2,7-substituted pyrrolo[2,1-f][1,2,4]triazine compounds with protein kinase inhibitory activity

Abstract

The present invention provides a triazine compound having protein kinase inhibitory activity, and a pharmaceutical composition containing the compound for the prevention, mitigation, or treatment of cancer. [Solution] The present invention provides a 2,7-substituted pyrrolo[2,1-f][1,2,4]triazine compound, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for the prevention, mitigation, or treatment of diseases induced by abnormal cell growth containing this compound as an active ingredient. The 2,7-substituted pyrrolo[2,1-f][1,2,4]triazine cyclized compound exhibits excellent inhibitory effects on various protein kinases involved in growth factor signaling, and is therefore useful as a preventive, mitigating, or therapeutic agent for abnormal cell growth diseases induced by these protein kinases.

Description

[Technical Field]

[0001] The present invention relates to a 2,7-substituted pyrrolo[2,1] having inhibitory activity of protein kinases. -f][1,2,4]triazine compounds, their pharmaceutically acceptable salts, and this compound Prevention, alleviation, or treatment of diseases induced by abnormal cell growth, containing the substance as an active ingredient. This relates to therapeutic pharmaceutical compositions. [Background technology]

[0002] In normal cells, protein kinases maintain a balance between active and inactive states, which contributes to cellular phenomena. Protein kinases are involved in signaling, transport, secretion, growth, cell division, and cycles. If hyperactivation occurs through submutation, amplification, or overexpression, the cellular signaling pathway becomes excessively activated. This induces the development, growth, and metastasis of cancer cells. When abnormally regulated, it can lead to the development of cancer cells. Kinases that induce growth include EGFR, ALK, DDR, BRAF, and FGFR. , VEGFR, BTK, MET, AKT, HER2, RET, NTRK, mTOR, ME K, ROS1, FLT3, c-kit, ABL1, and PDGFR are some representative examples.

[0003] Acute myeloid leukemia (AML) is the most A common form of leukemia characterized by an abnormal overgrowth of osteoblasts in the bone marrow or peripheral blood (2 (Accumulating a ratio of 0% or more), the proportion of normal hematopoietic cells decreases, thereby suppressing hematopoietic function. It is a disease in which 25-30% of AML patients have an internal FLT3 gene. When it mutates into l tandem duplication (FLT3-ITD) It is known that, in addition, punctures occur within the kinase domain of FLT3. Acquired mutations (such as F691L, D835Y, etc.) have been continuously reported. These induce continuous autophosphorylation of FLT3, hyperactivate signals related to cancer cell proliferation and division, and are widely known to induce AML.

[0004] Lung cancer refers to malignant tumors that occur in the lungs and is known as a major cause of cancer-related deaths worldwide. According to histological type, it can be classified into small cell lung cancer and non-small cell lung cancer, and about 85% of all lung cancer patients are non-small cell lung cancer patients. Non-small cell lung cancer can be cured by surgery in the early stage, but there are no symptoms in the early stage of lung cancer, making early diagnosis difficult and the proportion of patients eligible for surgery low. Also, even if the initial surgery is successful, the recurrence rate is high, and metastasis to other organs such as the brain, bones, liver, and lymph nodes occurs more frequently than in other cancers. Even when combined with anticancer drugs and radiotherapy, the prognosis is not as good as in other cancers. The 5-year survival rate is also very low, less than 10%.

[0005] <000097th> EGFR (Epidermal Growth Factor Receptor) is a tyrosine kinase receptor known as the most significant cause of non-small cell lung cancer. Among non-small cell lung cancer patients, 30 - 40% of Asian patients and 10 - 15% of patients in the United States and Europe carry EGFR mutations. Among EGFR mutations, approximately 95% are mutations that activate EGFR regardless of the presence or absence of ligand binding. Mutations in exon 19 of EGFR are the most frequent at 45%, and point mutations (L858R) in exon 21 account for 四十%. <00009)80>

[0006] <00009)86> Breast cancer refers to malignant tumors that occur in the breasts. Breast cancer is the most common cancer in women worldwide. Breast cancer accounts for 24.2% of all cancers in women, and has the highest mortality rate at approximately 15%. The number of breast cancer cases worldwide is steadily increasing. In 2015, the number of breast cancer cases was 156. The number of people increased by approximately 41% from 2019 (222,014 people) to 2019 (533 people). In particular, aggression Triple-negative breast cancer (TNBC), a type of breast cancer, accounts for 10-20% of all breast cancers in the United States. The mortality rate for breast cancer is approximately 50%.

[0007] Colorectal cancer ranks third in terms of awareness (6.1%) among all cancers, and has a mortality rate (9.2%). 5) It ranks second in this aspect. The total number of deaths from rectal cancer and colon cancer will increase by 2035. An increase of 60% and 71.5% is expected. More than 1.9 million new colorectal cancers in 2020. A case of cancer occurred.

[0008] Globally, approximately 1.3 million new cases of prostate cancer are diagnosed each year. Currently, there are about 10 million people affected. Of the men listed above, approximately 700,000 have been diagnosed with prostate cancer, and of those, about 700,000 have metastatic prostate cancer. Metastatic prostate cancer causes over 400,000 deaths annually, but the mortality rate for metastatic prostate cancer is... It is predicted that this will more than double by 2040.

[0009] Gastric cancer is the fourth leading cause of cancer death worldwide, and the median survival rate at advanced stages is 12 months. It is less than a month. At the time of gastric cancer diagnosis, the average age is 70 years, but about 10% are 45 years old or younger. Stomach cancer can be detected.

[0010] Liver cancer is projected to have a global prevalence of over 1 million cases by 2025. Hepatocellular carcinoma (HCC), the most common form, accounts for approximately 90% of all liver cancers. The main causes of the disease are hepatitis B virus and hepatitis C virus infection, but it is also associated with diabetes. Non-alcoholic steatohepatitis and metabolic syndromes are also risk factors for liver cancer.

[0011] As a result, the inventors have developed a novel substance that can overcome the aforementioned diseases. We conducted research to develop this invention and completed it. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] WO 2010-071885 [Patent Document 2] WO 2014-193932 [Non-patent literature]

[0013] [Non-Patent Document 1] Org.Lett.2011,13,4204-4207 [Non-Patent Document 2] J.Med.Chem. 2011, 54, 6328-6341 [Non-Patent Document 3] J.Med.Chem. 2012, 55, 115-125 [Overview of the project] [Problems that the invention aims to solve]

[0014] The object of the present invention is to provide a novel 2,7-substituted protein having inhibitory activity against protein kinases. The objective is to provide a rolo[2,1-f][1,2,4]triazine compound.

[0015] Another object of the present invention is to develop novel 2,7-substituted pyrroro[2,1-f][1,2 4] Triazine compounds, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof or A pharmaceutical compound containing this stereoisomer as an active ingredient is useful for the treatment, prevention, and alleviation of cancer. Its purpose is to provide finished products.

[0016] Another object of the present invention is to develop novel 2,7-substituted pyrroro[2,1-f][1,2 4] Triazine compounds, their pharmaceutically acceptable salts, their hydrates, their solvates or The objective is to provide a therapeutic agent for cancer containing the isomer as an active ingredient.

[0017] Another aspect of the present invention is to provide a method for producing the novel compound.

[0018] Furthermore, one aspect of the present invention is that a novel intermediate compound synthesized in the process of the above-mentioned manufacturing method is It is about providing. [Means for solving the problem]

[0019] One aspect of the present invention is the 2,7-substituted pyrrolo[2,1-f] represented by the following chemical formula 1. [1,2,4] Triazine compounds, pharmaceutically acceptable salts thereof, hydrates thereof or their solutions Provide a medium:

[0020] [ka]

[0021] In the aforementioned chemical formula 1,

[0022] R1, R2, and R3 are independently hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C3-C 10 Hete Rosicyl group;-C(O)-(C1-C 13 Alkyl); Amino group (-NR8R9); Ni Nitro group (-N(O)2); amide group (-(C=O)NR8R9); ester group (-C(O )OR8); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide group (-NHS(O)2R8); sulfide group (-SR8); sulfone group (-S(O)2R [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​b ga-Z b - When it is Q2, it is connected to Q2 to form a ring,

[0026] L b is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl; C1-C6 Coxy group; C3-C 10 Cyclyl group; C3-C 10 Heterocyclyl group; -C(O)-(C 1-C 13 Alkyl group; amino group (-NR8R9); nitro group (-N(O)2); amide Group (-(C=O)NR8R9); Carboxylic acid group (-C(O)OH); Ester group (-C( O)OR8); Nitrile group (-CN); Sulfonamide group (-NHS(O)2R8); S Rufid group (-SR8); sulfone group (-S(O)2R8); or -Z b -Q2; , the aforementioned -Z b -Q2, Q2 is L a ga-Z a When -Q1-M, it is connected to M and forms a ring Forming,

[0027] Said Z a or Z b These may exist independently or not exist at all, Z a or Z b but Yes, Z a or Z b These are independently -O-, -CO-, -COO-, and -C n H n+2 -, -O(C n H n+2 )-,-(C n H n+2 )O-, -(C n H n+2 )O (C m H m+2 )-,-C3-C 10cyclyl group -; or -C3-C 10 Heterocycline It is a lu-group;

[0028] Q1, Q2, and Q3 are each independently -C n H n+2 -, -O(C n H n+2 )-,-(OC2H4) n -,-(C2H4O) n -,-(C n H n+2 )O-, -(C n H n+2 )CO-, -NR8(C n H n+2 )-,-(NR8C2H4) n -,-(C 2H4NR8) n -,-(C n H n+2 )NR8-,-(C n H n+2 )O(C m H m+ 2)-,-(C n H n+2 )O(C m H m+2 )CO-, -C3-C 10 cyclyl group-; or -C3-C 10 It is a heterocyclyl group;

[0029] The above Q4 may or may not exist, and if it exists, -C n H n+2 -, -C n H n -, or -C n H n-2 -and,

[0030] The aforementioned M is -O-, -CO-, -COO-, -C2H2-, -C n H n+2 -, -O( C n H n+2 )-,-(Cn H n+2 )O−,−(C n H n+2 )O(C m H m+2 )− 、−NR8−;−NR8CH2−;−NHR8−;−NR8C(O)−;−NR8C(O )O−;−C(O)NR8−;−NR8C(O)NR8−;−NC(O)R8−;−NS (O)2R8−;−S(O)2−;−NR8S(O)2−; and −S(O)2NR8−; where

[0031] n and m are each independently an integer from 0 to 15,

[0032] E is

Chemical formula

Chemical formula

[0033] X2, X3, and X4 are each independently hydrogen; a halogen group; a C1-C 13 alkyl group; a C1-C6 haloalkyl; a C1-C6 alkoxy group; a C3-C 10 cyclic 3-C 10 [[ID=​​​​​​​​​​​​​Said X1 is either present or absent. When present, X1 is -CR8R9-, -O- or -NR 8-;

[0035] Said Y1, Y2, Y3 and Y4 are each independently a C6-C 10 aryl group; a C3- C 10 heteroaryl group; a C3-C 10 cyclic group; or a C3-C 10 heterocyclic group;

