, modified antibodies, antibody fragments and other proteins) as biological agents can be administered only on the first day of the treatment cycle, which can be such as The specific treatment cycles described herein. This is due to their long half-life in the patient's system.

The term antibody in the sense of the present invention includes all antibodies, antibody fragments and derivatives thereof capable of binding antigens, in this case the corresponding immune checkpoints mentioned above. This includes intact monoclonal antibodies and epitope binding fragments of these antibodies. In this regard, epitope binding fragments (also referred to herein as antibody fragments or antibody derivatives) include all regions of the antibody capable of binding antigen. Examples of specific antibody fragments according to the present invention include, but are specifically not limited to, Fab, Fab', F(ab')2, Fd, single chain (single chain) variable fragments (scFv), single chain antibodies, disulfide linkages the variable fragment (sdFv), and fragments comprising a light chain variable region (V _L) or heavy chain variable region (V _H) of the. In addition, they include recombinantly prepared antibodies such as diabodies and tetrabodies.

Antibody fragments contain the variable region alone or in combination with additional regions, such further regions and hinge region selected from first, second and third regions of the constant region _{(C H 1, C H 2} , C H 3) . In addition, the term antibody includes chimeric antibodies in which different regions of the antibody are derived from different species, for example, antibodies having murine variable regions combined with human constant regions.

The antibody fragments are optionally connected to each other by linkers. The linker contains a short (especially 10 to 20 amino acid residues) flexible peptide sequence, which is selected so that the antibody fragment has the following three-dimensional folding of VL and VH so that it exhibits the antigen specificity of a complete antibody. The specific linker is a _{glycine-serine linker having the structure (Gly x} Ser _y ), wherein x and y are selected from 1 to 10, especially 3 to 5. In addition, the specific linker is composed of a peptide sequence that can increase the protease resistance of the antibody derivative.

In a specific embodiment, pembrolizumab is administered at a dose of 2 mg/kg, or at a dose of 200 mg, or at a dose of 400 mg, and nivolumab is administered at a dose of 3 mg/kg, or at a dose of 240 mg. mg dose or 480 mg dose, aviruzumab 10 mg/kg dose or 800 mg dose, atezolizumab 1200 mg dose, duvaruzumab The monoclonal antibody was administered at a dose of 1500 mg. Specifically, pembrolizumab is administered at a dose of 2 mg/kg, more specifically every three weeks, or alternatively a (fixed) dose of 200 mg, more specifically every three weeks And, or alternatively in a fixed dose of 400 mg, administered every 6 weeks. Specifically, nivolumab is administered at a dose of 3 mg/kg, more specifically every two weeks, or alternatively a (fixed) dose of 240 mg, more specifically every two weeks , Or alternatively in a (fixed) dose of 480 mg, more specifically every four weeks. Specifically, aviruzumab is administered at a dose of 10 mg/kg, or alternatively, a fixed dose of 800 mg, more specifically every two weeks. Specifically, atezolizumab is administered in a (fixed) dose of 1200 mg, more specifically every three weeks. Specifically, duvaluzumab is administered in a (fixed) dose of 1500 mg, more specifically every four weeks.

In a specific embodiment, ipilimumab is administered at a dose of 3 mg/kg, more specifically every three weeks, even more specifically a total of 4 doses.

In other specific embodiments, specifically in the case of neoadjuvant therapy, ipilimumab is administered at a dose of 10 mg/kg, more specifically every 3 weeks, even more specifically a total of 4 doses, and then 10 mg/kg. The dose of mg/kg is administered every 12 weeks, specifically for a total of 3 years, more specifically 1-3 years, or even specifically 1-2 years.

In other specific embodiments, nivolumab is administered at a dose of 3 mg/kg, and on the same day, ipilimumab is administered at a dose of 1 mg/kg, both are administered every 3 weeks, Specifically 2-4 times, more specifically 4 doses, as needed followed by nivolumab at a dose of 240 mg every 2 weeks or alternatively at a dose of 480 mg every 4 weeks, more specifically It is administered intravenously over a course of 30 minutes, specifically for a total of 3 years, more specifically 1-3 years, even more specifically 1-2 years.

In a specific embodiment, tisililimumab is administered at a dose of 10 mg/kg, more specifically once every four weeks, even more specifically for a total of 6 doses, followed by 10 mg/kg every 12 weeks as needed. In other specific embodiments, Tecilimumab is administered at a dose of 15 mg/kg once every three months, followed by 240 mg every 2 weeks or alternatively 480 mg every 4 weeks as needed. Dosage administration of nivolumab, more specifically intravenous administration over a 30-minute course, specifically for a total of 3 years, more specifically 1-3 years, even more specifically 1-2 years.

The treatment cycle as described herein can be repeated one or more times, and is usually repeated as often as necessary, usually by the doctor, for example based on the disease state (progressive disease, stable disease, tumor regression, etc.) and/or tolerance of the treatment determine.

In certain embodiments, the cancer is a solid or hematological tumor.

In certain embodiments, the cancer is a cancer selected from the group consisting of: hepatocellular carcinoma, adrenal cortical carcinoma, AIDS-related cancers including AIDS-related lymphoma, anal cancer, basal cell carcinoma, cholangiocarcinoma, bone cancer, brain Tumors include brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma, malignant glioma, ependymoma, medulloblastoma, supratentorial primary neuroectodermal tumor, optic pathway, and hypothalamic glial Tumor, breast cancer, bronchial adenoma/carcinoid, Burkitt’s lymphoma, gastrointestinal cancer, cancer of unknown primary site, central nervous system lymphoma, cervical cancer, chronic myeloproliferative disorders, colon cancer, colorectal cancer, Skin T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor, eye cancer including intraocular melanoma and retinoblastoma, Gallbladder cancer, gastrointestinal carcinoid tumor, gestational trophoblastic tumor, glioma, childhood brainstem glioma, head and neck cancer, blood cancer, adult and child (primary) hepatocellular carcinoma, hypopharyngeal carcinoma, islet cells or pancreas Visceral cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia in adults and children, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer including non- Small cell lung cancer and small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstrom's macroglobulinemia, Merkel cell carcinoma, mesothelioma , Metastatic squamous neck cancer with hidden primary site, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic myelodysplastic Diseases, multiple myeloma, chronic myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma/bone malignant fibrous histiocytoma, ovarian cancer, ovarian epithelial cancer , Ovarian tumors of low malignant potential, pancreatic cancer, parathyroid cancer, penile cancer, pheochromocytoma, pineal blastoma and supratentorial primary neuroectodermal tumors, pituitary tumors, plasma cell tumors/multiple myeloma, Pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter cancer, transitional cell carcinoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma, Kaposi's sarcoma, soft tissue sarcoma, uterine sarcoma, Sezari syndrome, skin Cancers include melanoma and non-melanoma skin cancer, small bowel cancer, squamous cell carcinoma, gastric cancer, supratentorial primary neuroectodermal tumor, testicular cancer, thymoma, thymoma and thymic cancer, thyroid cancer, trophoblastic tumor, pregnancy Stage endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Welms’ tumor.

In certain specific embodiments, the cancer is refractory, non-responsive or relapsed to immune checkpoint inhibitor therapy, more specifically therapies using one or more immune checkpoint inhibitors of the present invention, and even more specifically PD-1 Or PD-L1 immune checkpoint inhibitor therapy, in which, even more specifically, "refractory" means that the immune checkpoint inhibitor therapy cannot be stabilized, and "non-responsive" means the immune checkpoint inhibitor therapy The best response achieved is a stable disease that lasts for 6 months or less, followed by disease progression. "Relapsed" means a transient decrease in the degree of response, followed by disease progression, and which can be based on, for example, RECIST or immune-related RECIST (irRECIST) standard version (refer to Eisenhauer et al. 2009 Eur J Cancer [European Journal of Cancer], 45, 228-247; Nishino M et al., Clin Cancer Res. [Clinical Cancer Research] July 15, 2013; 19 (14):3936-4 3) or through pathological evaluation (Tetzlaff et al., 2018) to determine the disease state including response, progression, and stable disease.

In certain specific embodiments, the cancer is an immunological hot cancer. Immunological fever specifically means that the tumor is fully infiltrated by T cells; the immune system is visible; it exhibits tumor antigen presentation, for example, by MHC I or II. This can be determined, for example, by immunohistochemistry, the methods of which are well known in the art, such as Arpita Kabiraj et al., Int J Biol Med Res. [International Journal of Biomedical Research] 2015; 6(3): 5204-5210 and among others The method described in the reference for a specific method: Specifically, cancer line immune cells infiltrate tumors corresponding to an immune score of 1-4, more specifically 2-4.

In certain embodiments, the subject or patient is refractory or non-responsive or relapsed to immune checkpoint inhibitor therapy. Specifically, the immune checkpoint inhibitor therapy is a checkpoint inhibitor therapy affected by adaptive immunity, more specifically, a therapy including the administration of PD-1, PD-L1 and/or CTLA-4 immune checkpoint inhibitors , Wherein the immune checkpoint inhibitor can be administered alone or in combination with other active agents.

In certain embodiments, the cancer exhibits a PD-L1 performance of less than 1%, especially compared to the average performance in non-cancerous cells of the same cell type.

In other embodiments, the cancer shows 1% to 5% of PD-L1 performance, especially compared to the average performance in non-cancerous cells of the same cell type.

In other embodiments, the cancer exhibits 5% to 50% PD-L1 performance, especially compared to the average performance in non-cancerous cells of the same cell type.

In other embodiments, the cancer exhibits PD-L1 performance greater than 50%, especially compared to the average performance in non-cancerous cells of the same cell type.

In certain embodiments, the efficacy of cancer for immune checkpoint inhibitor therapy is negatively predicted. In other embodiments, the efficacy of cancer for immune checkpoint inhibitor therapy is positively predicted. Specifically, the immune checkpoint inhibitor therapy is a checkpoint inhibitor therapy affected by adaptive immunity, more specifically, a therapy including the administration of PD-1, PD-L1 or CTLA-4 immune checkpoint inhibitors, wherein The immune checkpoint inhibitor can be administered alone or in combination with other active agents.

In certain embodiments, the cancer has a low or moderate tumor mutation burden, particularly less than 20 mutations per million nucleotide bases, more particularly less than one million nucleotide bases 10 mutations. In other embodiments, the cancer has a high tumor mutation burden, specifically more than 20 mutations per million nucleotide bases.

Immunological hot or cold tumors can be determined based on the following in some cases: certain cellular parameters, such as TGFbeta, PD-L1 and CD8 performance (such as Mariathasan, S. et al. 2018, Nature [Natural]. 554: 544-548. doi:10.1038/nature25501); mutation load (such as Yarchoan, M. et al., 2017, N. Engl. J. Med. [New England Journal of Medicine] 377:2500-2501. doi:10.1056 /NEJMc1713444); immune score (based on the location, number and type of immune cells) (eg Galon, J. et al. 2012, J. Transl. Med. [Journal of Translational Medicine] 10:1. doi:10.1186/1479 -5876-10-1); intestinal flora (degree of heterogeneity and prevalence of certain microbial species) (eg Routy, B. et al., 2017, Science [科学] (80-. ). 3706 :eaan3706. doi:10.1126/science.aan3706); immune cell population and its impact on the prognosis of cancer patients (eg Fridman, WH et al., 2017, Nat. Rev. Clin. Oncol. [Nature Review: Clinical Oncology学]5-8. doi:10.1038/nrclinonc.2017.101), and another factor as reviewed in (Ann Transl Med [Translational Medicine Yearbook] 2017;5(23):468): enrichment of feces Baseline microbiota of Bacillus and other Firmicutes; ratio of neutrophils to lymphocytes; number of neutrophils and LDH (lactate dehydrogenase) levels; relative eosinophil count and relative lymphocytes Count; the density of CD8 + T cells and β-catenin; the presence or absence of JAK 2 (Janus kinase 2) and β-2-microglobulin mutations; TIM-3 (T cell immunoglobulin Mucin-3) level; mutation load; tumor tetrapeptide sequence capable of binding to MHC class I molecules (neoantigens); neoantigen intratumoral heterogeneity and the amount of neoantigen burden of selection; PD-L1 (planned death 1 Receptor ligand) performance level; PTEN (phosphatase and tensin homolog) performance level; CD8+ T cell expansion; baseline T cell receptor pool (each β chain) breadth.

In certain specific embodiments, cancer is suitable for treatment with one or more immune checkpoint inhibitors of the present invention, wherein this is particularly cancer for which the therapy including one or more immune checkpoint inhibitors of the present invention is approved, that is, it has been at least A country’s regulatory agency’s listing approval.

In certain specific embodiments, the cancer is selected from the group consisting of: melanoma, head and neck cancer, kidney cancer, non-small cell lung cancer (NSCLC), microsatellite unstable cancer (Lynch syndrome, especially stomach Esophageal and colorectal cancer), urothelial cancer (including bladder cancer), Merkel cell carcinoma, Hodgkin’s lymphoma, gastric cancer, gastrointestinal cancer (microsatellite stable and unstable) (including colorectal cancer (CRC) )), Hepatocellular Carcinoma (HCC), Renal Cell Carcinoma (RCC), Nasopharyngeal Carcinoma, Basal Cell Carcinoma, Cervical Cancer, Anogenital Cancer, Kaposi’s Sarcoma, Adult T-Cell Leukemia, Primary Exudative Lymph Tumor, and Castman’s disease.

In some specific embodiments, the cancer is selected from the group consisting of breast cancer (especially triple-negative breast cancer), esophageal cancer, non-Hodgkin’s lymphoma, small cell lung cancer (SCLC), sarcoma, mesothelioma, Glioblastoma, microsatellite stable cancers (especially gastroesophageal cancer and colorectal cancer), pancreatic cancer, prostate cancer, skin T-cell lymphoma (CTCL), and squamous cell carcinoma.

In certain specific embodiments, the treatment of the present invention may involve adjuvant or neoadjuvant therapy. In a specific embodiment, in adjuvant therapy (also known as adjuvant therapy, adjuvant therapy, additive therapy, adjuvant care), in addition to the main therapy such as tumor resection (such as surgical resection), HDAC inhibitors and Combination of CTLA-4 inhibitor and PD-1 inhibitor or PD-L1 inhibitor (the "combination"). In adjuvant therapy, in certain typical embodiments, the combination is administered after the main therapy. Generally, the purpose of adjuvant therapy is to remove detectable tumors by the primary therapy, and to administer adjuvant therapy to reduce the risk of recurrence due to the presence of undetected tumor cells. In neoadjuvant therapy, in certain embodiments, the combination is administered before the main therapy such as tumor resection (eg, surgical resection). In certain specific embodiments, the neoadjuvant therapy may additionally include administration of the combination after the main therapy. Generally, the goal of neoadjuvant therapy is to affect tumor cells before the main therapy, and to eradicate or attenuate undetected tumor cells and/or attenuate detectable tumors before the main therapy to reduce the risk of recurrence.

In the context of the present invention, the number of immune cells and/or their ratio to the total number of cells in the tumor can be determined by standard methods known to those skilled in the art, and in a specific embodiment in formalin It can be determined from a fixed paraffin-embedded tumor sample, which can be obtained from the patient by the following process: 1) Cut 5-10 µM slices of the sample, 2) Fix the section in 4% PF (paraffin), 3) Rinse twice in PBS for 2 minutes, 4) Add commercially available serum (5% in PBS) and incubate for 20 minutes, 5) Add commercially available primary antibodies with appropriate markers for specific immune cells (such as CD3 + or CD8 + for total T cells and cytotoxic T cells, respectively), and incubate for 60 min (diluted 5 μg in PBS) ml), 6) Rinse twice in PBS for 2 minutes, 7) Add a biotinylated secondary antibody (binding to the constant region of the primary antibody) and incubate for 30 min, 8) Rinse twice in PBS for 2 minutes, 9) Add streptavidin-peroxidase (such as Jackson Immunoresearch), incubate for 30 min, 10) Rinse twice in PBS for 2 minutes, 11) Add a chromogen (such as AEC Substrate Chromogen Ready-to-Use, Dako#K3464), especially before full staining (usually observe the color under a microscope, usually for 5 min) 12) Rinse with water 13) Counter-staining with commercially available HTX solution 14) Mounting in water-based mounting tablets (such as DAKO) 15) Determine the number of specific immune cell subgroups, such as total T cells and cytotoxic T cells 16) If necessary, determine the cell number ratio by dividing the number of immune cells by the total number of cells in the tumor volume (for example, based on the number of typical cells in the specific cancer type); Or by the following determination

For each tumor sample, use an automated immunohistochemical staining instrument (BenchMark XT, Ventana) to stain an appropriate number of slides: for example, one with CD3 and one with CD8 ready-to-use monoclonal antibody (HalioDx).

Use the ultraView Universal DAB detection kit (Ventana) for staining, and then perform counterstaining (Bluing Reagent, Ventana).

The stained slides are washed, dehydrated, mounted and covered with a cover glass.

Use a full slide scanner (Nanozoomer XR, Hamamatsu) to obtain digital images of stained slides, and use software programs (Immunoscore ®Analyzer, HalioDx) to analyze or count to determine the number of cells and determine the number as appropriate The ratio mentioned above.

(As the case may be: a separate control slide with 3 external controls-1 negative tissue (placenta) and 2 positive (1 tissue: tonsil and cell line pellet)-in each The same is handled during IHC runs, and allows monitoring of staining and scanning steps.)

In certain embodiments, the patient suffering from the cancer has received at least one previous systemic treatment for the cancer, for example, at least one previous systemic chemotherapy for the cancer, for example, including one or more Invent at least one previous systemic treatment of the administration of immune checkpoint inhibitors.

In certain embodiments of the present invention, the previous systemic chemotherapy is a treatment by systemic administration of one or more chemotherapeutic agents, which can be used alone or in combination with other agents.

In certain embodiments of the present invention, the patient suffering from the cancer has received at least one previous systemic treatment for the cancer including the administration of one or more immune checkpoint inhibitors of the present invention, and the The patient is a non-responder or the cancer is refractory or recurring to the at least one previous systemic treatment.

In the present invention, the treatment may be the treatment of subjects suffering from cancer, particularly human subjects suffering from cancer (especially the specific cancer types described herein). The subject can also be referred to as a patient, as used herein in certain circumstances.

HDAC inhibitors are meant to include the corresponding salts, solvates and hydrates.

In the present invention, HDAC inhibitors and all immune checkpoint inhibitors of the present invention are usually administered in a therapeutically effective amount.

In certain specific embodiments, the HDAC inhibitor is specific for class I HDAC. Specifically, HDAC inhibitors have specificity for one or more class I HDAC enzymes (HDAC 1, HDAC 2 and/or HDAC3), where specificity refers specifically to the Ki comparison of the one or more class I HDAC enzymes. Other classes of HDAC enzymes (ie, in particular enzymes of the group consisting of HDAC IIA IIB, III and IV) are at least 2 times lower, more particularly at least 5 times, even more particularly at least 10 times, even more particularly at least 50 times. Assays that can determine HDAC inhibition are, for example, the assays described in WO 2005/087724 A2 and WO 2006/097474 A1.

其中 R1、R4和R5獨立地是氫、1-4C-烷基、鹵素、或1-4C-烷氧基， R2和R3獨立地是氫或1-4C-烷基， R6       係-T1-Q1，其中T1係鍵或1-4C-伸烷基， 或者 Q1       被R61和/或R62取代並且是Aa1、Hh1、Ha1、Ha2、Ha3、Ha4或Ah1， 或 Q1       係未取代的，並且是Ha2、Ha3或Ha4， 其中 R61     係1-4C-烷基、苯基-1-4C-烷基、1-4C-烷氧基、羥基、三氟甲基、氰基、鹵素、完全被氟取代的1-4C-烷氧基或其中超過一半的氫原子被氟原子替代的1-4C-烷氧基、羥基-1-4C-烷基、1-4C-烷氧基-1-4C-烷基、1-4C-烷基磺醯基胺基、甲苯基磺醯基胺基、苯基磺醯基胺基、1-4C-烷基羰基胺基、胺基甲醯基、胺磺醯基、單或二-1-4C-烷基胺基羰基、單或二-1-4C-烷基胺基磺醯基、-T2-N(R611)R612、-U-T3-N(R613)R614、-T4-Het3或-V-T5-Het4，其中 T2 係鍵或1-4C-伸烷基， R611   係氫、1-4C-烷基、3-7C-環烷基、3-7C-環烷基甲基、羥基-2-4C-烷基、1-4C-烷氧基-2-4C-烷基、1-4C-烷基羰基、或1-4C-烷基磺醯基， R612   係氫或1-4C-烷基， 或R611和R612一起並且與它們鍵合的氮原子一起形成雜環Het1，其中Het1係𠰌啉子基、硫代𠰌啉子基、S-側氧基-硫代𠰌啉子基、S,S-二側氧基-硫代𠰌啉子基、哌啶子基、吡咯啶子基、哌𠯤子基或4N-(1-4C-烷基)-哌𠯤子基， U  係-O-(氧)或-C(O)NH-， T3 係2-4C-伸烷基， R613   係氫、1-4C-烷基、3-7C-環烷基、3-7C-環烷基甲基、羥基-2-4C-烷基或1-4C-烷氧基-2-4C-烷基、1-4C-烷基羰基、或1-4C-烷基磺醯基 R614   係氫或1-4C-烷基， 或R613和R614一起並且同時包括它們所結合的氮原子形成雜環Het2，其中 Het2    係𠰌啉子基、硫代𠰌啉子基、S-側氧基-硫代𠰌啉子基、S,S-二側氧基-硫代𠰌啉子基、哌啶子基、吡咯啶子基、哌𠯤子基、或4N-(1-4C-烷基)-哌𠯤子基， T4 係鍵或1-4C-伸烷基， Het3    係1N-(1-4C-烷基)-哌啶基或1N-(1-4C-烷基)-吡咯啶基， V  係-O-(氧)或-C(O)NH-， T5 係鍵或1-4C-伸烷基， Het4    係1N-(1-4C-烷基)-哌啶基或1N-(1-4C-烷基)-吡咯啶基， R62     係1-4C-烷基、1-4C-烷氧基或鹵素， Aa1     係由兩個芳基基團構成的雙芳基基團， 該等芳基基團獨立地選自由苯基和萘基組成之群組，並且 藉由單鍵連接在一起， Hh1     係由兩個雜芳基基團構成的雙雜芳基基團， 該等雜芳基基團獨立地選自由包含一個或兩個雜原子的單環5-或6-員雜芳基基團組成之群組，該等雜原子中的每一個選自由氮、氧和硫組成之群組，並且 該等雜芳基基團藉由單鍵連接在一起， Ah1     係由選自由苯基和萘基組成之群組的芳基基團和選自由包括一個或兩個雜原子的單環5-或6-員雜芳基基團組成之群組的雜芳基基團構成的芳基雜芳基基團，由此所述芳基和雜芳基基團藉由單鍵連接在一起，並且由此Ah1藉由所述雜芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha1     係由選自由包括一個或兩個雜原子的單環5-或6-員雜芳基基團組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基基團，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha1藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha2     係由選自由包括一個、兩個或三個雜原子的稠合雙環9-或10-員雜芳基基團組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基基團，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha2藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha3     係由選自由包括三個或四個雜原子的單環5-員雜芳基基團組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基基團，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha3藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， Ha4     係由選自由包括不含雜原子的苯環和一個或兩個雜原子的部分飽和的稠合雙環9-或10-員雜芳基基團組成之群組的雜芳基基團和選自由苯基和萘基組成之群組的芳基基團構成的雜芳基芳基基團，由此所述雜芳基和芳基基團藉由單鍵連接在一起，並且由此Ha4藉由所述芳基部分與母體分子基團鍵合，該等雜原子中的每一個選自由氮、氧和硫組成之群組， R7       係羥基、或Cyc1，其中Cyc1係式 Ia 的環系統

其中 A和B 係C（碳）， R71和R72獨立地是氫、鹵素、1-4C-烷基、或1-4C-烷氧基， M 同時包括A和B係環Ar2或環Har2，其中Ar2係苯環，Har2係單環5-或6-員不飽和的雜芳環，該雜芳環包含一個至三個雜原子，該等雜原子中的每一個選自由氮、氧和硫組成之群組， 以及該等化合物的鹽。The HDAC inhibitor in the first aspect (Aspect A) is a compound of formula I

Wherein R1, R4 and R5 are independently hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy, R2 and R3 are independently hydrogen or 1-4C-alkyl, and R6 is -T1-Q1 , Wherein T1 is a bond or 1-4C-alkylene, or Q1 is substituted by R61 and/or R62 and is Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, or Q1 is unsubstituted and is Ha2 Ha3 or Ha4, where R61 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkoxy, hydroxy, trifluoromethyl, cyano, halogen, completely substituted by fluorine 1 -4C-alkoxy or 1-4C-alkoxy in which more than half of the hydrogen atoms are replaced by fluorine atoms, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-Alkylsulfonylamino, tosylsulfonylamino, phenylsulfonylamino, 1-4C-alkylcarbonylamino, aminomethanyl, sulfamoyl, mono Or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, -T2-N(R611)R612, -U-T3-N(R613)R614,- T4-Het3 or -V-T5-Het4, where T2 is a bond or 1-4C-alkylene, R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl Methyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl, or 1-4C-alkylsulfonyl, R612 is hydrogen or 1-4C-alkyl, or R611 and R612 together and together with the nitrogen atom to which they are bonded form a heterocyclic Het1, where Het1 is a sulfonyl group, a thiosulfonyl group, and an S-pendant oxy-thiosulfonyl group. Alpino, S,S-di-pendant oxy-thiolino, piperidino, pyrrolidino, piperidino or 4N-(1-4C-alkyl)-piperidino , U is -O-(oxygen) or -C(O)NH-, T3 is 2-4C-alkylene, R613 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C -Cycloalkylmethyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl, or 1-4C-alkylsulfonyl R614 Hydrogen or 1-4C-alkyl, or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is 𠰌alolino group, thio𠰌alolino group, S- pendant oxy- Thiothiolino, S,S-di-side oxy-thiothiolino, piperidino, pyrrolidino, piperidino, or 4N-(1-4C-alkyl)- Piperidine group, T4 bond or 1-4C-alkylene group, Het3 is 1N-(1-4C-alkyl)-piperidinyl or 1N-(1-4C-alkyl)-pyrrolidinyl, V is -O-(oxygen) or -C(O)NH-, T5 is bond or 1-4C-alkylene, Het4 is 1N-(1-4C-alkyl)-piperidinyl or 1N-(1 -4C-alkyl)-pyrrolidinyl, R62 is 1-4C-alkyl, 1-4C-alkoxy or halogen, Aa1 is a biaryl group composed of two aryl groups, these aryl groups Groups are independently selected from the group consisting of phenyl and naphthyl, and are linked together by a single bond. Hh1 is a diheteroaryl group composed of two heteroaryl groups, these heteroaryl groups The groups are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms, each of which heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur Group, and the heteroaryl groups are connected together by a single bond, Ah1 is an aryl group selected from the group consisting of phenyl and naphthyl and a single ring selected from the group consisting of one or two heteroatoms An aryl heteroaryl group consisting of heteroaryl groups of a group consisting of 5- or 6-membered heteroaryl groups, whereby the aryl and heteroaryl groups are connected together by a single bond , And thus Ah1 is bonded to the parent molecular group through the heteroaryl moiety, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and Ha1 is selected from the group consisting of one or two A heteroaryl group consisting of a monocyclic 5- or 6-membered heteroaryl group consisting of three heteroatoms and a heteroaryl aryl group consisting of an aryl group selected from the group consisting of phenyl and naphthyl Groups, whereby the heteroaryl and aryl groups are linked together by a single bond, and thus Ha1 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms A heteroaromatic group selected from the group consisting of nitrogen, oxygen and sulfur, Ha2 is a heteroaromatic group selected from the group consisting of fused bicyclic 9- or 10-membered heteroaryl groups including one, two or three heteroatoms A heteroaryl aryl group composed of a phenyl group and an aryl group selected from the group consisting of a phenyl group and a naphthyl group, whereby the heteroaryl group and the aryl group are connected together by a single bond, And thus Ha2 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and Ha3 is selected from three or four Heteroaryl groups consisting of heteroatomic monocyclic 5-membered heteroaryl groups and heteroaryl aryl groups consisting of aryl groups selected from the group consisting of phenyl and naphthyl, Thus the heteroaryl and aryl groups are linked together by a single bond, and thus Ha3 is bonded to the parent molecular group through the aryl moiety, and each of these heteroatoms is selected from nitrogen The group consisting of, oxygen and sulfur, Ha4 is selected from the group consisting of a benzene ring without heteroatoms and a partially saturated fused bicyclic 9- or 10-membered heteroaryl group with one or two heteroatoms Group of heteroaryl groups and heteroaryl aryl groups consisting of aryl groups selected from the group consisting of phenyl and naphthyl, whereby the heteroaryl and aryl groups are through a single bond connected, And thus Ha4 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group, or Cyc1, where Cyc1 is of the formula Ia's ring system

Wherein A and B are C (carbon), R71 and R72 are independently hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, M includes both A and B are ring Ar2 or ring Har2, wherein Ar2 is a benzene ring, Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring, the heteroaromatic ring contains one to three heteroatoms, each of which is selected from nitrogen, oxygen and sulfur The group, and the salts of these compounds.

其中 A和B 係C（碳）， R71和R72獨立地是氫、鹵素、1-4C-烷基、或1-4C-烷氧基， M 同時包括A和B，係環Ar2或者係環Har2，其中 Ar2     係苯環， Har2    係單環5-或6-員不飽和的雜芳環，該雜芳環包含一個至三個雜原子，該等雜原子中的每一個選自由氮、氧和硫組成之群組， 以及該等化合物的鹽。The HDAC inhibitor in the second aspect (aspect B) (this aspect is an embodiment of aspect A) is a compound of formula I, wherein R1, R4, and R5 are independently hydrogen, 1-4C-alkyl, halogen, or 1- 4C-Alkoxy, R2 and R3 are independently hydrogen or 1-4C-alkyl, R6 is -T1-Q1, where T1 is a bond or 1-4C-alkylene, or Q1 is substituted by R61 and/or R62 And is Aa1, Hh1, Ha1, Ha2, Ha3, or Ah1, or Q1 is unsubstituted, and is Ha2 or Ha3, where R61 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C -Alkoxy, hydroxy, trifluoromethyl, cyano, halogen, 1-4C-alkoxy completely substituted by fluorine or 1-4C-alkoxy in which more than half of the hydrogen atoms are replaced by fluorine atoms, hydroxyl -1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylsulfonylamino, tolylsulfonylamino, phenylsulfonylamino , 1-4C-Alkylcarbonylamino, aminomethanyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl Group, -T2-N(R611)R612, or -U-T3-N(R613)R614, where T2 is a bond or 1-4C-alkylene, R611 is hydrogen, 1-4C-alkyl, 3-7C -Cycloalkyl, 3-7C-cycloalkylmethyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, R612 is hydrogen or 1-4C-alkyl, Or R611 and R612 together and including the nitrogen atom to which they are combined form a heterocyclic Het1, where Het1 is a sulfonyl group, a thiosulfonyl group, an S-pendant oxy-thiosulfonyl group, S, S -Di-side oxy-thiolino, piperidino, pyrrolidino, piperidino, or 4N-(1-4C-alkyl)-piperidino, U is -O- (Oxygen) or -C(O)NH-, T3 is 2-4C-alkylene, R613 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl , Hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, R614 is hydrogen or 1-4C-alkyl, or R613 and R614 together and include the nitrogen atom to which they are combined Heterocyclic Het2 is formed, in which Het2 is ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? Pyridino, pyrrolidino, piperidino, or 4N-(1-4C-alkyl)-piperidino, R62 is 1-4C-alkyl, 1-4C-alkoxy or halogen, Aa1 is a double aryl group composed of two aryl groups, these aryl groups are independently selected from the group consisting of phenyl and naphthyl, and are connected together by a single bond, Hh1 is a diheteroaryl group composed of two heteroaryl groups, which are independently selected from monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms Each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and the heteroaryl groups are connected together by a single bond. Ah1 is selected from the group consisting of phenyl and Aryl groups in the group consisting of naphthyl and heteroaryl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms An aryl group, whereby the aryl and heteroaryl groups are linked together by a single bond, and thus Ah1 is bonded to the parent molecular group through the heteroaryl moiety, and among these heteroatoms Each of is selected from the group consisting of nitrogen, oxygen and sulfur, and Ha1 is a heteroaryl group selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms Group and a heteroaryl aryl group consisting of an aryl group selected from the group consisting of phenyl and naphthyl, whereby the heteroaryl and aryl groups are connected together by a single bond, and are This Ha1 is bonded to the parent molecular group through the aryl moiety, each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and Ha2 is selected from one, two or three Heteroaryl groups consisting of heteroatom-fused bicyclic 9- or 10-membered heteroaryl groups and heteroaryl groups consisting of aryl groups selected from the group consisting of phenyl and naphthyl Groups, whereby the heteroaryl and aryl groups are linked together by a single bond, and thus Ha2 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms A selected from the group consisting of nitrogen, oxygen and sulfur, Ha3 is a heteroaryl group selected from the group consisting of monocyclic 5-membered heteroaryl groups including three or four heteroatoms and selected from A heteroaryl aryl group composed of aryl groups of the group consisting of phenyl and naphthyl, whereby the heteroaryl and aryl groups are connected together by a single bond, and thus Ha3 is through The aryl moiety is bonded to the parent molecular group, and each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group, or Cyc1, wherein Cyc1 is a ring system of formula Ia

Wherein A and B are C (carbon), R71 and R72 are independently hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, M includes both A and B, ring Ar2 or ring Har2 , Wherein Ar2 is a benzene ring, Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring, the heteroaromatic ring contains one to three heteroatoms, each of which is selected from nitrogen, oxygen and Groups of sulfur, and the salts of these compounds.

其中 A和B係C（碳）， R71和R72獨立地是氫、鹵素、1-4C-烷基、或1-4C-烷氧基， M 同時包括A和B，係環Ar2或者係環Har2，其中Ar2係苯環， Har2    係單環5-或6-員不飽和的雜芳環，該雜芳環包含一個至三個雜原子，該等雜原子中的每一個選自由氮、氧和硫組成之群組， 以及該等化合物的鹽。The HDAC inhibitor in the third aspect (Aspect C) (this aspect is also an embodiment of Aspect A) is a compound of formula I, wherein R1, R4, and R5 are independently hydrogen, 1-4C-alkyl, halogen, or 1- 4C-Alkoxy, R2 and R3 are independently hydrogen or 1-4C-alkyl, R6 is -T1-Q1, where T1 is a bond or 1-4C-alkylene, or Q1 is substituted by R61 and/or R62 And is Aa1, Hh1, Ha1, Ha2, Ha3, or Ah1, or Q1 is unsubstituted, and is Ha2 or Ha3, where R61 is 1-4C-alkyl, 1-4C-alkoxy, hydroxyl, trifluoromethyl Group, cyano, halogen, 1-4C-alkoxy completely substituted by fluorine or 1-4C-alkoxy in which more than half of the hydrogen atoms are replaced by fluorine atoms, or -T2-N(R611)R612, wherein T2 bond or 1-4C-alkylene, R611 and R612 are independently hydrogen or 1-4C-alkyl, or R611 and R612 together and including the nitrogen atom to which they are bonded form a heterocyclic Het1, where Het1 is 𠰌 Alkyl, thiol, S-side oxy-thiol, S,S-di-side oxy-thiol, piperidino, pyrrolidino, Piperidine group or 4N-(1-4C-alkyl)-piperidyl group, R62 is 1-4C-alkyl, 1-4C-alkoxy or halogen, Aa1 is composed of two aryl groups These aryl groups are independently selected from the group consisting of phenyl and naphthyl, and are linked together by a single bond. Hh1 is a double composed of two heteroaryl groups. Heteroaryl groups, which are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms, each of these heteroatoms One is selected from the group consisting of nitrogen, oxygen and sulfur, and these heteroaryl groups are connected together by a single bond. Ah1 is a group selected from the group consisting of phenyl and naphthyl and An aryl-heteroaryl group composed of a heteroaryl group consisting of a monocyclic 5- or 6-membered heteroaryl group consisting of one or two heteroatoms, whereby the aryl group and The heteroaryl groups are linked together by single bonds, and thus Ah1 is bonded to the parent molecular group through the heteroaryl moiety, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur Group, Ha1 is a heteroaryl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms and a group selected from the group consisting of phenyl and naphthyl A heteroaryl aryl group constituted by a group of aryl groups, whereby the heteroaryl and aryl groups are connected together by a single bond, and thus Ha1 is connected to the parent molecule through the aryl moiety Group bonding, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha2 is selected from the group consisting of one, two or three heteroatoms Heteroaryl groups consisting of fused bicyclic 9- or 10-membered heteroaryl groups and heteroaryl aryl groups consisting of aryl groups selected from the group consisting of phenyl and naphthyl , Whereby the heteroaryl and aryl groups are linked together by a single bond, and thus Ha2 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms is selected from The group consisting of nitrogen, oxygen and sulfur, Ha3 is a heteroaryl group selected from the group consisting of monocyclic 5-membered heteroaryl groups including three or four heteroatoms and selected from the group consisting of phenyl and A heteroaryl aryl group constituted by an aryl group of a naphthyl group, whereby the heteroaryl and aryl groups are connected together by a single bond, and thus Ha3 is through the aryl The base part is bonded to the parent molecular group, each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group, or Cyc1, where Cyc1 is a ring system of formula Ia

Wherein A and B are C (carbon), R71 and R72 are independently hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, M includes A and B at the same time, ring Ar2 or ring Har2 , Wherein Ar2 is a benzene ring, Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring, the heteroaromatic ring contains one to three heteroatoms, each of which is selected from nitrogen, oxygen and Groups of sulfur, and the salts of these compounds.

1-4C-Alkyl means a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples that may be mentioned are butyl, isobutyl, secondary butyl, tertiary butyl, propyl, isopropyl and especially ethyl and methyl groups.

2-4C-alkyl means a straight or branched chain alkyl group having 2 to 4 carbon atoms. Examples that may be mentioned are butyl, isobutyl, secondary butyl, tertiary butyl, propyl, isopropyl and especially ethyl groups.

3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, among which cyclopropyl, cyclobutyl and cyclopentyl are specific examples.

The 3-7C-cycloalkylmethyl group represents a methyl group substituted with one of the above-mentioned 3-7C-cycloalkyl groups. Specific examples that may be mentioned are cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl groups.

The 1-4C-alkylene group is a branched or especially straight-chain alkylene group having 1 to 4 carbon atoms. Examples that may be mentioned are methylene (-CH ₂ -), ethylene (dimethylene) (-CH ₂ -CH ₂ -), trimethylene (-CH ₂ -CH ₂ -CH ₂ -) And tetramethylene (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -) group.

The 2-4C-alkylene group is a branched or especially straight chain alkylene group having 2 to 4 carbon atoms. Examples that may be mentioned are ethylene (dimethylene) (-CH ₂ -CH ₂ -), trimethylene (-CH ₂ -CH ₂ -CH ₂ -) and tetramethylene (-CH _2- CH ₂ -CH ₂ -CH ₂ -) group.

The 1-4C-alkoxy group means a group containing a linear or branched alkyl group having 1 to 4 carbon atoms in addition to an oxygen atom. Examples that may be mentioned are butoxy, isobutoxy, secondary butoxy, tertiary butoxy, propoxy, isopropoxy and especially ethoxy and methoxy groups.

1-4C-alkoxy-1-4C-alkyl represents one of the above-mentioned 1-4C-alkyl groups substituted by one of the above-mentioned 1-4C-alkoxy groups. Examples that may be mentioned are the methoxymethyl, 2-methoxyethyl, 3-methoxypropyl and 2-ethoxyethyl groups.

1-4C-alkoxy-2-4C-alkyl represents one of the aforementioned 2-4C-alkyl groups substituted with one of the aforementioned 1-4C-alkoxy groups. Examples that may be mentioned are the 2-methoxyethyl, 3-methoxypropyl and 2-ethoxyethyl groups.

Hydroxy-1-4C-alkyl represents one of the above-mentioned 1-4C-alkyl groups substituted by hydroxy. Examples that may be mentioned are hydroxymethyl groups, 2-hydroxyethyl groups or 3-hydroxypropyl groups.

Hydroxy-2-4C-alkyl represents one of the above-mentioned 2-4C-alkyl groups substituted by hydroxy. Examples that may be mentioned are the 2-hydroxyethyl group or the 3-hydroxypropyl group.

Phenyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups substituted by a phenyl group. Examples that may be mentioned are the benzyl and phenethyl groups.

The mono- or di-1-4C-alkylamino group contains one or two of the above-mentioned 1-4C-alkyl groups in addition to the nitrogen atom. Specific examples are di-1-4C-alkylamino groups, especially dimethylamino, diethylamino and diisopropylamino groups.

The mono- or di-1-4C-alkylaminocarbonyl group contains one of the above-mentioned mono- or di-1-4C-alkylamino groups in addition to the carbonyl group. Examples that may be mentioned are N-methyl-, N,N-dimethyl-, N-ethyl-, N-propyl-, N,N-diethyl- and N-isopropylaminocarbonyl Groups, where N,N-dimethylaminocarbonyl groups are specific examples.

The mono- or di-1-4C-alkylaminosulfonyl group represents a sulfonyl group bonded to one of the above-mentioned mono- or di-1-4C-alkylamino groups. Examples that may be mentioned are methylaminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl, where N,N-dimethylaminosulfonyl (dimethylaminosulfonyl) The acyl) group [(CH ₃ ) ₂ NS(O) ₂ -] is a specific example.

1-4C-Alkylcarbonylamino groups, for example, propylamino (C ₂ H ₅ C(O)NH-) and acetylamino (acetylamino) groups (CH ₃ C (O)NH-).

1-4C-Alkylsulfonylamino group system, for example, ethylsulfonylamino group (ethylsulfonylamino group) (C ₂ H ₅ S(O) ₂ NH-) and methylsulfonylamino group Amino (methylsulfonylamino) group (CH ₃ S(O) ₂ NH-).

The 1-4C-alkylsulfonyl group is a sulfonyl group bonded to one of the aforementioned 1-4C-alkyl groups. An example is the methylsulfonyl (methylsulfonyl) group (CH ₃ SO ₂ -).

The 1-4C-alkylcarbonyl group is a carbonyl group bonded to one of the aforementioned 1-4C-alkyl groups. An example is the acetyl group (CH ₃ CO-).

Tolyl alone or as part of another group includes o-tolyl, m-tolyl, and p-tolyl.

The halogen in the sense of the present invention is bromine, or especially chlorine or fluorine.

Aa1 is a diaryl group composed of two aryl groups, The aryl groups are independently selected from the group consisting of phenyl and naphthyl, and Connected together by a single key.

Aa1 may include, but is not limited to, a biphenyl group, for example, a 1,1'-biphenyl-4-yl or 1,1'-biphenyl-3-yl group.

其中取代基R61可以相對於苯環與苯基基團鍵合的結合位置在鄰位，或特別是間位或對位上附接，例如像，2’-(R61)-1,1’-聯苯-3-基、2’-(R61)-1,1’-聯苯-4-基，或特別是3’-(R61)-1,1’-聯苯-3-基或3’-(R61)-1,1’-聯苯-4-基，或特別是4’-(R61)-1,1’-聯苯-3-基或4’-(R61)-1,1’-聯苯-4-基。As non-limiting examples of R61 substituted derivatives of Aa1, the following groups may be mentioned:

Wherein the substituent R61 may be attached at the ortho position relative to the bonding position of the phenyl ring and the phenyl group, or especially at the meta or para position, for example, 2'-(R61)-1,1'- Biphenyl-3-yl, 2'-(R61)-1,1'-biphenyl-4-yl, or especially 3'-(R61)-1,1'-biphenyl-3-yl or 3'-(R61)-1,1'-biphenyl-4-yl, or especially 4'-(R61)-1,1'-biphenyl-3-yl or 4'-(R61)-1,1' -Biphenyl-4-yl.

As an exemplary R61-substituted Aa1 group, for example, 3'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'- Biphenyl-4-yl, 4'-(R61)-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-4-yl, where R61 Department-T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, and R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a pyrolino group or 4N-methyl-piperidino group, or a piperidino group or a pyrrolidino group; For example, selected from any of the following: 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-4-yl, 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-3-yl, 4' -(2-𠰌olin-4-yl-ethyl)-biphenyl-4-yl, 4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 3'-( 𠰌olin-4-yl-methyl)-biphenyl-3-yl, 4'-(𠰌lin-4-yl-methyl)-biphenyl-3-yl, 3'-(𠰌olin-4-yl -Methyl)-Biphenyl-4-yl, 4'-(𠰌olin-4-yl-methyl)-biphenyl-4-yl, 4'-(3-𠰌olin-4-yl-propyl) -Biphenyl-3-yl and 4'-(4-methyl-piperid-1-ylmethyl)-biphenyl-3-yl.

As an exemplary R61-substituted Aa1 group, for example, 2'-(R61)-1,1'-biphenyl-3-yl, 2'-(R61)-1,1'- Biphenyl-4-yl, 3'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'-biphenyl-4-yl, 4'-(R61 )-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-4-yl, where R61 is -T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, and Both R611 and R612 are methyl; For example, selected from any of the following: 2'-Dimethylaminomethyl-biphenyl-4-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 2'-dimethylaminomethyl-biphenyl- 3-yl, 4'-dimethylaminomethyl-biphenyl-3-yl, 3'-dimethylaminomethyl-biphenyl-4-yl and 3'-dimethylaminomethyl -Biphenyl-3-yl.

As an exemplary R61-substituted Aa1 group, for example, 2'-(R61)-1,1'-biphenyl-3-yl, 2'-(R61)-1,1'- Biphenyl-4-yl, 3'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'-biphenyl-4-yl, 4'-(R61 )-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-4-yl, where R61 Department-T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, and R611 is hydrogen, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R612 is hydrogen; E.g, or R611 is cyclopropyl or 2-methoxyethyl, and R612 is hydrogen, For example, selected from any of the following: 4'-(2-Methoxy-ethylamino)methyl-biphenyl-3-yl and 4'-cyclopropylaminomethyl-biphenyl-3-yl, or R611 is hydrogen, cyclopentyl, acetyl or methylsulfonyl, and R612 is hydrogen, For example, selected from any of the following: 4'-aminomethyl-biphenyl-3-yl, 4'-aminomethyl-biphenyl-4-yl, 4'-(acetamido)-methyl-biphenyl-4-yl , 4'-(Methylsulfonylamino)-methyl-biphenyl-4-yl, 3'-(acetamido)-methyl-biphenyl-3-yl, 3'-(formyl Sulfonylamino)-methyl-biphenyl-3-yl and 4'-cyclopentylaminomethyl-biphenyl-4-yl.

As an exemplary R61-substituted Aa1 group, for example, 3'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'- Biphenyl-4-yl, 4'-(R61)-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-4-yl, where R61 is -O-T3-N(R613)R614, where T3 is dimethylene or trimethylene, and R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a pyrrolidino group, a pyrrolidino group or a 4N-methyl-piperidino group, or a piperidino group; For example, selected from any of the following: 4'-(2-𠰌line-4-yl-ethoxy)-biphenyl-3-yl, 4'-(3-𠰌line-4-yl-propoxy)-biphenyl-3-yl, 4'-[2-(4-Methyl-piperid-1-yl)-ethoxy]-biphenyl-3-yl, 4'-(2-pyrrolidin-1-yl-ethoxy]- Biphenyl-3-yl, 3'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-4-yl, 4'-(3-pyrrolidin-1-yl-propoxy)- Biphenyl-4-yl, 3'-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-4-yl, 4'-(3-𠰌olin-4-yl-propoxy)- Biphenyl-4-yl, 3'-(3-𠰌olin-4-yl-propoxy)-biphenyl-4-yl, 3'-(2-𠰌olin-4-yl-ethoxy)- Biphenyl-4-yl, 4'-(2-𠰌lin-4-yl-ethoxy)-biphenyl-4-yl, 4'-[2-(4-methyl-piperid-1-yl )-Ethoxy]-biphenyl-4-yl, 4'-[3-(4-methyl-piperid-1-yl)-propoxy]-biphenyl-4-yl and 3'-[ 3-(4-Methyl-piperid-1-yl)-propoxy]-biphenyl-4-yl.

As an exemplary R61-substituted Aa1 group, for example, 3'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'- Biphenyl-4-yl, 4'-(R61)-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-4-yl, where R61 is -O-T5-Het4, where T5 is a bond, methylene, dimethyl or trimethylene, and Het4 is 1-methyl-piperidin-4-yl; For example, 4'-(2-(1-methyl-piperidin-4-yl)-ethoxy)-biphenyl-4-yl.

As an exemplary R61-substituted Aa1 group, for example, 2'-(R61)-1,1'-biphenyl-3-yl, 2'-(R61)-1,1'- Biphenyl-4-yl, 3'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'-biphenyl-4-yl, 4'-(R61 )-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-4-yl, where R61 is methylsulfonylamino, N,N-dimethylaminosulfonyl, acetamido, hydroxymethyl, amino, dimethylamino, linolino, hydroxyl, trifluoro Methyl or methoxy; E.g, or R61 is methylsulfonylamino, N,N-dimethylaminosulfonyl, acetamido or methylol, For example, it is selected from any one of the following items: 2'-methylsulfonylamino-biphenyl-4-yl, 3'-methylsulfonylamino-biphenyl-4-yl, 4 '-Methylsulfalamido-biphenyl-4-yl, 4'-methylsulfalamido-biphenyl-3-yl, 4'-dimethylsulfalamido-biphenyl-4 -Group, 3'-acetamido-biphenyl-4-yl, 4'-acetamido-biphenyl-4-yl and 3'-hydroxymethyl-biphenyl-4-yl, or R61 is an amino group, a dimethylamino group, a linolino group, a hydroxyl group, a trifluoromethyl group or a methoxy group, For example, it is selected from any one of the following: 3'-amino-biphenyl-4-yl, 4'-𠰌lin-4-yl-biphenyl-4-yl, 4'-hydroxy-biphenyl -4-yl, 3'-trifluoromethyl-biphenyl-4-yl, 3'-dimethylamino-biphenyl-4-yl and 4'-methoxy-biphenyl-4-yl.

As an exemplary R61-substituted Aa1 group, for example, 2'-(R61)-1,1'-biphenyl-3-yl, 2'-(R61)-1,1'- Biphenyl-4-yl, 3'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'-biphenyl-4-yl, 4'-(R61 )-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-4-yl, where R61 is -C(O)-N(H)-T3-N(R613)R614, where T3 is dimethylene or trimethylene, and Both R613 and R614 are methyl; For example, selected from any of the following: 3'-[(2-Dimethylamino-ethylamino)-carbonyl]-biphenyl-4-yl, 4'-[(2-dimethylamino-ethylamino)-carbonyl] -Biphenyl-4-yl and 4'-[(2-dimethylamino-ethylamino)-carbonyl]-biphenyl-3-yl.

An example of the Aa1 group substituted by R61 may be 3'-(R61)-1,1'-biphenyl-3-yl, wherein R61 is any one _{selected from the group G Aa1 consisting of: 3-} 𠰌olin-4-yl-propyl, 2- linolin-4-yl-ethyl, linolin-4-yl-methyl, 3-(4-methyl-piperid-1-yl)-propyl , 2-(4-Methyl-piperidin-1-yl)-ethyl, (4-methyl-piperidin-1-yl)-methyl, 3-pyrrolidin-1-yl-propyl, 2 -Pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-methyl, 3-piperidin-1-yl-propyl, 2-piperidin-1-yl-ethyl, piperidine-1- Base-methyl, 3-𠰌line-4-yl-propoxy, 2-𠰌line-4-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-pyrrolidine-1 -Yl-ethoxy, 3-(4-methyl-piperid-1-yl)-propoxy, 2-(4-methyl-piperid-1-yl)-ethoxy, 3-( 1-Methyl-piperidin-4-yl)-propoxy, 2-(1-methyl-piperidin-4-yl)-ethoxy, 3-piperidin-1-yl-propoxy, 2-piperidin-1-yl-ethoxy, dimethylaminomethyl, 2-dimethylamino-ethyl, 3-dimethylamino-propyl, methylsulfonylamino , Dimethyl sulfamoyl, acetamido, amino, dimethylamino, linolino, piperidino, pyrrolidino, 4-methyl-piperidino, hydroxyl, Trifluoromethyl, methoxy, (2-dimethylamino-ethylamino)-carbonyl, (2-methoxy-ethylamino)methyl, aminomethyl, acetylamine Group-methyl, methylsulfonylamino-methyl, cyclopentylaminomethyl, cyclopropylaminomethyl, and hydroxymethyl.

Another example of the Aa1 group substituted by R61 may be 3'-(R61)-1,1'-biphenyl-4-yl, wherein R61 is selected from any one _{of the G Aa1 groups given above.}

Another example of the Aa1 group substituted by R61 may be 4'-(R61)-1,1'-biphenyl-3-yl, wherein R61 is selected from any one _{of the G Aa1 groups given above.}

Another example of the Aa1 group substituted by R61 may be 4'-(R61)-1,1'-biphenyl-4-yl, wherein R61 is selected from any one _{of the G Aa1 groups given above.}

Specifically, as an exemplary R61 substituted Aa1 group, for example, any one selected from the following items can be explicitly mentioned: 3'-(2-𠰌olin-4-yl-ethyl)-biphenyl- 4-yl, 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-3-yl, 4'-(2-𠰌line-4-yl-ethyl)-biphenyl-4- Group, 4'-(2-𠰌lin-4-yl-ethyl)-biphenyl-3-yl, 3'-(𠰌olin-4-yl-methyl)-biphenyl-3-yl, 4' -(𠰌line-4-yl-methyl)-biphenyl-3-yl, 3'-(𠰌line-4-yl-methyl)-biphenyl-4-yl, 4'-(𠰌line-4 -Yl-methyl)-biphenyl-4-yl, 4'-(3-𠰌olin-4-yl-propyl)-biphenyl-3-yl, 4'-(4-Methyl-piperidin-1-ylmethyl)-biphenyl-3-yl, 4'-(2-𠰌olin-4-yl-ethoxy)-biphenyl-3-yl , 4'-(3-𠰌lin-4-yl-propoxy)-biphenyl-3-yl, 4'-[2-(4-methyl-piperid-1-yl)-ethoxy] -Biphenyl-3-yl, 4'-(2-pyrrolidin-1-yl-ethoxy]-biphenyl-3-yl, 3'-(3-pyrrolidin-1-yl-propoxy) -Biphenyl-4-yl, 4'-(3-pyrrolidin-1-yl-propoxy]-biphenyl-4-yl, 3'-(2-pyrrolidin-1-yl-ethoxy) -Biphenyl-4-yl, 4'-(3-𠰌olin-4-yl-propoxy)-biphenyl-4-yl, 3'-(3-𠰌olin-4-yl-propoxy) -Biphenyl-4-yl, 3'-(2-𠰌olin-4-yl-ethoxy)-biphenyl-4-yl, 4'-(2-𠰌olin-4-yl-ethoxy) -Biphenyl-4-yl, 4'-[2-(4-methyl-piperid-1-yl)-ethoxy]-biphenyl-4-yl, 4'-[3-(4-methyl Yl-piperidin-1-yl)-propoxy]-biphenyl-4-yl, 3'-[3-(4-methyl-piperidin-1-yl)-propoxy]-biphenyl- 4-base, 4'-(2-(1-methyl-piperidin-4-yl)-ethoxy)-biphenyl-4-yl, 2'-dimethylaminomethyl-biphenyl-4-yl, 4'-Dimethylaminomethyl-biphenyl-4-yl, 2'-dimethylaminomethyl-biphenyl-3-yl, 4'-dimethylaminomethyl-biphenyl- 3-yl, 3'-dimethylaminomethyl-biphenyl-4-yl, 3'-dimethylaminomethyl-biphenyl-3-yl, 3'-[(2-Dimethylamino-ethylamino)-carbonyl]-biphenyl-4-yl, 4'-[(2-dimethylamino-ethylamino)-carbonyl] -Biphenyl-4-yl, 4'-[(2-dimethylamino-ethylamino)-carbonyl]-biphenyl-3-yl, 2'-methylsulfonylamino-biphenyl -4-yl, 3'-methylsulfonylamine-biphenyl-4-yl, 4'-methylsulfonylamino-biphenyl-4-yl, 4'-methylsulfonylamine -Biphenyl-3-yl, 4'-dimethylsulfasulfonyl-biphenyl-4-yl, 3'-acetamido-biphenyl-4-yl, 4'-acetamido-biphenyl-4-yl, 3'-amino-biphenyl-4-yl, 4'-𠰌line-4 -Yl-biphenyl-4-yl, 4'-hydroxy-biphenyl-4-yl, 3'-trifluoromethyl-biphenyl-4-yl and 4'-methoxy-biphenyl-4-yl , 4'-(2-Methoxy-ethylamino)methyl-biphenyl-3-yl, 4'-aminomethyl-biphenyl-3-yl, 4'-aminomethyl-biphenyl -4-yl, 4'-(acetylamino)-methyl-biphenyl-4-yl, 4'-(methylsulfonylamino)-methyl-biphenyl-4-yl, 3 '-(Acetylamino)-methyl-biphenyl-3-yl, 3'-(methylsulfonylamino)-methyl-biphenyl-3-yl, 4'-cyclopentylaminomethyl-biphenyl-4-yl, 4'-cyclopropylaminomethyl-biphenyl-3-yl, and 3'-Hydroxymethyl-biphenyl-4-yl.

More specifically, as an exemplary R61 substituted Aa1 group, for example, a group selected from 4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 4' -(3-𠰌lin-4-yl-propoxy)-biphenyl-3-yl, 4'-[2-(4-methyl-piperid-1-yl)-ethoxy]-biphenyl Any one of -3-yl and 4'-dimethylaminomethyl-biphenyl-4-yl.

Hh1 is a diheteroaryl group composed of two heteroaryl groups, The heteroaryl groups are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms, and are linked together by a single bond, the heteroatoms Each of them is selected from the group consisting of nitrogen, oxygen and sulfur.

Hh1 may include, but is not limited to, bithienyl (such as thiophen-3-yl-thienyl or thiophen-2-yl-thienyl), bipyridyl, pyrazolyl-pyridyl (such as pyrazole-1-yl-pyridine) Group or pyrazol-4-yl-pyridyl, such as 6-(pyrazol-4-yl)-pyridin-3-yl), imidazolyl-pyridyl (for example imidazol-1-yl-pyridyl), pyrazole Group-thienyl (e.g. pyrazol-4-yl-thienyl such as 5-(pyrazol-4-yl)-thien-2-yl) or pyridyl-thienyl group (e.g. pyridin-2-yl- Thienyl, pyridin-3-yl-thienyl or pyridin-4-yl-thienyl, such as 5-(pyridin-2-yl)-thiophen-2-yl or 5-(pyridin-4-yl)-thiophene 2-yl), or thiazolyl-thienyl (such as thiazol-4-yl-thienyl, such as 5-(thiazol-4-yl)-thiophen-2-yl), or thiazolyl-pyridyl group (such as 6-(thiazol-4-yl)-pyridin-3-yl).

In a particular detailed description, exemplary Hh1 groups may include pyridyl-thienyl, such as 5-(pyridin-4-yl)-thiophen-2-yl. In another specific detailed description, exemplary Hh1 groups may include pyrazolyl-thienyl, such as 5-(pyrazol-4-yl)-thiophen-2-yl. In another specific detailed description, exemplary Hh1 groups may include bipyridyl, such as 2,4'-bipyridin-5-yl. In another specific detailed description, exemplary Hh1 groups may include thiazolyl-thienyl, such as 5-(thiazol-4-yl)-thiophen-2-yl. In another specific detailed description, exemplary Hh1 groups may include pyrazolyl-pyridyl, such as 6-(pyrazol-4-yl)-pyridin-3-yl. In another specific detailed description, exemplary Hh1 groups may include thiazolyl-pyridyl, such as 6-(thiazol-4-yl)-pyridin-3-yl.

As a non-limiting example of the R61-substituted derivative of Hh1, mention may be made of [1N-(1-4C-alkyl)-pyrazolyl]-thienyl, such as [1N-(1-4C-alkyl)- Pyrazol-4-yl]-thienyl, such as 5-[1N-(1-2C-alkyl)-pyrazol-4-yl]-thiophen-2-yl, for example, 5-(1-N-methyl Yl-pyrazol-4-yl)-thiophen-2-yl.

As a non-limiting example of the R61 substituted derivative of Hh1, mention may be made of [1N-(1-4C-alkyl)-pyrazolyl]-pyridyl, such as [1N-(1-4C-alkyl)- Pyrazol-4-yl]-pyridyl or 6-[1N-(1-4C-alkyl)-pyrazolyl]-pyridin-3-yl, such as 6-[1N-(1-2C-alkyl) -Pyrazol-4-yl]-pyridin-3-yl, for example 6-(1-N-methyl-pyrazol-4-yl)-pyridin-3-yl.

其中取代基R61可以相對於吡啶基環與噻吩基基團鍵合的結合位置在鄰位，或特別是間位或對位上附接，例如像[2-(R61)-吡啶-4-基]-噻吩基或[6-(R61)-吡啶-3-基]-噻吩基，如5-[2-(R61)-吡啶-4-基]-噻吩-2-基或5-[6-(R61)-吡啶-3-基]-噻吩-2-基。As a non-limiting example of the R61 substituted derivative of Hh1, [(R61)-pyridyl]-thienyl can be mentioned, such as the following groups:

The substituent R61 can be attached at the ortho position, or especially the meta or para position relative to the bonding position of the pyridyl ring and the thienyl group, for example, like [2-(R61)-pyridin-4-yl ]-Thienyl or [6-(R61)-pyridin-3-yl]-thienyl, such as 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6- (R61)-Pyridin-3-yl]-thiophen-2-yl.

例如像[2-(R61)-噻唑-4-基]-噻吩基，如5-[2-(R61)-噻唑-4-基]-噻吩-2-基。As a non-limiting example of the R61-substituted derivative of Hh1, [(R61)-thiazolyl]-thienyl can be mentioned, such as the following groups:

For example, like [2-(R61)-thiazol-4-yl]-thienyl, such as 5-[2-(R61)-thiazol-4-yl]-thiophen-2-yl.

其中取代基R61可以相對於末端吡啶基環與其他吡啶基基團鍵合的結合位置在鄰位，或特別是間位或對位上附接，例如像[2-(R61)-吡啶-4-基]-吡啶基或[6-(R61)-吡啶-3-基]-吡啶基或6-[(R61)-吡啶基]-吡啶-3-基，如6-[2-(R61)-吡啶-4-基]-吡啶-3-基[即2’-(R61)-2,4’-聯吡啶-5-基]或6-[6-(R61)-吡啶-3-基]-吡啶-3-基[即6’-(R61)-2,3’-聯吡啶-5-基]。As a non-limiting example of the R61-substituted derivative of Hh1, [(R61)-pyridyl]-pyridyl can be mentioned, such as the following groups:

The substituent R61 can be attached at the ortho position, or especially the meta or para position relative to the bonding position where the terminal pyridyl ring is bonded to other pyridyl groups, such as [2-(R61)-pyridine-4 -Yl]-pyridyl or [6-(R61)-pyridin-3-yl]-pyridyl or 6-[(R61)-pyridyl]-pyridin-3-yl, such as 6-[2-(R61) -Pyridin-4-yl]-pyridin-3-yl [ie 2'-(R61)-2,4'-bipyridin-5-yl] or 6-[6-(R61)-pyridin-3-yl] -Pyridin-3-yl [ie 6'-(R61)-2,3'-bipyridin-5-yl].

As an exemplary R61-substituted Hh1 group, for example, 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6-(R61)-pyridine can be mentioned in more detail -3-yl]-thiophen-2-yl, where R61 is -T2-N(R611)R612, where T2 is a key, and R611 and R612 are both hydrogen, or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a pyrolino group or 4N-methyl-piperidino group, or a piperidino group or a pyrrolidino group; For example, like 5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]-thiophen-2-yl.

As an exemplary R61-substituted Hh1 group, for example, 2'-(R61)-2,4'-bipyridin-5-yl or 6'-(R61)-2,3'-linked Pyridin-5-yl, where R61 is -T2-N(R611)R612, where T2 is a key, and R611 and R612 are both hydrogen, or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a pyrrolidino group, 4N-methyl-piperidino group, piperidino group or pyrrolidino group; For example, like 2'-(4-methyl-piperidin-1-yl)-2,4'-bipyridin-5-yl.

Specifically, as an exemplary R61-substituted Hh1 group, for example, a group selected from 5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]-thiophene- 2-yl, 5-(1N-methyl-pyrazol-4-yl)-thiophen-2-yl, 2'-(4-methyl-piperazol-1-yl)-2,4'-bipyridine -5-yl, 5-(2-methyl-thiazol-4-yl)-thiophen-2-yl, and 6-(1N-methyl-pyrazol-4-yl)-pyridin-3-yl Any one.

More specifically, as an exemplary R61-substituted Hh1 group, for example, 5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]-thiophene- 2-base.

Ah1 is an aryl group selected from the group consisting of phenyl and naphthyl and a heteroaromatic group selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms An aryl heteroaryl group constituted by a group, whereby the aryl and heteroaryl groups are linked together by a single bond, and thus Ah1 is connected to the parent molecular group through the heteroaryl moiety Bonding, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur.

Ah1 may include, but is not limited to, phenyl-thienyl, such as 5-phenyl-thiophen-2-yl, or phenyl-pyridyl, such as 6-phenyl-pyridin-3-yl group.

In a particular detailed description, exemplary Ah1 groups may include phenyl-thienyl, such as 5-(phenyl)-thiophen-2-yl.

In a particular detailed description, exemplary Ah1 groups may include phenyl-pyridyl, such as 6-(phenyl)-pyridin-3-yl.

其中取代基R61可以相對於苯基環與噻吩基基團鍵合的結合位置在鄰位，或特別是間位或對位上附接，例如像[3-(R61)-苯基]-噻吩基或[4-(R61)-苯基]-噻吩基，如5-[3-(R61)-苯基]-噻吩-2-基或5-[4-(R61)-苯基]-噻吩-2-基。As a non-limiting example of the R61 substituted derivative of Ah1, [(R61)-phenyl]-thienyl can be mentioned, such as the following groups:

Wherein the substituent R61 can be attached at the ortho position, or especially at the meta or para position relative to the bonding position where the phenyl ring is bonded to the thienyl group, such as [3-(R61)-phenyl]-thiophene Group or [4-(R61)-phenyl]-thiophene, such as 5-[3-(R61)-phenyl]-thiophen-2-yl or 5-[4-(R61)-phenyl]-thiophene -2-base.

其中取代基R61可以相對於苯基環與吡啶基基團鍵合的結合位置在鄰位，或特別是間位或對位上附接，例如像[3-(R61)-苯基]-吡啶基或[4-(R61)-苯基]-吡啶基或6-[(R61)-苯基]-吡啶-3-基，如6-[3-(R61)-苯基]-吡啶-3-基或6-[4-(R61)-苯基]-吡啶-3-基。As a non-limiting example of the R61 substituted derivative of Ah1, [(R61)-phenyl]-pyridyl can be mentioned, such as the following groups:

Wherein the substituent R61 can be attached at the ortho position relative to the bonding position of the phenyl ring and the pyridyl group, or especially at the meta or para position, such as [3-(R61)-phenyl]-pyridine Group or [4-(R61)-phenyl]-pyridyl or 6-[(R61)-phenyl]-pyridin-3-yl, such as 6-[3-(R61)-phenyl]-pyridine-3 -Group or 6-[4-(R61)-phenyl]-pyridin-3-yl.