[0036] Said R8 and R9 are each independently hydrogen; a C1-C6 alkyl group; a C1-C6 al kenyl group; a C1-C6 alkynyl group; a C6-C 10 aryl group; a C3-C 10 heteroaryl -yl group; a C3-C 10 cyclic group; a C3-C 10 heterocyclic group; or R8 is optionally combined with nitrogen or a carbon atom to which R9 is attached to contain at least one of N, O, S, NH, C=N, C=O, -NHC( O)-, -NHC(O)NH-, -NHS(O)2-, or SO2, and optionally form a 3- to 7-membered saturated ring that is substituted with at least one of hydrogen, a C1-C alkyl group, a C6-C aryl group, 13 [[ID=​​​​​​​​​​​​​​​​​​​​​​​R8R9); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR8); Ni Tolyl group (-CN); Urea group (-NR8(C=O)NR9-); Sulfonamide group (- NHS(O)2-); sulfide group (-S-); sulfone group (-S(O)2-); phospho Lyle group (-P(O)R8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl Base; and C3-C 10 Includes one or more substituents selected from the group consisting of heterocyclyl groups; fruit,

[0038] Said C6-C 10 Aryl group, C3-C 10 Heteroaryl group or C3-C 10 Hete The rosicyl group consists of hydrogen; a hydroxyl group; a halogen group; and a carbonyl group (-(C=O)R8R). 9); Halogen or C3-C 10 C1-C3 groups substituted or unsubstituted with heterocyclyl groups Lukyl group; halogen or C3-C 10 C1-C substituted or unsubstituted with heterocyclyl groups 3-alkoxy group; C6-C 10 Phenoxy; amino group (-NR8R9); amide group (-( C=O)NR8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl group and C 3-C 10 comprising one or more substituents selected from the group consisting of heterocyclyl groups;

[0039] Said C3-C 10 Heteroaryl group and C3-C 10 The heterocyclyl group consists of N, O, and It contains one or more heteroatoms selected from the group consisting of bi and S. [Effects of the Invention]

[0040] The present invention is characterized by the 2,7-substituted pyrrolo[2,1-f] represented by the chemical formula 1. [1,2,4] Triazine degrading compounds, their pharmaceutically acceptable salts, their hydrates or The solvates are ABL1, ABL2, ALK, ARK5, Aurora A, and Auro ra B, Aurora C, AXL, BLK, BMX, BRK, c-Kit, c-ME R, c-Src, CAMK2a, CAMK2d, CDK16, CDK17, CDK18, CDK2 / cyclin A, CDK2 / cyclin O, CDK4 / cyclin D1, CDK4 / cyclin D2, CDK4 / cyclin D3, CDK6 / cy clin D1, CDK6 / cyclin D3, CDK7 / cyclin H, CDK 9 / cyclin K, CDK9 / cyclin T1, CDK9 / cyclin T2 , CK2a, CK2a2, CLK1, CLK2, CLK4, DAPK1, DAPK2, D DR1, DDR2, DRAK1, DYRK1 / DYRK1A, DYRK1B, DYRK3 , EPHA1, EPHA2, EPHA4, EPHA5, EPHA6, EPHA7, EPH B1, EPHB2, ERBB4 / HER4, ERK7 / MAPK15, ERN2 / IRE 2, FAK / PTK2, FER, FES / FPS, FGFR1, FGFR2, FGFR3 , FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FR K / PTK5, FYN, GLK / MAP4K3, GSK3a, HIPK2, HIPK3, HIPK4, HPK1 / MAP4K1, IGF1R, IKKe / IKBKE, IR, IR AK1, IRR / INSRR, JAK1, JAK2, JAK3, JNK1, JNK2, J NK3, KDR / VEGFR2, KHS / MAP4K5, LCK, LIMK1, LIMK 2, LRRK2, LYN, LYN B, MAK, MARK1, MARK2 / PAR-1B a, MARK3, MARK4, MAST3, MEKK2, MELK, MLCK2 / MYL K2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11 , MUSK, MYLK4, NEK1, NEK2, NEK5, NEK9, p70S6K / R PS6KB1, PAK4, PAK5, PAK6, PDGFRa, PDGFRb, PHKg 1, PHKg2, PKAcb, PKCa, PKCb2, PKCg, PKCmu / PRKD 1, PKCnu / PRKD3, PKD2 / PRKD2, PKN1 / PRK1, PLK4 / SAK, PRKX, PYK2, RET, ROS / ROS1, RSK2, RSK3, RSK 4, SIK1, SIK2, SLK / STK2, SNARK / NUAK2, STK16, S TK22D / TSSK1, STK33, STK38 / NDR1, STK38L / NDR2 , STK39 / STLK3, SYK, TBK1, TEC, TIE2 / TEK, TLK2, TNK1, TRKA, TRKB, TRKC, TYK2, TYRO3 / SKY, ULK1, ULK2, ULK3, WEE1, YES / YES1, YSK4 / MAP3K19 and ZI The ability to degrade and inhibit the activity of one or more kinases, namely PK / DAPK3. Because it is excellent, it is used as a preventive, mitigating, or therapeutic agent for diseases induced by abnormal cell growth. It is useful.

[0041] The abnormal cell growth diseases that can be prevented and treated with the compounds according to the present invention include gastric cancer, lung cancer, liver cancer, Colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer Head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer , blood cancers such as leukemia (acute myeloid leukemia), multiple myeloma, myelodysplastic syndrome, Hodg Various types of lymphomas selected from Kin's disease, non-Hodgkin lymphoma, or fibroadenoma, etc. This includes tumor diseases. [Brief explanation of the drawing]

[0042] [Figure 1] This is the result of Experimental Example 3 of the present invention. [Modes for carrying out the invention]

[0043] definition

[0044] Unless otherwise specified, the ingredients, reaction conditions, and ingredient content used in this specification are not expressed. Any number, value, and / or expression that does so is essentially derived from something else. Since it is an approximation that reflects the various uncertainties of measurement that occur in obtaining such a value, In such cases, it must be understood that it is modified by the term "approximately". When a numerical range is disclosed in the description, such a range is continuous and does not require any particular attention to be paid to. Unless otherwise specified, all values ​​from the minimum to the maximum within such a range include the maximum value. This includes. Furthermore, if such a range refers to an integer, unless otherwise specified, It includes all integers from the minimum value up to the maximum value.

[0045] In this specification, when a range is described for a variable, the variable is described in the range. It is understood to include all values ​​within the range of the description, including the endpoint. For example, "5-10 The range of "" is not limited to the values ​​5, 6, 7, 8, 9, and 10, but also includes 6-10, 7-10, and 6 This includes any sub-range such as ~9, 7~9, etc., and 5.5, 6.5, 7.5, 5.5~8.5 and It is understood that this includes any integer value within the range specified, such as 6.5 to 9. For example, the range "10-30%" could be 10%, 11%, 12%, 13%, etc. Not only any integer including the value and up to 30%, but also 10-15%, 12-18%, 20% This includes any lower range such as ~30%, and is written as 10.5%, 15.5%, 25.5%, etc. It is understood that this includes any value between valid integers within the range specified.

[0046] The terms "individual(s)", "subject(s)", and "patient(s)" used in this invention. This refers to any mammal. In some embodiments, the mammal is a human. In the embodiments described, mammals are not humans. Any term used by healthcare professionals ( For example, doctors, registered nurses, trainee nurses, medical assistants, general laborers, or hospice workers. It does not require a situation characterized by supervision (e.g., constant or intermittent), or It is not limited to that.

[0047] "Treatment" is performed with the intention of preventing the progression or alteration of a disease lesion. This is an attempt to do so. Therefore, "treatment" refers to both therapeutic and preventive measures. This also refers to the condition that requires treatment, not just the condition that already has a disease. This includes conditions that must be prevented. In tumor treatment, therapeutic agents treat the pathology of tumor cells. To directly reduce tumor cells, or to use other therapeutic agents such as radiation and / or chemotherapy. / or means something that makes the subject more sensitive to treatment by immunotherapy. (Terminology used herein) "Reduced" or "treated" refers to the normalized value measured by a standard statistical test. This means signs approaching the normalized value. Here, signs approaching the normalized value are, for example, signs of being healthy. Values ​​obtained from patients or individuals that show a difference of less than 50% from normalized values, undesirable. Ideally, the difference should be less than 25%, even more preferably less than 10%, and further Ideally, the value should not differ significantly from the normalized value.

[0048] "Cancer treatment" means one or more of the following effects: 1) i) slowing or i i) Suppression of tumor growth, including complete cessation of growth; 2) Reduction in the number of tumor cells; 3) Preservation of tumor size 4) Reduction in tumor size; 5) i) Reduction or ii) Slowing down or iii) Complete prevention Inhibition of tumor cell infiltration into peripheral organs; 6) i) reduction or ii) slowing or iii) complete Suppression of metastasis, including complete prevention; 7) Improvement of antitumor immune response, i) Preservation of tumor size or i i) reduction in tumor size or iii) slowing of tumor growth or iv) reduction or slowing of invasiveness or Enhancement of antitumor immune responses, which can lead to prevention.

[0049] The “effective dose” or “therapeutic effective dose” used herein refers to the dose that must be used for treatment. Symptoms of a disease or condition (e.g., cancer or inflammatory disease, periodontal disease or soft tissue calcification) This means a sufficient amount of the compounds disclosed herein to mitigate the effect to some extent. Some examples In this regard, the results indicate 1) a reduction and / or alleviation of the signs, symptoms or causes of the disease, and 2) Any other desirable modification of the biological system in a clinical setting. In some concrete examples... Therefore, in any individual case, the appropriate "effective" amount can be determined using techniques such as volume increase studies. It is determined by using it.

[0050] In some specific examples, the "effective dose" is the amount disclosed for monotherapy or combination therapy. When administered in the quantity of the compound, i.e., one or more volumes, in individuals not treated with the compound, E Compare with GFR activity, or compare with EGFR activity in an individual before or after treatment with the compound. When compared, EGFR was reduced by approximately 20% (20% suppression), at least approximately 30% (30% suppression), and less At least about 40% (40% reduction), at least about 50% (50% reduction), about 60% or more ( 60% suppression), about 70% or more (70% suppression), about 80% or more (80% suppression), about 90% or more The higher the value (90% suppression), the more effective the amount for suppression.

[0051] In some specific examples, the "therapeutic effective dose" is disclosed for single-therapy or combination therapy. The amount of the compound administered, i.e., when administered in one or more volumes, does not treat with the compound. Compare the tumor burden of the subject, or compare it to the tumor burden of the subject before or after treatment with the compound. When compared, the tumor burden on the subject was approximately 20%, approximately 30% or more, approximately 40% or more, approximately 50% or more, and It is effective to reduce the amount by more than 60%, more than 70%, more than 80%, and more than 90%. This is a considerable amount. The term "tumor burden" as used herein refers to the tumors present in an object that has cancer. It represents the total mass of the organization.

[0052] In some specific examples, the "therapeutic effective dose" is disclosed for single-therapy or combination therapy. The amount of the compound administered, i.e., when administered in one or more volumes, does not treat with the compound. Compared to the volume of radiotherapy required to observe tumor shrinkage in the subject, The amount of radiation therapy needed for observation is approximately 20%, over 30%, over 40%, and over 50%. Effective in reducing by more than %, approximately 60% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more It is a quantity.

[0053] Pharmaceutical compositions

[0054] Pharmacochemically acceptable excipients such as vehicles, auxiliaries, carriers, or diluents are common. It is easily accessible to engineers. pH adjusters and buffers, isotonic adjusters, stabilizers, wetting agents. Pharmaceutically acceptable adjuvants such as these are readily available to the average technician.

[0055] In some embodiments, the compounds of the present invention are formulated with an aqueous buffer. The buffers include acetic acid, succinic acid, citric acid, and phosphate buffers with varying strengths from 5 to 1000 mM. This includes, but is not limited to, aqueous buffers. In some specific examples, aqueous buffers are isotonic. The reagents include a solution. Such reagents include sodium chloride, sugar, for example, mannitol. This includes, but is not limited to, dextrose, sucrose, etc. In this embodiment, the aqueous buffer is a nonionic bloc such as polysorbate 20 or 80. It further contains an surfactant. Optionally, the formulation may further contain a preservative. Suitable preservatives include It contains diluent alcohol, phenol, chlorobutanol, benzalkonium chloride, etc. However, it is not limited to these. In other specific examples, the dosage form is stored at approximately 4°C. The preparations are also freeze-dried, and these are generally made from sucrose, trehalose, lactose, and ma. Contains antifreeze agents such as lutose and mannitol. Lyophilized formulations can be stored at room temperature for extended periods. It can be stored over time.

[0056] In this specification, a pharmaceutical composition is a compound disclosed in the present invention, or a pharmaceutically effective compound thereof. Includes, or is essentially constitutes, acceptable salts, their isomers, and their tautomers, and additionally, drugs. The pharmaceutical composition contains or is essentially composed of one or more additional activators of interest. A substance is provided. Any convenient activator is used in this method together with the compound of the present invention. In the example, in combination therapy, not only additional therapeutic agents as described in the present invention, but also the present invention These compounds and immune checkpoint inhibitors are administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or It is administered via other routes. In other specific examples, the compounds and chemotherapy preparations of the present invention (especially (chemotherapeutic agents that can induce the production of cGAMP in vivo), and combination therapies The additional therapeutic agents described in this invention may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or otherwise. It is administered via the following route. The compound of the present invention and the second activator (if present) are administered via the same route. Alternatively, it may be administered by a different route of administration. The therapeutic agent may be administered orally, rectally, to the affected organ. Any injection, including but not limited to nasal, topical, vaginal, parenteral, intravenous, intranasal, and intratumor injections. It is administered by the appropriate means.

[0057] The compounds of the present invention are administered in unit dose form and by any method well known to those skilled in the art. It can be manufactured by using one of one or more auxiliary components of the present invention. This step includes combining it with a pharmaceutically acceptable carrier or diluent that constitutes it. The carrier to be used is selected based on the chosen route of administration and standard pharmaceutical practice. The carrier is compatible with the other components of the formulation and does not harm the subject or patient. It must be "pharmaceutically acceptable". This carrier is solid or liquid, and type The choice depends on the commonly used dosage type.

[0058] Suitable solid carriers include lactose, sucrose, gelatin, agar, and bulk powders. Examples of suitable liquid carriers include water, pharmaceutically acceptable fats and oils, alcohol or Other organic solvents, such as esters, emulsions, syrups or elixirs (e Includes solutions and / or suspensions reconstituted from lixirs), suspensions, and non-foaming granules. Such liquid carriers include, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, and sweeteners. It may contain flavoring agents, thickeners, and melting agents.

[0059] The present invention will be described in detail below.

[0060] One aspect of the present invention is the 2,7-substituted pyrrolo[2,1-f] represented by the following chemical formula 1. [1,2,4] Triazine compounds, pharmaceutically acceptable salts thereof, hydrates thereof or their solutions Provide a medium:

[0061] [ka]

[0062] In the aforementioned chemical formula 1,

[0063] R1, R2, and R3 are independently hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C3-C 10 Hete Rosicyl group;-C(O)-(C1-C 13 Alkyl); Amino group (-NR8R9); Ni Toro group (-N(O)2); amide group (-(C=O)NR8R9); ester group (-C(O )OR8); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Sulfonamide Group (-NHS(O)2R8); sulfide group (-SR8); sulfone group (-S(O)2R 8); or a phosphoryl group (-P(O)R8R9);

[0064] A and B are each independently C6-C 10 Aryl group; C3-C 10 Cyclyl group; C 3-C 10 Heteroaryl group; or C3-C 10 A heterocyclyl group;

[0065] R4, R5, R6, and R7 are independently hydrogen; hydroxyl group; halogen group; and C 1-C 13 Alkyl group; C1-C6 haloalkyl; C1-C6 alkoxy group; C3-C1 0 cyclyl group; C3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl) ; Amino group (-NR8R9); Nitro group (-N(O)2); Amide group (-(C=O)NR 8R9); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR8); Nitrile CN group; Sulfonamide group (-NHS(O)2R8); Sulfide group (-SR8) ); with a sulfone group (-S(O)2R8); or a phosphoryl group (-P(O)R8R9); can be,

[0066] L a is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl alkyl group; -Z a -Q3- E; or -Z a -Q1-M; and the aforementioned -Z a -Q1-M, where M is L b ga-Z b - When it is Q2, it is connected to Q2 to form a ring,

[0067] L b is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl; C1-C6 Coxy group; C3-C 10 Cyclyl group; C3-C 10 Heterocyclyl group; -C(O)-(C 1-C 13 Alkyl group; amino group (-NR8R9); nitro group (-N(O)2); amide Group (-(C=O)NR8R9); Carboxylic acid group (-C(O)OH); Ester group (-C( O)OR8); Nitrile group (-CN); Sulfonamide group (-NHS(O)2R8); S Rufid group (-SR8); sulfone group (-S(O)2R8); or -Z b -Q2; , the aforementioned -Z b -Q2, Q2 is L a ga-Z a When -Q1-M, it is connected to M and forms a ring Forming,

[0068] Said Z a or Z b These may exist independently or not exist at all, Z a or Z b but Yes, Z a or Z b These are independently -O-, -CO-, -COO-, and -C n H n+2 -, -O(C n H n+2 )-,-(C n H n+2 )O-, -(C n H n+2 )O (C m H m+2 )-,-C3-C 10 cyclyl group -; or -C3-C 10 Heterocycline It is a lu-group;

[0069] Q1, Q2, and Q3 are each independently -C n H n+2 -, -O(C n H n+2 )-,-(OC2H4) n -,-(C2H4O) n -,-(C n H n+2 )O-, -(C n H n+2 )CO-, -NR8(C n H n+2 )-,-(NR8C2H4) n -,-(C 2H4NR8) n -,-(C n H n+2 )NR8-,-(C n H n+2 )O(C m H m+ 2)-,-(C n H n+2 )O(C m H m+2 )CO-, -C3-C 10 cyclyl group-; or -C3-C 10 It is a heterocyclyl group;

[0070] The above Q4 may or may not exist, and if it exists, -C n H n+2 -, -C n H n -, or -C n H n-2 -and,

[0071] The aforementioned M is -O-, -CO-, -COO-, -C2H2-, -C n H n+2 -, -O( C n H n+2 )-,-(C n H n+2 )O-, -(C n H n+2 )O(C mH m+2 )- , -NR8-;-NR8CH2-;-NHR8-;-NR8C(O)-;-NR8C(O )O-;-C(O)NR8-;-NR8C(O)NR8-;-NC(O)R8-;-NS (O)2R8-;-S(O)2-;-NR8S(O)2-; and -S(O)2NR8-; And,

[0072] The aforementioned n and m are each independent integers between 0 and 15.

[0073] The aforementioned E is, [ka] or [ka] And,

[0074] The aforementioned X2, X3, and X4 are each independently hydrogen; halogen group; C1-C 13 Alki C1-C6 haloalkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C 3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl group; amino group (-N R8R9); Nitro group (-N(O)2); Amide group (-(C=O)NR8R9); Carbo Acid group (-C(O)OH); ester group (-C(O)OR8); nitrile group (-CN); Sulfonamide group (-NHS(O)2R8); sulfide group (-SR8); sulfone group ( -S(O)2R8); or phosphoryl group (-P(O)R8R9);

[0075] The aforementioned X1 may or may not exist, and if present, X1 is -CR8R9-, -O-, or -NR 8-,

[0076] Y1, Y2, Y3, and Y4 are each independently C6-C 10 Aryl group; C3- C 10 Heteroaryl group; C3-C 10 Cyclyl group; or C3-C 10 heterocycline It is the basis;

[0077] R8 and R9 are each independently hydrogen; C1-C6 alkyl; C1-C6 Kenyl group; C1-C6 alkynyl group; C6-C 10 Aryl group; C3-C 10 Heterozygous ants group;C3-C 10 Cyclyl group; C3-C 10 Heterocyclyl group; or R8 is R9 N, O, S, NH, C=N, C=O, -NHC( At least one of the following: O)-, -NHC(O)NH-, -NHS(O)2-, or SO2 It can contain any species, including hydrogen and C1-C 13 Alkyl alkyl group, C6-C 10 Aryl group, C3-C 10 Among heteroaryl groups, hydroxyl groups, halide groups, and cyano groups, at least Each of them forms a 3- to 7-membered saturated ring that can be arbitrarily substituted by one type.

[0078] The C1-C6 alkoxy group, C1-C 13 Alkyl or C3-C 10 cyclyl group is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl alkyl groups; C1-C6 alkoxy Groups; amino group (-NR8R9); nitro group (-N(O)2); amide group (-(C=O)N R8R9); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR8); Ni Tolyl group (-CN); Urea group (-NR8(C=O)NR9-); Sulfonamide group (- NHS(O)2-); sulfide group (-S-); sulfone group (-S(O)2-); phospho Lyle group (-P(O)R8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl Base; and C3-C 10 Includes one or more substituents selected from the group consisting of heterocyclyl groups; fruit,

[0079] Said C6-C 10 Aryl group, C3-C 10 Heteroaryl group or C3-C 10 Hete The rosicyl group consists of hydrogen; a hydroxyl group; a halogen group; and a carbonyl group (-(C=O)R8R). 9); Halogen or C3-C 10 C1-C3 groups substituted or unsubstituted with heterocyclyl groups Lukyl group; halogen or C3-C 10 C1-C substituted or unsubstituted with heterocyclyl groups 3-alkoxy group; C6-C 10 Phenoxy; amino group (-NR8R9); amide group (-( C=O)NR8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl group and C 3-C 10 comprising one or more substituents selected from the group consisting of heterocyclyl groups;

[0080] Said C3-C 10 Heteroaryl group and C3-C 10 The heterocyclyl group consists of N, O, and It contains one or more heteroatoms selected from the group consisting of bi and S.