As an exemplary R61 substituted Ah1 group, for example, 5-[3-(R61)-phenyl]-thiophen-2-yl or 5-[4-(R61)-phenyl]- Thiophen-2-yl, where R61 is -T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, and R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a pyrolino group or 4N-methyl-piperidino group, or a piperidino group or a pyrrolidino group; For example, it is selected from any one of the following items: 5-[4-(2-𠰌line-4-yl-ethyl)-phenyl]-thiophen-2-yl, 5-[4-(𠰌line- 4-yl-methyl)-phenyl]-thiophen-2-yl and 5-[3-(𠰌olin-4-yl-methyl)-phenyl]-thiophen-2-yl.

As an exemplary R61 substituted Ah1 group, for example, 5-[3-(R61)-phenyl]-thiophen-2-yl or 5-[4-(R61)-phenyl]- Thiophen-2-yl, where R61 is -T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, and Both R611 and R612 are methyl; For example, selected from any of the following: 5-(4-Dimethylaminomethyl-phenyl)-thiophen-2-yl and 5-(3-dimethylaminomethyl-phenyl)-thiophen-2-yl.

As an exemplary R61 substituted Ah1 group, for example, 5-[3-(R61)-phenyl]-thiophen-2-yl or 5-[4-(R61)-phenyl]- Thiophen-2-yl, where R61 is -T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, and R611 is hydrogen, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R612 is hydrogen; For example, it is selected from any one of the following: 5-(3-aminomethyl-phenyl)-thiophen-2-yl, 5-[3-(acetamido)-methyl-benzene Yl]-thiophen-2-yl and 5-[3-(methylsulfonylamino)-methyl-phenyl]-thiophen-2-yl.

As an exemplary R61 substituted Ah1 group, for example, 5-[3-(R61)-phenyl]-thiophen-2-yl or 5-[4-(R61)-phenyl]- Thiophen-2-yl, where R61 is methylsulfonylamino, N,N-dimethylaminosulfonyl, acetamido, hydroxymethyl, amino, dimethylamino, linolino, hydroxyl, trifluoro Methyl or methoxy; For example, like 5-(4-dimethylsulfamoyl-phenyl)-thiophen-2-yl.

As an exemplary R61 substituted Ah1 group, for example, 5-[3-(R61)-phenyl]-thiophen-2-yl or 5-[4-(R61)-phenyl]- Thiophen-2-yl, where R61 is -O-T3-N(R613)R614, where T3 is dimethylene or trimethylene, and R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a pyrrolidino group, a pyrrolidino group or a 4N-methyl-piperidino group, or a piperidino group; For example, it is selected from any one of the following: 5-[4-(2-𠰌olin-4-yl-ethoxy)-phenyl]-thiophen-2-yl, 5-[4-(3 -𠰌olin-4-yl-propoxy)-phenyl]-thiophen-2-yl, 5-{4-[2-(4-methyl-piperid-1-yl)-ethoxy]- Phenyl}-thiophen-2-yl and 5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiophen-2-yl.

As an exemplary R61 substituted Ah1 group, for example, 6-[3-(R61)-phenyl]-pyridin-3-yl or 6-[4-(R61)-phenyl]- Pyridin-3-yl, where R61 is -T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, and Both R611 and R612 are methyl; For example, selected from any of the following: 6-(4-Dimethylaminomethyl-phenyl)-pyridin-3-yl and 6-(3-dimethylaminomethyl-phenyl)-pyridin-3-yl.

As an exemplary R61 substituted Ah1 group, for example, 6-[3-(R61)-phenyl]-pyridin-3-yl or 6-[4-(R61)-phenyl]- Pyridin-3-yl, where R61 is -O-T3-N(R613)R614, where T3 is dimethylene or trimethylene, and R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a pyrrolidino group, a piperidino group, a pyrrolidino group or a 4N-methyl-piperidino group; For example, like 6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-3-yl.

An example of the Ah1 group substituted by R61 may be [4-(R61)-phenyl]-pyridyl, such as 6-[4-(R61)-phenyl]-pyridin-3-yl, wherein R61 is selected from the group consisting of Any one of the group G _Ah1 composed of various items: 3-𠰌line-4-yl-propyl, 2-𠰌line-4-yl-ethyl, 𠰌line-4-yl-methyl, 3-( 4-methyl-piperidin-1-yl)-propyl, 2-(4-methyl-piperidin-1-yl)-ethyl, (4-methyl-piperidin-1-yl)-methan Yl, 3-pyrrolidin-1-yl-propyl, 2-pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-methyl, 3-piperidin-1-yl-propyl, 2- Piperidin-1-yl-ethyl, piperidin-1-yl-methyl, 3-𠰌line-4-yl-propoxy, 2-𠰌line-4-yl-ethoxy, 3-pyrrolidine -1-yl-propoxy, 2-pyrrolidin-1-yl-ethoxy, 3-(4-methyl-piperid-1-yl)-propoxy, 2-(4-methyl- Piper-1-yl)-ethoxy, 3-(1-methyl-piperidin-4-yl)-propoxy, 2-(1-methyl-piperidin-4-yl)-ethoxy , 3-piperidin-1-yl-propoxy, 2-piperidin-1-yl-ethoxy, dimethylaminomethyl, 2-dimethylamino-ethyl, 3-di Methylamino-propyl, methylsulfamate, dimethylsulfamate, acetamido, amino, dimethylamino, pyrolino, piperidino, pyrrolidine Sub-group, 4-methyl-piperidino, hydroxyl, trifluoromethyl, methoxy, (2-dimethylamino-ethylamino)-carbonyl, (2-methoxy-ethyl Amino) methyl, aminomethyl, acetamido-methyl, methylsulfonylamino-methyl, cyclopentylaminomethyl, cyclopropylaminomethyl, and hydroxymethyl .

Another example of the Ah1 group substituted by R61 may be [3-(R61)-phenyl]-pyridyl, such as 6-[3-(R61)-phenyl]-pyridin-3-yl, where R61 is selected From any of the groups G _Ah1 given above. Another example of the Ah1 group substituted by R61 can be [4-(R61)-phenyl]-thienyl, such as 5-[4-(R61)-phenyl]-thiophen-2-yl, where R61 is selected From any of the groups G _Ah1 given above. Another example of the Ah1 group substituted by R61 may be [3-(R61)-phenyl]-thienyl, such as 5-[3-(R61)-phenyl]-thiophen-2-yl, where R61 is selected From any of the groups G _Ah1 given above.

Specifically, as an exemplary R61 substituted Ah1 group, for example, any one selected from the following can be explicitly mentioned: 5-[4-(2-𠰌olin-4-yl-ethyl)-benzene Yl]-thiophen-2-yl, 5-[4-(𠰌line-4-yl-methyl)-phenyl]-thiophen-2-yl, 5-[3-(𠰌line-4-yl-methyl) Yl)-phenyl]-thiophen-2-yl, 5-[4-(2-𠰌olin-4-yl-ethoxy)-phenyl]-thiophen-2-yl, 5-[4-(3 -𠰌olin-4-yl-propoxy)-phenyl]-thiophen-2-yl, 5-{4-[2-(4-methyl-piperid-1-yl)-ethoxy]- Phenyl}-thiophen-2-yl, 5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiophen-2-yl, 5-(4-Dimethylaminomethyl-phenyl)-thiophen-2-yl, 5-(3-dimethylaminomethyl-phenyl)-thiophen-2-yl, 6-(4-Dimethylaminomethyl-phenyl)-pyridin-3-yl, 6-(3-dimethylaminomethyl-phenyl)-pyridin-3-yl, and 6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-3-yl, 5-(3-aminomethyl-phenyl)-thiophen-2-yl, 5-[3-(Acetylamino)-methyl-phenyl]-thiophen-2-yl, 5-[3-(methylsulfonylamino)-methyl-phenyl]-thiophene- 2-yl, and 5-(4-dimethylsulfamoyl-phenyl)-thiophen-2-yl.

More specifically, as an exemplary R61-substituted Ah1 group, for example, 5-(4-dimethylaminomethyl-phenyl)-thiophen-2-yl can be more specifically mentioned.

It should be noted that each of the groups Hh1 and Ah1 is bonded to the moiety T1 via a ring carbon atom.

Ha1 is a heteroaryl group selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms and an aromatic group selected from the group consisting of phenyl and naphthyl A heteroaryl aryl group constituted by a group, whereby the heteroaryl and aryl groups are connected together by a single bond, and thus Ha1 is bonded to the parent molecular group through the aryl moiety Together, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur.

The specific embodiment of the Hal group refers to a heteroaryl-phenyl group, especially a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group.

Ha1 may include, but is not limited to, furyl-phenyl, thienyl-phenyl, pyrazolyl-phenyl (for example, pyrazol-1-yl-phenyl or pyrazol-4-yl-phenyl), imidazolyl- Phenyl (for example, imidazol-1-yl-phenyl), isoxazolyl-phenyl, or pyridyl-phenyl group, or thiazolyl-phenyl (for example, thiazol-4-yl-phenyl group) ).

In a particular detailed description, exemplary Hal groups may include pyrazolyl-phenyl, such as 3-(pyrazolyl)-phenyl or 4-(pyrazolyl)-phenyl. In a particular detailed description, exemplary Hal groups may include pyridyl-phenyl, such as 4-(pyridyl)-phenyl or 3-(pyridyl)-phenyl. In a particular detailed description, exemplary Hal groups may include isoxazolyl-phenyl, such as 4-(isoxazolyl)-phenyl or 3-(isoxazolyl)-phenyl. In a particular detailed description, exemplary Hal groups may include thiazolyl-phenyl, such as 4-(thiazolyl)-phenyl or 3-(thiazolyl)-phenyl.

In another specific detailed description, exemplary Ha1 groups may include 3-(pyrazol-1-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyridine- 4-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 4-(pyridin-3-yl)-phenyl, 3-(pyridin-3-yl)-phenyl, 4-( Isoxazol-4-yl)-phenyl, 3-(isoazol-4-yl)-phenyl, 3-(pyrazol-4-yl)-phenyl or 4-(pyrazol-4-yl )-Phenyl.

As a non-limiting example of the R61-substituted derivative of Ha1, mention may be made of [1N-(1-4C-alkyl)-pyrazolyl]-phenyl, such as [1N-(1-4C-alkyl)- Pyrazol-4-yl]-phenyl, such as 3-[1N-(1-2C-alkyl)-pyrazol-4-yl]-phenyl or 4-[1N-(1-2C-alkyl) -Pyrazol-4-yl]-phenyl, for example 3-(1N-methyl-pyrazol-4-yl)-phenyl or 4-(1N-methyl-pyrazol-4-yl)-phenyl .

As non-limiting examples of the R61 and/or R62 substituted derivatives of Hal, mention may be made of (methyl-isoxazolyl)-phenyl or (dimethyl-isoxazolyl)-phenyl, for example, 3-(3,5-Dimethyl-isoxazol-4-yl)-phenyl or 4-(3,5-dimethyl-isoxazol-4-yl)-phenyl.

其中取代基R61可以相對於吡啶基環與苯基基團鍵合的結合位置在鄰位，或特別是間位或對位上附接，例如像3-[2-(R61)-吡啶-4-基]-苯基、4-[2-(R61)-吡啶-4-基]-苯基、3-[6-(R61)-吡啶-3-基]-苯基或4-[6-(R61)-吡啶-3-基]-苯基。As a non-limiting example of the R61-substituted derivative of Ha1, [(R61)-pyridyl]-phenyl can be mentioned, such as the following groups:

Wherein the substituent R61 can be attached at the ortho position relative to the bonding position of the pyridyl ring and the phenyl group, or especially at the meta or para position, such as 3-[2-(R61)-pyridine-4 -Yl]-phenyl, 4-[2-(R61)-pyridin-4-yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl or 4-[6- (R61)-Pyridin-3-yl]-phenyl.

As an exemplary R61 substituted Ha1 group, for example, 3-[2-(R61)-pyridin-4-yl]-phenyl, 4-[2-(R61)-pyridine-4- Yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, wherein R61 is -T2-N(R611)R612, where T2 is a key, and R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a pyrolino group or 4N-methyl-piperidino group, or a piperidino group or a pyrrolidino group; For example, selected from any of the following: 4-[2-(4-Methyl-piperid-1-yl)-pyridin-4-yl]-phenyl and 3-[2-(4-methyl-piperid-1-yl)-pyridine- 4-yl]-phenyl.

As an exemplary R61 substituted Ha1 group, for example, 3-[2-(R61)-pyridin-4-yl]-phenyl, 4-[2-(R61)-pyridine-4- Yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, wherein R61 is -T2-N(R611)R612, where T2 is a key, and Both R611 and R612 are hydrogen; For example, any one selected from 4-[6-amino-pyridin-3-yl]-phenyl and 3-[6-amino-pyridin-3-yl]-phenyl.

As an exemplary R61 substituted Ha1 group, for example, 3-[2-(R61)-pyridin-4-yl]-phenyl, 4-[2-(R61)-pyridine-4- Yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, where R61 is methoxy ; For example, any one selected from 4-[6-methoxy-pyridin-3-yl]-phenyl and 3-[6-methoxy-pyridin-3-yl]-phenyl.

Specifically, as an exemplary R61 substituted Ha1 group, for example, a group selected from 4-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]-phenyl can be explicitly mentioned , 3-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl]-phenyl, 4-[6-amino-pyridin-3-yl]-phenyl, 3- [6-Amino-pyridin-3-yl]-phenyl, 4-[6-methoxy-pyridin-3-yl]-phenyl, 3-[6-methoxy-pyridin-3-yl] -Phenyl, 3-(1N-methyl-pyrazol-4-yl)-phenyl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, and 4-(3,5- Any one of dimethyl-isoxazol-4-yl)-phenyl.

More specifically, as an exemplary R61 substituted Ha1 group, for example, a group selected from 4-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]- Phenyl, 3-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]-phenyl, 4-[6-amino-pyridin-3-yl]-phenyl, And any one of 4-(1N-methyl-pyrazol-4-yl)-phenyl.

As part of the groups Hh1, Ah1 and Ha1, the mentioned heteroaryl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms are optional From, for example, the group consisting of: 5-membered heteroaryl groups, pyrrolyl, furyl, thienyl, azolyl, isoazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazole And 6-membered heteroaryl groups, pyridyl, pyrimidinyl, pyrimidinyl, and pyridyl, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur.

Ha2 is a heteroaryl group selected from the group consisting of fused bicyclic 9- or 10-membered heteroaryl groups including one, two or three heteroatoms and one selected from the group consisting of phenyl and naphthyl A heteroaryl aryl group constituted by a group of aryl groups, whereby the heteroaryl and aryl groups are connected together by a single bond, and thus Ha2 is connected to the parent by the aryl moiety The molecular groups are bonded, and each of the heteroatoms is selected from the group consisting of nitrogen, oxygen, and sulfur.

The specific embodiment of the Ha2 group refers to a heteroaryl-phenyl group, especially a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group.

Another specific embodiment of the Ha2 group refers to a heteroaryl-phenyl group, especially a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group, where the hetero The aryl part contains a benzene ring.

Another specific embodiment of the Ha2 group refers to a heteroaryl-phenyl group, especially a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group, where the hetero The aryl moiety contains a benzene ring, and thus the heteroaryl moiety is attached to the phenyl moiety through the benzene ring.

Ha2 may include, but is not limited to, indolyl-phenyl, benzothienyl-phenyl, benzofuranyl-phenyl, benzoxazolyl-phenyl, benzothiazolyl-phenyl, indazolyl- Phenyl, benzimidazolyl-phenyl, benzisothiazolyl-phenyl, benzisothiazolyl-phenyl, benzofurazanyl-phenyl, benzotriazolyl-phenyl, benzo Thiadiazolyl-phenyl, quinolinyl-phenyl, isoquinolinyl-phenyl, quinazolinyl-phenyl, quinolinyl-phenyl, octolinyl-phenyl, indolenyl- Phenyl or oronaridinyl-phenyl.

In a particular detailed description, exemplary Ha2 groups may include 3-(indolyl)-phenyl or 4-(indolyl)-phenyl.

In another specific detailed description, exemplary Ha2 groups may include 3-(indol-5-yl)-phenyl or 4-(indol-5-yl)-phenyl.

Ha3 is a heteroaryl group selected from the group consisting of monocyclic 5-membered heteroaryl groups including three or four heteroatoms and an aryl group selected from the group consisting of phenyl and naphthyl A heteroaryl aryl group constituted by a group, whereby the heteroaryl and aryl groups are linked together by a single bond, and thus Ha3 is bonded to the parent molecular group through the aryl moiety, Each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, The specific embodiment of the Ha3 group refers to a heteroaryl-phenyl group, especially a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group.

Ha3 may include, but is not limited to, thiadiazolyl-phenyl (e.g. [1,3,4]thiadiazol-2-yl-phenyl or [1,2,5]thiadiazol-3-yl-phenyl ), Diazolyl-Phenyl (for example [1,3,4] Diazol-2-yl-Phenyl or [1,2,4] Diazol-5-yl-Phenyl), Triazole Group-phenyl (such as triazol-1-yl-phenyl or [1,2,3] triazol-4-yl) or tetrazolyl-phenyl (such as tetrazol-1-yl-phenyl or tetrazol-1-yl-phenyl) Azol-5-yl-phenyl) group.

In a specific detailed description, exemplary Ha3 groups may include triazolyl-phenyl, such as 3-(triazolyl)-phenyl or 4-(triazolyl)-phenyl. In another specific detailed description, exemplary Ha3 groups may include 3-[1,2,3]triazol-4-yl-phenyl or 4-[1,2,3]triazole-4-基-phenyl.

As a non-limiting example of the R61 substituted derivative of Ha3 may be mentioned {1N-(R61)-[1,2,3]triazolyl}-phenyl, such as {1N-(R61)-[1, 2,3]triazol-4-yl}-phenyl, such as 3-{1N-(R61)-[1,2,3]triazol-4-yl}-phenyl or 4-{1N-(R61 )-[1,2,3]triazol-4-yl}-phenyl.

As an exemplary R61 substituted Ha3 group, for example, 3-[1N-(R61)-1,2,3-triazol-4-yl]-phenyl or 4-{1N-( R61)-[1,2,3]triazol-4-yl}-phenyl, wherein R61 Department-T2-N(R611)R612, where T2 is dimethylene or trimethylene, and R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a piperidino, pyrrolidino, linolino or 4N-methyl-piperidino group; For example, 4-{1-(2-𠰌lin-4-yl-ethyl)-[1,2,3]triazol-4-yl}-phenyl or 4-{1-(2-piperidine -1-yl-ethyl)-[1,2,3]triazol-4-yl}-phenyl.

Ha4 is a heteroaryl group selected from the group consisting of a benzene ring without heteroatoms and a partially saturated fused bicyclic 9- or 10-membered heteroaryl group with one or two heteroatoms and selected A heteroaryl aryl group composed of an aryl group consisting of a phenyl group and a naphthyl group, whereby the heteroaryl group and the aryl group are linked together by a single bond, and thus Ha4 borrows The aryl moiety is bonded to the parent molecular group, and each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, The specific embodiment of the Ha4 group refers to a heteroaryl-phenyl group, especially a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group.

Another specific embodiment of the Ha4 group refers to a heteroaryl-phenyl group, especially a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group, whereby The heteroaryl moiety is attached to the phenyl moiety through its benzene ring.

Ha4 may include, but is not limited to, indolinyl-phenyl, isoindolinyl-phenyl, (1,2,3,4-tetrahydroquinolinyl)-phenyl or (1,2,3 ,4-Tetrahydroisoquinolinyl)-phenyl, (2,3-dihydrobenzofuranyl)-phenyl, (2,3-dihydrobenzothienyl)-phenyl, (benzo[ 1,3]dioxolyl)-phenyl, (2,3-dihydrobenzo[1,4]dioxolenyl)-phenyl, chromanyl- Phenyl, benzopiperanyl-phenyl or (2,3-dihydrobenzo[1,4]㗁𠯤yl)-phenyl.

In a specific detailed description, exemplary Ha4 groups may include (benzo[1,3]dioxolyl)-phenyl, such as 3-(benzo[1,3]dioxa Cyclopentenyl)-phenyl or 4-(benzo[1,3]dioxolyl)-phenyl, such as (benzo[1,3]dioxol-5- Yl)-phenyl, such as 3-(benzo[1,3]dioxol-5-yl)-phenyl or 4-(benzo[1,3]dioxol-5 -Radical)-phenyl. In a specific detailed description, exemplary Ha4 groups may include (2,3-dihydrobenzofuranyl)-phenyl, such as 3-(2,3-dihydrobenzofuranyl)-phenyl Or 4-(2,3-dihydrobenzofuranyl)-phenyl, such as (2,3-dihydrobenzofuran-5-yl)-phenyl or (2,3-dihydrobenzofuran -6-yl)-phenyl, for example 3-(2,3-dihydrobenzofuran-5-yl)-phenyl or 4-(2,3-dihydrobenzofuran-5-yl)-benzene base. In another specific detailed description, exemplary Ha4 groups may include 4-(2,3-dihydrobenzofuran-5-yl)-phenyl.

Har2 represents a monocyclic 5- or 6-membered unsaturated heteroaromatic ring. The heteroaromatic ring contains one to three heteroatoms, and each of the heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur.

Har2 may include, but is not limited to, thiophene, oxazole, isoazole, thiazole, isothiazole, imidazole, pyrazole, triazole, thiadiazole, pyridine, pyrimidine, pyridine, or pyrimidine.

In a specific detailed description, an exemplary Har2 group may be pyridine.

Cyc1 represents the ring system of formula Ia, which is bonded to the nitrogen atom of the carboxyamide group via part A. Cyc1 may include, but is not limited to, 2-aminophenyl substituted with R71 and/or R72. In a particular detailed description, an exemplary Cyc1 group may be 2-aminophenyl.

Naphthyl alone or as part of another group includes naphth-1-yl and naphth-2-yl.

In the meaning of the present invention, it should be understood that when two structural parts of the compound according to the present invention are connected by a component having the meaning of "bond", then the two parts are directly attached to the other by a single bond.

When R61 has the meaning of -U-T3-N(R613)R614, where U represents -C(O)NH-, then R61 is a group -C(O)NH-T3-N(R613)R614.

As known to those skilled in the art, the expressions 𠰌olino group, 4N-(1-4C-alkyl)-piperidino group, pyrrolidino group, etc. represent 𠰌olin-4-yl, 4N-( 1-4C-alkyl)-piperidin-1-yl, pyrrolidin-1-yl and the like.

Generally speaking, unless otherwise mentioned, the heterocyclic groups mentioned herein refer to all possible isomeric forms thereof. Unless otherwise stated, the heterocyclic groups mentioned herein specifically refer to all possible positional isomers thereof. Thus, for example, the term pyridyl (pyridyl or pyridinyl) alone or as part of another group includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

Unless otherwise stated, components optionally substituted as described herein can be substituted at any possible position.

Unless otherwise stated, the carbocyclic groups mentioned herein alone or as part of other groups may be substituted by their given substituents or parent molecular groups at any substitutable ring carbon atom.

Unless otherwise specified, the heterocyclic groups mentioned herein, alone or as part of other groups, may be at any possible position, such as at any substitutable ring carbon or ring nitrogen atom by their given substituents. Or the parent molecular group is substituted.

Rings containing quaternizable imino-type ring nitrogen atoms (-N=) can be specifically not quaternized by the mentioned substituents or parent molecular groups on these imino-type ring nitrogen atoms .

It is assumed that any heteroatom of the heterocyclic ring with unsaturated valence mentioned herein has one or more hydrogen atoms satisfying the valence.

When any variable occurs more than once in any component, each definition is independent.

According to professional knowledge, the compounds of formula I and their salts of the present invention may contain different amounts of solvents, for example, when isolated in crystalline form. Therefore, included within the scope of the present invention are all solvates and especially all hydrates of the compound of formula I, and all solvates and especially all hydrates of the salt of the compound of formula I.

The substituents R61 and R62 of the compound of formula I can be attached at any possible position of the Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1 group, thereby emphasizing the attachment on the terminal ring; In another embodiment, Q1 is monosubstituted by R61 and is Aa1, Hh1, Ha1 or Ah1, thereby emphasizing the attachment of R61 on the terminal ring; In another embodiment, R6 is Aa1, Hal or Ha2, each of which is monosubstituted by R61, thereby emphasizing the attachment of R61 on the terminal ring; In another embodiment, R6 is Aa1, Hh1, Ha1, Ha2, or Ah1, each of which is monosubstituted by R61, thereby emphasizing the attachment of R61 on the terminal ring; In another embodiment, R6 is Aa1, Hh1, Ha1, Ha2, Ha3, or Ah1, each of which is monosubstituted by R61, thereby emphasizing the attachment of R61 on the terminal ring;

In another embodiment, R6 is Ha2, Ha3, or Ha4, each of which is unsubstituted.

Within the meaning of the present invention, the terminal ring of Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1 refers to those ring parts of these groups that are not directly attached to the T1 part.

The skilled person knows from his/her professional knowledge that certain combinations of variable characteristics mentioned in the specification of the present invention may lead to compounds with poor chemical stability. This may apply, for example, to certain compounds, where-in a way that is detrimental to chemical stability-two heteroatoms (S, N or O) will directly meet or will be separated by only one carbon atom. Specifically, the compounds according to the present invention are those in which the combination of the above-mentioned variable substituents does not result in a chemically less stable compound.

More worthy of mention are the compounds according to aspect A of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are independently hydrogen or 1-4C-alkyl, R6 Department-T1-Q1, where T1 is a key, or Q1 is replaced by R61 and/or R62 and is Aa1, Hh1, Ha1, Ha2, Ha3, Ha4, or Ah1, Or Q1 is unsubstituted and is Ha2, Ha3 or Ha4, among them R61 is 1-4C-alkyl, 1-4C-alkoxy, hydroxy, trifluoromethyl, halogen, hydroxy-1-4C-alkyl, 1-4C-alkylsulfonylamino, tolylsulfonate Amino, phenylsulfonylamino, 1-4C-alkylcarbonylamino, di-1-4C-alkylaminosulfonyl, -T2-N(R611)R612, -U-T3 -N(R613)R614, -T4-Het3 or -V-T5-Het4, where T2 is a bond or 1-4C-alkylene, R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl, or 1-4C-alkylsulfonyl醯基, R612 is hydrogen or 1-4C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-4C-alkyl)-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is 2-4C-alkylene, R613 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl, or 1-4C-alkylsulfonyl醯基, R614 is hydrogen or 1-4C-alkyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-4C-alkyl)-piperidino, T4 bond or 1-4C-alkylene, Het3 is 1N-(1-4C-alkyl)-piperidinyl or 1N-(1-4C-alkyl)-pyrrolidinyl, V is -O- (oxygen) or -C(O)NH-, T5 is a bond, or 1-4C-alkylene, Het4 is 1N-(1-4C-alkyl)-piperidinyl or 1N-(1-4C-alkyl)-pyrrolidinyl, R62 is 1-4C-alkyl, Aa1 is biphenyl, Hh1 is a diheteroaryl group composed of two heteroaryl groups, The heteroaryl groups are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms, each of which is selected from nitrogen and oxygen And sulfur group, and These heteroaryl groups are linked together by single bonds, Ah1 is a phenyl-heteroaryl group consisting of a phenyl group and a heteroaryl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms Groups, whereby the phenyl and heteroaryl groups are linked together by a single bond, and thus Ah1 is bonded to the parent molecular group by the heteroaryl moiety, each of these heteroatoms Selected from the group consisting of nitrogen, oxygen and sulfur, Ha1 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms Groups, whereby the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha1 is bonded to the parent molecular group by the phenyl moiety, each of these heteroatoms is selected The group of free nitrogen, oxygen and sulfur, Ha2 is a heteroaryl group selected from the group consisting of a fused bicyclic 9- or 10-membered heteroaryl group including one, two or three heteroatoms and a phenyl group A group-phenyl group, whereby the heteroaryl group and the phenyl group are linked together by a single bond, and thus Ha2 is bonded to the parent molecular group through the phenyl moiety, these heteroatoms Each of them is selected from the group consisting of nitrogen, oxygen and sulfur, Ha3 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5-membered heteroaryl groups including three or four heteroatoms, Thus the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha3 is bonded to the parent molecular group via the phenyl moiety, each of these heteroatoms is selected from nitrogen , Oxygen and sulfur, Ha4 is a heteroaryl group selected from the group consisting of a benzene ring without a heteroatom and a partially saturated fused bicyclic 9- or 10-membered heteroaryl group with one or two heteroatoms and A heteroaryl-phenyl group constituted by a phenyl group, whereby the heteroaryl and phenyl group are connected together by a single bond, and thus Ha4 is connected to the parent molecular group through the phenyl moiety Group bonding, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

Particularly worth mentioning are the compounds according to aspect A of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is replaced by R61 and/or R62 on the end ring and is Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, Or Q1 is unsubstituted and is Ha2, Ha3 or Ha4, among them R61 is 1-2C-alkyl, 1-2C-alkoxy, hydroxy, trifluoromethyl, halogen, hydroxy-1-2C-alkyl, 1-2C-alkylsulfonylamino, 1-2C -Alkylcarbonylamino, di-1-2C-alkylaminosulfonyl, -T2-N(R611)R612, -U-T3-N(R613)R614, -T4-Het3, or -V-T5-Het4, where T2 bond or straight chain 1-4C-alkylene, R611 is hydrogen, 1-2C-alkyl, 3-5C-cycloalkyl, 1-2C-alkoxy-2-3C-alkyl, 1-2C-alkylcarbonyl, or 1-2C-alkylsulfonyl醯基, R612 is hydrogen or 1-2C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-2C-alkyl)-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is a linear 2-4C-alkylene group, R613 is hydrogen, 1-2C-alkyl, 3-5C-cycloalkyl, 1-2C-alkoxy-2-3C-alkyl, 1-2C-alkylcarbonyl, or 1-2C-alkylsulfonyl醯基, R614 is hydrogen or 1-2C-alkyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-2C-alkyl)-piperidino, T4 bond or straight chain 1-4C-alkylene, Het3 is 1N-(1-2C-alkyl)-piperidinyl or 1N-(1-2C-alkyl)-pyrrolidinyl, V is -O- (oxygen) or -C(O)NH-, T5 bond or straight chain 1-4C-alkylene, Het4 is 1N-(1-2C-alkyl)-piperidinyl or 1N-(1-2C-alkyl)-pyrrolidinyl, R62 is 1-2C-alkyl, Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, Hh1 is a diheteroaryl group composed of two heteroaryl groups, The heteroaryl groups are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms, each of which is selected from nitrogen and oxygen And sulfur, and these heteroaryl groups are connected together by a single bond, Ah1 is a phenyl-heteroaryl group consisting of a phenyl group and a heteroaryl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms Groups, whereby the phenyl and heteroaryl groups are linked together by a single bond, and thus Ah1 is bonded to the parent molecular group by the heteroaryl moiety, each of these heteroatoms Selected from the group consisting of nitrogen, oxygen and sulfur, Ha1 is a 3-(heteroaryl group) each consisting of a heteroaryl group and a phenyl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms )-Phenyl or 4-(heteroaryl)-phenyl group, whereby the heteroaryl group and the phenyl group are connected together by a single bond, and thus Hal is connected to the phenyl group by the phenyl moiety The parent molecular group is bonded, and each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha2 is each composed of a heteroaryl group and a phenyl group selected from the group consisting of a fused bicyclic 9- or 10-membered heteroaryl group including one or two heteroatoms and a phenyl group. Aryl)-phenyl or 4-(heteroaryl)-phenyl groups, whereby the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha2 is through the phenyl Partly bonded to the parent molecular group, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha3 is a 3-(heteroaryl) group each consisting of a heteroaryl group and a phenyl group selected from the group consisting of a monocyclic 5-membered heteroaryl group including three or four heteroatoms A phenyl or 4-(heteroaryl)-phenyl group, whereby the heteroaryl and phenyl group are linked together by a single bond, and thus Ha3 is connected to the parent molecule through the phenyl moiety Groups are bonded, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha4 is a heteroaryl group each selected from the group consisting of a benzene ring without a heteroatom and a partially saturated fused bicyclic 9- or 10-membered heteroaryl group with one or two heteroatoms A 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group formed with a phenyl group, whereby the heteroaryl and phenyl group are connected together by a single bond , And thus Ha4 is bonded to the parent molecular group through the phenyl moiety, and each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