[0081] In one aspect of the present invention, A and B are each independently furan, benzofuran, Pyrrole, indole, thiophene, benzothiophene, imidazole, benzimidazole uryl, purine, pyrazole, indazole, oxazole, benzoxazole, thia Zole, benzothiazole, benzene, naphthalene, anthracene, pyridine, quinoli Pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, syn 2,7-substituted pyro, represented by chemical formula 1, which is noline, phthalazine, or triazine [2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable salts, and their water Provides a compound or its solvent compound.

[0082] In one aspect of the present invention, A and B are each independently benzene, pyrazole, Pyridine, indazole, pyrimidine, quinoline or thiazole, and the above R1, R2 and R3 are independently hydrogen, halogen group, and C1-C 13 Alkyl or C 3-C 10 The cyclyl group is represented by the 2,7-substituted pyrrolo[2,1-f] of chemical formula 1. [1,2,4] Triazine compounds, pharmaceutically acceptable salts thereof, hydrates thereof or Provides a solvide.

[0083] In one aspect of the present invention, R4, R5, R6, and R7 are each independently hydrogen; Hydroxyl group; halogen group; -NHCH3; -NHMs; -CO(NH)CH3; -OC H3;-OC2H5;or-OC6H 12 COOCH3 is represented by chemical formula 1. ,7-substituted pyrrolo[2,1-f][1,2,4]triazine compounds, their pharmaceutically The present invention provides acceptable salts, their hydrates, or their solvates.

[0084] In one aspect of the present invention, the compound is represented by the following chemical formula 2,

[0085] [ka]

[0086] In the aforementioned chemical formula 2,

[0087] R1, R2, and R3 are independently hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C3-C 10 Hete Rosicyl group;-C(O)-(C1-C 13 Alkyl); Amino group (-NR8R9); Ni Toro group (-N(O)2); amide group (-(C=O)NR8R9); ester group (-C(O )OR8); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Sulfonamide Group (-NHS(O)2R8); sulfide group (-SR8); sulfone group (-S(O)2R 8); or a phosphoryl group (-P(O)R8R9);

[0088] A and B are each independently C6-C 10 Aryl group; C3-C 10 Cyclyl group; C 3-C 10 Heteroaryl group; or C3-C 10 A heterocyclyl group;

[0089] R4, R5, R6, and R7 are independently hydrogen; hydroxyl group; halogen group; and C 1-C 13 Alkyl group; C1-C6 haloalkyl; C1-C6 alkoxy group; C3-C1 0 cyclyl group; C3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl) ; Amino group (-NR8R9); Nitro group (-N(O)2); Amide group (-(C=O)NR 8R9); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR8); Nitrile CN group; Sulfonamide group (-NHS(O)2R8); Sulfide group (-SR8) ); with a sulfone group (-S(O)2R8); or a phosphoryl group (-P(O)R8R9); can be,

[0090] L b is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl; C1-C6 Coxy group; C3-C 10 Cyclyl group; C3-C 10 Heterocyclyl group; -C(O)-(C 1-C 13 Alkyl group; amino group (-NR8R9); nitro group (-N(O)2); amide Group (-(C=O)NR8R9); Carboxylic acid group (-C(O)OH); Ester group (-C( O)OR8); Nitrile group (-CN); Sulfonamide group (-NHS(O)2R8); S It is a rufid group (-SR8); or a sulfone group (-S(O)2R8);

[0091] Said Z a -O-, -CO-, -COO-, -C n H n+2 -, -O(C n H n+2 )-,-(C n H n+2 )O-, -(C n H n+2 )O(C m H m+2 )-,-C3-C 10 cyclyl group -; or -C3-C 10 It is a heterocyclyl group;

[0092] The above Q3 is -C n Hn+2 -, -O(C n H n+2 )-,-(OC2H4)n-,- (C2H4O) n -,-(C n H n+2 )O-, -(C n H n+2 )CO-, -NR8( C n H n+2 )-, -(NR8C2H4)n-, -(C2H4NR8) n -,-(C n H n+2 )NR8-,-(C n H n+2 )O(C m H m+2 )-,-(C n H n+2 )O( C m H m+2 )CO-, -C3-C 10 cyclyl group -; or -C3-C 10 Heterocycline It is a lyl group;

[0093] The above Q4 may or may not exist, and if it exists, -C n H n+2 -, -C n H n -, or -C n H n-2 -and,

[0094] The aforementioned n and m are each independent integers between 0 and 15.

[0095] The aforementioned E is, [ka] or [ka] And,

[0096] The aforementioned X2, X3, and X4 are each independently hydrogen; halogen group; C1-C 13 Alki C1-C6 haloalkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C 3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl group; amino group (-N R8R9); Nitro group (-N(O)2); Amide group (-(C=O)NR8R9); Carbo Acid group (-C(O)OH); ester group (-C(O)OR8); nitrile group (-CN); Sulfonamide group (-NHS(O)2R8); sulfide group (-SR8); sulfone group ( -S(O)2R8); or phosphoryl group (-P(O)R8R9);

[0097] The aforementioned X1 may or may not exist, and if present, X1 is -CR8R9-, -O-, or -NR 8-,

[0098] Y1, Y2, Y3, and Y4 are each independently C6-C 10 Aryl group; C3- C 10 Heteroaryl group; C3-C 10 Cyclyl group; or C3-C 10 heterocycline It is the basis;

[0099] R8 and R9 are each independently hydrogen; C1-C6 alkyl; C1-C6 Kenyl group; C1-C6 alkynyl group; C6-C 10 Aryl group; C3-C 10 Heterozygous ants group;C3-C 10 Cyclyl group; C3-C 10 Heterocyclyl group; or R8 is R9 N, O, S, NH, C=N, C=O, -NHC( At least one of the following: O)-, -NHC(O)NH-, -NHS(O)2-, or SO2 It can contain any species, including hydrogen and C1-C 13 Alkyl alkyl group, C6-C 10 Aryl group, C3-C 10 Among heteroaryl groups, hydroxyl groups, halide groups, and cyano groups, at least Each of them forms a 3- to 7-membered saturated ring that can be arbitrarily substituted by one type.

[0100] The C1-C6 alkoxy group, C1-C 13 Alkyl or C3-C 10 cyclyl group is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl alkyl groups; C1-C6 alkoxy Groups; amino group (-NR8R9); nitro group (-N(O)2); amide group (-(C=O)N R8R9); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR8); Ni Tolyl group (-CN); Urea group (-NR8(C=O)NR9-); Sulfonamide group (- NHS(O)2-); sulfide group (-S-); sulfone group (-S(O)2-); phospho Lyle group (-P(O)R8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl Base; and C3-C 10 Includes one or more substituents selected from the group consisting of heterocyclyl groups; fruit,

[0101] Said C6-C 10 Aryl group, C3-C 10 Heteroaryl group or C3-C 10 Hete The rosicyl group consists of hydrogen; a hydroxyl group; a halogen group; and a carbonyl group (-(C=O)R8R). 9); Halogen or C3-C 10 C1-C3 groups substituted or unsubstituted with heterocyclyl groups Lukyl group; halogen or C3-C 10 C1-C substituted or unsubstituted with heterocyclyl groups 3-alkoxy group; C6-C 10 Phenoxy; amino group (-NR8R9); amide group (-( C=O)NR8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl group and C 3-C 10 comprising one or more substituents selected from the group consisting of heterocyclyl groups;

[0102] Said C3-C 10 Heteroaryl group and C3-C 10 The heterocyclyl group consists of N, O, and A 2,7- ion represented by chemical formula 1, which contains one or more heteroatoms selected from the group consisting of S and ions. Substituted pyrrolo[2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable Salts, their hydrates, or their solvates.

[0103] In one embodiment, in the chemical formula 2, A and B are each independently of benzyl In addition to thiazoles, pyrazoles, pyridines, indazoles, pyrimidines, quinolines, or thiazoles. Yes, R1, R2 and R3 are each independently hydrogen, halogen group, and C1-C 13 a Lukyl group or C3-C 10 It is a cyclyl group, and R4, R5, R6, and R7 are Each is independently hydrogen; hydroxyl group; halogen group; -NHCH3; -NHMs; -CO(N H)CH3;-OCH3;-OC2H5;or-OC6H 12 COOCH3; The aforementioned Y1 is, [ka] Y a and Y bThese are, independently, hydrogen; halogen group; C1-C 13 alkyl group ;C1-C6 haloalkyl;C1-C6 alkoxy group;C3-C 10 cyclyl group; C3- C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl group; amino group (-NR8) R9); Nitro group (-N(O)2); Amide group (-(C=O)NR8R9); Carboxylic acid Group (-C(O)OH); Ester group (-C(O)OR8); Nitrile group (-CN); Sulfur Honamide group (-NHS(O)2R8); sulfide group (-SR8); sulfone group (-S (O)2R8); or phosphoryl group (-P(O)R8R9); and Y c and Y d teeth -O-, -CO-, -COO-, -C n H n+2 -, -O(C n H n +2 )-,-(C n H n+2 )O-, -(C n H n+2 )O(C m H m+2 )-,-C3 -C 10 cyclyl group -; or -C3-C 10 Heterocyclyl group -; and Y e C 6-C 10 Aryl group; C3-C 10 Cyclyl group; C3-C 10 Heteroaryl group; also is C3-C 10 A heterocyclyl group; represented by chemical formula 1, is a 2,7-substituted pyrroleum group. [2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable salts, and their hydrated To provide a substance or its solvate.

[0104] In one example, in the above chemical formula 2, E is E1, E2, E3, E4, E5 , E6, E7, E8, E9, E10, E11, E12, E13, E14 or E15 ru,

[0105] [ka]

[0106] 2,7-substituted pyrrolo[2,1-f][1,2,4]triazi, represented by chemical formula 1. The present invention provides compound, pharmaceutically acceptable salt thereof, its hydrate or solvate thereof.

[0107] In one example, in the chemical formula 2,

[0108] Q3 is -(CH2)n-, -(OC2H4)n-, and -(CH2)nCO- respectively It is one of the following, n is an integer, and A and B are heteroaryl rings and rings, respectively. It is one or more of a hydrocarbon and an alkyl group, and n is 0, 1, An integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and the heterogeneous The phenyl ring is one of the following: phenyl, substituted phenyl, pyrazole, or substituted indole. It is one of the following, and the cyclic hydrocarbon is one or more of piperazine and piperidine. The present invention provides a compound, a pharmaceutically acceptable salt thereof, its hydrate, or its solvide.

[0109] In one aspect of the present invention, the compound is represented by the following chemical formula 3,

[0110] [ka]

[0111] In the aforementioned chemical formula 3,

[0112] R1, R2, and R3 are independently hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C3-C 10 Hete Rosicyl group;-C(O)-(C1-C 13 Alkyl); Amino group (-NR8R9); Ni Toro group (-N(O)2); amide group (-(C=O)NR8R9); ester group (-C(O )OR8); Carboxylic acid group (-C(O)OH); Nitrile group (-CN); Sulfonamide Group (-NHS(O)2R8); sulfide group (-SR8); sulfone group (-S(O)2R 8); or a phosphoryl group (-P(O)R8R9);

[0113] A and B are each independently C6-C 10 Aryl group; C3-C 10 Cyclyl group; C 3-C 10 Heteroaryl group; or C3-C 10 A heterocyclyl group;

[0114] R4, R5, R6, and R7 are independently hydrogen; hydroxyl group; halogen group; and C 1-C 13 Alkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C3-C1 0 heterocyclyl group; -C(O)-(C1-C 13 Alkyl group; amino group (-NR8R9) ); Nitro group (-N(O)2); Amide group (-(C=O)NR8R9); Carboxylic acid group ( -C(O)OH; ester group (-C(O)OR8); nitrile group (-CN); sulfone Amide group (-NHS(O)2R8); sulfide group (-SR8); sulfone group (-S(O) )2R8); or phosphoryl group (-P(O)R8R9);

[0115] Said Z a or Z b These are independently -O-, -CO-, -COO-, and -C n H n +2 -, -O(C n H n+2 )-,-(C n H n+2 )O-, -(C n H n+2 )O(C m H m+2 )-,-C3-C 10 cyclyl group -; or -C3-C 10 heterocyclyl group -; and

[0116] Q1 and Q2 are each independently -C n H n+2 -, -O(C n H n+2 )-, -(OC2H4) n -,-(C2H4O) n -,-(C n H n+2 )O-, -(C n H n +2 )CO-, -NR8(C n H n+2 )-,-(NR8C2H4) n -,-(C2H4 NR8) n -,-(C n H n+2 )NR8-,-(C n H n+2 )O(C m H m+2 )- ,-(C n H n+2 )O(C m H m+2 )CO-, -C3-C 10 cyclyl group-; or -C3-C 10 It is a heterocyclyl group;

[0117] The aforementioned M is -O-, -CO-, -COO-, -C2H2-, -C n H n+2 -, -O( C n H n+2 )-,-(C n H n+2 )O-, -(C n H n+2 )O(C m H m+2 )- , -NR8-;-NR8CH2-;-NHR8-;-NR8C(O)-;-NR8C(O )O-;-C(O)NR8-;-NR8C(O)NR8-;-NC(O)R8-;-NS (O)2R8-;-S(O)2-;-NR8S(O)2-; and -S(O)2NR8-; And,

[0118] The aforementioned E is, [ka] or [ka] And,

[0119] The aforementioned X2, X3, and X4 are each independently hydrogen; halogen group; C1-C 13 Alki C1-C6 haloalkyl group; C1-C6 alkoxy group; C3-C 10 Cyclyl group; C 3-C 10 Heterocyclyl group; -C(O)-(C1-C 13 Alkyl group; amino group (-N R8R9); Nitro group (-N(O)2); Amide group (-(C=O)NR8R9); Carbo Acid group (-C(O)OH); ester group (-C(O)OR8); nitrile group (-CN); Sulfonamide group (-NHS(O)2R8); sulfide group (-SR8); sulfone group ( -S(O)2R8); or phosphoryl group (-P(O)R8R9);

[0120] The aforementioned X1 may or may not exist, and if present, X1 is -CR8R9-, -O-, or -NR 8-,

[0121] Y1, Y2, Y3, and Y4 are each independently C6-C 10 Aryl group; C3- C 10 Heteroaryl group; C3-C 10 Cyclyl group; or C3-C 10 heterocycline It is the basis;

[0122] The aforementioned n and m are each independent integers between 0 and 15.

[0123] R8 and R9 are each independently hydrogen; C1-C6 alkyl; C1-C6 Kenyl group; C1-C6 alkynyl group; C6-C 10 Aryl group; C3-C 10 Heterozygous ants group;C3-C 10 Cyclyl group; C3-C 10 Heterocyclyl group; or R8 is R9 N, O, S, NH, C=N, C=O, -NHC( At least one of the following: O)-, -NHC(O)NH-, -NHS(O)2-, or SO2 It can contain any species, including hydrogen and C1-C 13 Alkyl alkyl group, C6-C 10 Aryl group, C3-C 10 Among heteroaryl groups, hydroxyl groups, halide groups, and cyano groups, at least Each of them forms a 3- to 7-membered saturated ring that can be arbitrarily substituted by one type.

[0124] The C1-C6 alkoxy group, C1-C 13 Alkyl or C3-C 10 cyclyl group is hydrogen; hydroxyl group; halogen group; C1-C 13 Alkyl alkyl groups; C1-C6 alkoxy Groups; amino group (-NR8R9); nitro group (-N(O)2); amide group (-(C=O)N R8R9); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR8); Ni Tolyl group (-CN); Urea group (-NR8(C=O)NR9-); Sulfonamide group (- NHS(O)2-); sulfide group (-S-); sulfone group (-S(O)2-); phospho Lyle group (-P(O)R8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl Base; and C3-C 10 Includes one or more substituents selected from the group consisting of heterocyclyl groups; fruit,

[0125] Said C6-C 10 Aryl group, C3-C 10 Heteroaryl group or C3-C 10 Hete The rosicyl group consists of hydrogen; a hydroxyl group; a halogen group; and a carbonyl group (-(C=O)R8R). 9); Halogen or C3-C 10 C1-C3 groups substituted or unsubstituted with heterocyclyl groups Lukyl group; halogen or C3-C 10 C1-C substituted or unsubstituted with heterocyclyl groups 3-alkoxy group; C6-C 10 Phenoxy; amino group (-NR8R9); amide group (-( C=O)NR8R9);C6-C 10 Aryl group; C3-C 10 Heteroaryl group and C 3-C 10 comprising one or more substituents selected from the group consisting of heterocyclyl groups;

[0126] Said C3-C 10 Heteroaryl group and C3-C 10 The heterocyclyl group consists of N, O, and A 2,7- ion represented by chemical formula 1, which contains one or more heteroatoms selected from the group consisting of S and ions. Substituted pyrrolo[2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable We provide salts, their hydrates, or their solvates.

[0127] In one example, in the chemical formula 3, A and B are each independently of benz In addition to thiazoles, pyrazoles, pyridines, indazoles, pyrimidines, quinolines, or thiazoles. Yes, R1, R2 and R3 are each independently hydrogen, halogen group, and C1-C 13 a Lukyl group or C3-C 10 It is a cyclyl group, and R4, R5, R6, and R7 are Each is independently hydrogen; hydroxyl group; halogen group; -NHCH3; -NHMs; -CO(N H)CH3;-OCH3;-OC2H5;or-OC6H 12 COOCH3; The 2,7-substituted pyrroro[2,1-f][1,2,4]triazine fermentation represented by formula 1 The present invention provides compounds, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof.

[0128] In one example, in the above chemical formula 3, E is E1, E2, E3, E4, E5 E6, E7, E8, E9, E 10 , E 11 , E 12 , E 13 , E 14 or E 15 dea ru

[0129] [ka]

[0130] 2,7-substituted pyrrolo[2,1-f][1,2,4]triazi, represented by chemical formula 1. The present invention provides compound, pharmaceutically acceptable salt thereof, its hydrate or solvate thereof.

[0131] In one example, in the above chemical formula 3, Q1 and Q2 are -(CH2) n -, -O(CH2) n -, -N(CH2) n - and -NH(CH2) n - any one of the following There are two such rings, n is an integer, and A and B are heteroaryl rings, cyclic hydrocarbons, and It is one of the alkyl groups, and M is -CHCH-, -CH2CH2-, or -NH CO-, -CONH-, -NMe-, -NAc-, -NMs-, -NHCONHR 10 - , -NHCOR 10 -, -NHSONR 10 - and -O- are either one of these, At that time, R 10 Among alkyl groups, cyclic hydrocarbons, phenyl groups, and substituted phenyl groups one of the following, where n is an integer of 0, 1, 2, 3 or 4, and the heterogeneous The ring is one of phenyl, pyridine, substituted phenyl, and pyrazole. The cyclic hydrocarbon is one or more of piperazine and cyclohexane. The present invention provides compounds, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof.

[0132] In one aspect of the present invention, the compound is from the group consisting of the following compound numbers 1 to 126. A 2,7-substituted pyrrolo[2,1- f][1,2,4]triazine compounds, their pharmaceutically acceptable salts, their hydrates or so Provides the solvide of:

[0133] (Compound number 1)(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- 1(1,4)-Benzenecycloundecaffeine;

[0134] (Compound number 2)(2 1 Z,4 4 E)-8-methyl-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -pyrazola-1(1,4)-benzenecycloundecaffeine;

[0135] (Compound number 3) 1-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffei-8-yl)ethane-1-one;

[0136] (Compound number 4) 1-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffeinate-8-yl)butan-1-one;

[0137] (Compound number 5)(2 1 Z,4 4 E)-41 H-11-oxa-3,8-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- 1(1,4)-Benzenecycloundecaffeinate-8-yl)(4-chlorophenyl) Tanon;

[0138] (Compound number 6)(2 1 Z,4 4 E)-N-cyclohexyl-4 1 H-11-oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-Pyrazola-1(1,4)-Benzenecycloundecaffeine-8-carboxy Amido;

[0139] (Compound number 7)(2 1 Z,4 4 E)-N-(3-methoxyphenyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8- Carboxamide;

[0140] (Compound number 8)(2 1 Z,4 4 E)-N-ethyl-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazola-1(1,4)-benzenecycloundecaffeine-8-carboxamide;

[0141] (Compound number 9)(2 1 Z,4 4 E)-8-(methylsulfonyl)-4 1 H-11-O Xa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine -4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine;

[0142] (Compound number 10)(2 1 Z,4 4 E)-8-((3,4-difluorophenyl)sulfur Honil)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f [1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclo Undecaffeinated;

[0143] (Compound number 11)(2 1 Z,4 4 E)-8-(phenylsulfonyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine;

[0144] (Compound number 12)(2 1 Z,4 4 E)-8-(cyclopropylsulfonyl)-4 1 H -11-oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine ;

[0145] (Compound number 13)(2 1 Z,4 4 E)-8-(propylsulfonyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine;

[0146] (Compound number 14)(2 1 Z,4 4 E)-8-((5-chlorothiophen-2-yl) Sulfonyl)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1 -f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-benzenesyl Undecaffeinated;

[0147] (Compound number 15)(2 1 Z,4 4 E)-8-(cyclohexylsulfonyl)-4 1 H -11-oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine ;

[0148] (Compound number 16)(Z)-5-oxa-3,9,15-triazine-2(7,2)- Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclo Pentadecapan-10-on;

[0149] (Compound number 17)(1 4 Z,2 1 Z)-1 1 H-5-oxa-3,9-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-1(4,1)-pyrazola- 4(1,4)-Benzenecyclohexadecapan-10-one;

[0150] (Compound number 18)(1 4 Z,2 1 Z,4 4 E)-1 1 H, 4 1 H-3,8-diaza- 2(7,2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(4,1)-di Pyrazolacyclopentadecapan-9-one;

[0151] (Compound number 19)(1 4 Z,2 1 Z)-1 1 H-3-Aza-2(7,2)-Pirolo[ 2,1-f][1,2,4]triazine-5(1,4)-piperazine-1(4,1)-pi Lazola-4(1,4)-benzenecyclododecapan-9-one;

[0152] (Compound number 20)(Z)-13-fluoro-5,17-dioxa-3,9-diaza- 2(7,2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-di Benzenecycloheptadecapan-10-one;