More particularly worthy of mention are the compounds according to aspect A of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is replaced by R61 and/or R62 on the end ring and is Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, Or Q1 is unsubstituted and is Ha2, Ha3 or Ha4, among them R61 Methyl, methoxy, hydroxyl, trifluoromethyl, hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611) R612, -U-T3-N(R613) R614, -T4-Het3, or -V-T5-Het4, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino, piperidino or 4-methyl-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is dimethylene or trimethylene, R613 is hydrogen, methyl, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R614 is hydrogen or methyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4-methyl-piperidino, T4 tether, methylene, dimethyl or trimethylene, Het3 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl, V is -O- (oxygen) or -C(O)NH-, T5 tether, methylene, dimethyl or trimethylene, Het4 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl, R62 is a methyl group, Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, Hh1 is a bi-heteroaryl group composed of two heteroaryl groups, and these aryl groups are independently selected from pyrrolyl, furyl, thienyl, azolyl, isoazolyl, thiazolyl, The group consisting of isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridyl and pyridyl, and Connected together by a single button, For example like, Hh1 is pyridyl-thienyl, thiazolyl-thienyl, pyrazolyl-thienyl, bipyridyl, pyrazolyl-pyridyl, or thiazolyl-pyridyl, Ah1 is composed of phenyl group and selected from pyrrolyl, furyl, thienyl, azolyl, isothiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridine A phenyl-heteroaryl group consisting of a heteroaryl group consisting of a group consisting of a phenyl group and a tado group, whereby the phenyl group and the heteroaryl group are connected together by a single bond, and thus Ah1 By bonding the heteroaryl moiety to the parent molecular group, For example like, Ah1 is phenyl-thienyl or phenyl-pyridyl, Ha1 is each selected from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, isothiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazolyl, and pyridyl. 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group consisting of heteroaryl groups and phenyl groups in the group consisting of groups, whereby the heteroaryl group and the phenyl group constitute a 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group The phenyl groups are connected together by a single bond, and thus Ha1 is bonded to the parent molecular group through the phenyl moiety, For example like, Ha1 is 3-(pyridyl)-phenyl, 3-(thiazolyl)-phenyl, 3-(pyrazolyl)-phenyl, 3-(isoazolyl)-phenyl, 4-(pyridyl) )-Phenyl, 4-(thiazolyl)-phenyl, 4-(pyrazolyl)-phenyl, or 4-(isoxazolyl)-phenyl, Ha2 is each selected from the group consisting of indolyl, benzothienyl, benzofuranyl, benzoazolyl, benzothiazolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benziso Thiazolyl, benzofurazanyl, benzotriazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinolinyl, octolinyl, indolenyl and mouth A 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group composed of a heteroaryl group and a phenyl group of the group consisting of nalidinyl, whereby the heteroaryl The phenyl group and the phenyl group are connected together by a single bond, and thus Ha2 is bonded to the parent molecular group through the phenyl moiety, For example like, Ha2 is 3-(indolyl)-phenyl or 4-(indolyl)-phenyl, Ha3 is a 3-(heteroaryl)-phenyl group each consisting of a heteroaryl group and a phenyl group selected from the group consisting of thiadiazolyl, ethadiazolyl, triazolyl and tetrazolyl Or 4-(heteroaryl)-phenyl group, whereby the heteroaryl and phenyl group are connected together by a single bond, and thus Ha3 is connected to the parent molecular group through the phenyl moiety Bond, For example like, Ha3 is 3-(triazolyl)-phenyl or 4-(triazolyl)-phenyl, Ha4 is each selected from indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2, 3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]diox Heteroaryl groups and phenyl groups in the group consisting of heterocyclohexenyl, benzodihydropiperanyl, benzopiperanyl, and 2,3-dihydrobenzo[1,4]㗁𠯤yl 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl group constituted by the group, whereby the heteroaryl and phenyl groups are connected together by a single bond, and thus Ha3 is bonded to the parent molecular group through the phenyl moiety, For example like, Ha4 is 3-(benzo[1,3]dioxolyl)-phenyl, 4-(benzo[1,3]dioxolyl)-phenyl, 3-(2 ,3-Dihydrobenzofuranyl)-phenyl, or 4-(2,3-dihydrobenzofuranyl)-phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

It is emphasized that the compounds according to aspect A of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; or Q1 is replaced by R61 on the end ring, and is Aa1 or Ah1, where Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, For example like, 3'-(R61)-1,1'-biphenyl-3-yl, 4'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'- Biphenyl-4-yl or 4'-(R61)-1,1'-biphenyl-4-yl, Ah1 is phenyl-thienyl or phenyl-pyridyl, For example like, [3-(R61)-Phenyl]-thienyl, [4-(R61)-phenyl]-thienyl, [3-(R61)-phenyl]-pyridyl or [4-(R61)-benzene Yl]-pyridyl, For example, 5-[3-(R61)-phenyl]-thiophen-2-yl, 5-[4-(R61)-phenyl]-thiophen-2-yl, 2-[3-(R61)-phenyl ]-Pyridin-4-yl, 2-[4-(R61)-phenyl]-pyridin-4-yl, 6-[3-(R61)-phenyl]-pyridin-3-yl or 6-[4 -(R61)-phenyl]-pyridin-3-yl, among them R61 is methoxy, hydroxyl, trifluoromethyl, hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612,- U-T3-N(R613)R614, -T4-Het3, or -V-T5-Het4, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4-methyl-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is dimethylene or trimethylene, R613 and R614 are methyl groups, Or R613 and R614 together and including the nitrogen atom to which they are bonded form a heterocyclic Het2, where Het2 is a linolino, piperidino, pyrrolidino, or 4-methyl-piperidino, T4 tether, methylene, dimethyl or trimethylene, Het3 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl, V is -O- (oxygen) or -C(O)NH-, T5 tether, methylene, dimethyl or trimethylene, Het4 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl; or Q1 is replaced by R61 on the end ring, and is Hh1 or Ha1, where Hh1 is pyridyl-thienyl or bipyridyl, For example like, [2-(R61)-pyridin-4-yl]-thienyl or [6-(R61)-pyridin-3-yl]-thienyl, For example, 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6-(R61)-pyridin-3-yl]-thiophen-2-yl, or [2-(R61)-pyridin-4-yl]-pyridyl or [6-(R61)-pyridin-3-yl]-pyridyl, For example, 2-[2-(R61)-pyridin-4-yl]-pyridin-4-yl, 2-[6-(R61)-pyridin-3-yl]-pyridin-4-yl, 6-[2- (R61)-pyridin-4-yl]-pyridin-3-yl or 6-[6-(R61)-pyridin-3-yl]-pyridin-3-yl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, For example like, 3-[2-(R61)-pyridin-4-yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl, 4-[2-(R61)-pyridine-4 -Yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, among them R61 is methoxy or -T2-N(R611)R612, where T2 key, R611 and R612 are independently hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino; or Q1 is 3-(1-methyl-pyrazolyl)-phenyl, 4-(1-methyl-pyrazolyl)-phenyl, 3-(methyl-thiazolyl)-phenyl, 4-( Methyl-thiazolyl)-phenyl, 3-(dimethyl-isoxazolyl)-phenyl, 4-(dimethyl-isoxazolyl)-phenyl, (1-methyl-pyrazole Yl)-thienyl, (1-methyl-pyrazolyl)-pyridyl, (methyl-thiazolyl)-thienyl, (Methyl-thiazolyl)-pyridyl, 3-(benzo[1,3]dioxolyl)-phenyl, 4-(benzo[1,3]dioxolyl )-Phenyl, 3-(2,3-dihydrobenzofuranyl)-phenyl, 4-(2,3-dihydrobenzofuranyl)-phenyl, 3-(1-methyl-indyl) Dolyl)-phenyl, or 4-(1-methyl-indolyl)-phenyl, For example like, 3-(1-methyl-pyrazol-4-yl)-phenyl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 3-(2-methyl-thiazole-4- Yl)-phenyl, 4-(2-methyl-thiazol-4-yl)-phenyl, 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl, 4-( 3,5-Dimethyl-isoxazol-4-yl)-phenyl, (1-methyl-pyrazol-4-yl)-thienyl such as 5-(1-methyl-pyrazole-4- Yl)-thiophen-2-yl, (1-methyl-pyrazol-4-yl)-pyridyl such as 6-(1-methyl-pyrazol-4-yl)-pyridin-3-yl or 2- (1-Methyl-pyrazol-4-yl)-pyridin-4-yl, (2-methyl-thiazol-4-yl)-thienyl such as 5-(2-methyl-thiazol-4-yl) -Thien-2-yl, (2-methyl-thiazol-4-yl)-pyridyl such as 6-(2-methyl-thiazol-4-yl)-pyridin-3-yl or 2-(2-methyl -Thiazol-4-yl)-pyridin-4-yl, 3-(benzo[1,3]dioxol-5-yl)-phenyl, 4-(benzo[1,3] Dioxol-5-yl)-phenyl, 3-(2,3-dihydrobenzofuran-5-yl)-phenyl, 4-(2,3-dihydrobenzofuran-5 -Yl)-phenyl, 3-(1-methyl-indol-5-yl)-phenyl or 4-(1-methyl-indol-5-yl)-phenyl; or Q1 is 3-[1N-(R61)-pyrazolyl]-phenyl, 4-[1N-(R61)-pyrazolyl]-phenyl, [1N-(R61)-pyrazolyl)-thienyl , [1N-(R61)-pyrazolyl)-pyridyl, 3-[1N-(R61)-triazolyl]-phenyl, or 4-[1N-(R61)-triazolyl]-phenyl , For example like, 3-[1N-(R61)-pyrazol-4-yl]-phenyl, 4-[1N-(R61)-pyrazol-4-yl]-phenyl, [1N-(R61)-pyrazole- 4-yl)-thienyl such as 5-[1N-(R61)-pyrazol-4-yl)-thiophen-2-yl, [1N-(R61)-pyrazol-4-yl)-pyridinyl such as 2 -[1N-(R61)-pyrazol-4-yl)-pyridin-4-yl or 6-[1N-(R61)-pyrazol-4-yl)-pyridin-3-yl, 3-[1N- (R61)-triazol-4-yl]-phenyl or 4-[1N-(R61)-triazol-4-yl]-phenyl, among them R61 is -T2-N(R611)R612, or -T4-Het3, where T2 is dimethylene or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4-methyl-piperidino, T4 tether, methylene, dimethyl or trimethylene, Het3 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl; R7 is a hydroxyl group; And the salts of these compounds.

It is emphasized that the other compounds according to aspect A of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 key; or Q1 is replaced by R61 on the end ring, and is Aa1 or Ah1, where Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, For example like, 3'-(R61)-1,1'-biphenyl-3-yl, 4'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'- Biphenyl-4-yl or 4'-(R61)-1,1'-biphenyl-4-yl, Ah1 is phenyl-thienyl or phenyl-pyridyl, For example like, [3-(R61)-Phenyl]-thienyl, [4-(R61)-phenyl]-thienyl, [3-(R61)-phenyl]-pyridyl or [4-(R61)-benzene Yl]-pyridyl, For example, 5-[3-(R61)-phenyl]-thiophen-2-yl, 5-[4-(R61)-phenyl]-thiophen-2-yl, 2-[3-(R61)-phenyl ]-Pyridin-4-yl, 2-[4-(R61)-phenyl]-pyridin-4-yl, 6-[3-(R61)-phenyl]-pyridin-3-yl or 6-[4 -(R61)-phenyl]-pyridin-3-yl, among them R61 is methoxy, hydroxyl, trifluoromethyl, hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612,- U-T3-N(R613)R614, -T4-Het3, or -V-T5-Het4, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4-methyl-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is dimethylene or trimethylene, R613 is a methyl group, R614 is a methyl group, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino or 4-methyl-piperidino, T4 tether, methylene, dimethyl or trimethylene, Het3 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl, V is -O- (oxygen) or -C(O)NH-, T5 tether, methylene, dimethyl or trimethylene, Het4 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl; or Q1 is replaced by R61 on the end ring, and is Hh1 or Ha1, where Hh1 is pyridyl-thienyl or bipyridyl, For example like, [2-(R61)-pyridin-4-yl]-thienyl or [6-(R61)-pyridin-3-yl]-thienyl, For example, 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6-(R61)-pyridin-3-yl]-thiophen-2-yl, or [2-(R61)-pyridin-4-yl]-pyridyl or [6-(R61)-pyridin-3-yl]-pyridyl, For example, 2-[2-(R61)-pyridin-4-yl]-pyridin-4-yl, 2-[6-(R61)-pyridin-3-yl]-pyridin-4-yl, 6-[2- (R61)-pyridin-4-yl]-pyridin-3-yl or 6-[6-(R61)-pyridin-3-yl]-pyridin-3-yl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, For example like, 3-[2-(R61)-pyridin-4-yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl, 4-[2-(R61)-pyridine-4 -Yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, among them R61 is methoxy or -T2-N(R611)R612, where T2 key, R611 is hydrogen or methyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino; or Q1 is 3-(1-methyl-pyrazolyl)-phenyl, 4-(1-methyl-pyrazolyl)-phenyl, 3-(methyl-thiazolyl)-phenyl, 4-( Methyl-thiazolyl)-phenyl, 3-(dimethyl-isoxazolyl)-phenyl, 4-(dimethyl-isoxazolyl)-phenyl, Methyl-pyrazolyl)-thienyl, (1-methyl-pyrazolyl)-pyridyl, (methyl-thiazolyl)-thienyl, (Methyl-thiazolyl)-pyridyl, 3-(benzo[1,3]dioxolyl)-phenyl, 4-(benzo[1,3]dioxolyl )-Phenyl, 3-(2,3-dihydrobenzofuranyl)-phenyl, 4-(2,3-dihydrobenzofuranyl)-phenyl, 3-(1-methyl-indyl) Dolyl)-phenyl, or 4-(1-methyl-indolyl)-phenyl, For example like, 3-(1-methyl-pyrazol-4-yl)-phenyl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 3-(2-methyl-thiazole-4- Yl)-phenyl, 4-(2-methyl-thiazol-4-yl)-phenyl, 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl, 4-( 3,5-Dimethyl-isoxazol-4-yl)-phenyl, (1-methyl-pyrazol-4-yl)-thienyl such as 5-(1-methyl-pyrazole-4- Yl)-thiophen-2-yl, (1-methyl-pyrazol-4-yl)-pyridyl such as 6-(1-methyl-pyrazol-4-yl)-pyridin-3-yl or 2- (1-Methyl-pyrazol-4-yl)-pyridin-4-yl, (2-methyl-thiazol-4-yl)-thienyl such as 5-(2-methyl-thiazol-4-yl) -Thien-2-yl, (2-methyl-thiazol-4-yl)-pyridyl such as 6-(2-methyl-thiazol-4-yl)-pyridin-3-yl or 2-(2-methyl -Thiazol-4-yl)-pyridin-4-yl, 3-(benzo[1,3]dioxol-5-yl)-phenyl, 4-(benzo[1,3] Dioxol-5-yl)-phenyl, 3-(2,3-dihydrobenzofuran-5-yl)-phenyl, 4-(2,3-dihydrobenzofuran-5 -Radical)-phenyl, 3-(1-methyl-indol-5-yl)-phenyl or 4-(1-methyl-indol-5-yl)-phenyl; or Q1 is 3-[1N-(R61)-pyrazolyl]-phenyl, 4-[1N-(R61)-pyrazolyl]-phenyl, [1N-(R61)-pyrazolyl)-thienyl , [1N-(R61)-pyrazolyl)-pyridyl, 3-[1N-(R61)-triazolyl]-phenyl, or 4-[1N-(R61)-triazolyl]-phenyl , For example like, 3-[1N-(R61)-pyrazol-4-yl]-phenyl, 4-[1N-(R61)-pyrazol-4-yl]-phenyl, [1N-(R61)-pyrazole- 4-yl)-thienyl such as 5-[1N-(R61)-pyrazol-4-yl)-thiophen-2-yl, [1N-(R61)-pyrazol-4-yl)-pyridinyl such as 2 -[1N-(R61)-pyrazol-4-yl)-pyridin-4-yl or 6-[1N-(R61)-pyrazol-4-yl)-pyridin-3-yl, 3-[1N-(R61)-triazol-4-yl]-phenyl or 4-[1N-(R61)-triazol-4-yl]-phenyl, among them R61 is -T2-N(R611)R612, or -T4-Het3, where T2 is dimethylene or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl, 2-methoxyethyl, acetyl or methylsulfonyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4-methyl-piperidino, T4 tether, methylene, dimethyl or trimethylene, Het3 is 1-methyl-piperidinyl or 1-methyl-pyrrolidinyl; R7 is 2-aminophenyl; And the salts of these compounds.

To be more emphasized, the compounds according to aspect A of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; or Q1 is replaced by R61 on the end ring, and is Aa1 or Ah1, where Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, For example like, 3'-(R61)-1,1'-biphenyl-3-yl, 4'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'- Biphenyl-4-yl or 4'-(R61)-1,1'-biphenyl-4-yl, Ah1 is phenyl-thienyl or phenyl-pyridyl, For example like, [3-(R61)-Phenyl]-thienyl, [4-(R61)-phenyl]-thienyl, [3-(R61)-phenyl]-pyridyl or [4-(R61)-benzene Yl]-pyridyl, For example, 5-[3-(R61)-phenyl]-thiophen-2-yl, 5-[4-(R61)-phenyl]-thiophen-2-yl, 2-[3-(R61)-phenyl ]-Pyridin-4-yl, 2-[4-(R61)-phenyl]-pyridin-4-yl, 6-[3-(R61)-phenyl]-pyridin-3-yl or 6-[4 -(R61)-phenyl]-pyridin-3-yl, among them R61 is selected from any one of the following: 3-(line)-4-yl-propyl, 2-(lineline-4-yl-ethyl, 3-(lineline-4-yl-methyl), 3-(4) -Methyl-piperidin-1-yl)-propyl, 2-(4-methyl-piperidin-1-yl)-ethyl, (4-methyl-piperidin-1-yl)-methyl , 3-pyrrolidin-1-yl-propyl, 2-pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-methyl, 3-piperidin-1-yl-propyl, 2-piperidine Pyridin-1-yl-ethyl, piperidin-1-yl-methyl, 3-𠰌line-4-yl-propoxy, 2-𠰌line-4-yl-ethoxy, 3-pyrrolidine- 1-yl-propoxy, 2-pyrrolidin-1-yl-ethoxy, 3-(4-methyl-piper-1-yl)-propoxy, 2-(4-methyl-piper 𠯤-1-yl)-ethoxy, 3-(1-methyl-piperidin-4-yl)-propoxy, 2-(1-methyl-piperidin-4-yl)-ethoxy , 3-piperidin-1-yl-propoxy, 2-piperidin-1-yl-ethoxy, dimethylaminomethyl, 2-dimethylamino-ethyl, 3-dimethyl Amino-propyl, methylsulfamate, dimethylsulfamate, acetamido, amino, dimethylamino, pyrolino, piperidino, pyrrolidine Group, 4-methyl-piperidino, hydroxyl, trifluoromethyl, methoxy, (2-dimethylamino-ethylamino)-carbonyl, (2-methoxy-ethylamine Group) methyl, aminomethyl, acetamido-methyl, methylsulfonylamino-methyl, cyclopentylaminomethyl, cyclopropylaminomethyl and hydroxymethyl; or Q1 is replaced by R61 on the end ring, and is Hh1 or Ha1, where Hh1 is pyridyl-thienyl or bipyridyl, For example like, [2-(R61)-pyridin-4-yl]-thienyl or [6-(R61)-pyridin-3-yl]-thienyl, For example, 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6-(R61)-pyridin-3-yl]-thiophen-2-yl, or [2-(R61)-pyridin-4-yl]-pyridyl or [6-(R61)-pyridin-3-yl]-pyridyl, For example, 2-[2-(R61)-pyridin-4-yl]-pyridin-4-yl, 2-[6-(R61)-pyridin-3-yl]-pyridin-4-yl, 6-[2- (R61)-pyridin-4-yl]-pyridin-3-yl or 6-[6-(R61)-pyridin-3-yl]-pyridin-3-yl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, For example like, 3-[2-(R61)-pyridin-4-yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl, 4-[2-(R61)-pyridine-4 -Yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, among them R61 is selected from any one of the following: methylsulfonylamino, acetylamino, amino, dimethylamino, linolino, piperidino, pyrrolidino, 4 -Methyl-piperidino, hydroxyl, trifluoromethyl and methoxy; or Q1 is 3-(1-methyl-pyrazol-4-yl)-phenyl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 3-(2-methyl-thiazole- 4-yl)-phenyl, 4-(2-methyl-thiazol-4-yl)-phenyl, 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl, 4 -(3,5-Dimethyl-isoxazol-4-yl)-phenyl, (1-methyl-pyrazol-4-yl)-thienyl such as 5-(1-methyl-pyrazole- 4-yl)-thiophen-2-yl, (1-methyl-pyrazol-4-yl)-pyridyl such as 6-(1-methyl-pyrazol-4-yl)-pyridin-3-yl or 2-(1-Methyl-pyrazol-4-yl)-pyridin-4-yl, (2-methyl-thiazol-4-yl)-thienyl such as 5-(2-methyl-thiazole-4- Yl)-thiophen-2-yl, (2-methyl-thiazol-4-yl)-pyridyl such as 6-(2-methyl-thiazol-4-yl)-pyridin-3-yl or 2-(2 -Methyl-thiazol-4-yl)-pyridin-4-yl, 3-(benzo[1,3]dioxol-5-yl)-phenyl, 4-(benzo[1, 3] Dioxol-5-yl)-phenyl, 3-(2,3-dihydrobenzofuran-5-yl)-phenyl, 4-(2,3-dihydrobenzofuran -5-yl)-phenyl, 3-(1-methyl-indol-5-yl)-phenyl, or 4-(1-methyl-indol-5-yl)-phenyl; or Q1 is 3-[1N-(R61)-pyrazol-4-yl]-phenyl, 4-[1N-(R61)-pyrazol-4-yl]-phenyl, [1N-(R61)-pyridine (Azol-4-yl)-thienyl such as 5-[1N-(R61)-pyrazol-4-yl)-thiophen-2-yl, [1N-(R61)-pyrazol-4-yl)-pyridyl For example 2-[1N-(R61)-pyrazol-4-yl)-pyridin-4-yl or 6-[1N-(R61)-pyrazol-4-yl)-pyridin-3-yl, 3-[1N-(R61)-triazol-4-yl]-phenyl, or 4-[1N-(R61)-triazol-4-yl]-phenyl, among them R61 is any one selected from the following: 3-𠰌line-4-yl-propyl, 2-𠰌line-4-yl-ethyl, 3-(4-methyl-piperid-1-yl )-Propyl, 2-(4-methyl-piperidin-1-yl)-ethyl, 3-pyrrolidin-1-yl-propyl, 2-pyrrolidin-1-yl-ethyl, 3- Piperidin-1-yl-propyl, 2-piperidin-1-yl-ethyl, 2-dimethylamino-ethyl and 3-dimethylamino-propyl; R7 is a hydroxyl group; And the salts of these compounds.

To be more emphasized, the compounds according to aspect A of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; or Q1 is replaced by R61 on the end ring, and is Aa1 or Ah1, where Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, For example like, 3'-(R61)-1,1'-biphenyl-3-yl, 4'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'- Biphenyl-4-yl or 4'-(R61)-1,1'-biphenyl-4-yl, Ah1 is phenyl-thienyl or phenyl-pyridyl, For example like, [3-(R61)-Phenyl]-thienyl, [4-(R61)-phenyl]-thienyl, [3-(R61)-phenyl]-pyridyl or [4-(R61)-benzene Yl]-pyridyl, For example, 5-[3-(R61)-phenyl]-thiophen-2-yl, 5-[4-(R61)-phenyl]-thiophen-2-yl, 2-[3-(R61)-phenyl ]-Pyridin-4-yl, 2-[4-(R61)-phenyl]-pyridin-4-yl, 6-[3-(R61)-phenyl]-pyridin-3-yl or 6-[4 -(R61)-phenyl]-pyridin-3-yl, among them R61 is selected from any one of the following: 3-(line)-4-yl-propyl, 2-(lineline-4-yl-ethyl, 3-(lineline-4-yl-methyl), 3-(4) -Methyl-piperidin-1-yl)-propyl, 2-(4-methyl-piperidin-1-yl)-ethyl, (4-methyl-piperidin-1-yl)-methyl , 3-pyrrolidin-1-yl-propyl, 2-pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-methyl, 3-piperidin-1-yl-propyl, 2-piperidine Pyridin-1-yl-ethyl, piperidin-1-yl-methyl, 3-𠰌line-4-yl-propoxy, 2-𠰌line-4-yl-ethoxy, 3-pyrrolidine- 1-yl-propoxy, 2-pyrrolidin-1-yl-ethoxy, 3-(4-methyl-piper-1-yl)-propoxy, 2-(4-methyl-piper 𠯤-1-yl)-ethoxy, 3-(1-methyl-piperidin-4-yl)-propoxy, 2-(1-methyl-piperidin-4-yl)-ethoxy , 3-piperidin-1-yl-propoxy, 2-piperidin-1-yl-ethoxy, dimethylaminomethyl, 2-dimethylamino-ethyl, 3-dimethyl Amino-propyl, methylsulfamate, dimethylsulfamate, acetamido, amino, dimethylamino, pyrolino, piperidino, pyrrolidine Group, 4-methyl-piperidino, hydroxyl, trifluoromethyl, methoxy, (2-dimethylamino-ethylamino)-carbonyl, (2-methoxy-ethylamine Group) methyl, aminomethyl, acetamido-methyl, methylsulfonylamino-methyl, cyclopentylaminomethyl, cyclopropylaminomethyl and hydroxymethyl; or Q1 is replaced by R61 on the end ring, and is Hh1 or Ha1, where Hh1 is pyridyl-thienyl or bipyridyl, For example like, [2-(R61)-pyridin-4-yl]-thienyl or [6-(R61)-pyridin-3-yl]-thienyl, For example, 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6-(R61)-pyridin-3-yl]-thiophen-2-yl, or [2-(R61)-pyridin-4-yl]-pyridyl or [6-(R61)-pyridin-3-yl]-pyridyl, For example, 2-[2-(R61)-pyridin-4-yl]-pyridin-4-yl, 2-[6-(R61)-pyridin-3-yl]-pyridin-4-yl, 6-[2- (R61)-pyridin-4-yl]-pyridin-3-yl or 6-[6-(R61)-pyridin-3-yl]-pyridin-3-yl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, For example like, 3-[2-(R61)-pyridin-4-yl]-phenyl, 3-[6-(R61)-pyridin-3-yl]-phenyl, 4-[2-(R61)-pyridine-4 -Yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, among them R61 is selected from any one of the following: methylsulfonylamino, acetylamino, amino, dimethylamino, linolino, piperidino, pyrrolidino, 4 -Methyl-piperidino, hydroxyl, trifluoromethyl and methoxy; or Q1 is 3-(1-methyl-pyrazol-4-yl)-phenyl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 3-(2-methyl-thiazole- 4-yl)-phenyl, 4-(2-methyl-thiazol-4-yl)-phenyl, 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl, 4 -(3,5-Dimethyl-isoxazol-4-yl)-phenyl, (1-methyl-pyrazol-4-yl)-thienyl such as 5-(1-methyl-pyrazole- 4-yl)-thiophen-2-yl, (1-methyl-pyrazol-4-yl)-pyridyl such as 6-(1-methyl-pyrazol-4-yl)-pyridin-3-yl or 2-(1-Methyl-pyrazol-4-yl)-pyridin-4-yl, (2-methyl-thiazol-4-yl)-thienyl such as 5-(2-methyl-thiazole-4- Yl)-thiophen-2-yl, (2-methyl-thiazol-4-yl)-pyridyl such as 6-(2-methyl-thiazol-4-yl)-pyridin-3-yl or 2-(2 -Methyl-thiazol-4-yl)-pyridin-4-yl, 3-(benzo[1,3]dioxol-5-yl)-phenyl, 4-(benzo[1, 3] Dioxol-5-yl)-phenyl, 3-(2,3-dihydrobenzofuran-5-yl)-phenyl, 4-(2,3-dihydrobenzofuran -5-yl)-phenyl, 3-(1-methyl-indol-5-yl)-phenyl, or 4-(1-methyl-indol-5-yl)-phenyl; or Q1 is 3-[1N-(R61)-pyrazol-4-yl]-phenyl, 4-[1N-(R61)-pyrazol-4-yl]-phenyl, [1N-(R61)-pyrazol-4-yl)-thienyl such as 5-[1N-(R61)-pyrazol-4-yl)-thiophen-2-yl, [1N-(R61)-pyrazol-4-yl)-pyridinyl such as 2-[1N-(R61)-pyrazol-4-yl)-pyridin-4-yl or 6-[1N-(R61)- Pyrazol-4-yl)-pyridin-3-yl, 3-[1N-(R61)-triazol-4-yl]-phenyl, or 4-[1N-(R61)-triazol-4-yl ]-Phenyl, among them R61 is any one selected from the following: 3-𠰌line-4-yl-propyl, 2-𠰌line-4-yl-ethyl, 3-(4-methyl-piperid-1-yl )-Propyl, 2-(4-methyl-piperidin-1-yl)-ethyl, 3-pyrrolidin-1-yl-propyl, 2-pyrrolidin-1-yl-ethyl, 3- Piperidin-1-yl-propyl, 2-piperidin-1-yl-ethyl, 2-dimethylamino-ethyl and 3-dimethylamino-propyl; R7 is 2-aminophenyl; And the salts of these compounds.