[0153] (Compound number 21)(2 1 Z,4 4 E)-13-fluoro-4 1 H-16-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-Pyrazola-1(1,4)-benzenecyclohexadecapan-9-one;

[0154] (Compound No. 22)(Z)-1 3 -fluoro-13-oxa-3-aza-2(7,2) -Pyrro[2,1-f][1,2,4]triazine-5(1,4)-piperazine-1,4 (1,4)-Dibenzenecyclotridecapan-6-one;

[0155] (Compound number 23) (Z)-17-oxa-3,9-diaza-2(7,2)-pyrolo[ 2,1-f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4) -Dibenzenecycloheptadecapan-10-one;

[0156] (Compound number 24)(Z)-13-oxa-3-aza-2(7,2)-pyrolo[2,1 -f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4)-gibe Nzencyclotridecapane-6-on;

[0157] (Compound number 25)(2 1 Z,4 4 E)-4 1 H-11-oxa-3-aza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecapan-6-one;

[0158] (Compound number 26)(2 1 Z,4 4 E)-4 1 H-15-oxa-3,9-diaza-2 (7,2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-Piperidine n-4(4,1)-pyrazola-1(1,4)-benzenecyclopentadecapane-10-o hmm;

[0159] (Compound number 27)(2 1 Z,4 4 E)-4 1 H-17-oxa-3,9-diaza-2 (7,2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-Piperidine n-4(4,1)-pyrazola-1(1,4)-benzenecycloheptadecapan-10-o hmm;

[0160] (Compound number 28)(Z)-5,12,15-trioxa-3,9-diaza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzene Cyclopentadecapane-10-on;

[0161] (Compound number 29)(Z)-5,17-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclo Putadecapan-10-on;

[0162] (Compound number 30)(Z)-5,12-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclod Decaffeinated;

[0163] (Compound number 31)(Z)-1-(5,12-dioxa-3,9-diaza-2(7,2 )-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenes Clododecapan-9-yl)propane-1-one;

[0164] (Compound number 32)(Z)-5,12-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclod Decapan-9-yl(4-chlorophenyl)methanone;

[0165] (Compound number 33)(2 1 Z,7Z)-5,10-dioxa-3-aza-2(7,2) -Pyrro[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenesic Rodekapan-7-en;

[0166] (Compound No. 34)(Z)-4 2 -Methoxy-5,12,15-trioxa-3,9- Diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-1,4(1, 4)-Dibenzenecyclopentadecapan-10-one;

[0167] (Compound number 35)(2 1 Z,4 4 E)-4 1 H-11,14-dioxa-3,8-di Aza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4(4,1)- Pyrazola-1(1,4)-benzenecyclotetradecapan-9-one;

[0168] (Compound number 36)(2 1 Z,4 4 E)-4 1 H-14-oxa-3,8-diaza-2 (7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola -1(1,4)-benzenecyclotetradecapan-9-one;

[0169] (Compound number 37)(2 1 Z,4 4 E)-4 1 H-16-oxa-3,8-diaza-2 (7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola -1(1,4)-benzenecyclohexadecapan-9-one;

[0170] (Compound number 38) (Z)-5,15-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclopeptide Ntadekapan-10-on;

[0171] (Compound number 39) N-(3-(2-((4-(4-(5-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)pent (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0172] (Compound number 40) N-(3-(2-((4-(4-(3-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)pro Pyr)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0173] (Compound number 41) N-(3-(2-((4-(4-(7-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)hep (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0174] (Compound number 42) N-(3-(2-((4-(4-(11-((2-(2,6-Geo Xopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy) (Ndecyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0175] (Compound number 43) N-(3-(2-((4-(4-(2-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)eth (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Riazin-7-yl)phenyl)methanesulfonamide;

[0176] (Compound number 44) N-(3-(2-((4-(4-(4-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)buty (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Riazin-7-yl)phenyl)methanesulfonamide;

[0177] (Compound number 45) N-(3-(2-((4-(4-(6-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)hex Sil)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0178] (Compound number 46) N-(3-(2-((4-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)oxy (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0179] (Compound number 47) N-(3-(2-((4-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)noni (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Riazin-7-yl)phenyl)methanesulfonamide;

[0180] (Compound number 48) N-(3-(2-((4-(4-(2-(2-((1,3-Dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0181] (Compound number 49) N-(3-(2-((4-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl) Piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide;

[0182] (Compound number 50) N-(3-(2-((4-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide;

[0183] (Compound number 51) N-(3-(2-((4-(4-((1-(2-(2,6-Dioxy Sopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl )piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0184] (Compound No. 52) N-(3-(2-((1-(1-(9-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperidine-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0185] (Compound No. 53) 3-(2-((1-(1-(9-((2-(2,6-Dioxopipette Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)piper Zin-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)-N-methylbenzamide;

[0186] (Compound number 54) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-phenylpyrrolo[2,1-f][1,2,4]triazine-2-yl )amino)-1H-pyrazole-1-yl)piperidine-1-yl)nonyl)oxy) Soindrin-1,3-dione;

[0187] (Compound number 55) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-(1-methyl-1H-pyrazole-4-yl)pyrrolo[2,1-f] [1,2,4] Triazine-2-yl)amino)-1H-pyrazole-1-yl)piper Zin-1-yl)nonyl)oxy)isoindoline-1,3-dione;

[0188] (Compound number 56) 4-((9-(4-(4-((7-(1H-indole-6-yl )pyrolo[2,1-f][1,2,4]triazine-2-yl)amino)-1H-pyrazo (Ir-1-yl)piperidine-1-yl)nonyl)oxy)-2-(2,6-dioxop Peridine-3-yl)isoindorin-1,3-dione;

[0189] (Compound number 57) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-(4-hydroxyphenyl)pyrrolo[2,1-f][1,2,4]to Riazin-2-yl)amino)-1H-pyrazole-1-yl)piperidine-1-yl) Nonyl(oxy)isoindoline-1,3-dione;

[0190] (Compound number 58) Methyl-7-(4-(2-((1-(1-(9-((2-(2,6 (-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-4-yl) C)nonyl)piperidine-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl(phenoxy)heptanate;

[0191] (Compound number 59) N-(3-(2-((4-(4-(5-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)pent (Tyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0192] (Compound number 60) N-(3-(2-((4-(4-(3-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)propyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0193] (Compound number 61) N-(3-(2-((4-(4-(7-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0194] (Compound number 62) N-(3-(2-((4-(4-(11-((2-(2,6-Geo Xopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)unde Sil)piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0195] (Compound number 63) N-(3-(2-((4-(4-(2-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)ethyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0196] (Compound number 64) N-(3-(2-((4-(4-(4-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0197] (Compound number 65) N-(3-(2-((4-(4-(6-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0198] (Compound number 66) N-(3-(2-((4-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)octyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0199] (Compound number 67) N-(3-(2-((4-(4-(9-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0200] (Compound number 68) N-(3-(2-((4-(4-(2-(2-((1,3-Dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2, 1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0201] (Compound number 69) N-(3-(2-((4-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0202] (Compound number 70) N-(3-(2-((4-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0203] (Compound number 71) N-(3-(2-((6-(4-(5-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)pentyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0204] (Compound number 72) N-(3-(2-((6-(4-(3-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)propyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0205] (Compound number 73) N-(3-(2-((6-(4-(7-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0206] (Compound number 74) N-(3-(2-((6-(4-(11-((2-(2,6-Geo Xopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)unde Sil)piperazin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0207] (Compound number 75) N-(3-(2-((6-(4-(2-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)ethyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0208] (Compound number 76) N-(3-(2-((6-(4-(4-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0209] (Compound number 77) N-(3-(2-((6-(4-(6-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0210] (Compound number 78) N-(3-(2-((6-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)octyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0211] (Compound number 79) N-(3-(2-((6-(4-(9-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0212] (Compound number 80) N-(3-(2-((6-(4-(2-(2-((1,3-Dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1- f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0213] (Compound number 81) N-(3-(2-((6-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0214] (Compound number 82) N-(3-(2-((6-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0215] (Compound number 83)(2S,4R)-1-((S)-3,3-dimethyl-2-(2-( 2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1- f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1-yl) Ethoxyacetaminobutanoyl-4-hydroxy-N-(4-(4-methylthia) Zole-5-yl)benzyl)pyrroridine-2-carboxyamide;

[0216] (Compound number 84) (2S,4R)-1-((S)-3,3-dimethyl-2-(3-( 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2 ,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1- Butanoyl-4-hydroxy-N-(4 -(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxyamide;

[0217] (Compound number 85)(2S,4R)-1-((S)-3,3-dimethyl-2-(3-( 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2 ,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1- (Iyl)ethoxy)ethoxy)propanamide)butanoyl)-4-hydroxy-N-(( S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine- 2-Carboxamide;

[0218] (Compound number 86) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(4-(trifluoromethoxy)phenyl)pyrrolo[2,1-f][ [1,2,4] Triazine-2-yl)amino)pyridine-2-yl)piperazine-1-yl Pentyl oxyisoindoline-1,3-dione;

[0219] (Compound number 87) 4-((5-(4-(5-((7-(3,5-difluorophenyl )Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2- Il)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine) -3-yl)isoindoline-1,3-dione;

[0220] (Compound number 88) 4-((5-(4-(5-((7-(2-aminopyridine-5-i (Lu) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2 -yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine) (n-3-yl)isoindoline-1,3-dione;

[0221] (Compound number 89) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(Quinoline-3-yl)pirolo[2,1-f][1,2,4]tria (Zin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy C) Isoindoline-1,3-dione;

[0222] (Compound No. 90) tert-butyl 4-(3-(2-((6-(4-(5-((2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindoline-4-yl (Lu)oxy)pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)benzyl)piperazine-1-carb nitrate;

[0223] (Compound number 91)(E)-2-(2,6-dioxopiperidine-3-yl)-4-( (5-(4-(5-((7-Styrylpyrrolo[2,1-f][1,2,4]triazine- 2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy) Soindrin-1,3-dione;

[0224] (Compound No. 92) tert-butyl 4-(4-(2-((6-(4-(5-((2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindoline-4-yl (Lu)oxy)pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)-1H-pyrazole-1-yl)pi Peridine-1-carboxylate salt;

[0225] (Compound number 93) 4-((5-(4-(5-((7-(4-(dimethylamino)phen Nyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine- 2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperazine Zin-3-yl)isoindoline-1,3-dione;

[0226] (Compound number 94) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(pyridine-4-yl)pyrrolo[2,1-f][1,2,4]tri (Zin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy C) Isoindoline-1,3-dione;

[0227] (Compound number 95) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(thiazole-5-yl)pyrrolo[2,1-f][1,2,4]to (Riadin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl) Oxy)isoindoline-1,3-dione;

[0228] (Compound number 96) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole Ru-5-yl)pyrolo[2,1-f][1,2,4]triazine-2-yl)amino)pi Lysine-2-yl)piperazine-1-yl)pentyl)oxy)isoindoline-1,3 - Zeon;

[0229] (Compound number 97) 4-((5-(4-(5-((7-((3,5-difluoropheny (Lu)ethinyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pi Lysine-2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxy) Sopiperidine-3-yl)isoindorine-1,3-dione;