To be more emphasized, the compounds according to aspect A of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; Q1 is selected from any of the following groups: 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-4-yl, 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-3-yl, 4' -(2-𠰌olin-4-yl-ethyl)-biphenyl-4-yl, 4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 3'-( 𠰌olin-4-yl-methyl)-biphenyl-3-yl, 4'-(𠰌lin-4-yl-methyl)-biphenyl-3-yl, 3'-(𠰌olin-4-yl) -Methyl)-Biphenyl-4-yl, 4'-(𠰌olin-4-yl-methyl)-biphenyl-4-yl, 4'-(3-𠰌olin-4-yl-propyl) -Biphenyl-3-yl, 4'-(3-𠰌olin-4-yl-propyl)-biphenyl-4-yl, 3'-(3-𠰌olin-4-yl-propyl)-bi Phen-3-yl, 3'-(3-𠰌lin-4-yl-propyl)-biphenyl-4-yl, 4'-(4-methyl-piperid-1-ylmethyl)-bi Phen-3-yl, 4'-(4-methyl-piper-1-ylmethyl)-biphenyl-4-yl, 3'-(4-methyl-piper-1-ylmethyl) -Biphenyl-3-yl, 3'-(4-methyl-piper-1-ylmethyl)-biphenyl-4-yl, 4'-(2-𠰌olin-4-yl-ethoxy )-Biphenyl-3-yl, 4'-(2-𠰌olin-4-yl-ethoxy)-biphenyl-4-yl, 3'-(2-𠰌olin-4-yl-ethoxy )-Biphenyl-3-yl, 3'-(2-𠰌olin-4-yl-ethoxy)-biphenyl-4-yl, 4'-(3-𠰌olin-4-yl-propoxy )-Biphenyl-3-yl, 4'-(3-𠰌olin-4-yl-propoxy)-biphenyl-4-yl, 3'-(3-𠰌olin-4-yl-propoxy )-Biphenyl-3-yl, 3'-(3-𠰌lin-4-yl-propoxy)-biphenyl-4-yl, 4'-[2-(4-methyl-piper𠯤-1 -Yl)-ethoxy]-biphenyl-3-yl, 4'-[2-(4-methyl-piperid-1-yl)-ethoxy]-biphenyl-4-yl, 3' -[2-(4-Methyl-piperidin-1-yl)-ethoxy]-biphenyl-3-yl, 3'-[2-(4-methyl-piperidin-1-yl)- Ethoxy]-biphenyl-4-yl, 4'-(2-pyrrolidin-1-yl-ethoxy]-biphenyl-3-yl, 4'-(2-pyrrolidin-1-yl- Ethoxy]-biphenyl-4-yl, 3'-(2-pyrrolidin-1-yl-ethoxy]-biphenyl-3-yl, 3'-(2-pyrrolidin-1-yl- Ethoxy]-biphenyl-4-yl, 3'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-4-yl, 4'-(3-pyrrolidin-1-yl- Propoxy]-biphenyl-4-yl, 3'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-3-yl, 4'-(3-pyrrolidin-1-yl- Propoxy]-biphenyl-3-yl, 4'-[3-(4-methyl-piperid-1-yl)-propoxy]-biphenyl-4-yl, 3'-[3- (4-Methyl-piperidin-1-yl)-propoxy]-biphenyl-4-yl, 4'-[3-(4-methyl-piperidin-1 -Yl)-propoxy]-biphenyl-3-yl, 3’-[3-(4-methyl-piperid-1-yl)-propoxy]-biphenyl-3-yl, 4'-(2-(1-methyl-piperidin-4-yl)-ethoxy)-biphenyl-4-yl, 4'-(2-(1-methyl-piperidin-4-yl) )-Ethoxy)-biphenyl-3-yl, 3'-(2-(1-methyl-piperidin-4-yl)-ethoxy)-biphenyl-4-yl, 3'-(2-(1-methyl-piperidin-4-yl) )-Ethoxy)-biphenyl-3-yl, 2'-Dimethylaminomethyl-biphenyl-4-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 2'-dimethylaminomethyl-biphenyl- 3-yl, 4'-dimethylaminomethyl-biphenyl-3-yl, 3'-dimethylaminomethyl-biphenyl-4-yl, 3'-dimethylaminomethyl -Biphenyl-3-yl, 3'-[(2-dimethylamino-ethylamino)-carbonyl]-biphenyl-4-yl, 4'-[(2-dimethylamino- Ethylamino)-carbonyl]-biphenyl-4-yl, 4'-[(2-dimethylamino-ethylamino)-carbonyl]-biphenyl-3-yl, 3'-[( 2-Dimethylamino-ethylamino)-carbonyl]-biphenyl-3-yl, 2'-methylsulfonylamino-biphenyl-4-yl, 3'-methylsulfonyl Amino-biphenyl-4-yl, 4'-methylsulfonylamino-biphenyl-4-yl, 2'-methylsulfonylamino-biphenyl-3-yl, 3'-methyl Sulfonylamino-biphenyl-3-yl, 4'-methylsulfonylamino-biphenyl-3-yl, 4'-methylsulfonylamino-biphenyl-3-yl, 4'-Dimethylsulfasulfonyl-biphenyl-4-yl, 4'-dimethylsulfasulfonyl-biphenyl-3-yl, 3'-dimethylsulfasulfonyl-biphenyl- 4-yl, 3'-dimethylsulfamoyl-biphenyl-3-yl, 3'-acetamido-biphenyl-4-yl, 4'-acetamido-biphenyl-4- Group, 3'-acetamido-biphenyl-3-yl, 4'-acetamido-biphenyl-3-yl, 3'-amino-biphenyl-4-yl, 3'-dimethyl Amino-biphenyl-4-yl, 4'-𠰌lin-4-yl-biphenyl-4-yl, 4'-hydroxy-biphenyl-4-yl, 3'-trifluoromethyl-biphenyl -4-yl, 4'-methoxy-biphenyl-4-yl, 3'-amino-biphenyl-3-yl, 3'-dimethylamino-biphenyl-3-yl, 4' -𠰌lin-4-yl-biphenyl-3-yl, 4'-hydroxy-biphenyl-3-yl, 3'-trifluoromethyl-biphenyl-3-yl, 4'-methoxy-biphenyl Phen-3-yl, 4'-amino-biphenyl-4-yl, 4'-dimethylamino-biphenyl-4-yl, 3'-𠰌lin-4-yl-biphenyl-4- Group, 3'-hydroxy-biphenyl-4-yl, 4'-trifluoromethyl-biphenyl-4-yl, 3'-methoxy-biphenyl-4-yl, 4'-amino-biphenyl Phen-3-yl, 4'-dimethylamino-biphenyl-3-yl, 3'-𠰌lin-4-yl-biphenyl-3-yl, 3'-hydroxy-biphenyl-3-yl , 4'-trifluoromethyl-biphenyl-3-yl and 3'-methoxy-biphenyl-3-yl, 4'-(2-methoxy-ethylamino)methyl-biphenyl-3-yl, 4'-(2-methoxy-ethylamino)methyl-biphenyl-4-yl, 3'-(2-methoxy-ethylamino)methyl-biphenyl-3-yl, 3'-(2-methoxy-ethylamino)methyl-biphenyl-4-yl, 4'-aminomethyl-biphenyl-3-yl, 4'-aminomethyl-biphenyl-4-yl, 3'-aminomethyl-biphenyl-3-yl, 3'-amino Methyl-biphenyl-4-yl, 4'-(acetamido)-methyl-biphenyl-4-yl, 4'-(methylsulfonylamino)-methyl-biphenyl- 4-yl, 3'-(acetamido)-methyl-biphenyl-3-yl, 3'-(methylsulfonylamino)-methyl-biphenyl-3-yl, 4' -(Acetylamino)-Methyl-Biphenyl-3-yl, 4'-(Methylsulfonylamino)-Methyl-Biphenyl-3-yl, 3'-(Acetylamine Yl)-methyl-biphenyl-4-yl, 3'-(methylsulfonylamino)-methyl-biphenyl-4-yl, 4'-cyclopentylaminomethyl-biphenyl- 4-yl, 4'-cyclopentylaminomethyl-biphenyl-3-yl, 3'-cyclopentylaminomethyl-biphenyl-4-yl, 3'-cyclopentylaminomethyl -Biphenyl-3-yl, 4'-cyclopropylaminomethyl-biphenyl-3-yl, 4'-cyclopropylaminomethyl-biphenyl-4-yl, 3'-cyclopropyl Aminomethyl-biphenyl-3-yl, 3'-cyclopropylaminomethyl-biphenyl-4-yl, 3'-hydroxymethyl-biphenyl-4-yl, 3'-hydroxymethyl -Biphenyl-3-yl, 4'-hydroxymethyl-biphenyl-4-yl, 4'-hydroxymethyl-biphenyl-3-yl, 5-[2-(4-methyl-piperidin-1-yl)-pyridine-4 -Yl]-thiophen-2-yl, 5-(1-methyl-pyrazol-4-yl)-thiophen-2-yl, 6-(1-methyl-pyrazol-4-yl)-pyridine- 3-base, 2'-(4-Methyl-piperidin-1-yl)-2,4'-bipyridin-5-yl, 5-(2-methyl-thiazol-4-yl)-thiophen-2-yl, 5-[4-(2-𠰌olin-4-yl-ethyl)-phenyl]-thiophen-2-yl, 5-[3-(2-𠰌olin-4-yl-ethyl)-phenyl ]-Thiophen-2-yl, 5-[4-(𠰌line-4-yl-methyl)-phenyl]-thiophen-2-yl, 5-[3-(𠰌line-4-yl-methyl)-phenyl]-thiophene- 2-base, 5-[4-(2-𠰌olin-4-yl-ethoxy)-phenyl]-thiophen-2-yl, 5-[3-(2-𠰌olin-4-yl-ethoxy)- Phenyl]-thiophen-2-yl, 5-[4-(3-𠰌olin-4-yl-propoxy)-phenyl]-thiophen-2-yl, 5-[3-(3-𠰌line -4-yl-propoxy)-phenyl]-thiophen-2-yl, 5-{4-[2-(4-methyl-piperid-1-yl)-ethoxy]-phenyl} -Thien-2-yl, 5-{3-[2-(4-methyl-piperid-1-yl)-ethoxy]-phenyl}-thiophen-2-yl, 5-[4-( 2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiophen-2-yl, 5-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiophene- 2-yl, 5-(4-dimethylaminomethyl-phenyl)-thiophen-2-yl, 5-(3-dimethylaminomethyl-phenyl)-thiophen-2-yl, 6-(4-Dimethylaminomethyl-phenyl)-pyridin-3-yl, 6-(3-dimethylaminomethyl-phenyl)-pyridin-3-yl, 6-[4 -(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-3-yl, 6-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- Pyridin-3-yl, 5-(3-aminomethyl-phenyl)-thiophen-2-yl, 5-[3-(acetamido)-methyl-phenyl]-thiophen-2- Group, 5-[3-(Methylsulfamylamino)-methyl-phenyl]-thiophen-2-yl, 5-(4-Dimethylsulfamyl-phenyl)-thiophene-2 -Yl, 5-(4-aminomethyl-phenyl)-thiophen-2-yl, 5-[4-(acetamido)-methyl-phenyl]-thiophen-2-yl, 5 -[4-(Methylsulfonylamino)-methyl-phenyl]-thiophen-2-yl, 5-(3-dimethylsulfamoyl-phenyl)-thiophen-2-yl, 4-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl]-phenyl, 3-[2-(4-methyl-piperidin-1-yl)-pyridine- 4-yl)-phenyl, 4-(6-amino-pyridin-3-yl)-phenyl, 3-(6-amino-pyridin-3-yl)-phenyl, 4-(6-methyl Oxy-pyridin-3-yl)-phenyl, 3-(6-methoxy-pyridin-3-yl)-phenyl, 3-(1-methyl-pyrazol-4-yl)-phenyl , 4-(1-methyl-pyrazol-4-yl)-phenyl, 4-(3,5-dimethyl-isoxazol-4-yl)-phenyl, 3-(3,5- Dimethyl-isoxazol-4-yl)-phenyl, 4-(1-methyl-indol-5-yl)-phenyl, 3-(1-methyl-indol-5-yl) -Phenyl, 4-{1-(2-𠰌line-4-yl-ethyl)-[1,2,3]triazol-4-yl}-phenyl, 4-{1-(2-piperidine-1- -Ethyl)-[1,2,3]triazol-4-yl}-phenyl, 3-{1-(2-𠰌olin-4-yl-ethyl)-[1,2,3] Triazol-4-yl}-phenyl, 3-{1-(2-piperidin-1-yl-ethyl)-[1,2,3]triazol-4-yl}-phenyl, 4- (2,3-Dihydrobenzofuran-5-yl)-phenyl, and 4-(benzo[1,3]dioxol-5-yl)-phenyl, 3-(2, 3-dihydrobenzofuran-5-yl)-phenyl, and 3-(benzo[1,3]dioxol-5-yl)-phenyl, R7 is a hydroxyl group, And the salts of these compounds.

To be more emphasized, the compounds according to aspect A of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; Q1 is selected from any of the following groups: 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-4-yl, 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-3-yl, 4' -(2-𠰌olin-4-yl-ethyl)-biphenyl-4-yl, 4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 3'-( 𠰌olin-4-yl-methyl)-biphenyl-3-yl, 4'-(𠰌lin-4-yl-methyl)-biphenyl-3-yl, 3'-(𠰌olin-4-yl -Methyl)-Biphenyl-4-yl, 4'-(𠰌olin-4-yl-methyl)-biphenyl-4-yl, 4'-(3-𠰌olin-4-yl-propyl) -Biphenyl-3-yl, 4'-(3-𠰌olin-4-yl-propyl)-biphenyl-4-yl, 3'-(3-𠰌olin-4-yl-propyl)-bi Phen-3-yl, 3'-(3-𠰌lin-4-yl-propyl)-biphenyl-4-yl, 4'-(4-Methyl-piperidin-1-ylmethyl)-biphenyl-3-yl, 4'-(4-methyl-piperidin-1-ylmethyl)-biphenyl-4- base, 3'-(4-Methyl-piperid-1-ylmethyl)-biphenyl-3-yl, 3'-(4-methyl-piperid-1-ylmethyl)-biphenyl-4- base, 4'-(2-𠰌line-4-yl-ethoxy)-biphenyl-3-yl, 4'-(2-𠰌line-4-yl-ethoxy)-biphenyl-4-yl, 3'-(2-𠰌line-4-yl-ethoxy)-biphenyl-3-yl, 3'-(2-𠰌line-4-yl-ethoxy)-biphenyl-4-yl, 4'-(3-𠰌line-4-yl-propoxy)-biphenyl-3-yl, 4'-(3-𠰌line-4-yl-propoxy)-biphenyl-4-yl, 3'-(3-𠰌line-4-yl-propoxy)-biphenyl-3-yl, 3'-(3-𠰌line-4-yl-propoxy)-biphenyl-4-yl, 4'-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-biphenyl-3-yl, 4'-[2-(4-methyl-piperidin-1-yl) )-Ethoxy]-biphenyl-4-yl, 3'-[2-(4-methyl-piperid-1-yl)-ethoxy]-biphenyl-3-yl, 3'-[ 2-(4-Methyl-piperidin-1-yl)-ethoxy]-biphenyl-4-yl, 4'-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-3 -Yl, 4'-(2-pyrrolidin-1-yl-ethoxy]-biphenyl-4-yl, 3'-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-3 -Yl, 3'-(2-pyrrolidin-1-yl-ethoxy]-biphenyl-4-yl, 3'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-4 -Yl, 4'-(3-pyrrolidin-1-yl-propoxy]-biphenyl-4-yl, 3'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-3 -Radical, 4'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-3-yl, 4'-[3-(4-Methyl-piperidin-1-yl)-propoxy]-biphenyl-4-yl, 3'-[3-(4-methyl-piperidin-1-yl) )-Propoxy]-biphenyl-4-yl, 4'-[3-(4-methyl-piperid-1-yl)-propoxy]-biphenyl-3-yl, 3'-[ 3-(4-Methyl-piperidin-1-yl)-propoxy)-biphenyl-3-yl, 4'-(2-(1-methyl-piperidin-4-yl)-ethoxy Yl)-biphenyl-4-yl, 4'-(2-(1-methyl-piperidin-4-yl)-ethoxy)-biphenyl-3-yl, 3'-(2-(1 -Methyl-piperidin-4-yl)-ethoxy)-biphenyl-4-yl, 3'-(2-(1-methyl-piperidin-4-yl)-ethoxy)-biphenyl Phen-3-yl, 2'-dimethylaminomethyl-biphenyl-4-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 2'-dimethylamino Methyl-biphenyl-3-yl, 4'-dimethylaminomethyl-biphenyl-3-yl, 3'-dimethylaminomethyl-biphenyl-4-yl, 3'-di Methylaminomethyl-biphenyl-3-yl, 3'-[(2-dimethylamino-ethylamino)-carbonyl]-biphenyl-4-yl, 4'-[(2- Dimethylamino-ethylamino)-carbonyl]-biphenyl-4-yl, 4'-[(2-dimethylamino-ethylamino)-carbonyl]-biphenyl-3-yl , 3'-[(2-Dimethylamino-ethylamino)-carbonyl]-biphenyl-3-yl, 2'-Methylsulfonylamino-biphenyl-4-yl, 3'-methylsulfonylamino-biphenyl-4-yl, 4'-methylsulfonylamino-biphenyl- 4-yl, 2'-methylsulfonylamino-biphenyl-3-yl, 3'-methylsulfonylamino-biphenyl-3-yl, 4'-methylsulfonylamino -Biphenyl-3-yl, 4'-methylsulfonylamino-biphenyl-3-yl, 4'-Dimethylsulfasulfonyl-biphenyl-4-yl, 4'-dimethylsulfasulfonyl-biphenyl-3-yl, 3'-dimethylsulfasulfonyl-biphenyl- 4-yl, 3'-dimethylsulfamoyl-biphenyl-3-yl, 3'-acetamido-biphenyl-4-yl, 4'-acetamido-biphenyl-4- Group, 3'-acetamido-biphenyl-3-yl, 4'-acetamido-biphenyl-3-yl, 3'-amino-biphenyl-4-yl, 3'-dimethyl Amino-biphenyl-4-yl, 4'-𠰌lin-4-yl-biphenyl-4-yl, 4'-hydroxy-biphenyl-4-yl, 3'-trifluoromethyl-biphenyl -4-yl, 4'-methoxy-biphenyl-4-yl, 3'-amino-biphenyl-3-yl, 3'-dimethylamino-biphenyl-3-yl, 4' -𠰌lin-4-yl-biphenyl-3-yl, 4'-hydroxy-biphenyl-3-yl, 3'-trifluoromethyl-biphenyl-3-yl, 4'-methoxy-biphenyl Phen-3-yl, 4'-amino-biphenyl-4-yl, 4'-dimethylamino-biphenyl-4-yl, 3'-𠰌lin-4-yl-biphenyl-4- Group, 3'-hydroxy-biphenyl-4-yl, 4'-trifluoromethyl-biphenyl-4-yl, 3'-methoxy-biphenyl-4-yl, 4'-amino-biphenyl Phen-3-yl, 4'-dimethylamino-biphenyl-3-yl, 3'-𠰌lin-4-yl-biphenyl-3-yl, 3'-hydroxy-biphenyl-3-yl , 4'-Trifluoromethyl-biphenyl-3-yl and 3'-methoxy-biphenyl-3-yl, 4'-(2-methoxy-ethylamino)methyl-biphenyl -3-yl, 4'-(2-methoxy-ethylamino)methyl-biphenyl-4-yl, 3'-(2-methoxy-ethylamino)methyl-biphenyl -3-yl, 3'-(2-methoxy-ethylamino) methyl-biphenyl-4-yl, 4'-aminomethyl-biphenyl-3-yl, 4'-amino Methyl-biphenyl-4-yl, 3'-aminomethyl-biphenyl-3-yl, 3'-aminomethyl-biphenyl-4-yl, 4'-(acetamido) -Methyl-biphenyl-4-yl, 4'-(methylsulfonylamino)-methyl-biphenyl-4-yl, 3'-(acetamido)-methyl-biphenyl -3-yl, 3'-(methylsulfonylamino)-methyl-biphenyl-3-yl, 4'-(acetamido)-methyl-biphenyl-3-yl, 4 '-(Methylsulfonylamino)-methyl-biphenyl-3-yl, 3'-(acetamido)-methyl-biphenyl-4-yl, 3'-(methylsulfonyl (Amino)-methyl-biphenyl-4-yl, 4'-cyclopentylaminomethyl-biphenyl-4-yl, 4'-cyclopentylaminomethyl-biphenyl-3- Group, 3'-cyclopentylaminomethyl-biphenyl-4-yl, 3'-cyclopentylaminomethyl-biphenyl-3-yl, 4'-cyclopropylaminomethyl-biphenyl Phen-3-yl, 4'-cyclopropylaminomethyl-biphenyl-4-yl, 3'-cyclopropylaminomethyl-biphenyl-3-yl, 3'-cyclopropylamino Methyl-biphenyl-4-yl, 3'-hydroxymethyl-biphenyl-4-yl, 3'-hydroxymethyl-biphenyl-3-yl, 4'-hydroxymethyl-biphenyl-4-yl, 4'-hydroxymethyl-biphenyl-3-yl, 5-[2-(4-methyl-piperidin-1-yl)-pyridine-4 -Yl]-thiophen-2-yl, 5-(1-methyl-pyrazol-4-yl)-thiophen-2-yl, 6-(1-methyl-pyrazol-4-yl)-pyridine- 3-base, 2’-(4-Methyl-piperidin-1-yl)-2,4’-bipyridin-5-yl, 5-(2-methyl-thiazol-4-yl)-thiophen-2-yl, 5-[4-(2-𠰌olin-4-yl-ethyl)-phenyl]-thiophen-2-yl, 5-[3-(2-𠰌olin-4-yl-ethyl)-phenyl ]-Thiophen-2-yl, 5-[4-(𠰌line-4-yl-methyl)-phenyl]-thiophen-2-yl, 5-[3-(𠰌line-4-yl-methyl)-phenyl]-thiophene- 2-base, 5-[4-(2-𠰌olin-4-yl-ethoxy)-phenyl]-thiophen-2-yl, 5-[3-(2-𠰌olin-4-yl-ethoxy)- Phenyl]-thiophen-2-yl, 5-[4-(3-𠰌olin-4-yl-propoxy)-phenyl]-thiophen-2-yl, 5-[3-(3-𠰌line -4-yl-propoxy)-phenyl]-thiophen-2-yl, 5-{4-[2-(4-methyl-piperid-1-yl)-ethoxy]-phenyl} -Thien-2-yl, 5-{3-[2-(4-methyl-piperid-1-yl)-ethoxy]-phenyl}-thiophen-2-yl, 5-[4-( 2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiophen-2-yl, 5-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiophene- 2-yl, 5-(4-dimethylaminomethyl-phenyl)-thiophen-2-yl, 5-(3-dimethylaminomethyl-phenyl)-thiophen-2-yl, 6-(4-Dimethylaminomethyl-phenyl)-pyridin-3-yl, 6-(3-dimethylaminomethyl-phenyl)-pyridin-3-yl, 6-[4 -(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-3-yl, 6-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- Pyridin-3-yl, 5-(3-aminomethyl-phenyl)-thiophen-2-yl, 5-[3-(acetamido)-methyl-phenyl]-thiophen-2- Group, 5-[3-(Methylsulfamylamino)-methyl-phenyl]-thiophen-2-yl, 5-(4-Dimethylsulfamyl-phenyl)-thiophene-2 -Yl, 5-(4-aminomethyl-phenyl)-thiophen-2-yl, 5-[4-(acetamido)-methyl-phenyl]-thiophen-2-yl, 5 -[4-(Methylsulfonylamino)-methyl-phenyl]-thiophen-2-yl, 5-(3-dimethylsulfamoyl-phenyl)-thiophen-2-yl, 4-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl]-phenyl, 3-[2-(4-methyl-piperidin-1-yl)-pyridine- 4-yl)-phenyl, 4-(6-amino-pyridin-3-yl)-phenyl, 3-(6-amino-pyridin-3-yl)-phenyl, 4-(6-methyl Oxy-pyridin-3-yl)-phenyl, 3-(6-methoxy-pyridin-3-yl)-phenyl, 3-(1-methyl-pyrazol-4-yl)-phenyl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 4-(3,5-dimethyl-iso Azol-4-yl)-phenyl, 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl, 4-(1-methyl-indol-5-yl)- Phenyl, 3-(1-methyl-indol-5-yl)-phenyl, 4-{1-(2-𠰌line-4-yl-ethyl)-[1,2,3]triazol-4-yl}-phenyl, 4-{1-(2-piperidine-1- -Ethyl)-[1,2,3]triazol-4-yl}-phenyl, 3-{1-(2-𠰌olin-4-yl-ethyl)-[1,2,3] Triazol-4-yl}-phenyl, 3-{1-(2-piperidin-1-yl-ethyl)-[1,2,3]triazol-4-yl}-phenyl, 4- (2,3-Dihydrobenzofuran-5-yl)-phenyl, and 4-(benzo[1,3]dioxol-5-yl)-phenyl, 3-(2, 3-dihydrobenzofuran-5-yl)-phenyl, and 3-(benzo[1,3]dioxol-5-yl)-phenyl, R7 is 2-aminophenyl, And the salts of these compounds.

To be more emphasized, the compounds according to aspect B of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are independently hydrogen or 1-4C-alkyl, R6 Department-T1-Q1, where T1 is a key; or Q1 is replaced by R61 and/or R62 and is Aa1, Hh1, Ha1, Ha2, Ha3 or Ah1, Or Q1 is unsubstituted and is Ha2 or Ha3, among them R61 is 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy-1-4C-alkyl, 1-4C-alkylsulfonylamino, tosylsulfonylamino, phenyl Sulfonylamino, 1-4C-alkylcarbonylamino, di-1-4C-alkylaminosulfonyl, -T2-N(R611)R612, or -U-T3-N(R613)R614 ,among them T2 bond or 1-4C-alkylene, R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-2-4C-alkyl, R612 is hydrogen or 1-4C-alkyl, Or R611 and R612 together and including the nitrogen atom to which they are combined form a heterocyclic Het1, where Het1 is a linolino, piperidino, pyrrolidino, piperidino or 4N-(1-4C-alkane基)-piperazino group, U is -O- (oxygen) or -C(O)NH-, T3 is 2-4C-alkylene, R613 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-2-4C-alkyl, R614 is hydrogen or 1-4C-alkyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-4C-alkyl)-piperidino, R62 is 1-4C-alkyl, Aa1 is biphenyl, Hh1 is a diheteroaryl group composed of two heteroaryl groups, The heteroaryl groups are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms, each of which is selected from nitrogen and oxygen And sulfur, and these heteroaryl groups are connected together by a single bond, Ah1 is a phenyl-heteroaryl group consisting of a phenyl group and a heteroaryl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms Groups, whereby the phenyl and heteroaryl groups are linked together by a single bond, and thus Ah1 is bonded to the parent molecular group by the heteroaryl moiety, each of these heteroatoms Selected from the group consisting of nitrogen, oxygen and sulfur, Ha1 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms Groups, whereby the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha1 is bonded to the parent molecular group by the phenyl moiety, each of these heteroatoms is selected The group of free nitrogen, oxygen and sulfur, Ha2 is a heteroaryl group selected from the group consisting of a fused bicyclic 9- or 10-membered heteroaryl group including one, two or three heteroatoms and a phenyl group A group-phenyl group, whereby the heteroaryl group and the phenyl group are linked together by a single bond, and thus Ha2 is bonded to the parent molecular group through the phenyl moiety, these heteroatoms Each of them is selected from the group consisting of nitrogen, oxygen and sulfur, Ha3 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5-membered heteroaryl groups including three or four heteroatoms, Thus the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha3 is bonded to the parent molecular group via the phenyl moiety, each of these heteroatoms is selected from nitrogen , Oxygen and sulfur, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

To be more emphasized, the compounds according to aspect B of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; Q1 is replaced by R61 and/or R62 on the end ring and is Aa1, Hh1, Ha1, Ha2 or Ah1, among them R61 is 1-2C-alkyl, 1-2C-alkoxy, halogen, hydroxy-1-2C-alkyl, 1-2C-alkylsulfonylamino, 1-2C-alkylcarbonylamino, Di-1-2C-alkylaminosulfonyl, -T2-N(R611)R612, or -U-T3-N(R613)R614, where T2 bond or straight chain 1-4C-alkylene, R611 is hydrogen, 1-2C-alkyl, 3-5C-cycloalkyl or 1-2C-alkoxy-2-3C-alkyl, R612 is hydrogen or 1-2C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-2C-alkyl)-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is a linear 2-4C-alkylene group, R613 is hydrogen, 1-2C-alkyl, 3-5C-cycloalkyl or 1-2C-alkoxy-2-3C-alkyl, R614 is hydrogen or 1-2C-alkyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-4C-alkyl)-piperidino, R62 is 1-2C-alkyl, Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, Hh1 is a bi-heteroaryl group consisting of heteroaryl groups and thienyl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms, Thus the heteroaryl and thienyl groups are linked together by a single bond, and thus Hh1 is bonded to the parent molecular group via the thienyl moiety, and each of these heteroatoms is selected from nitrogen , Oxygen and sulfur, Ah1 is phenyl-thienyl, Ha1 is a 3-(heteroaryl group) each consisting of a heteroaryl group and a phenyl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms )-Phenyl or 4-(heteroaryl)-phenyl group, whereby the heteroaryl group and the phenyl group are connected together by a single bond, and thus Hal is connected to the phenyl group by the phenyl moiety The parent molecular group is bonded, and each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha2 is each composed of a heteroaryl group and a phenyl group selected from the group consisting of a fused bicyclic 9- or 10-membered heteroaryl group including one or two heteroatoms and a phenyl group. Aryl)-phenyl or 4-(heteroaryl)-phenyl groups, whereby the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha2 is through the phenyl Partly bonded to the parent molecular group, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

To be more emphasized, the compounds according to aspect B of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; Q1 is replaced by R61 and/or R62 on the end ring and is Aa1, Hh1, Ha1, Ha2 or Ah1, among them R61 is 1-2C-alkyl, 1-2C-alkoxy, hydroxy, trifluoromethyl, halogen, hydroxy-1-2C-alkyl, 1-2C-alkylsulfonylamino, 1-2C -Alkylcarbonylamino, di-1-2C-alkylaminosulfonyl, -T2-N(R611)R612, or -U-T3-N(R613)R614, wherein T2 bond or straight chain 1-4C-alkylene, R611 is hydrogen, 1-2C-alkyl, 3-5C-cycloalkyl or 1-2C-alkoxy-2-3C-alkyl, R612 is hydrogen or 1-2C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-2C-alkyl)-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is a linear 2-4C-alkylene group, R613 is hydrogen, 1-2C-alkyl, 3-5C-cycloalkyl or 1-2C-alkoxy-2-3C-alkyl, R614 is hydrogen or 1-2C-alkyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4N-(1-4C-alkyl)-piperidino, R62 is 1-2C-alkyl, Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, Hh1 is a bi-heteroaryl group consisting of heteroaryl groups and thienyl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms, Thus the heteroaryl and thienyl groups are linked together by a single bond, and thus Hh1 is bonded to the parent molecular group via the thienyl moiety, and each of these heteroatoms is selected from nitrogen , Oxygen and sulfur, Ah1 is phenyl-thienyl or phenyl-pyridyl, Ha1 is a 3-(heteroaryl group) each consisting of a heteroaryl group and a phenyl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms )-Phenyl or 4-(heteroaryl)-phenyl group, whereby the heteroaryl group and the phenyl group are connected together by a single bond, and thus Hal is connected to the phenyl group by the phenyl moiety The parent molecular group is bonded, and each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha2 is each composed of a heteroaryl group and a phenyl group selected from the group consisting of a fused bicyclic 9- or 10-membered heteroaryl group including one or two heteroatoms and a phenyl group. Aryl)-phenyl or 4-(heteroaryl)-phenyl groups, whereby the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha2 is through the phenyl Partly bonded to the parent molecular group, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

To be more emphasized, the compounds according to aspect B of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key; Q1 is replaced by R61 on the end ring, and is Aa1 or Ah1, where Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, Ah1 is phenyl-thienyl, R61 is methoxy, hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612 or -U-T3-N(R613 ) R614, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl or 2-methoxyethyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is a quinolino, piperidino, pyrrolidino, piperidino or 4N-methyl-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is dimethylene or trimethylene, R613 is hydrogen, methyl, cyclopropyl or 2-methoxyethyl, R614 is hydrogen or methyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4N-methyl-piperidino, or Q1 is replaced by R61 on the end ring, and is Hh1 or Ha1, where Hh1 is pyridyl-thienyl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, R61 is methoxy or -T2-N(R611)R612, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl or 2-methoxyethyl, R612 is hydrogen or methyl, Or R611 and R612 together and including the nitrogen atom to which they are combined form a heterocyclic Het1, where Het1 is a linolino, piperidino, pyrrolidino, piperidino or 4N-methyl-piperidino base, or Q1 is 3-(1N-methyl-pyrazolyl)-phenyl, 4-(1N-methyl-pyrazolyl)-phenyl, 3-(1N-methyl-indolyl)-phenyl or 4-(1N-methyl-indolyl)-phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

More particularly worthy of mention are the compounds according to aspect B of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q is (1N-methyl-pyrazolyl)-thienyl, 3-(dimethyl-isoxazolyl)-phenyl or 4-(dimethyl-isoxazolyl)-phenyl, And the salts of these compounds.

In another embodiment, the compounds according to aspect B of the invention that are more particularly worth mentioning are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is replaced by R61 on the end ring, and is Aa1 or Ah1, where Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, Ah1 is phenyl-thienyl or phenyl-pyridyl, R61 is methoxy, hydroxyl, trifluoromethyl, hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612 or- U-T3-N(R613)R614, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl or 2-methoxyethyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is a quinolino, piperidino, pyrrolidino, piperidino or 4N-methyl-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is dimethylene or trimethylene, R613 is hydrogen, methyl, cyclopropyl, cyclopentyl or 2-methoxyethyl, R614 is hydrogen or methyl, Or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino, piperidino or 4N-methyl-piperidino, or Q1 is replaced by R61 on the end ring, and is Hh1 or Ha1, where Hh1 is pyridyl-thienyl or bipyridyl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, R61 is methoxy or -T2-N(R611)R612, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl or 2-methoxyethyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is a quinolino, piperidino, pyrrolidino, piperidino or 4N-methyl-piperidino, or Q1 is 3-(1N-methyl-pyrazolyl)-phenyl, 4-(1N-methyl-pyrazolyl)-phenyl, (1N-methyl-pyrazolyl)-thienyl, (1N-methyl-pyrazolyl)-pyridyl, 3-(methyl-thiazolyl)-phenyl, 4-(methyl-thiazolyl)-phenyl, (Methyl-thiazolyl)-thienyl, (methyl-thiazolyl)-pyridyl, 3-(dimethyl-isoxazolyl)-phenyl, 4-(dimethyl-isoxazolyl)-phenyl, 3-(1N-methyl-indolyl)-phenyl or 4-(1N-methyl-indolyl)-phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

It is emphasized that the compounds according to aspect B of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is replaced by R61 on the end ring, and is Aa1 or Ah1, where Aa1 is 1,1’-biphenyl-3-yl or 1,1’-biphenyl-4-yl, Ah1 is phenyl-thienyl, R61 is hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612, or -U-T3-N(R613)R614, where T2 is methylene, dimethyl or trimethylene, R611 is methyl, cyclopropyl or 2-methoxyethyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, U is -O- (oxygen) or -C(O)NH-, T3 is dimethylene or trimethylene, R613 and R614 are methyl groups, Or R613 and R614 together and including the nitrogen atom to which they are combined form a heterocyclic Het2, where Het2 is a linolino group, a piperidino group, a pyrrolidino group or a 4N-methyl-piperidino group, or Q1 is replaced by R61 on the end ring, and is Hh1 or Ha1, where Hh1 is pyridyl-thienyl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, R61 is methoxy or -T2-N(R611)R612, where T2 key, R611 and R612 are independently hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or Q1 is 3-(1N-methyl-pyrazolyl)-phenyl, 4-(1N-methyl-pyrazolyl)-phenyl, 3-(1N-methyl-indolyl)-phenyl or 4-(1N-methyl-indolyl)-phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

It is emphasized that the compounds according to aspect B of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q is (1N-methyl-pyrazol-4-yl)-thienyl, 3-(dimethyl-isoxazolyl)-phenyl or 4-(dimethyl-isoxazolyl)-phenyl, And the salts of these compounds.