[0230] (Compound number 98) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-((3-methoxyphenyl)ethynyl)pyrrolo[2,1-f][1, 2,4] Triazine-2-yl)amino)aminopyridine-2-yl)piperazine-1- Il)pentyl)oxy)isoindoline-1,3-dione;

[0231] (Compound number 99)N-(3-(2-((4-(4-(2-(2-(3-(4-((4 -(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo Isoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)- 3-Oxopropoxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino) Pyrrolo[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone Amido;

[0232] (Compound number 100)N-(3-(4-(3-(2,4-dihydroxy-5-isopro Pyrphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)pheno Xy)propyl)-3-(2-(2-(4-(4-((7-(3-(methanesulfone ammonium (d)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)f Ethoxy)piperazine-1-yl)ethoxy)propanamide;

[0233] (Compound number 101) N-(2-((3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl )Phenoxy)propyl)amino)-2-oxoethyl)-3-(2-(2-(4-(4 -((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][1,2, 4] Triazine-2-yl)amino)phenyl)piperazine-1-yl)ethoxy)eth Xy)propanamide;

[0234] (Compound number 102) N-(3-(2-((4-(4-(2-(2-(3-(4-(4 -(3-(2,4-dihydroxy-5-isophenylpropyl)-5-hydroxy-4H -1,2,4-triazole-4-yl)benzyl)piperazine-1-yl)-3-oxy Sopropoxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0235] (Compound number 103) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy C-4H-1,2,4-triazole-4-yl)benzyl)piperazine-1-yl) (Tyl)piperidine-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazine -1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7- Iyl(phenyl)methanesulfonamide;

[0236] (Compound number 104) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindorin-5-yl) Methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazin (1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7 -yl)phenyl)methanesulfonamide;

[0237] (Compound number 105) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 4-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindoline-5 -yl)methyl)piperazine-1-yl)methyl)piperidine-1-yl)-3-oxo Propoxy)ethoxy)ethyl)piperazine-1)yl)phenyl)amino)pyrrolo[2 ,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0238] (Compound number 106) 2-amino-4-(2,4-dichloro-5-(2-(4-(3- (2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[ 2,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1 -yl)ethoxy)ethoxy)propanoyl)piperazine-1-yl)ethoxy)pheni (Lu)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide;

[0239] (Compound number 107)N-(3-(2-((4-(4-((4-((4-((2-(2, 4-Dihydroxy-5-isopropylbenzoate)isoindoline-5-yl)methyl) Piperazine-1-yl)methyl)benzoate)piperazine-1-yl)phenyl)amino)pi Roro[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone Mido;

[0240] (Compound number 108) N-(3-(2-((4-(4-(1-((2-(2,4-dihy) Droxy-5-isopropylbenzoate (isoindorin-5-yl)methyl)piperidine -4-carbonyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][ [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0241] (Compound number 109) 4-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-Benzenecycloundecaffeinate-8-yl)ethoxy )-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione;

[0242] (Compound number 110) 4-(3-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl)propoxy C)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione ;

[0243] (Compound number 111) 4-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-2-(2-oxopiperidine-3-yl)isoindorine-1,3 - Zeon;

[0244] (Compound number 112) 4-((6-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)hex Sil)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1, 3-Zeon;

[0245] (Compound number 113) 4-((8-((2 1 Z,4 4 E)-41 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl) (Tyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1, 3-Zeon;

[0246] (Compound number 114) 4-((8-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl) (Tyl)oxy)-2-(2-oxopiperidine-3-yl)isoindoline-1,3-di on;

[0247] (Compound number 115) 4-((11-((2 1 Z,4 4 E)-4 1 H-11-oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-Pyrazole-1(1,4)-Benzenecycloundecaffeine-8-yl) (ndecyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline- 1,3-Zeon;

[0248] (Compound number 116) 4-((9-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-Pyrazola-1(1,4)-Benzenecycloundecaffeine-8-yl)nonyl )oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3- Dioneundecaffeine;

[0249] (Compound number 117) 5-(4-((1-(3-(2-(2-((2 1 Z,4 4 E)- 4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2 [4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaf (Chen-8-yl)ethoxy)ethoxy)propanoyl)piperidine-4-yl)methyl )piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)-6-full Oroisoindoline-1,3-dione;

[0250] (Compound number 118) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-N-(3-(4-(3-(2,4-dihydroxy-5-isopropyl (Phenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)phenoxy C) Propyl) Propanamide;

[0251] (Compound number 119) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-Pyrazole-1(1,4)-Benzenecycloundecaffeine-8-yl) Ethoxy)ethoxy)-N-(2-((3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl Phenoxypropyl amino-2-oxoethyl propanamide;

[0252] (Compound number 120) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropyl) (Phenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl )piperazine-1-yl)propan-1-one;

[0253] (Compound number 121) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((4-(4-(3-(2,4-dihydroxy-5-I (Sopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl) Benzyl piperazine-1-yl methyl piperidine-1-yl propan-1-one ;

[0254] (Compound number 122) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((2-(2,4-dihydroxy-5-isopropylbe Isoindoline-5-yl)methylpiperazine-1-yl)propane-1- on;

[0255] (Compound number 123)3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((4-((2,4-dihydroxy-5-isopropyl Ropyrubenzoyl isoindolin-5-yl methyl piperazine-1-yl methyl )piperidine-1-yl)propan-1-one;

[0256] (Compound number 124) 4-(5-(2-(4-(3-(2-(2-((2 1 Z,4 4 E )-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1 [2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclounden Caffeine-8-yl)ethoxy)ethoxy)propanoyl)piperazine-1-yl) Toxy)-2,4-dichlorophenyl)-2-amino-N-ethylthieno[2,3-d] Pyrimidine-6-carboxyamide;

[0257] (Compound number 125)(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazo La-1(1,4)-benzenecycloundecaffei-8-yl)(4-((4-((2 -(2,4-dihydroxy-5-isopropylbenzoyl)isoindorin-5-yl) Methyl)piperazine-1-yl)methyl)phenyl)methanone; and

[0258] (Compound number 126)(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazo La-1(1,4)-benzenecycloundecaffeine-8-yl)(1-((2-(2, 4-Dihydroxy-5-isopropylbenzoate)isoindoline-5-yl)methyl) Peridine-4-yl)methanone.

[0259] In one aspect of the present invention, the pharmaceutically acceptable salt is hydrochloric acid, hydrobromic acid, sulfuric acid, and Nitric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid Fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid Maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, Cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid 2,7-sodium, represented by chemical formula 1, is a salt of an inorganic or organic acid selected from the group consisting of the following: The replaced pyrrolo[2,1-f][1,2,4]triazine compound, its pharmaceutically acceptable We provide salts, their hydrates, or their solvates.

[0260] Another aspect of the present invention is that any one of the compounds in the aforementioned aspect of the present invention is used as an active ingredient. The present invention provides pharmaceutical compositions for the prevention, reduction, or treatment of cancer.

[0261] In another aspect of the present invention, the cancer is characterized by abnormal cell growth due to protein kinase activity. The present invention provides pharmaceutical compositions for the prevention, mitigation, or treatment of cancer, a disease induced by [unspecified cause].

[0262] In another aspect of the present invention, the compound inhibits protein kinase at 1 μM. The present invention provides a pharmaceutical composition for the prevention, mitigation, or treatment of cancer, with a toxicity rate of 80% or more.

[0263] In another aspect of the present invention, the protein kinase is ABL1, ABL2, ALK , ARK5, Aurora A, Aurora B, Aurora C, AXL, BLK , BMX, BRK, c-Kit, c-MER, c-Src, CAMK2a, CAMK2d , CDK16, CDK17, CDK18, CDK2 / cyclin A, CDK2 / cy clin O, CDK4 / cyclin D1, CDK4 / cyclin D2, CDK 4 / cyclin D3, CDK6 / cyclin D1, CDK6 / cyclin D 3, CDK7 / cyclin H, CDK9 / cyclin K, CDK9 / cycli n T1, CDK9 / cyclin T2, CK2a, CK2a2, CLK1, CLK2 , CLK4, DAPK1, DAPK2, DDR1, DDR2, DRAK1, DYRK1 / DYRK1A、DYRK1B、DYRK3、EPHA1、EPHA2、EPHA4、EP HA5、EPHA6、EPHA7、EPHB1、EPHB2、ERBB4 / HER4、E RK7 / MAPK15、ERN2 / IRE2、FAK / PTK2、FER、FES / FP S、FGFR1、FGFR2、FGFR3、FGR、FLT1 / VEGFR1、FLT3 、FLT4 / VEGFR3、FMS、FRK / PTK5、FYN、GLK / MAP4K3 、GSK3a、HIPK2、HIPK3、HIPK4、HPK1 / MAP4K1、IGF 1R、IKKe / IKBKE、IR、IRAK1、IRR / INSRR、JAK1、JA K2、JAK3、JNK1、JNK2、JNK3、KDR / VEGFR2、KHS / MA P4K5、LCK、LIMK1、LIMK2、LRRK2、LYN、LYN B、MAK 、MARK1、MARK2 / PAR-1Ba、MARK3、MARK4、MAST3、M EKK2、MELK、MLCK2 / MYLK2、MLK1 / MAP3K9、MLK2 / M AP3K10、MLK3 / MAP3K11、MUSK、MYLK4、NEK1、NEK2 、NEK5、NEK9、p70S6K / RPS6KB1、PAK4、PAK5、PAK6 、PDGFRa、PDGFRb、PHKg1、PHKg2、PKAcb、PKCa、PK Cb2、PKCg、PKCmu / PRKD1、PKCnu / PRKD3、PKD2 / PR KD2、PKN1 / PRK1、PLK4 / SAK、PRKX、PYK2、RET、ROS / ROS1、RSK2、RSK3、RSK4、SIK1、SIK2、SLK / STK2、 SNARK / NUAK2、STK16、STK22D / TSSK1、STK33、STK 38 / NDR1、STK38L / NDR2、STK39 / STLK3、SYK、TBK1 , TEC, TIE2 / TEK, TLK2, TNK1, TRKA, TRKB, TRKC, T YK2, TYRO3 / SKY, ULK1, ULK2, ULK3, WEE1, YES / YE One or more of the following: S1, YSK4 / MAP3K19, and ZIPK / DAPK3. To provide pharmaceutical compositions for the prevention, reduction, or treatment of cancer.

[0264] In another aspect of the present invention, the disease is gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer Brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, type A Adenocarcinoma, parathyroid cancer, new intestine cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma Blood cancers such as myelodysplastic syndrome, and lymphomas such as Hodgkin's disease and non-Hodgkin's lymphoma. A drug for the prevention, reduction, or treatment of cancer, which is a disease selected from the group consisting of , and fibroadenoma. To provide a scientific composition.

[0265] The manufacturing method of the present invention is as follows.