In another embodiment, it is emphasized that the compounds according to aspect B of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is 2'-(R61)-1,1'-biphenyl-3-yl, 2'-(R61)-1,1'-biphenyl-4-yl, 3'-(R61)-1,1 '-Biphenyl-3-yl, 3'-(R61)-1,1'-Biphenyl-4-yl, 4'-(R61)-1,1'-Biphenyl-3-yl or 4'- (R61)-1,1'-biphenyl-4-yl, where R61 is methoxy, hydroxyl, trifluoromethyl, hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612 or- U-T3-N(R613)R614, where T2 bond, methylene, dimethyl or trimethylene, R611 is hydrogen, methyl, cyclopropyl, cyclopentyl or 2-methoxyethyl, R612 is hydrogen or methyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or U is -O- (oxygen), T3 is dimethylene or trimethylene, R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or U is -C(O)NH-, T3 is dimethylene or trimethylene, R613 and R614 are methyl groups, or Q1 is 5-[3-(R61)-phenyl]-thiophen-2-yl, 5-[4-(R61)-phenyl]-thiophen-2-yl, 2-[3-(R61)-benzene Yl]-pyridin-4-yl, 2-[4-(R61)-phenyl]-pyridin-4-yl, 6-[3-(R61)-phenyl]-pyridin-3-yl or 6-[ 4-(R61)-phenyl]-pyridin-3-yl, where R61 is methoxy, hydroxyl, trifluoromethyl, hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612 or- U-T3-N(R613)R614, where T2 bond, methylene, dimethyl or trimethylene, or R611 is methyl, cyclopropyl, cyclopentyl or 2-methoxyethyl, R612 is hydrogen, Or R611 and R612 are hydrogen, Or R611 and R612 are methyl groups, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or U is -O- (oxygen), T3 is dimethylene or trimethylene, R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, wherein Het2 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or Q1 is 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6-(R61)-pyridin-3-yl]-thiophen-2-yl, where R61 is an amino group, methoxy group, dimethylamino group, or -T2-N(R611)R612, where T2 key, R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or Q1 is 2-[2-(R61)-pyridin-4-yl]-pyridin-4-yl, 2-[6-(R61)-pyridin-3-yl]-pyridin-4-yl, 3-[2 -(R61)-pyridin-4-yl]-pyridin-6-yl or 3-[6-(R61)-pyridin-3-yl]-pyridin-6-yl, wherein R61 is an amino group, methoxy group, dimethylamino group, or -T2-N(R611)R612, where T2 key, R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or Q1 is 3-[2-(R61)-pyridin-4-yl]-phenyl, 4-[2-(R61)-pyridin-4-yl]-phenyl, 3-[6-(R61)-pyridine -3-yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, where R61 is an amino group, methoxy group, dimethylamino group, or -T2-N(R611)R612, where T2 key, R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino, piperidino, pyrrolidino or 4N-methyl-piperidino, or Q1 is 3-(1N-methyl-pyrazol-4-yl)-phenyl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, 5-(1N-methyl-pyrazol-4-yl)-thiophen-2-yl, 6-(1N-methyl-pyrazol-4-yl)-pyridin-3-yl, 5-(2-Methyl-thiazol-4-yl)-thiophen-2-yl, 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl, 4-(3,5 -Dimethyl-isoxazol-4-yl)-phenyl, 3-(1N-methyl-indol-5-yl)-phenyl or 4-(1N-methyl-indol-5-yl) )-Phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

To be more emphasized, the compounds according to aspect B of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is 2'-(R61)-1,1'-biphenyl-3-yl, 2'-(R61)-1,1'-biphenyl-4-yl, 3'-(R61)-1,1 '-Biphenyl-3-yl, 3'-(R61)-1,1'-Biphenyl-4-yl, 4'-(R61)-1,1'-Biphenyl-3-yl or 4'- (R61)-1,1'-biphenyl-4-yl, where R61 is hydroxymethyl, methylsulfonylamino, methylcarbonylamino, dimethylaminosulfonyl, -T2-N(R611)R612, or -U-T3-N(R613)R614, where T2 is methylene, dimethyl or trimethylene, R611 is methyl, cyclopropyl or 2-methoxyethyl, R612 is hydrogen or methyl, Or R611 and R612 together and including the nitrogen atom to which they are bonded form a heterocyclic Het1, where Het1 is a pyrrolidino group, a pyrrolidino group or a 4N-methyl-piperidino group, or U is -O- (oxygen), T3 is dimethylene or trimethylene, R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, wherein Het2 is a linolino group, a pyrrolidino group or a 4N-methyl-piperidino group, or U is -C(O)NH-, T3 is dimethylene or trimethylene, R613 and R614 are methyl groups, or Q1 is 5-[3-(R61)-phenyl]-thiophen-2-yl or 5-[4-(R61)-phenyl]-thiophen-2-yl, where R61 is -T2-N(R611)R612 or -U-T3-N(R613)R614, where T2 is methylene, dimethyl or trimethylene, R611 and R612 are methyl groups, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is a linolino, pyrrolidino or 4N-methyl-piperidino, U is -O- (oxygen), T3 is dimethylene or trimethylene, R613 and R614 together and including the nitrogen atom to which they are bonded form a heterocyclic Het2, where Het2 is a pyrrolidino group, a pyrrolidino group or a 4N-methyl-piperidino group, or Q1 is 5-[2-(R61)-pyridin-4-yl]-thiophen-2-yl or 5-[6-(R61)-pyridin-3-yl]-thiophen-2-yl, where R61 is an amino group, or -T2-N(R611)R612, where T2 is a bond, R611 and R612 together and including the nitrogen atom to which they are combined form a heterocyclic Het1, where Het1 is a pyrrolidino group, a pyrrolidino group or a 4N-methyl-piperidino group, Q1 is 3-[2-(R61)-pyridin-4-yl]-phenyl, 4-[2-(R61)-pyridin-4-yl]-phenyl, 3-[6-(R61)-pyridine -3-yl]-phenyl or 4-[6-(R61)-pyridin-3-yl]-phenyl, where R61 is an amino group, a methoxy group, or -T2-N(R611)R612, where T2 is a bond, R611 and R612 together and including the nitrogen atom to which they are combined form a heterocyclic Het1, where Het1 is a pyrrolidino group, a pyrrolidino group or a 4N-methyl-piperidino group, or Q1 is 3-(1N-methyl-pyrazol-4-yl)-phenyl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, 3-(1N-methyl-indol-5-yl)-phenyl or 4-(1N-methyl-indol-5-yl)-phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

To be more emphasized, the compounds according to aspect B of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q is 5-(1N-methyl-pyrazol-4-yl)-thiophen-2-yl, 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl or 4-(3,5-dimethyl-isoxazol-4-yl)-phenyl, And the salts of these compounds.

Particularly emphasized that the compounds according to aspect B of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is selected from any of the following groups: 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-4-yl, 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-3-yl, 4' -(2-𠰌olin-4-yl-ethyl)-biphenyl-4-yl, 4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 3'-( 𠰌line-4-yl-methyl)-biphenyl-3-yl, 4'-(𠰌line-4-yl-methyl)-biphenyl-3-yl, 4'-(3-𠰌line-4 -Yl-propyl)-biphenyl-3-yl, 4'-(4-methyl-piperidin-1-ylmethyl)-biphenyl-3-yl, 4'-(2-𠰌line-4 -Yl-ethoxy)-biphenyl-3-yl, 4'-(3-𠰌olin-4-yl-propoxy)-biphenyl-3-yl, 4'-[2-(4-methyl Yl-piperidin-1-yl)-ethoxy]-biphenyl-3-yl, 4'-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-3-yl, 2'- Dimethylaminomethyl-biphenyl-4-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 2'-dimethylaminomethyl-biphenyl-3-yl , 4'-dimethylaminomethyl-biphenyl-3-yl, 3'-[(2-dimethylamino-ethylamino)-carbonyl]-biphenyl-4-yl, 4' -[(2-Dimethylamino-ethylamino)-carbonyl]-biphenyl-4-yl, 4'-[(2-dimethylamino-ethylamino)-carbonyl]-linked Phen-3-yl, 2'-methylsulfonylamino-biphenyl-4-yl, 3'-methylsulfonylamino-biphenyl-4-yl, 4'-methylsulfonylamino Amino-biphenyl-4-yl, 4'-dimethylsulfamoyl-biphenyl-4-yl, 3'-acetamido-biphenyl-4-yl, 4'-acetamido -Biphenyl-4-yl, 4'-(2-methoxy-ethylamino)methyl-biphenyl-3-yl, 4'-cyclopropylaminomethyl-biphenyl-3-yl , 3'-hydroxymethyl-biphenyl-4-yl, 5-[2-(4-Methyl-piperid-1-yl)-pyridin-4-yl]-thiophen-2-yl, 5-(1N-methyl-pyrazol-4-yl)-thiophene- 2-base, 5-[4-(2-𠰌line-4-yl-ethyl)-phenyl]-thiophen-2-yl, 5-[4-(𠰌line-4-yl-methyl)-phenyl]- Thiophen-2-yl, 5-[3-(𠰌line-4-yl-methyl)-phenyl]-thiophen-2-yl, 5-[4-(2-𠰌line-4-yl-ethoxy Yl)-phenyl)-thiophen-2-yl, 5-[4-(3-𠰌lin-4-yl-propoxy)-phenyl]-thiophen-2-yl, 5-{4-[2-(4-methyl-piperid-1-yl )-Ethoxy]-phenyl}-thiophen-2-yl, 5-(4-dimethylaminomethyl-phenyl)-thiophen-2-yl, 4-[2-(4-methyl -Piperidin-1-yl)-pyridin-4-yl]-phenyl, 3-[2-(4-methyl-piperidin-1-yl)-pyridin-4-yl]-phenyl, 4- [6-Amino-pyridin-3-yl]-phenyl, 3-[6-amino-pyridin-3-yl]-phenyl, 4-[6-methoxy-pyridin-3-yl]- Phenyl, 3-[6-methoxy-pyridin-3-yl]-phenyl, 3-(1N-methyl-pyrazol-4-yl)-phenyl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, 4-(3,5-dimethyl-iso Azol-4-yl)-phenyl, and 4-(1N-methyl-indol-5-yl)-phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

In one embodiment, the compounds according to aspect B of the present invention to be more particularly emphasized are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is selected from any of the following groups: 4’-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 4’-(3-𠰌olin-4-yl-propoxy)-biphenyl-3-yl, 4’-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-biphenyl-3-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 5-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl]-thiophen-2-yl, 5-(4-dimethylaminomethyl-phenyl)-thiophene -2-base, 4-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl]-phenyl, 3-[2-(4-methyl-piperidin-1-yl)-pyridine- 4-yl]-phenyl, 4-[6-Amino-pyridin-3-yl]-phenyl, and 4-(1N-methyl-pyrazol-4-yl)-phenyl. R7 is a hydroxyl group, And the salts of these compounds.

In another embodiment, the compounds according to aspect B of the invention to be more particularly emphasized are those of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is selected from any of the following groups: 4’-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 4’-(3-𠰌olin-4-yl-propoxy)-biphenyl-3-yl, 4’-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-biphenyl-3-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 5-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl]-thiophen-2-yl, 5-(4-dimethylaminomethyl-phenyl)-thiophene -2-yl, 4-[2-(4-methyl-piperidin-1-yl)-pyridin-4-yl]-phenyl, 3-[2-(4-methyl-piperidin-1-yl Yl)-pyridin-4-yl]-phenyl, 4-[6-amino-pyridin-3-yl]-phenyl, and 4-(1N-methyl-pyrazol-4-yl)-phenyl , R7 is 2-aminophenyl, And the salts of these compounds.

In the first embodiment (embodiment C1) of aspect C of the present invention, the compounds according to aspect C of the present invention that are more worth mentioning are those of formula I, wherein R1, R2, R3, R4 and R5 are independently hydrogen, or 1-4C-alkyl, R6 Department-T1-Q1, where T1 is a key, or Q1 is replaced by R61 and/or R62 and is Aa1, Hh1, Ha1, Ha2, Ha3 or Ah1, Or Q1 is unsubstituted and is Ha2 or Ha3, among them R61 is 1-4C-alkyl, 1-4C-alkoxy, halogen, or -T2-N(R611)R612, where T2 bond or 1-4C-alkylene, R611 and R612 are independently hydrogen or 1-4C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is quinolino, piperidino, pyrrolidino, piperidino, or 4N-methyl-piperidino, R62 is 1-4C-alkyl, Aa1 is biphenyl, Hh1 is a diheteroaryl group composed of two heteroaryl groups, The heteroaryl groups are independently selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups containing one or two heteroatoms, each of which is selected from nitrogen and oxygen And sulfur, and these heteroaryl groups are connected together by a single bond, Ah1 is a phenyl-heteroaryl group consisting of a phenyl group and a heteroaryl group selected from the group consisting of a monocyclic 5- or 6-membered heteroaryl group including one or two heteroatoms Groups, whereby the phenyl and heteroaryl groups are linked together by a single bond, and thus Ah1 is bonded to the parent molecular group by the heteroaryl moiety, each of these heteroatoms Selected from the group consisting of nitrogen, oxygen and sulfur, Ha1 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms Groups, whereby the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha1 is bonded to the parent molecular group by the phenyl moiety, each of these heteroatoms is selected The group of free nitrogen, oxygen and sulfur, Ha2 is a heteroaryl group selected from the group consisting of a fused bicyclic 9- or 10-membered heteroaryl group including one, two or three heteroatoms and a phenyl group A group-phenyl group, whereby the heteroaryl group and the phenyl group are linked together by a single bond, and thus Ha2 is bonded to the parent molecular group through the phenyl moiety, these heteroatoms Each of them is selected from the group consisting of nitrogen, oxygen and sulfur, Ha3 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5-membered heteroaryl groups including three or four heteroatoms, Thus the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha3 is bonded to the parent molecular group via the phenyl moiety, each of these heteroatoms is selected from nitrogen , Oxygen and sulfur, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

In the second embodiment of aspect C (embodiment C2), the compounds according to aspect C of the present invention that are more worth mentioning are those of formula I, wherein R1, R2, R3, R4 and R5 are independently hydrogen, or 1-4C-alkyl, R6 Department-T1-Q1, where T1 is a key, or Q1 is replaced by R61, and is Aa1, Ha1, Ha2 or Ha3, Or Q1 is unsubstituted and is Ha2 or Ha3, among them R61 is 1-4C-alkyl, 1-4C-alkoxy, halogen, or -T2-N(R611)R612, where T2 bond or 1-4C-alkylene, R611 and R612 are independently hydrogen or 1-4C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is quinolino, piperidino, pyrrolidino, piperidino, or 4N-methyl-piperidino, Aa1 is biphenyl, Ha1 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5- or 6-membered heteroaryl groups including one or two heteroatoms Groups, whereby the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha1 is bonded to the parent molecular group by the phenyl moiety, each of these heteroatoms is selected The group of free nitrogen, oxygen and sulfur, Ha2 is a heteroaryl group selected from the group consisting of a fused bicyclic 9- or 10-membered heteroaryl group including one, two or three heteroatoms and a phenyl group A group-phenyl group, whereby the heteroaryl group and the phenyl group are linked together by a single bond, and thus Ha2 is bonded to the parent molecular group through the phenyl moiety, these heteroatoms Each of them is selected from the group consisting of nitrogen, oxygen and sulfur, Ha3 is a heteroaryl-phenyl group consisting of heteroaryl groups and phenyl groups selected from the group consisting of monocyclic 5-membered heteroaryl groups including three or four heteroatoms, Thus the heteroaryl and phenyl groups are linked together by a single bond, and thus Ha3 is bonded to the parent molecular group via the phenyl moiety, each of these heteroatoms is selected from nitrogen , Oxygen and sulfur, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

Particularly worth mentioning are the compounds of embodiment C1 according to aspect C of the invention are those compounds of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is replaced by R61 on the end ring and is Aa1, Hh1, Ha1 or Ah1, Or Q1 is [1N-(1-4C-alkyl)-indolyl]-phenyl, [1N-(1-4C-alkyl)-pyrazolyl]-phenyl, [1N-(1-4C -Alkyl)-imidazolyl]-phenyl, [1N-(1-4C-alkyl)-triazolyl]-phenyl, [1N-(1-4C-alkyl)-tetrazolyl]-benzene Group, [1N-(1-4C-alkyl)-benzimidazolyl]-phenyl, [1N-(1-4C-alkyl)-benzotriazolyl]-phenyl, or [1N-( 1-4C-alkyl)-indazole]-phenyl, Or Q1 is [1N-(1-4C-alkyl)-indolyl]-thienyl, [1N-(1-4C-alkyl)-pyrazolyl]-thienyl, [1N-(1-4C -Alkyl)-imidazolyl]-thienyl, [1N-(1-4C-alkyl)-triazolyl]-thienyl, [1N-(1-4C-alkyl)-tetrazolyl]-thiophene Group, [1N-(1-4C-alkyl)-benzimidazolyl]-thienyl, [1N-(1-4C-alkyl)-benzotriazolyl]-thienyl, or [1N-( 1-4C-alkyl)-indazolyl]-thienyl, Or Q1 is [mono-or di-(1-4C-alkyl)-isoxazolyl]-phenyl, or [mono-or di-(1-4C-alkyl)-isoxazolyl]-thiophene base, among them R61 is 1-4C-alkyl, 1-4C-alkoxy, halogen, or -T2-N(R611)R612, where T2 bond or 1-4C-alkylene, R611 is hydrogen or 1-4C-alkyl, R612 is hydrogen or 1-4C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is quinolino, piperidino, pyrrolidino, piperidino, or 4N-methyl-piperidino, Aa1 is 1,1'-biphenyl-4-yl or 1,1'-biphenyl-3-yl, Hh1 is pyridyl-thienyl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, Ah1 is phenyl-thienyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

Particularly worth mentioning are the compounds of embodiment C2 according to aspect C of the invention are those compounds of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is replaced by R61 on the end ring, and is Aa1 or Ha1, Or Q1 is [1N-(1-4C-alkyl)-indolyl]-phenyl, [1N-(1-4C-alkyl)-pyrazolyl]-phenyl, [1N-(1-4C -Alkyl)-imidazolyl]-phenyl, [1N-(1-4C-alkyl)-triazolyl]-phenyl, [1N-(1-4C-alkyl)-tetrazolyl]-benzene Group, [1N-(1-4C-alkyl)-benzimidazolyl]-phenyl, [1N-(1-4C-alkyl)-benzotriazolyl]-phenyl, or [1N-( 1-4C-alkyl)-indazole]-phenyl, among them R61 is 1-4C-alkyl, 1-4C-alkoxy, halogen, or -T2-N(R611)R612, where T2 bond or 1-4C-alkylene, R611 is hydrogen or 1-4C-alkyl, R612 is hydrogen or 1-4C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is quinolino, piperidino, pyrrolidino, piperidino, or 4N-methyl-piperidino, Aa1 is 1,1'-biphenyl-4-yl or 1,1'-biphenyl-3-yl, Ha1 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

More particularly worth mentioning are the compounds of embodiment C1 according to aspect C of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is substituted by R61 on the pyridine ring, and is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, Or Q1 is 2'-(R61)-1,1'-biphenyl-4-yl, 3'-(R61)-1,1'-biphenyl-4-yl, 4'-(R61)-1, 1'-biphenyl-4-yl, 2'-(R61)-1,1'-biphenyl-3-yl, 3'-(R61)-1,1'-biphenyl-3-yl or 4' -(R61)-1,1'-biphenyl-3-yl, Or Q1 is substituted by R61 on the pyridine ring and is pyridyl-thienyl, Or Q1 is substituted by R61 on the benzene ring and is phenyl-thienyl, Or Q1 is 3-[1N-methyl-indolyl]-phenyl, 4-[1N-methyl-indolyl]-phenyl, 3-[1N-methyl-pyrazolyl]-phenyl Or 4-[1N-methyl-pyrazolyl]-phenyl, Or Q1 is [1N-methyl-pyrazolyl]-thienyl, Or Q1 is 3-[dimethyl-isoazolyl]-phenyl or 4-[dimethyl-isoazolyl]-phenyl, among them R61 is 1-2C-alkoxy, amino, or -T2-N(R611)R612, where T2 bond, methylene, dimethyl or trimethylene, R611 is 1-2C-alkyl, R612 is 1-2C-alkyl, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is a linolino, pyrrolidino or 4N-methyl-piperidino, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

More particularly worth mentioning are the compounds of embodiment C2 according to aspect C of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is substituted by R61 on the pyridine ring, and is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, Or Q1 is 3’-(R61)-1,1’-biphenyl-4-yl or 4’-(R61)-1,1’-biphenyl-4-yl, Or Q1 is 3-[1N-methyl-indolyl]-phenyl, 4-[1N-methyl-indolyl]-phenyl, 3-[1N-methyl-pyrazolyl]-phenyl Or 4-[1N-methyl-pyrazolyl]-phenyl, among them R61 is 1-2C-alkoxy, amino, or -T2-N(R611)R612, where T2 bond or 1-2C-alkylene, R611 and R612 are 1-2C-alkyl groups, Or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is a linonyl group, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

In one embodiment, it is emphasized that the compounds of embodiment C1 according to aspect C of the present invention are those of the formula, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is 3-(6-amino-pyridin-3-yl)-phenyl, 4-(6-amino-pyridin-3-yl)-phenyl, 3-(6-methoxy-pyridine-3 -Yl)-phenyl or 4-(6-methoxy-pyridin-3-yl)-phenyl, Or Q1 is 3-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-phenyl or 4-[2-(4-methyl-piperid-1-yl) )-Pyridin-4-yl)]-phenyl, Or Q1 is 3’-(R61)-1,1’-biphenyl-4-yl or 4’-(R61)-1,1’-biphenyl-4-yl, Or Q1 is 5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-thiophen-2-yl, Or Q1 is 5-[4-(R61)-phenyl]-thiophen-2-yl or 5-[3-(R61)-phenyl]-thiophen-2-yl, Or Q1 is 3-(1N-methyl-indol-5-yl)-phenyl, 4-(1N-methyl-indol-5-yl)-phenyl, 3-(1N-methyl-pyridine Oxazol-4-yl)-phenyl or 4-(1-N-methyl-pyrazol-4-yl)-phenyl, Or Q1 is 5-(1N-methyl-pyrazol-4-yl)-thiophen-2-yl, Or Q1 is 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl or 4-(3,5-dimethyl-isoxazol-4-yl)-phenyl, among them R61 Department-T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, or Both R611 and R612 are methyl, or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino or 4N-methyl-piperidino, R7 is a hydroxyl group, And the salts of these compounds.

In another embodiment, it is emphasized that the compounds of embodiment C1 according to aspect C of the invention are those compounds of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is 3-(6-amino-pyridin-3-yl)-phenyl, 4-(6-amino-pyridin-3-yl)-phenyl, 3-(6-methoxy-pyridine-3 -Yl)-phenyl or 4-(6-methoxy-pyridin-3-yl)-phenyl, Or Q1 is 3-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-phenyl or 4-[2-(4-methyl-piperid-1-yl) )-Pyridin-4-yl)]-phenyl, Or Q1 is 3’-(R61)-1,1’-biphenyl-4-yl or 4’-(R61)-1,1’-biphenyl-4-yl, Or Q1 is 5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-thiophen-2-yl, Or Q1 is 5-[4-(R61)-phenyl]-thiophen-2-yl or 5-[3-(R61)-phenyl]-thiophen-2-yl, Or Q1 is 3-(1N-methyl-indol-5-yl)-phenyl, 4-(1N-methyl-indol-5-yl)-phenyl, 3-(1N-methyl-pyridine Oxazol-4-yl)-phenyl or 4-(1-N-methyl-pyrazol-4-yl)-phenyl, Or Q1 is 5-(1N-methyl-pyrazol-4-yl)-thiophen-2-yl, Or Q1 is 3-(3,5-dimethyl-isoxazol-4-yl)-phenyl or 4-(3,5-dimethyl-isoxazol-4-yl)-phenyl, among them R61 is -T2-N(R611)R612, where T2 is methylene, dimethyl or trimethylene, or Both R611 and R612 are methyl, or R611 and R612 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het1, where Het1 is linolino or 4N-methyl-piperidino, R7 is 2-aminophenyl, And the salts of these compounds.

It is emphasized that the compounds of embodiment C2 according to aspect C of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, or Q1 is 3-(6-amino-pyridin-3-yl)-phenyl, 4-(6-amino-pyridin-3-yl)-phenyl, 3-(6-methoxy-pyridine-3 -Yl)-phenyl or 4-(6-methoxy-pyridin-3-yl)-phenyl, Or Q1 is 3’-(R61)-1,1’-biphenyl-4-yl or 4’-(R61)-1,1’-biphenyl-4-yl, Or Q1 is 3-(1N-methyl-indol-5-yl)-phenyl, 4-(1N-methyl-indol-5-yl)-phenyl, 3-(1N-methyl-pyridine Oxazol-4-yl)-phenyl or 4-(1-N-methyl-pyrazol-4-yl)-phenyl, among them R61 is -T2-N(R611)R612, where T2 is 1-2C-alkylene, R611 and R612 together and at the same time include the nitrogen atom to which they are bonded to form a heterocyclic Het1, where Het1 is a linolino group, R7 is a hydroxyl group or 2-aminophenyl group, And the salts of these compounds.

In one embodiment, the compounds of embodiment C1 according to aspect C of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is selected from any one of the following: 3-(6-amino-pyridin-3-yl)-phenyl, 4-(6-amino-pyridin-3-yl)-phenyl, 3- (6-Methoxy-pyridin-3-yl)-phenyl, 4-(6-methoxy-pyridin-3-yl)-phenyl, 3-[2-(4-methyl-piper𠯤- 1-yl)-pyridin-4-yl)]-phenyl, 4-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-phenyl, 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-4-yl, 3'-(2-𠰌line-4-yl-ethyl)-biphenyl-3-yl, 4' -(2-𠰌olin-4-yl-ethyl)-biphenyl-4-yl, 4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl, 3'-( 𠰌line-4-yl-methyl)-biphenyl-3-yl, 4'-(𠰌line-4-yl-methyl)-biphenyl-3-yl, 4'-(3-𠰌line-4 -Yl-propyl)-biphenyl-3-yl, 4'-(4-methyl-piperidin-1-yl-methyl)-biphenyl-3-yl, 2'-Dimethylaminomethyl-biphenyl-4-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 2'-dimethylaminomethyl-biphenyl- 3-yl, 4'-dimethylaminomethyl-biphenyl-3-yl, 5-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl)]-thiophen-2-yl, 5-[4-(2-𠰌olin-4-yl-ethyl )-Phenyl]-thiophen-2-yl, 5-[4-(𠰌line-4-yl-methyl)-phenyl]-thiophen-2-yl, 5-[3-(𠰌line-4-yl -Methyl)-phenyl)-thiophen-2-yl, 4-(1N-methyl-indol-5-yl)-phenyl, 3-(1N-methyl-pyrazol-4-yl) -Phenyl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, 5-(4-dimethylaminomethyl-phenyl)-thiophen-2-yl, 5-(1N-methyl-pyrazol-4-yl)-thiophen-2-yl and 4-(3,5-dimethyl-isoxazol-4-yl)-phenyl, R7 is a hydroxyl group, And the salts of these compounds.

In another embodiment, the compounds of embodiment C1 according to aspect C of the invention are those of formula I, where R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is selected from any one of the following: 3-(6-amino-pyridin-3-yl)-phenyl, 4-(6-amino-pyridin-3-yl)-phenyl, 3- (6-Methoxy-pyridin-3-yl)-phenyl, 4-(6-methoxy-pyridin-3-yl)-phenyl, 3-[2-(4-Methyl-piperidin-1-yl)-pyridin-4-yl)]-phenyl, 4-[2-(4-methyl-piperidin-1-yl)-pyridine -4-yl))-phenyl, 3'-(2-𠰌olin-4-yl-ethyl)-biphenyl-4-yl, 3'-(2-𠰌olin-4-yl-ethyl) -Biphenyl-3-yl, 4'-(2-𠰌line-4-yl-ethyl)-biphenyl-4-yl, 4'-(2-𠰌line-4-yl-ethyl)-bi Phenyl-3-yl, 3'-(𠰌line-4-yl-methyl)-biphenyl-3-yl, 4'-(𠰌line-4-yl-methyl)-biphenyl-3-yl, 4'-(3-𠰌lin-4-yl-propyl)-biphenyl-3-yl, 4'-(4-methyl-piperidin-1-yl-methyl)-biphenyl-3-yl , 2'-Dimethylaminomethyl-biphenyl-4-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 2'-dimethylaminomethyl-biphenyl -3-,4'-Dimethylaminomethyl-biphenyl-3-yl, 5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-thiophene -2-base, 5-[4-(2-𠰌line-4-yl-ethyl)-phenyl]-thiophen-2-yl, 5-[4-(𠰌line-4-yl-methyl)-phenyl]- Thiophen-2-yl, 5-[3-(𠰌olin-4-yl-methyl)-phenyl]-thiophen-2-yl, 4-(1N-methyl-indol-5-yl)-benzene Group, 3-(1N-methyl-pyrazol-4-)-phenyl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, 5-(4-Dimethylaminomethyl-phenyl)-thiophen-2-yl, 5-(1N-methyl-pyrazol-4-yl)-thiophen-2-yl, and 4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl, R7 is 2-aminophenyl, And the salts of these compounds.

In one embodiment, the compounds of embodiment C1 according to aspect C of the present invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is selected from any one of the following: 4-(6-amino-pyridin-3-yl)-phenyl, 4-[2-(4-methyl-piperid-1-yl)-pyridine -4-yl)]-phenyl, 3-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-phenyl, 4'-(2-𠰌line-4 -Yl-ethyl)-biphenyl-3-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 5-[2-(4-methyl-piperid-1-yl) -Pyridin-4-yl))-thiophen-2-yl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, and 5-(4-dimethylaminomethyl-phenyl )-Thiophen-2-yl, R7 is a hydroxyl group, And the salts of these compounds.

In another embodiment, the compounds of embodiment C1 according to aspect C of the invention are those of formula I, wherein R1, R2, R3, R4 and R5 are hydrogen, R6 Department-T1-Q1, where T1 is a key, Q1 is selected from any one of the following: 4-(6-amino-pyridin-3-yl)-phenyl, 4-[2-(4-methyl-piperid-1-yl)-pyridine -4-yl)]-phenyl, 3-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-phenyl, 4'-(2-𠰌line-4 -Yl-ethyl)-biphenyl-3-yl, 4'-dimethylaminomethyl-biphenyl-4-yl, 5-[2-(4-methyl-piperid-1-yl) -Pyridin-4-yl))-thiophen-2-yl, 4-(1N-methyl-pyrazol-4-yl)-phenyl, and 5-(4-dimethylaminomethyl-phenyl )-Thiophen-2-yl, R7 is 2-aminophenyl, And the salts of these compounds.

Special attention to the compounds according to the invention means that those compounds of the invention-within the scope of the invention-are encompassed by one of the following embodiments or a combination of several of the following embodiments (where possible): One embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R7 is a hydroxyl group. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R7 is 2-aminophenyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R7 is an aminopyridyl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R7 is Cyc1, whereby in its sub-embodiments, Cyc1 is 2-phenyl.

Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein the T1 is a bond.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is substituted by R61 and is Aa1, Ha1 or Ha2. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is substituted by R61 and is Ah1 or Hh1. Another embodiment of the compounds according to this invention relates to those compounds of formula I, wherein R6 is substituted by R61 and is Ha3. Another embodiment of the compound according to the present invention relates to those compounds of formula I, wherein R6 is 3-(pyridyl)-phenyl or 4-(pyridyl)-phenyl, each of which is on the pyridyl moiety Replaced by R61. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl, 4-(pyridine -3-yl)-phenyl, or 4-(pyridin-4-yl)-phenyl, each of which is substituted with R61 on the pyridyl moiety. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3-(pyridin-3-yl)-phenyl or 4-(pyridin-3-yl)-phenyl, each of Substituted by R61 on the pyridyl moiety. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3-[6-(R61)-pyridin-3-yl]-phenyl or 4-[6-(R61)-pyridine- 3-yl]-phenyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3-(pyridin-4-yl)-phenyl or 4-(pyridin-4-yl)-phenyl, each of Substituted by R61 on the pyridyl moiety. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3-[2-(R61)-pyridin-4-yl]-phenyl or 4-[2-(R61)-pyridine- 4-yl]-phenyl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is 1,1'-biphenyl-4-yl or 1,1'-biphenyl-3-yl, each of which is at the end The phenyl moiety is substituted by R61. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3'-(R61)-1,1'-biphenyl-4-yl, 4'-(R61)-1,1' -Biphenyl-4-yl, 3'-(R61)-1,1'-biphenyl-3-yl or 4'-(R61)-1,1'-biphenyl-3-yl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3'-(R61)-1,1'-biphenyl-4-yl or 4'-(R61)-1,1' -Biphenyl-4-yl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3'-(R61)-1,1'-biphenyl-3-yl or 4'-(R61)-1,1' -Biphenyl-3-yl.

Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is 4'-(R61)-1,1'-biphenyl-3-yl or 4'-(R61)-1,1' -Biphenyl-4-yl.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is pyridyl-thienyl, which is substituted by R61 on the pyridyl moiety. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [2-(R61)-pyridin-4-yl]-thienyl, for example like 5-[2-(R61)-pyridine- 4-yl]-thiophen-2-yl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [6-(R61)-pyridin-3-yl]-thienyl, for example like 5-[6-(R61)-pyridine- 3-yl]-thiophen-2-yl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is a bipyridyl group, which is substituted by R61 on the terminal pyridyl moiety. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [2-(R61)-pyridin-4-yl]-pyridyl, for example like 2-[2-(R61)-pyridine- 4-yl]-pyridin-4-yl or 6-[2-(R61)-pyridin-4-yl]-pyridin-3-yl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [6-(R61)-pyridin-3-yl]-pyridyl, for example like 2-[6-(R61)-pyridine- 3-yl]-pyridin-4-yl or 6-[6-(R61)-pyridin-3-yl]-pyridin-3-yl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is a phenyl-thienyl group, which is substituted by R61 on the phenyl moiety. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [3-(R61)-phenyl]-thienyl, for example like 5-[3-(R61)-phenyl]-thiophene -2-base. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [4-(R61)-phenyl]-thienyl, for example like 5-[4-(R61)-phenyl]-thiophene -2-base. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is phenyl-pyridyl, which is substituted by R61 on the phenyl moiety. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [3-(R61)-phenyl]-pyridyl, for example like 2-[3-(R61)-phenyl]-pyridine -4-yl or 6-[3-(R61)-phenyl]-pyridin-3-yl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [4-(R61)-phenyl]-pyridyl, for example like 2-[4-(R61)-phenyl]-pyridine -4-yl or 6-[4-(R61)-phenyl]-pyridin-3-yl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [1N-(1-4C-alkyl)-indolyl]-phenyl or [1N-(1-4C-alkyl) )-Pyrazolyl]-phenyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is [1N-(1-2C-alkyl)-indol-5-yl]-phenyl or [1N-(1-2C -Alkyl)-pyrazol-4-yl]-phenyl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is 3-(1N-methyl-pyrazol-4-yl)-phenyl or 4-(1N-methyl-pyrazole- 4-yl)-phenyl. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is [1N-(1-2C-alkyl)-pyrazol-4-yl]-pyridyl, for example like 2-(1N- Methyl-pyrazol-4-yl)-pyridin-4-yl or 6-(1N-methyl-pyrazol-4-yl)-pyridin-3-yl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is triazolyl-phenyl, which is substituted by R61 on the triazolyl moiety. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R6 is {1N-(R61)-[1,2,3]triazol-4-yl}-phenyl, for example like 3-{ 1N-(R61)-[1,2,3]triazol-4-yl}-phenyl or 4-{1N-(R61)-[1,2,3]triazol-4-yl}-phenyl . Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R61 is -T2-N(R611)R612.

Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein the T2 is a bond. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein T2 is a 1-4C-alkylene group, for example like 1-2C-alkylene group. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein T2 is a methylene group. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein T2 is a dimethylene group.

Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein T2 is a trimethylene group. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R611 and R612 are both hydrogen.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R611 and R612 are both methyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R611 and R612 together and at the same time including the nitrogen atom to which they are attached form a linolino ring. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R611 and R612 together and simultaneously including the nitrogen atom to which they are attached form a 4N-methyl-piperidino ring. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R611 and R612 together and simultaneously including the nitrogen atom to which they are attached form a pyrrolidino ring. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R611 and R612 together and simultaneously including the nitrogen atom to which they are attached form a piperidino ring. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R61 is -O-T3-N(R613)R614.

Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein T3 is a dimethylene group. Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein T3 is a trimethylene group.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R613 and R614 are both methyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R613 and R614 together and at the same time including the nitrogen atom to which they are attached form a linolino ring. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R613 and R614 together and simultaneously including the nitrogen atom to which they are attached form a 4N-methyl-piperidino ring. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R613 and R614 together and simultaneously including the nitrogen atom to which they are attached form a pyrrolidino ring. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R613 and R614 together and simultaneously including the nitrogen atom to which they are attached form a piperidino ring.

Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R61 is -T4-Het3, wherein T4 tether, methylene, dimethyl or trimethylene, and Het3 is 1N-methyl-piperidin-4-yl.

Another embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R61 is -O-T5-Het4, wherein T5 tether, methylene, dimethyl or trimethylene, and Het4 is 1N-methyl-piperidin-4-yl.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R61 is selected from any one of the following: 3-𠰌olin-4-yl-propyl, 2-𠰌olin-4-yl -Ethyl, 𠰌olin-4-yl-methyl, 3-(4-methyl-piperidin-1-yl)-propyl, 2-(4-methyl-piperidin-1-yl)-ethyl Group, (4-methyl-piperidin-1-yl)-methyl, 3-pyrrolidin-1-yl-propyl, 2-pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl- Methyl, 3-piperidin-1-yl-propyl, 2-piperidin-1-yl-ethyl, piperidin-1-yl-methyl, 3-𠰌olin-4-yl-propoxy, 2-𠰌lin-4-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-pyrrolidin-1-yl-ethoxy, 3-(4-methyl-piperidin- 1-yl)-propoxy, 2-(4-methyl-piperidin-1-yl)-ethoxy, 3-(1-methyl-piperidin-4-yl)-propoxy, 2 -(1-Methyl-piperidin-4-yl)-ethoxy, 3-piperidin-1-yl-propoxy, 2-piperidin-1-yl-ethoxy, dimethylamino Methyl, 2-dimethylamino-ethyl, 3-dimethylamino-propyl, methylsulfamate, dimethylsulfamate, acetamido, amino, two Methylamino, pyrolino, piperidino, pyrrolidino, 4-methyl-piperidino, hydroxyl, trifluoromethyl, methoxy, (2-dimethylamino- Ethylamino)-carbonyl, (2-methoxy-ethylamino)methyl, aminomethyl, acetylamino-methyl, methylsulfonylamino-methyl, cyclopentan Aminomethyl, cyclopropylaminomethyl, and hydroxymethyl; and R7 is a hydroxyl group.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R61 is selected from any one of the following: 3-𠰌olin-4-yl-propyl, 2-𠰌olin-4-yl -Ethyl, 𠰌olin-4-yl-methyl, 3-(4-methyl-piperidin-1-yl)-propyl, 2-(4-methyl-piperidin-1-yl)-ethyl Group, (4-methyl-piperidin-1-yl)-methyl, 3-pyrrolidin-1-yl-propyl, 2-pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl- Methyl, 3-piperidin-1-yl-propyl, 2-piperidin-1-yl-ethyl, piperidin-1-yl-methyl, 3-𠰌olin-4-yl-propoxy, 2-𠰌lin-4-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-pyrrolidin-1-yl-ethoxy, 3-(4-methyl-piperidin- 1-yl)-propoxy, 2-(4-methyl-piperidin-1-yl)-ethoxy, 3-(1-methyl-piperidin-4-yl)-propoxy, 2 -(1-Methyl-piperidin-4-yl)-ethoxy, 3-piperidin-1-yl-propoxy, 2-piperidin-1-yl-ethoxy, dimethylamino Methyl, 2-dimethylamino-ethyl, 3-dimethylamino-propyl, methylsulfamate, dimethylsulfamate, acetamido, amino, two Methylamino, pyrolino, piperidino, pyrrolidino, 4-methyl-piperidino, hydroxyl, trifluoromethyl, methoxy, (2-dimethylamino- Ethylamino)-carbonyl, (2-methoxy-ethylamino)methyl, aminomethyl, acetylamino-methyl, methylsulfonylamino-methyl, cyclopentan Aminomethyl, cyclopropylaminomethyl and hydroxymethyl; and R7 is 2-aminophenyl.

Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 4-(6-amino-pyridin-3-yl)-phenyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 4-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-phenyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 3-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-phenyl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-yl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 4'-dimethylaminomethyl-biphenyl-4-yl. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl)]-thiophene-2 -base. Another embodiment of the compounds according to the present invention relates to those compounds of formula I, wherein R6 is 5-(4-dimethylaminomethyl-phenyl)-thiophen-2-yl.

A particular embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, and R7 is a hydroxyl group. Another particular embodiment of the compounds according to the invention relates to those compounds of formula I, wherein R1, R2, R3, R4 and R5 are all hydrogen, and R7 is 2-aminophenyl.

It should be understood that the present invention also includes any or all possible combinations and subsets of the previously defined embodiments.

Exemplary compounds according to the present invention may include any one selected from the following 1. (E)-N-Hydroxy-3-{1-[4-(1-methyl-1H-indol-5-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-propene Amide, 2. (E)-N-Hydroxy-3-{1-[4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-propene Amide, 3. (E)-N-Hydroxy-3-{1-[4-(6-methoxy-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide , 4. (E)-3-{1-[4-(6-Amino-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-hydroxy-acrylamide, 5. (E)-N-(2-Amino-phenyl)-3-{1-[4-(6-methoxy-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrole- 3-yl}-acrylamide, 6. (E)-N-(2-Amino-phenyl)-3-{1-[4-(6-amino-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 7. (E)-N-(2-Amino-phenyl)-3-{1-[4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H- Pyrrol-3-yl}-acrylamide, 8. (E)-N-Hydroxy-3-{1-[4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-4-sulfonyl]-1H-pyrrole-3- Yl}-acrylamide, 9. (E)-N-Hydroxy-3-{1-[3'-(2-𠰌olin-4-yl-ethyl)-biphenyl-4-sulfonyl]-1H-pyrrole-3- Yl}-acrylamide, 10. (E)-3-{1-[3-(6-Amino-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-hydroxy-acrylamide, 11. (E)-N-Hydroxy-3-{1-[3-(6-methoxy-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide , 12. (E)-N-Hydroxy-3-{1-[3-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-propene Amide, 13. (E)-N-Hydroxy-3-{1-[3-(1-methyl-1H-indol-5-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-propene Amide, 14. (E)-N-(2-Amino-phenyl)-3-{1-[3-(6-methoxy-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrole- 3-yl}-acrylamide, 15. (E)-N-(2-Amino-phenyl)-3-{1-[3-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H- Pyrrol-3-yl}-acrylamide, 16. (E)-N-Hydroxy-3-{1-[4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-sulfonyl]-1H-pyrrole-3- Yl}-acrylamide, 17. (E)-N-(2-Amino-phenyl)-3-{1-[3-(6-amino-pyridin-3-yl)-benzenesulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 18. (E)-N-(2-Amino-phenyl)-3-{1-[3'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-sulfonyl ]-1H-pyrrol-3-yl}-acrylamide, 19. (E)-N-(2-Amino-phenyl)-3-{1-[4'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-sulfonyl ]-1H-pyrrol-3-yl}-acrylamide, 20. (E)-N-hydroxy-3-{1-[3'-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-sulfonyl]-1H-pyrrole-3- Yl}-acrylamide, 21. (E)-N-Hydroxy-3-[1-(2'-Methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide 22. (E)-N-Hydroxy-3-[1-(3'-Methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide 23. (E)-N-Hydroxy-3-[1-(4'-Methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide 24. 4'-[3-((E)-2-Hydroxyaminomethyl-vinyl)-pyrrole-1-sulfonyl]-biphenyl-4-carboxylic acid (2-dimethylamine Yl-ethyl)-amide, 25. 4'-[3-((E)-2-Hydroxyaminomethyl-vinyl)-pyrrole-1-sulfonyl]-biphenyl-3-carboxylic acid (2-dimethylamine Yl-ethyl)-amide, 26. (E)-3-[1-(4'-Dimethylaminomethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 27. (E)-3-[1-(2'-Dimethylaminomethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 28. (E)-N-hydroxy-3-(1-{4-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]benzenesulfonyl}-1H-pyrrole -3-yl)-acrylamide, 29. (E)-N-hydroxy-3-{1-[4'-(toluene-4-sulfonylamino)-biphenyl-4-sulfonyl]-1H-pyrrol-3-yl} -Acrylamide, 30. 3'-[3-((E)-2-Hydroxyaminomethyl-vinyl)-pyrrole-1-sulfonyl]-biphenyl-4-carboxylic acid (2-dimethylamine Yl-ethyl)-amide, 31. (E)-N-Hydroxy-3-[1-(3'-𠰌lin-4-ylmethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-propenyl amine, 32. (E)-N-hydroxy-3-(1-{4'-[2-(4-methyl-piperid-1-yl)-ethoxy]-biphenyl-3-sulfonyl }-1H-pyrrol-3-yl)-acrylamide, 33. (E)-N-hydroxy-3-(1-{3-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]benzenesulfonyl}-1H-pyrrole -3-yl)-acrylamide, 34. (E)-N-Hydroxy-3-{1-[4'-(2-𠰌olin-4-yl-ethoxy)-biphenyl-3-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 35. (E)-N-(2-Amino-phenyl)-3-{1-[4-(1-benzyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H- Pyrrol-3-yl}-acrylamide, 36. (E)-N-Hydroxy-3-[1-(4'-𠰌lin-4-ylmethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-propenyl amine, 37. (E)-3-[1-(4'-Dimethylaminomethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 38. (E)-N-Hydroxy-3-{1-[4'-(3-𠰌olin-4-yl-propoxy)-biphenyl-3-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 39. (E)-N-(2-Amino-phenyl)-3-[1-(4'Dimethylsulfamoyl-biphenyl-4-sulfonyl)-1H-pyrrole-3 -Yl]-acrylamide, 40. (E)-3-[1-(3'-Acetylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-(2-amino-benzene Yl)-acrylamide, 41. (E)-3-[1-(2'-Dimethylaminomethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 42. (E)-N-hydroxy-3-(1-{5-[2-(4-methyl-piper-1-yl)-pyridin-4-yl]-thiophen-2-sulfonyl) -1H-pyrrol-3-yl)-acrylamide, 43. (E)-N-hydroxy-3-{1-[4'-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-3-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 44. 4'-{3-[(E)-2-(2-Amino-phenylaminomethanyl)-vinyl]-pyrrole-1-sulfonyl}-biphenyl-3-carboxy Acid (2-dimethylamino-ethyl)-amide, 45. (E)-N-Hydroxy-3-{1-[4'-(3-𠰌olin-4-yl-propyl)-biphenyl-3-sulfonyl]-1H-pyrrole-3- Yl}-acrylamide, 46. (E)-3-{1-[5-(4-Dimethylaminomethyl-phenyl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl}-N-hydroxy -Acrylamide, 47. (E)-N-(2-Amino-phenyl)-3-[1-(4'-dimethylaminomethyl-biphenyl-4-sulfonyl)-1H-pyrrole- 3-yl]-acrylamide, 48. (E)-N-(2-Amino-phenyl)-3-(1-{4-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]benzene Sulfonyl}-1H-pyrrol-3-yl)-acrylamide, 49. (E)-3-[1-(4'-Acetylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-(2-amino-benzene Yl)-acrylamide, 50. (E)-N-hydroxy-3-{1-[5-(3-𠰌olin-4-ylmethyl-phenyl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl }-Acrylamide, 51. (E)-N-(2-Amino-phenyl)-3-[1-(3'-hydroxymethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl] -Acrylamide, 52. (E)-N-(2-Amino-phenyl)-3-{1-[4-(3,5-dimethyl-isoazol-4-yl)-benzenesulfonyl]- 1H-pyrrol-3-yl}-acrylamide, 53. (E)-N-(2-Amino-phenyl)-3-[1-(4'-Methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrole-3 -Yl]-acrylamide, 54. (E)-N-Hydroxy-3-{1-[5-(4-𠰌olin-4-ylmethyl-phenyl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl }-Acrylamide, 55. (E)-N-hydroxy-3-[1-(5-{4-[2-(4-methyl-piper-1-yl)-ethoxy]-phenyl}-thiophene-2 -Sulfonyl)-1H-pyrrol-3-yl]-acrylamide, 56. (E)-N-Hydroxy-3-(1-{5-[4-(2-𠰌olin-4-yl-ethoxy)-phenyl]-thiophen-2-sulfonyl)-1H -Pyrrol-3-yl)-acrylamide, 57. (E)-N-hydroxy-3-(1-{5-[4-(3-𠰌olin-4-yl-propoxy)-phenyl]-thiophen-2-sulfonyl)-1H -Pyrrol-3-yl)-acrylamide, 58. (E)-N-hydroxy-3-(1-{4'-[(2-methoxy-ethylamino)-methyl]-biphenyl-3-sulfonyl}-1H- (Pyrrol-3-yl)-acrylamide, 59. (E)-N-(2-Amino-phenyl)-3-[1-(3'-Methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrole-3 -Yl]-acrylamide, 60. (E)-Hydroxy-3-{1-[5-(1-methyl-1H-pyrazol-4-yl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl}- Acrylamide, 61. (E)-N-hydroxy-3-(1-{5-[4-(2-𠰌olin-4-yl-ethyl)-phenyl]-thiophen-2-sulfonyl)-1H- (Pyrrol-3-yl)-acrylamide, 62. (E)-N-hydroxy-3-{1-[4'-(4-methyl-piperid-1-ylmethyl)-biphenyl-3-sulfonyl]-1H-pyrrole- 3-yl}-acrylamide, and 63. (E)-3-[1-(4'-Cyclopropylaminomethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , And its salt. In addition, the exemplary compound according to the present invention may further include any one selected from the following 64. (E)-N-Hydroxy-3-[1-(3'-𠰌lin-4-ylmethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-propenyl amine, 65. (E)-3-[1-(4-Benzo[1,3]dioxol-5-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy -Acrylamide, 66. (E)-3-[1-(3'-Amino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, 67. (E)-N-hydroxy-3-[1-(4'-hydroxy-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-propenamide, 68. (E)-N-hydroxy-3-(1-{4'-[2-(1-methyl-piperidin-4-yl)-ethoxy]-biphenyl-4-sulfonyl }-1H-pyrrol-3-yl)-acrylamide, 69. (E)-3-[1-(3'-Dimethylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, 70. (E)-3-{1-[4-(2,3-Dihydro-benzofuran-5-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-hydroxy- Acrylamide, 71. (E)-N-hydroxy-3-[1-(4'-𠰌lin-4-yl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-propenamide, 72. (E)-N-Hydroxy-3-{1-[3'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-4-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 73. (E)-N-hydroxy-3-(1-{3'-[3-(4-methyl-piperid-1-yl)-propoxy]-biphenyl-4-sulfonyl }-1H-pyrrol-3-yl)-acrylamide, 74. (E)-N-Hydroxy-3-{1-[3'-(3-𠰌olin-4-yl-propoxy)-biphenyl-4-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 75. (E)-N-hydroxy-3-[1-(3'-𠰌lin-4-ylmethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-propenyl amine, 76. (E)-N-hydroxy-3-(1-{4'-[2-(4-methyl-piperid-1-yl)-ethoxy]-biphenyl-4-sulfonyl }-1H-pyrrol-3-yl)-acrylamide, 77. (E)-N-Hydroxy-3-{1-[4'-(2-𠰌olin-4-yl-ethoxy)-biphenyl-4-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 78. (E)-N-hydroxy-3-{1-[4'-(3-𠰌olin-4-yl-propoxy)-biphenyl-4-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 79. (E)-N-hydroxy-3-(1-{4'-[3-(4-methyl-piperid-1-yl)-propoxy]-biphenyl-4-sulfonyl }-1H-pyrrol-3-yl)-acrylamide, 80. (E)-N-hydroxy-3-{1-[3'-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-4-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 81. (E)-N-Hydroxy-3-{1-[4'-(3-pyrrolidin-1-yl-propoxy)-biphenyl-4-sulfonyl]-1H-pyrrole-3 -Yl}-acrylamide, 82. (E)-N-hydroxy-3-[1-(4'-methoxy-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-propenamide, 83. (E)-N-hydroxy-3-(1-{4-[1-(2-𠰌olin-4-yl-ethyl)-1H-[1,2,3]triazol-4-yl ]Phenylsulfonyl}-1H-pyrrol-3-yl)-acrylamide, 84. (E)-3-[1-(4'-Cyclopentylaminomethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 85. (E)-N-hydroxy-3-[1-(3'-trifluoromethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide, 86. (E-3-{1-[5-(3-Dimethylaminomethyl-phenyl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl}-N-hydroxy- Acrylamide, 87. (E)-3-[1-(3`-Dimethylaminomethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 88. (E)-N-Hydroxy-3-{1-[4`-(2-𠰌olin-4-yl-ethyl)-biphenyl-3-sulfonyl]-1H-pyrrole-3- Yl}-acrylamide, 89. (E)-N-(2-Amino-phenyl)-3-{1-[6-(4-Dimethylaminomethyl-phenyl)-pyridine-3-sulfonyl]- 1H-pyrrol-3-yl}-acrylamide, 90. (E)-N-hydroxy-3-{1-[5-(2-methyl-thiazol-4-yl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl}-propene Amide, 91. (E)-3-[1-(4`-Aminomethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, 92. (E)-N-hydroxy-3-(1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridine-3-sulfonyl}-1H -Pyrrol-3-yl)-acrylamide, 93. (E)-3-[1-(4`-Aminomethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-(2-amino-phenyl )-Acrylamide, 94. (E)-3-{1-[5-(3-Aminomethyl-phenyl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl}-N-hydroxy-acrylic acid amine, 95. (E)-N-(2-Amino-phenyl)-3-{1-[5-(4-dimethylaminomethyl-phenyl)-thiophen-2-sulfonyl]- 1H-pyrrol-3-yl}-acrylamide, 96. (E)-N-(2-Amino-phenyl)-3-[1-(3`-Dimethylaminomethyl-biphenyl-4-sulfonyl)-1H-pyrrole- 3-yl]-acrylamide, 97. (E)-3-{1-[4`-(Acetylamino-methyl)-biphenyl-4-sulfonyl]-1H-pyrrol-3-yl}-N-(2 -Amino-phenyl)-acrylamide, 98. (E)-N-(2-Amino-phenyl)-3-{1-[4`-(methylsulfonylamino-methyl)-biphenyl-4-sulfonyl]- 1H-pyrrol-3-yl}-acrylamide, 99. (E)-N-hydroxy-3-(1-{5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiophen-2-sulfonyl}-1H -Pyrrol-3-yl)-acrylamide, 100. (E)-3-{1-[5-(4-Dimethylsulfamoyl-phenyl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl}-N-hydroxy -Acrylamide, 101. (E)-N-(2-Amino-phenyl)-3-[1-(4`-Methanesulfonylamino-biphenyl-3-sulfonyl)-1H-pyrrole-3 -Yl]-acrylamide, 102. (E)-N-(2-Amino-phenyl)-3-[1-(4`-dimethylaminomethyl-biphenyl-3-sulfonyl)-1H-pyrrole- 3-yl]-acrylamide, 103. (E)-N-hydroxy-3-{1-[2`-(4-methyl-piper-1-yl)-[2,4`]bipyridine-5-sulfonyl]-1H -Pyrrol-3-yl}-acrylamide, 104. (E)-N-(2-Amino-phenyl)-3-{1-[5-(1-methyl-1H-pyrazol-4-yl)-thiophene-2-sulfonyl] -1H-pyrrol-3-yl}-acrylamide, 105. (E)-3-{1-[6-(4-Dimethylaminomethyl-phenyl)-pyridine-3-sulfonyl]-1H-pyrrol-3-yl}-N-hydroxy -Acrylamide, 106. (E)-N-(2-Amino-phenyl)-3-(1-{5-[2-(4-methyl-piperid-1-yl)-pyridin-4-yl]- Thiophen-2-sulfonyl}-1H-pyrrol-3-yl)-propenamide, 107. (E)-N-(2-Amino-phenyl)-3-[1-(4`-𠰌olin-4-ylmethyl-biphenyl-4-sulfonyl)-1H-pyrrole -3-yl]-acrylamide, 108. (E)-N-(2-Amino-phenyl)-3-{1-[4`-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-4-sulfonyl Yl]-1H-pyrrol-3-yl}-acrylamide, 109. (E)-N-hydroxy-3-(1-{4-[1-(2-piperidin-1-yl-ethyl)-1H-[1,2,3]triazol-4-yl ]Phenylsulfonyl}-1H-pyrrol-3-yl)-acrylamide, 110. (E)-3-[1-(3`-Dimethylaminomethyl-biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 111. (E)-N-(2-Amino-phenyl)-3-(1-{5-[4-(Methanesulfonylamino-methyl)-phenyl]-thiophene-2-sulfon Acryl}-1H-pyrrol-3-yl)-acrylamide, 112. (E)-N-(2-Amino-phenyl)-3-{1-[3`-(Methylsulfonylamino-methyl)-Biphenyl-3-sulfonyl]- 1H-pyrrol-3-yl}-acrylamide, 113. (E)-3-(1-{5-[4-(Acetylamino-methyl)-phenyl]-thiophen-2-sulfonyl}-1H-pyrrol-3-yl)- N-(2-Amino-phenyl)-acrylamide, 114. (E)-N-(2-Amino-phenyl)-3-{1-[5-(3-dimethylaminomethyl-phenyl)-thiophen-2-sulfonyl]- 1H-pyrrol-3-yl}-acrylamide, 115. (E)-N-(2-Amino-phenyl)-3-[1-(3`-Dimethylaminomethyl-biphenyl-3-sulfonyl)-1H-pyrrole- 3-yl]-acrylamide, 116. (E)-3-[1-(3´-Dimethylaminomethyl-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide , 117. (E)-3-{1-[5-(3-Dimethylaminomethyl-phenyl)-thiophen-2-sulfonyl]-1H-pyrrol-3-yl}-N-hydroxy -Acrylamide, 118. (E)-3-{1-[3`-(Acetylamino-methyl)-biphenyl-3-sulfonyl]-1H-pyrrol-3-yl}-N-(2 -Amino-phenyl)-acrylamide, 119. (E)-N-(2-Amino-phenyl)-3-{1-[6-(1-methyl-1H-pyrazol-4-yl)-pyridine-3-sulfonyl] -1H-pyrrol-3-yl}-acrylamide, 120. (E)-N-Hydroxy-3-{1-[6-(1-methyl-1H-pyrazol-4-yl)-pyridine-3-sulfonyl]-1H-pyrrol-3-yl }-Acrylamide, and 121. (E)-3-{1-[6-(3-Dimethylaminomethyl-phenyl)-pyridine-3-sulfonyl]-1H-pyrrol-3-yl}-N-hydroxy -Acrylamide, And its salt.

In one embodiment of the foregoing, exemplary compounds according to the present invention may include, among others, compounds selected from the group consisting of 2, 4, 7, 16, 26, 28, 32, 33, 38, 42, and 46, as mentioned above. And any one of the group consisting of its salt.

As used herein, domasstat and (E)-N-(2-aminophenyl)-3-(1-((4-(1-methyl-1H-pyrazol-4-yl)phenyl )Sulfonyl)-1H-pyrrol-3-yl)propenamide (its chemical name) can be used interchangeably and both refer to compounds of the following formula:

Suitable salts for HDAC inhibitors are acid addition salts or salts with bases. Specific mention may be made of pharmacologically tolerable inorganic and organic acids, as well as pharmacologically commonly used bases. Those suitable salts, on the one hand, are water-insoluble and, in particular, water-soluble acid addition salts, which acids are used in salt formulations in equimolar ratios or in different ratios, especially in etc. The molar ratio is used. On the other hand, salts with bases-depending on the substitution-are equally suitable, and these bases are used in salt formulations in equimolar ratios or different ratios therefrom. The pharmacologically intolerable salt (which can be obtained as a process product during the industrial-scale preparation of HDAC inhibitors, for example) is converted into a pharmacologically tolerable salt by methods known to those skilled in the art. According to the present invention, for example, when isolated in a crystalline form, the HDAC inhibitor and its salt may contain different amounts of solvent. Therefore, all solvates, and in particular all hydrates and all solvates of HDAC inhibitors, and particularly all hydrates of HDAC inhibitors are included within the scope of the present invention, and in particular, each molecule of HDAC inhibitor or its salt contains Such solvates or hydrates of about 0.5, 1 or 2 solvates or water molecules.

In the context of the present invention, specific salts are domazestat with HBr, methanesulfonic acid, half ethane-1,2-disulfonic acid, benzenesulfonic acid, toluenesulfonic acid and 2-naphthalenesulfonic acid, more specifically Ground is a salt of toluenesulfonic acid, especially the molar ratio is about 1:1.

HDAC inhibitors, particularly domazestat and its salts can be prepared, for example, as described in detail in WO 2006/097474 A1 and WO 2009/112522 A1, respectively.

The ability of the immune checkpoint inhibitor of the present invention as a biological agent (such as an antibody) to bind to the immune checkpoint of the present invention can be performed using the purification domain of the target protein or cell, using ELISA or flow cytometry methods, and using various assays. (E.g. ELISA assay as described herein), assessed by in vitro/in vivo and/or cell-based assays.

The HDAC inhibitors of the present invention, especially domazestat and its corresponding salts, and the biological and medical properties of the immune checkpoint inhibitors of the present invention are described in the prior art (including but not limited to the references cited herein). Detailed Description.

In certain embodiments of the present invention, the HDAC inhibitor and the immune checkpoint inhibitor of the present invention may be administered simultaneously, sequentially or separately.

In some embodiments, the HDAC inhibitor can be administered within 30 minutes after breakfast or light breakfast or within 30 minutes after dinner or light dinner.

In the further context of the present invention, the term "active agent" refers to a pharmaceutical preparation that exerts a medical effect (for example, alleviation thereof) on a disease or medical condition, and the term specifically includes HDAC inhibitors and immune checkpoint suppression of the present invention Agent.

In an embodiment of the present invention, the active agent may be provided in a pharmaceutical composition comprising one or more of the active agent and a pharmaceutically acceptable carrier or diluent. Specifically, the HDAC inhibitor and the immune checkpoint inhibitor of the present invention can be provided in separate drugs.

Such pharmaceutical compositions can be provided in the context of pharmaceutical products, which include, for example, one or more pharmaceutical compositions and packaging materials. The packaging material typically includes a label or package insert that indicates that one or more active agents can be used to treat the diseases detailed herein. The packaging materials, labels and packaging inserts are otherwise similar to or similar to the standard packaging materials, labels and packaging inserts of drugs that are generally considered to have relevant utility.

The pharmaceutical composition according to the present invention is prepared by a method known per se and familiar to those skilled in the art. As a pharmaceutical composition, the active agents are used as they are, or specifically combined with suitable pharmaceutical adjuvants and/or excipients, such as tablets, coated tablets, capsules, caplets, suppositories, patches (such as It is used in combination in the form of TTS), emulsion, suspension, gel, or solution. The content of the active agent is advantageously between 0.1% and 95%, and by appropriate selection of adjuvants and/or excipients, A drug administration form (for example, a sustained-release form or an enteric form) that is completely suitable for the active agent and/or suitable for the desired effect can be realized.

The skilled person is familiar with adjuvants, vehicles, excipients, diluents, carriers or adjuvants suitable for the desired pharmaceutical formulation, preparation or composition due to his/her professional knowledge. In addition to solvents, gel forming agents, ointment bases, and other excipients (for example, antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents, or penetration enhancers) can be used.

In practicing the present invention and depending on the details, features or purposes of its use mentioned above, the active agents according to the present invention may be used in combination therapy separately, sequentially, simultaneously or alternately in chronological order (for example, as Combined unit dosage form (in the case of an orally applicable immune checkpoint inhibitor of the present invention, such as in the case of small molecules), as a single unit dosage form or adjacent discrete unit dosage forms, as a fixed (in the immune checkpoint inhibitor of the present invention) Orally applicable, such as in the case of small molecules) or non-fixed combinations, as kit-of-parts or mixtures (in the case of the immune checkpoint inhibitor of the present invention, applicable orally, such as in the case of small molecules) ) Investment.

"Fixed combination" is defined as a combination in which the first active ingredient and at least one additional active ingredient are present together in a unit dose or as a single entity (in the immune checkpoint inhibitor system of the present invention which is orally applicable, such as small molecule Case). An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the additional active ingredient are present as a mixture for simultaneous administration, such as in a single formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the additional active ingredient are present in one unit instead of as a mixture.

A "kit" is defined as a combination in which the first active ingredient and the additional active ingredient are present in more than one unit. An example of a "kit" is a combination in which the first active ingredient and the additional active ingredient are present separately. The components of the kit can be administered separately, sequentially, simultaneously, or crosswise in chronological order.

The first active ingredient and the additional active ingredient of the combination or kit according to the present invention can be provided in the following form: as separate formulations (ie independently of each other), which are then put together for simultaneous use in combination therapy Used sequentially, separately, or in chronological order; or packaged and presented together as the individual components of the combination package for simultaneous, sequential, separate, or chronological cross-use in combination therapy .

The type of pharmaceutical formulations of the first active ingredient and the other active ingredient of the combination or kit according to the present invention can be similar, that is, both ingredients are formulated in separate tablets or capsules, or can be different That is, it is suitable for different administration forms, for example, one active ingredient is formulated as a tablet or capsule, and the other is formulated for, for example, parenteral, especially intravenous administration.

Another aspect of the invention is a combination comprising a non-fixed form of HDAC inhibitor and one or more additional therapeutic agents for sequential, separate, simultaneous or chronological cross-use in therapy in any order. If necessary, the combination includes instructions for using it in therapy.

Another aspect of the present invention is a combination preparation, such as a kit, which contains an HDAC inhibitor, a pharmaceutically acceptable carrier or diluent, and one or more additional therapeutic agents; and, if necessary, simultaneously during therapy , Sequence, separate or cross-use instructions in chronological order.

Another aspect of the present invention is a kit comprising a dosage unit of HDAC inhibitor, a dosage unit of one or more additional therapeutic agents, and instructions for simultaneous, sequential, or separate use in therapy as needed .

Another aspect of the present invention is a pharmaceutical product that contains an HDAC inhibitor, or one or more pharmaceutical compositions containing the compound; and one or more additional therapeutic agents, or one or more of the therapeutic agents. Multiple pharmaceutical compositions for simultaneous, sequential or separate use in therapy. If necessary, the drug product includes instructions for use in the therapy.

Another aspect of the present invention is a pharmaceutical composition as a single dosage form. The pharmaceutical composition contains an HDAC inhibitor, one or more additional therapeutic agents, and optionally a pharmacologically acceptable carrier, diluent or agent in the form of a mixture. excipient.

Another aspect of the invention is a commercial package that includes the HDAC inhibitor together with instructions for simultaneous, sequential or separate use with one or more additional therapeutic agents.

In addition, the combination according to the present invention can be used for preoperative or postoperative treatment.

Moreover, in addition, the combination according to the present invention can be used in combination with radiotherapy, particularly in terms of sensitizing patients to standard radiotherapy.

The administration of the combination according to the present invention and the pharmaceutical composition according to the present invention can be carried out in any generally accepted mode of administration available in the art. Illustrative examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal, and rectal delivery. In a specific embodiment of the present invention, the HDAC inhibitor is administered by oral delivery and the immune checkpoint inhibitor of the present invention, specifically all the immune checkpoint inhibitors of the present invention are administered parenterally, especially It is intravenous in the case of biologics, for example by oral delivery in the case of small molecules.

In the embodiments of the present invention, the dose refers to the amount of the compound relative to the free form of the compound (ie, the free acid form or the free base form of the compound). Therefore, such adducts, salts, etc. in the form of free acid or free base will actually be administered in a correspondingly higher dose in order to account for the weight of the counterion or addition partner. For example, with regard to domazestat tosylate, the "100 mg dose of domazestat" refers to (rounded up) 138 mg domazestat tosylate-including 100 mg domazestat free base and 38 mg toluenesulfonic acid (molecular weight of domazestat = 447.513 g/mol; molecular weight of domazestat tosylate = 619.711 g/mol; therefore 100: 447.513 * 619.711 = 138).

Having described the present invention in detail, the scope of the present invention is not limited to those described features or embodiments. As it will be obvious to those familiar with the technology, it can be based on knowledge known in the field and/or, in particular, in the disclosure of the present invention (for example, explicit, implicit or inherent disclosure) On the basis of, without departing from the spirit or scope of the present invention as defined in the scope of the appended patent application, the described invention is modified, analogized, changed, derived, assimilated and adapted.

As used herein, unless otherwise stated, the term "including" should be understood to mean "including but not limited to." Similarly, "including" should be understood as generally not limited to the items listed in each instance, but may include additional items.

As used herein and in the scope of the appended application, the singular forms "a/kind" and "the" include multiple referents unless otherwise specified. For example, "a" excipient includes one or more excipients.

The term "about" as used herein when referring to a value specifically encompasses 90% to 110% of the stated value, more specifically 95% to 105% of the stated value.

As used in this article, expressions such as "to be voted" also mean "to be voted."

The "inhibition" of a reaction or parameter includes blocking and/or inhibiting the reaction or parameter when compared with other conditions of the same except the parameter of interest, or alternatively compared with another condition, for example, with Compared with the presence of PD-1 ligand and no PD-1 inhibitor, PD-1 transmission is reduced in the presence of PD-1 ligand and PD-1 inhibitor.

The "effective amount" of the medicament disclosed herein is an amount sufficient to achieve the stated purpose. The "effective amount" can be determined empirically according to the stated purpose. The "effective amount" or "sufficient amount" of an agent is an amount sufficient to achieve the desired biological effect, such as beneficial results, including beneficial clinical results. The term "therapeutically effective amount" refers to the amount of an agent that is effective to "treat" a disease or condition in a subject (e.g., a mammal, such as a human). In the case of combination therapy, "effective amount" refers to the amount of active agents in combination (for example, HDAC inhibitors and, for example, CTLA-4 inhibitors and PD-1 inhibitors or PD-L1 inhibitors). Together to effectively "treat" the subject's disease or condition. An "effective amount" or "sufficient amount" of one or more agents can be administered in one or more doses.

The term "treating or treatment" of a disease refers to the implementation of a regimen in an attempt to alleviate the signs or symptoms of the disease. The regimen may include the administration of one or more drugs to an individual (human or other). Therefore, "treating (treating or treatment)" does not require complete alleviation of symptoms or symptoms, and does not require cure, and specifically includes a plan that only has a palliative effect on the individual. As used herein, and as is well known in the art, "treatment" is a method used to obtain beneficial or desired results (including clinical results). Beneficial or desired clinical results include, but are not limited to, reduction or improvement of one or more symptoms, reduction of disease severity, stable (i.e., non-deteriorating) state of disease, prevention of disease transmission, delay or slowing of disease progression, and improvement of disease state Improvement or mitigation, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonged survival compared to the expected survival of an individual not receiving treatment. To "alleviate" a disease or condition means that the degree of the disease or condition and/or adverse clinical manifestations are reduced and/or the time course of progression of the disease or condition is slowed compared to the expected untreated result. In addition, palliative treatment does not necessarily occur by administering one dose, but usually occurs when administering a series of doses.

For the sake of clarity, the use of a combination of HDAC inhibitors with CTLA-4 inhibitors and PD-1 inhibitors or PD-L1 inhibitors etc. according to the present invention is intended to involve the use of HDAC inhibitors, CTLA-4 inhibitors and PD -1 triple combination of inhibitors, or triple combination of HDAC inhibitors, CTLA-4 inhibitors and PD-L1 inhibitors.

As used herein, the treatment of cancer can also refer to the treatment of subjects suffering from cancer, such as human subjects suffering from cancer or cancer patients.

In the present invention, the administration of the active agent may follow a certain plan, and the certain plan may include a time period during which the active agent is administered daily and a time period in which only one active agent is administered or no active agent is administered. Specifically, such a program includes a treatment cycle, in which such a treatment cycle can usually be repeated as often as necessary (that is, as deemed appropriate by the doctor in charge of the treatment).

The treatment period is especially 12-16 days treatment period, 2 weeks treatment period, 17-25 days treatment period, 3 weeks treatment period, 24-32 days treatment period, 4 weeks treatment period, 30-40 days treatment period, 5 weeks treatment period Cycle, 37-47 days treatment cycle, or 6-week treatment cycle, more particularly 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks treatment cycle, even more particularly 2 weeks, 3 weeks, or 4 weeks Weekly treatment cycles, even more particularly 2 or 3 week treatment cycles, even more particularly 3 week treatment cycles.

In some embodiments, where the immune checkpoint inhibitors of the present invention are biological agents, they are only administered on the first day of each treatment cycle. The treatment cycle then follows the conventional administration cycle of the immune checkpoint inhibitor of the present invention, for example, as commonly used by doctors and/or as approved by government agencies. In the case of the immune checkpoint inhibitors of the present invention which are suitable for oral administration, such as small molecules, they can usually be administered after the HDAC inhibitor administration schedule or continuously, or according to different modes. For example, this article aims at HDAC inhibition. The different modes described (for example, the HDAC inhibitor is administered every other day, and the immune checkpoint inhibitor of the present invention is administered orally applied every day.

In certain embodiments, treatment may include a first treatment cycle in which only HDAC inhibitors are administered (ie, no immune checkpoint inhibitors of the invention are administered). Then after the first treatment cycle, treatment is performed with the combination of the immune checkpoint inhibitor of the present invention and the HDAC inhibitor as detailed herein. The treatment cycle may be the same as the treatment cycle described herein in other ways (except for the administration of the immune checkpoint inhibitor of the present invention) in duration and administration of the HDAC inhibitor.

In certain embodiments, in each treatment cycle, the HDAC inhibitor can be administered for a certain number of days, followed by no HDAC inhibitor for several days. In a specific embodiment, the HDAC inhibitor is administered daily for 14 days in a three-week treatment cycle, or daily for 7 days in a two-week treatment cycle, with no HDAC inhibitor administered for the next 7 days in each case .

In other specific embodiments, the HDAC inhibitor is administered continuously, that is, a daily dose is administered every day for the duration of the treatment.

In a specific embodiment, the PD-1 or PD-L1 inhibitor is administered on day 1 of a 2-week or 3-week treatment cycle.

In a specific embodiment, the CTLA-4 inhibitor is administered every 2-4 days, especially every 3 days.

References and claims to the use of certain compounds in their general and specific forms for the manufacture of drugs for the treatment of cancer in combination with certain other agents also relates to: a) The use of said compounds in the manufacture of said other drugs The use of certain combinations of drugs for the treatment of cancer; b) a method of treating the disease or medical condition, the method comprising administering a therapeutically effective amount of the certain compound to a subject in need, and Administering to the subject a therapeutically effective amount of the additional certain agents; c) a method of treating the disease or medical condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of Said certain compound, said certain compound is used in combination with said other certain agent; d) A composition containing said certain compound, used in combination with said other certain agent to treat said disease or Medical condition; e) a composition containing the certain compound for the treatment of the disease or medical condition, and the composition is used in combination with the other certain agents; f) used with the other The certain compound used in the treatment of the disease or medical condition in combination with some of the medicaments; g) the certain compound used in the treatment of the disease or medical condition in combination with the other certain medicament Compound; and vice versa. Instance

The following examples are used to further illustrate the present invention without limiting the present invention. Materials and methods 1.1. Test substance • Domazestat (tosylate). • Anti-PD1 antibody (clone: RMP1-14, catalog: BE0146, isotype: rat IgG2a, Bioxcell), • Anti-CTLA-4 antibody (clone: 9H10, catalog: BE0131, isotype: Syrian hamster IgG, Bioxcell) ), 1.2. Vehicles • Suspend domazestat in 2% methylcellulose aqueous solution at 2 mg/ml (active compound). • Dilute the anti-PD-1 antibody with PBS to reach a final concentration of 1 mg/ml. • Dilute anti-CTLA-4 antibody with PBS to reach a final concentration of 0.5 mg/ml. 1.3. Therapeutic dose • Based on domazestat free base, domazestat is administered twice a day at a dose of 20 mg/kg for up to two weeks. • Anti-PD-1 antibodies are injected twice a week at a dose of 10 mg/kg each for up to two weeks, • 10 mg/kg each injection and 5 mg/kg anti-CTLA-4 antibodies twice a week , Lasts up to two weeks. 1.4. Administration route • Domasstat is administered by oral gavage (oral, PO) via a feeding tube. • Inject the antibody intraperitoneally into the peritoneal cavity of the mouse. • In all cases, the administration volume is 10 mL/kg, adjusted to the individual body weight of the mouse closest. 1.5. Cancer cell lines and culture conditions • CT-26 cell line is murine colon adenocarcinoma (American Type Culture Collection, USA). CT-26 cell line BALB/c nude mice N-nitroso-N-methylurethane-(NNMU) induced undifferentiated colon cancer cell line [WANG M., et al. J. Immunol. [Immunology] Journal] 154: 4685-4692, 1995]. By the 200 μL RPMI 1640 of 1 x 10 ⁶ th CT-26 cells were injected subcutaneously into Balb / c mice right flank induced tumors. 1.6. Use of animals 1.6.1. Animals • Maintain animals in SPF health according to FELASA guidelines, • According to French and European Regulations and NRC Laboratory Animal Care and Use Guidelines (NRC Guide for the Care and Use of Laboratory Animals) to realize animal feeding and experimental procedures, • Use RFID reactors to individually identify animals, • Each cage is marked with a specific code. 1.6.2. Feeding conditions • Keep animals in the breeding room under controlled environmental conditions: • Temperature: 22°C ± 2°C, • Humidity 55% ± 10%, • Photoperiod (12 h light/12 h dark), • HEPA filtered air, • 15 air exchanges per hour, no recirculation. • Animal enclosures provide sterile and sufficient space, as well as bedding, food and water, environmental and social enrichment (group feeding): top filter polycarbonate Eurostandard type III or IV cages; corn cob bedding (reference: LAB COB 12, SERLAB, France); 25 kGy irradiated food (Ssniff® Soest, Germany); whole food for immunodeficient rodents-NM extrudate; whole food for immunocompetent rodents-R/MH extrusion Materials; sterile, filtered water at 0.2 µm; environmental enrichment (SIZZLE-dri kraft-D20004 SERLAB, France). 1.6.3. Treatment plan • ^{Start treatment when the tumor reaches an average volume of 100 mm 3} (day 8). Use Vivo Manager ^® software (Biosystemes, Couternon, France), according to their respective tumor volume of animals were randomized into groups each having 8 animals. A statistical test (analysis of variance, ANOVA) was performed to test the homogeneity between the groups. The treatment options are as follows: • Animals from group 1 receive PO administration of vehicle twice a day (2Q1Dx14) for 14 consecutive days. The twice-daily treatments will be separated by a 12-hour period. • Animals from Group 2 will receive a PO administration of 20 mg/kg/adm domazestat twice a day (2Q1Dx14) for 14 consecutive days. The two-day treatments will be separated by a 12-hour period, • Animals from group 3 receive an IP injection of 5 mg/kg of anti-CTLA-4 twice a week (TWx2) for two consecutive weeks, • from group 4 Of animals received a 10 mg/kg IP injection of anti-PD1 twice a week (TWx2) for two consecutive weeks, • animals from group 5 received 5 mg/kg twice a week (TWx2) for two consecutive weeks One dose of anti-CTLA-4 IP injection combined with 20 mg/kg/adm domasstat twice a day (2Q1Dx14) PO administration for 14 consecutive days. The two treatments per day will be separated by a 12-hour period. Anti-CTLA4 antibody treatment was performed 6 hours after morning domasstat treatment, • Animals from group 6 received a combination of 10 mg/kg anti-PD1 IP injections twice a week (TWx2) for two consecutive weeks Domasstat was administered twice a day (2Q1Dx14) PO administration of 20 mg/kg/adm for 14 consecutive days. The two treatments per day will be separated by a 12-hour period. Anti-PD1 antibody treatment was performed 6 hours after morning domasstat treatment. • Animals from group 7 received a combination of 10 mg/kg anti-PD1 IP injections twice a week (TWx2) for two consecutive weeks One IP injection of 5 mg/kg of anti-CTLA-4 twice a week (TWx2) for two consecutive weeks. Anti-CTLA4 antibody treatment was performed 15 minutes before anti-PD1 treatment. • Animals from group 8 received a combination of 5 mg/kg anti-CTLA-4 IP injection twice a week (TWx2) for two consecutive weeks and 10 mg twice a week (TWx2) for two consecutive weeks One-dose IP injection of anti-PD1/kg combination of 20 mg/kg/adm domazestat was administered twice a day (2Q1Dx14) PO administration for 14 consecutive days. The two treatments per day will be separated by a 12-hour period. Anti-CTLA4 antibody treatment was performed 6 hours after morning domasstat treatment. Anti-PD1 antibody treatment was performed 15 minutes after anti-CTLA-4 treatment. 1.6.4. Tumor and clinical monitoring • All research data, including animal weight measurement, tumor volume, clinical and mortality records, and treatment are arranged and recorded in the Vivo Manager ^® database (Biosystemes, Dijon, France) )in. • Record survivability and behavior every day. Measure your body weight twice a week. Use a caliper to measure the length and width of the tumor twice a week, and estimate the volume of the tumor by the following formula: Tumor volume = width ² × length / 2

The 16th day was defined as the end of the study, because after the 16th day, a large number of animal tumors in the study exceeded 1500 mm ³ (ethical standard) and had to be sacrificed.

The data showed that anti-CTLA-4 antibodies and domasstat as monotherapy reduced tumor growth to some extent (groups B and C), while the anti-PD-1 antibody alone (group D) had no effect. It is worth noting that the dual combination display of domazestat + anti-CTLA-4 (group E), domazestat + anti-PD-1 (group F) and anti-CTLA-4 + anti-PD-1 (group G) Outcomes the beneficial effects of domasstat alone (group B) and anti-CTLA-4 (group C). Interestingly, although anti-PD-1 alone did not show any anti-tumor effects, compared with domasstat alone (group B), the dual combination of domasstat + anti-PD-1 (group F) )More effective.

Most strikingly, the triple combination of domazestat with anti-CTLA-4 and anti-PD-1 antibodies (group H) unexpectedly resulted in a further significant increase and decrease in tumor growth compared to monotherapy and dual combination Overall best anti-tumor efficacy. The anti-tumor effect of this group is very significant, p = 0.003 (**) (see Figure 2). Interestingly, this triple combination (group H) resulted in the most uniform anti-tumor effect (Figure 3).

no

[Figure 1]: According to the CT26 model in the example part, it is the average value of all animals in each group at each time point, with the number of days on the x-axis and the tumor volume (mm ³ ) on the y-axis. Remove the standard deviation for better legibility; for an indication of the standard deviation, see Figure 2 of the box plot with the 16th day data points. A: vehicle; B: domasstat, C: anti-CTLA-4, D: anti-PD-1, E: domasstat + anti-CTLA-4, F: domasstat + anti-PD-1, G: anti-CTLA-4 + anti-PD-1, and H: domasstat + anti-CTLA-4 + anti-PD-1;

[Figure 2]: According to the CT26 model of the example part, the box-and-whisker plot of the data points on the 16th day according to the CT26 model of the example part, the tumor volume (mm ³ ) is on the y-axis. All points are displayed, the box plot shows 5-95 percentiles, and + represents the average value. A: vehicle; B: domasstat, C: anti-CTLA-4, D: anti-PD-1, E: domasstat + anti-CTLA-4, F: domasstat + anti-PD-1, G: anti-CTLA-4 + anti-PD-1, and H: domasstat + anti-CTLA-4 + anti-PD-1; before the 16th day, remove one animal from each group in groups A, C and D, and The tumor volume of these animals was analyzed graphically and statistically. Statistics: The Kruskal-Wallis test and Dune's multiple comparison were performed in the treatment group relative to the vehicle, ns was not significant, group H The only one statistically different from group A, p = 0.003 (**)

[Figure 3]: According to the CT26 model of the example part, the individual tumor curve, the x-axis is the number of days, and the y-axis is the tumor volume (mm ³ ). A: vehicle; B: domasstat, C: anti-CTLA-4, D: anti-PD-1, E: domasstat + anti-CTLA-4, F: domasstat + anti-PD-1, G: anti-CTLA-4 + anti-PD-1, and H: domasstat + anti-CTLA-4 + anti-PD-1

no

Claims (8)

The use of an HDAC inhibitor in combination with a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor for the manufacture of drugs for the treatment of cancer, wherein the HDAC inhibitor is a molecule of general formula I

Wherein R1, R4 and R5 are independently hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy, R2 and R3 are independently hydrogen or 1-4C-alkyl, and R6 is -T1-Q1 , Wherein T1 is a bond or 1-4C-alkylene, or Q1 is substituted by R61 and/or R62 and is Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, or Q1 is unsubstituted and is Ha2, Ha3 Or Ha4, where R61 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkoxy, hydroxy, trifluoromethyl, cyano, halogen, 1- 4C-alkoxy or 1-4C-alkoxy in which more than half of the hydrogen atoms are replaced by fluorine atoms, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1 -4C-Alkylsulfonylamino, tosylsulfonylamino, phenylsulfonylamino, 1-4C-alkylcarbonylamino, aminomethanyl, sulfamoyl, mono-or Di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, -T2-N(R611)R612, -U-T3-N(R613)R614, -T4 -Het3 or -V-T5-Het4, where T2 is a bond or 1-4C-alkylene, R611 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethane Group, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl, or 1-4C-alkylsulfonyl, R612 is hydrogen or 1 -4C-Alkyl, or R611 and R612 together and including the nitrogen atom to which they are combined form a heterocyclic Het1, where Het1 is a sulfonyl group, a thiosulfonyl group, and an S-pendant oxy-thiosulfonyl group Sub-group, S,S-di-pendant oxy-thio-thiolino, piperidino, pyrrolidino, piperidino, or 4N-(1-4C-alkyl)-piperidino , U is -O-(oxygen) or -C(O)NH-, T3 is 2-4C-alkylene, R613 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C -Cycloalkylmethyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, 1-4C-alkylcarbonyl, or 1-4C-alkylsulfonyl R614 Hydrogen or 1-4C-alkyl, or R613 and R614 together and at the same time include the nitrogen atom to which they are bound to form a heterocyclic Het2, where Het2 is 𠰌alolino group, thio𠰌alolino group, S- pendant oxy- Thiothiolino, S,S-di-side oxy-thiothiolino, piperidino, pyrrolidino, piperidino, or 4N-(1-4C-alkyl)- Piperidine group, T4 bond or 1-4C-alkylene group, Het3 is 1N-(1-4C-alkyl)-piperidinyl or 1N-(1-4C-alkyl)-pyrrolidinyl, V Is -O- (oxygen) or -C(O)NH-, T5 bond or 1-4C-alkylene, Het4 is 1N-(1-4C-alkyl)-piperidinyl or 1N-(1-4C-alkyl)-pyrrolidine R62 is 1-4C-alkyl, 1-4C-alkoxy or halogen, Aa1 is a diaryl radical composed of two aryl groups, and these aryl groups are independently selected from phenyl Hh1 is a bi-heteroaryl radical composed of two heteroaryl groups, and these heteroaryl groups are independently selected from containing one or A group consisting of two heteroatomic monocyclic 5- or 6-membered heteroaryl radicals, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and the heteroaryl groups Groups are linked together by single bonds, Ah1 is an aryl group selected from the group consisting of phenyl and naphthyl and a monocyclic 5- or 6-membered heteroaryl group selected from the group consisting of one or two heteroatoms An arylheteroaryl radical composed of heteroaryl groups in a group consisting of radicals, whereby the aryl and heteroaryl groups are linked together by a single bond, and thus Ah1 is through the The heteroaryl moiety is bonded to the parent molecular group, and each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and Ha1 is selected from the group consisting of monocyclic 5-or containing one or two heteroatoms. Heteroaryl groups consisting of 6-membered heteroaryl radicals and heteroaryl aryl radicals consisting of aryl groups selected from the group consisting of phenyl and naphthyl, whereby the hetero The aryl and aryl groups are linked together by a single bond, and thus Ha1 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur Ha2 is a heteroaryl group selected from the group consisting of fused bicyclic 9- or 10-membered heteroaryl radicals including one, two or three heteroatoms and is selected from the group consisting of phenyl and Heteroaryl aryl radicals composed of aryl groups of the naphthyl group, whereby the heteroaryl and aryl groups are connected together by a single bond, and thus Ha2 is through the aryl The base moiety is bonded to the parent molecular group, and each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, and Ha3 is selected from the group consisting of monocyclic 5-membered heteroatoms including three or four heteroatoms. Heteroaryl groups consisting of aryl radicals and heteroaryl aryl radicals consisting of aryl groups selected from the group consisting of phenyl and naphthyl, whereby the heteroaryl and aryl radicals The groups are joined together by single bonds, and thus Ha3 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, Ha4 is a heteroaryl group selected from the group consisting of a benzene ring containing no heteroatoms and a partially saturated fused bicyclic 9- or 10-membered heteroaryl radical with one or two heteroatoms and selected A heteroaryl aryl radical composed of an aryl group consisting of a phenyl and naphthyl group, whereby the heteroaryl and aryl groups are connected by a single bond Together, and thus Ha4 is bonded to the parent molecular group through the aryl moiety, each of these heteroatoms is selected from the group consisting of nitrogen, oxygen and sulfur, R7 is a hydroxyl group, or Cyc1, where Cyc1 The ring system of formula Ia

Wherein A and B are C (carbon), R71 and R72 are independently hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy, M includes both A and B are ring Ar2 or ring Har2, wherein Ar2 is a benzene ring, Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring, the heteroaromatic ring contains one to three heteroatoms, each of which is selected from nitrogen, oxygen and sulfur The group of, or the molecule of general formula III:

(III) Wherein: R ⁰ is halogen; p is 0, 1, or 2; W is -NHC(O) (C ₁ -C ₆ alkyl) or -CH ₂ NH-V; and V is -CO _2- CH ₂ -(heteroaryl), -C(O)-CH=CH-(heteroaryl), or a heteroaryl group substituted with 1-3 heteroaryl groups as needed, or a salt or solvate thereof. The use according to claim 1, wherein the HDAC inhibitor is specific for class I HDAC. The use according to any one of claim 1 or 2, wherein the HDAC inhibitor is (E)-N-(2-aminophenyl)-3-(1-((4-(1-methyl -1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)acrylamide or a salt or solvate thereof. The use according to any one of claims 1 to 3, wherein the HDAC inhibitor is (E)-N-(2-aminophenyl)-3-(1-((4-(1-methyl) -1H-pyrazol-4-yl)phenyl)sulfonyl)-1H-pyrrol-3-yl)acrylamide tosylate. The use according to any one of claims 1 to 4, wherein the CTLA-4 inhibitor is selected from the group consisting of: ipilimumab (Medarex Inc), tisili Tremelimumab (Pfizer Inc), AGEN-1884 (4-Antibody AG), AK-104 (Akeso Biopharma Inc), BMS-986218 ( Bristol-Myers Squibb Co), BMS-986249 (CytomX Therapeutics Inc), KN-046 (Suzhou Alphamab Co Ltd), ADU-1604 (Aduro BioTech Inc), AGEN-1181 (Agenus Inc), ATOR-1015 (Alligator Bioscience AB), BCD-145 ( Biocad Ltd), CS-1002 (CStone Pharmaceuticals Co Ltd), FPT-155 (Five Prime Therapeutics Inc), MEDI-5752 (Midi Medimmune Oncology Inc), MGD-019 (MacroGenics Inc), MK-1308 (Merck Sharp & Dohme Corp), PF-06753512 (Pfizer), PF -06936308 (Pfizer), REGN-4659 (Regeneron Pharmaceuticals Inc), XmAb-20717 (Xencor Inc), XmAb-22841 (Zancor)), AGEN-2041 (An Dijunsi), ALPN-202 (Alpine Immune Sciences Inc), APL-509 (Crown Bioscience Inc), aptCTLA-4 (Academia Sinica), ATOR-1144 (Alligator Biosciences Company), BA-3071 (Atala Biological Company (BioA tla Llc)), BCD-217 (Biocard), BPI-002 (BeyondSpring Pharmaceuticals Inc), CCC-0701 (Zenyaku Kogyo Co Ltd), CG- 0161 (Cold Genesys Inc), HBM-4003-2 (Harbour BioMed), Irr-VACV-CTLA-4 (Genelux Corp), JS-007 (Shanghai Junshi Biosciences Co., Ltd. (Shanghai Junshi Biosciences Co Ltd), KN-044 (Corning Jerry (Suzhou) Co., Ltd.), ONC-392 (OncoImmune Inc), ONCR-177 (OncoImmune Inc) Company (Oncorus Inc), PBI-5D3H5 (Premier Biomedical Inc), PRS-300 A series (Pieris Pharmaceuticals Inc), PSB-205 (Sound Biologics) ), RP-2 (Replimune Group Inc), RP-3 (Replimune Group Inc), and SN-CA21 (Synovel Sciences Inc), TBio-6517 (Teen Stone Biological Products Company (Turnstone Biologics Inc) and JHL-1155 (HumOrigin Inc). The use according to any one of claims 1 to 5, wherein the PD-1 inhibitor is selected from the group consisting of: pinclizumab (CT-011, CureTech), AMP- 224 (MedImmune Co., Ltd. (MedImmune)), AB122 (Harbin/Wuxi/Arcus), AMP-224 (MedImmune Co., Ltd.), MEDI-5752 (MedImmune) Medimmune Oncology Inc), PD1-PIK (Huashan Hospital), PF-06936308 (Pfizer Inc), RG-7769 (Hoffmann-La Roche AG) , F-520 (Shandong New Time Pharmaceutical Co Ltd), CAB PD-1 antibody (BioAtla Llc), AK-123 (Akeso Biopharma Inc), MEDI-3387 (Midi Muni Co., Ltd.), MEDI-5771 (Midi Muni Co., Ltd.), 4H1128Z-E27 (Eureka Therapeutics Inc); Memorial Sloan-Kate Lin Cancer Center (Memorial Sloan-Kettering Cancer Center), REMD-288 (Shandong Danhong Pharmaceutical Co Ltd), SG-001 (Hangzhou Sumgen Biotechnology Co Ltd) ), BY-24.3 (Beijing Beyond Biotechnology Co Ltd; Hangzhou Shangjian Biotechnology Co., Ltd.), CB-201 (Crescendo Biologics Ltd), IBI -319 (Adimab LLC; Eli Lilly &Co; Innovent Biologics Inc), ONCR-177 (Oncorus Inc), Max -1 (Maxinovel Pharmaceuticals Inc), CS-4100 (Shenzhen Microchip Biotechnology Co., Ltd. (Shenzhe n Chipscreen Biosciences Ltd), JBI-426 (Jubilant Biosys Ltd), CCC-0701 (Zenyaku Kogyo Co Ltd), CCX-4503 (ChemoCentryx Inc) ), Nivolumab (BMS), Pembrolizumab (MSD), BCD-100 (Biocad), Seprolizumab (Regeneron Pharmaceuticals), Sintilizumab Anti-(IBI-308, Eli Lilly/Cinda Biopharmaceuticals), JNJ-3283 (Johnson & Johnson), Spartizumab (PDR-001, Novartis Group), Carrelizumab (SHR-1210, Incyte Corp/Jiangsu Hengrui), Tilelizumab (BeiGene Ltd), AGEN-2034 (Antigens Corp ( Agenus Inc)), MEDI-0680 (AMP-514; Amplimmune/Midimuone Co., Ltd.), Teriplimumab (JS-001, Shanghai Junshi Biomedical Technology Co., Ltd. (Shanghai Junshi Bioscience Co Ltd), Dotalizumab (TSR-042, Tesaro), ABBV-181 (AbbVie Inc), AK-104 (Kangfang Biomedicine Company), AK- 105 (Kangfang Biopharmaceutical Company), BAT-1306 (Bio-Thera Solutions Ltd), BI-754091 (Boehringer Ingelheim), CBT-501, Genozumab (CBT Pharmaceutical company (CBT Pharmaceuticals Inc/Genor), GLS-010 (Harbin Gloria/Wuxi/Axis), LZM-009 (Livzon Pharmaceutical Group Inc), MGA-012 (Insett/MacroGenics), MGD-013 (MacroGenics), PF-06801591 (Pfizer), Sym-021 (Sifogen Group), CS-1003 (Cornerstone Pharmaceuticals) Industry Co., Ltd. (CStone Pharmaceuticals Co Ltd), HLX-10 (Henlix Biotech)/Shanghai Fuhong Hanlin Biotech Co., Ltd. (Shangh ai Henlius Biotech Co Ltd), AK-103 (Kangfang Biomedicine Company), AM-0001 (Amo Biosciences Company), TILT-123 (TILT Biotherapeutics Ltd), BH-2922 (Beijing Hanmi Pharmaceutical (Beijing Hanmi Pharmaceutical), BH-2941 (Beijing Hanmi Pharmaceutical), BH-2950 (Beijing Hanmi Pharmaceutical), CX-188 (CytomX Therapeutics Inc), ENUM-244C8 ( Enumeral Biomedical Holdings), ENUM-388D4 (Enumeral Biomedical Holdings), HAB-21 (Suzhou Stainwei Biotech Inc), HEISCOIII-003 ( Sichuan Haisco Pharmaceutical (Sichuan Haisco Pharmaceutical), IKT-202 (Icell Kealex Therapeutics), JS-003 (Shanghai Junshi Biomedical Technology), JTX-4014 (Johnson Medical Corporation ( Jounce Therapeutics Inc), MCLA-134 (Merus NV), MGD-019 (Macro Gene Company), MT-17000 (Molecular Templates Inc), PEGMP-7 (D5Pharma) ), PRS-332 (Pieris Pharmaceuticals Inc), RXI-762 (RXi Pharmaceuticals Corp), STI-1110 (Les Laboratoires Servier, France)/ Sorrento (Sorrento), VXM-10 (Vaximm AG), XmAb-20717 (Zanco), XmAb-23104 (Zanco), AK-112 (Kangfang Biomedical Company) ), HLX-20 (Hanlius Biotech/Shanghai Fuhong Henlius Biotechnology Co., Ltd.), SSI-361 (Lyvgen Biopharma Ltd), AT-16201 (Aim Medical Co., Ltd.) AIMM Therapeutics BV) and SNA-01 (Fountain Biopharma I nc)). The use according to any one of claims 1 to 6, wherein the PD-L1 inhibitor is selected from the group consisting of: BCD-135 (Biocard), APL-502 (CBT-402 or TQB2450) , Innovative Biopharmaceutical Company), MDX-1105 (BMS-936559, Bristol-Myers Squibb), IMC-001 (ImmuneOncia Medical Company; Sorrento Medical Company), KD-045 (Nanjing Kaidi Biotechnology Company), INBRX- 105 (Kewang Biopharmaceutical Company; INHIBRx Company), KN-046 (Corning Jerry (Suzhou) Co., Ltd.), INCB-086550 (Insett), IMC-2102 (ImmuneOncia Medical Company), IMC-2101 (ImmuneOncia Medical company), anti-PDL1-TGFbRIIecd (Johns Hopkins University; Y-Trapp Company), KD-005 (Nanjing Kaidi Biotechnology Company), PM-PDL-GEX (Glactop Company), IMM-2502 (Immuno-Oncology Biopharmaceutical Co., Ltd.), 89Zr-CX-072 (Sitomax Medical Co.; Groningen University Medical Center, KY-1055 (Kamaibo Co., Ltd., MEDI-1109 (Midi Muuni Co., Ltd.) Company), MT-5594 (Molecular Template Company), 89Zr-DFO-6E11 (Minerva Imaging; Thermo Fisher Scientific), SL-279252 (Saudi Crabs Company; Takeda Pharmaceutical Co., Ltd.), DSP-106 (KAHR Medical Co., Ltd.; University of Groningen Medical Center), Gensci-047 (Jinsai Pharmaceutical Co., Ltd.), REMD-290 (Shandong Danhong Pharmaceutical Co., Ltd.), N-809 (Nantwest Company; American National Cancer Institute), PRS-344 (Pieris Pharmaceuticals; Servier), FS-222 (F-Star Biotechnology Co., Ltd.), GEN-1046 (BioNTech SE; Genmab Holdings), BH-29xx ( Beijing Hanmei Pharmaceutical Co., Ltd.), Atezolizumab (Genentech), Avirulumab (Merck Group/Pfizer), Duvaluzumab (AstraZeneca/Midimuu) Co., Ltd.), BGB-A333 (BeiGene Co., Ltd.), CX-072 (Xitomax Medical), GNS-1480 (Yue Yuen Company/Kino Cisco), AMP-224 (Midi Muni Co., Ltd.) , CA-170 (Orekini Discovery Technology Co., Ltd.), CK-301 (Checkpoint Medical/TG Medical), CS-1001 (Cornerstone Pharmaceutical Co., Ltd.), FAZ-053 (Novartis Group), Iwafli Resistance (ASC22 or KN-035; Corning Jerry (Suzhou)/Side Di (3DMed)), LY-3300054 (Eli Lilly), M-7824 (Merck Group), HTI-1088 (HTI-131, SHR-1316; Atridia and Jiangsu Hengrui Pharmaceutical Company), MSB-2311 (Maebs Biosciences (Suzhou) Co., Ltd. Company (MabSpace Biosciences (Suzhou) Co Ltd), STI-A1014 (Lee's Pharmaceutical/Sorrento), AK-106 (Kangfang Biomedicine Company), AVA-004 (Avicta Life Sciences Co., Ltd.), BBI-801 (Boston Biomedical Inc), CA-327 (Aurigene/Curis), CBA-0710 (Sorrento Medical Corporation) , CBT-502 (CBT Pharmaceutical/Chia Tai Tianqing Pharmaceutical), FPT-155 (Five Prime Therapeutics Inc), FS-118 (F-Star Biotechnology Co., Ltd.), IKT-201 (Iser Kelex Medical), IKT-703 (Iser Kelex Medical), IO-103 (IO Biotech ApS), JS-003 (Shanghai Junshi Biomedical Science and Technology), KD-033 (Kadmon Corp/Jinghua Pharmaceutical), KY-1003 (Kamaibo Co., Ltd.), MCLA-145 (Merus Group/Insett), MT -5050 (Molecular Template Company), and SNA-02 (Quan Sheng Biopharmaceutical Company). The use according to any one of claims 1 to 7, wherein the cancer is selected from the group consisting of melanoma (especially ocular and uveal melanoma, but also skin melanoma); Head and neck cancer; kidney cancer; non-small cell lung cancer (NSCLC); microsatellite unstable cancer (Lynch syndrome, especially gastroesophageal and colorectal cancer); urothelial cancer, including bladder cancer; Merkel cell carcinoma Hodgkin’s lymphoma; gastric cancer; gastrointestinal cancer (microsatellite stable and unstable), including colorectal cancer (CRC); hepatocellular carcinoma (HCC); renal cell carcinoma (RCC); nasopharyngeal carcinoma; basal cell Cancer; cervical cancer; anogenital cancer; Kaposi’s sarcoma; adult T-cell leukemia; primary exudative lymphoma; and Casterman’s disease, or selected from the group consisting of: breast cancer, especially three Negative breast cancer; esophageal cancer; non-Hodgkin’s lymphoma; small cell lung cancer (SCLC); osteosarcoma; mesothelioma; glioblastoma; microsatellite stable cancers (especially gastroesophageal cancer and colorectal cancer); Pancreatic cancer; prostate cancer; skin T-cell lymphoma (CTCL); and squamous cell carcinoma.

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