[0266] The 2,7-substituted pyrrolo[2,1-f][1, 2,4] pharmaceutically acceptable salts of triazine compounds are prepared by methods commonly used in the art. It can be manufactured by [method]. Pharmaceutically acceptable salts have low toxicity to the human body and are biocompatible with the parent compound. It must not adversely affect the chemical activity and physicochemical properties. Pharmaceutically acceptable salts are those that are pharmaceutically acceptable. Scientifically usable free acids and acid addition salts of base compounds of chemical formula 1, and alkali metal salts ( Sodium salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), and organic salts and chemical It is composed of an organic base addition salt of the carboxylic acid of formula 1, and an amino acid addition salt. Pharmaceutically permitted Free acids used in the production of dissolved salts can be divided into inorganic acids and organic acids. Inorganic acids include hydrochloric acid. Sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and bromate are used. Organic acids include acetic acid and methanesulfuric acid. Fumaric acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, Malic acid, oxalic acid, benzoic acid, benzoic acid, aspartic acid, glutamic acid, etc. are used. The organic base used in the production of organic base addition salts is tris(hydroxymethyl)methyl. These include amines and dicyclohexylamines. These are amino acids used in the production of amino acid addition salts. These are natural amino acids such as alanine and glycine.

[0267] The 2,7-substituted pyrrolo[2,1-f][1, [2,4] Triazine compounds, together with the pharmaceutically acceptable salts, any hydrate, and And also includes solvates. The hydrates and solvates are 2,7-substituted, represented by the chemical formula 1. The pyrolo[2,1-f][1,2,4]triazine compound was mixed with methanol, ethanol, and After dissolving cetone in a water-miscible solvent such as 1,4-dioxane, free acid is released. Alternatively, crystallization or recrystallization may occur after the addition of a free base. In such cases, Solvorides (especially hydrates) may be formed. Therefore, the compound of the present invention can be freeze-dried. In addition to various amounts of water-containing compounds that can be produced by methods such as those described above, stoichiometric solvents including hydrates. This includes monsters as well.

[0268] To elaborate further on the substituents used to define the compounds according to the present invention, It is as follows:

[0269] In this invention, "halogen atom" refers to fluorine, chlorine, bromine, or iodine atom.

[0270] In this invention, "alkyl group" refers to methyl, ethyl, n-propyl, i-propyl, and ethyl alkyl groups. Ropropyl, n-butyl, i-butyl, t-butyl, cyclobutyl, cyclopropylmethyl Lu, n-pentyl, i-pentyl, neopentyl, t-pentyl, cyclopentyl, cyk Butylmethyl, n-hexyl, i-hexyl, cyclohexyl, cyclopentylmethyl This refers to aliphatic saturated hydrocarbon groups having one to six carbon atoms, including those mentioned above.

[0271] In this invention, "haloalkyl group" refers to one or more halomethyl groups. This refers to an alkyl group in which a hydrogen atom is substituted by an nucleotide.

[0272] In this invention, "alkoxy group" refers to methoxy, ethoxy, n-propoxy, i-propoxy Selected from the alkyl groups of CC, including xyl, n-butoxy, i-butoxy, and t-butoxy. This refers to a hydroxyl group in which a hydrogen atom has been substituted by a substituted compound.

[0273] In this invention, "heteroaryl group" refers to pyrrolyl, furanyl, thiophenyl, and pyrazoli Lu, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, to Liazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl Lu, pyridazinyl, pyrimidinyl, triazolyl, indolyl, isoindolyl, benzo Furanil, benzofuranil, dibenzofuranil, isobenzofuranil, indazolyl, Benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl , dibenzothiophenyl, naphthyridine, benzisothiazolyl, quinolinyl, isoquino It contains linyl, quinoxalinyl, phthalazinyl, thinolinyl, quinazolinyl, etc. This refers to a monocyclic, dicyclic, or tricyclic aromatic heterohydrocarbon group containing one or more atoms.

[0274] In this invention, "heterocyclic group" refers to a morpholinyl group, a piperidine group, a piperazinyl group, A heterocarbon containing one or more heteroatoms, such as an N-protected piperazinyl group. It means a hydrogen ring group.

[0275] As mentioned above, the 2,7-substituted pyrrolo[2,1-f][1] represented by chemical formula 1 More specifically, examples of triazine-cyclized compounds are as follows:

[0276] (Compound number 1)(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- 1(1,4)-Benzenecycloundecaffeine;

[0277] (Compound number 2)(2 1 Z,4 4 E)-8-methyl-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -pyrazola-1(1,4)-benzenecycloundecaffeine;

[0278] (Compound number 3) 1-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffei-8-yl)ethane-1-one;

[0279] (Compound number 4) 1-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffeinate-8-yl)butan-1-one;

[0280] (Compound number 5)(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- 1(1,4)-Benzenecycloundecaffeinate-8-yl)(4-chlorophenyl) Tanon;

[0281] (Compound number 6)(2 1 Z,4 4 E)-N-cyclohexyl-4 1 H-11-oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-Pyrazola-1(1,4)-Benzenecycloundecaffeine-8-carboxy Amido;

[0282] (Compound number 7)(2 1 Z,4 4 E)-N-(3-methoxyphenyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8- Carboxamide;

[0283] (Compound number 8)(2 1 Z,4 4 E)-N-ethyl-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazola-1(1,4)-benzenecycloundecaffeine-8-carboxamide;

[0284] (Compound number 9)(2 1 Z,4 4 E)-8-(methylsulfonyl)-4 1 H-11-O Xa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine -4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine;

[0285] (Compound number 10)(2 1 Z,4 4 E)-8-((3,4-difluorophenyl)sulfur Honil)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f [1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclo Undecaffeinated;

[0286] (Compound number 11)(2 1 Z,4 4 E)-8-(phenylsulfonyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine;

[0287] (Compound number 12)(2 1 Z,4 4 E)-8-(cyclopropylsulfonyl)-4 1 H -11-oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine ;

[0288] (Compound number 13)(2 1 Z,4 4 E)-8-(propylsulfonyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine;

[0289] (Compound number 14)(2 1 Z,4 4 E)-8-((5-chlorothiophen-2-yl) Sulfonyl)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1 -f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-benzenesyl Undecaffeinated;

[0290] (Compound number 15)(2 1 Z,4 4 E)-8-(cyclohexylsulfonyl)-4 1 H -11-oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine ;

[0291] (Compound number 16)(Z)-5-oxa-3,9,15-triazine-2(7,2)- Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclo Pentadecapan-10-on;

[0292] (Compound number 17)(1 4 Z,2 1 Z)-1 1 H-5-oxa-3,9-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-1(4,1)-pyrazola- 4(1,4)-Benzenecyclohexadecapan-10-one;

[0293] (Compound number 18)(1 4 Z,2 1 Z,4 4 E)-1 1 H, 4 1 H-3,8-diaza- 2(7,2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(4,1)-di Pyrazolacyclopentadecapan-9-one;

[0294] (Compound number 19)(1 4 Z,2 1 Z)-1 1 H-3-Aza-2(7,2)-Pirolo[ 2,1-f][1,2,4]triazine-5(1,4)-piperazine-1(4,1)-pi Lazola-4(1,4)-benzenecyclododecapan-9-one;

[0295] (Compound number 20)(Z)-13-fluoro-5,17-dioxa-3,9-diaza- 2(7,2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-di Benzenecycloheptadecapan-10-one;

[0296] (Compound number 21)(2 1 Z,4 4 E)-13-fluoro-4 1 H-16-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-Pyrazola-1(1,4)-benzenecyclohexadecapan-9-one;

[0297] (Compound No. 22)(Z)-1 3 -fluoro-13-oxa-3-aza-2(7,2) -Pyrro[2,1-f][1,2,4]triazine-5(1,4)-piperazine-1,4 (1,4)-Dibenzenecyclotridecapan-6-one;

[0298] (Compound number 23) (Z)-17-oxa-3,9-diaza-2(7,2)-pyrolo[ 2,1-f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4) -Dibenzenecycloheptadecapan-10-one;

[0299] (Compound number 24)(Z)-13-oxa-3-aza-2(7,2)-pyrolo[2,1 -f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4)-gibe Nzencyclotridecapane-6-on;

[0300] (Compound number 25)(2 1 Z,4 4 E)-4 1 H-11-oxa-3-aza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecapan-6-one;

[0301] (Compound number 26)(2 1 Z,4 4 E)-4 1 H-15-oxa-3,9-diaza-2 (7,2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-Piperidine n-4(4,1)-pyrazola-1(1,4)-benzenecyclopentadecapane-10-o hmm;

[0302] (Compound number 27)(2 1 Z,4 4 E)-4 1 H-17-oxa-3,9-diaza-2 (7,2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-Piperidine n-4(4,1)-pyrazola-1(1,4)-benzenecycloheptadecapan-10-o hmm;

[0303] (Compound number 28)(Z)-5,12,15-trioxa-3,9-diaza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzene Cyclopentadecapane-10-on;

[0304] (Compound number 29)(Z)-5,17-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclo Putadecapan-10-on;

[0305] (Compound number 30)(Z)-5,12-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclod Decaffeinated;

[0306] (Compound number 31)(Z)-1-(5,12-dioxa-3,9-diaza-2(7,2 )-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenes Clododecapan-9-yl)propane-1-one;

[0307] (Compound number 32)(Z)-5,12-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclod Decapan-9-yl(4-chlorophenyl)methanone;

[0308] (Compound number 33)(2 1 Z,7Z)-5,10-dioxa-3-aza-2(7,2) -Pyrro[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenesic Rodekapan-7-en;

[0309] (Compound No. 34)(Z)-4 2 -Methoxy-5,12,15-trioxa-3,9- Diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-1,4(1, 4)-Dibenzenecyclopentadecapan-10-one;

[0310] (Compound number 35)(2 1 Z,4 4 E)-4 1 H-11,14-dioxa-3,8-di Aza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4(4,1)- Pyrazola-1(1,4)-benzenecyclotetradecapan-9-one;

[0311] (Compound number 36): (2 1 Z,4 4 E)-4 1 H-14-oxa-3,8-diaza- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazo La-1(1,4)-benzenecyclotetradecapan-9-one;

[0312] (Compound number 37)(2 1 Z,4 4 E)-4 1H-16-oxa-3,8-diaza-2 (7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola -1(1,4)-benzenecyclohexadecapan-9-one;

[0313] (Compound number 38) (Z)-5,15-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclopeptide Ntadekapan-10-on;

[0314] (Compound number 39) N-(3-(2-((4-(4-(5-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)pent (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0315] (Compound number 40) N-(3-(2-((4-(4-(3-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)pro Pyr)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0316] (Compound number 41) N-(3-(2-((4-(4-(7-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)hep (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0317] (Compound number 42) N-(3-(2-((4-(4-(11-((2-(2,6-Geo Xopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy) (Ndecyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0318] (Compound number 43) N-(3-(2-((4-(4-(2-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)eth (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Riazin-7-yl)phenyl)methanesulfonamide;

[0319] (Compound number 44) N-(3-(2-((4-(4-(4-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)buty (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Riazin-7-yl)phenyl)methanesulfonamide;

[0320] (Compound number 45) N-(3-(2-((4-(4-(6-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)hex Sil)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0321] (Compound number 46) N-(3-(2-((4-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)oxy (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0322] (Compound number 47) N-(3-(2-((4-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)noni (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Riazin-7-yl)phenyl)methanesulfonamide;

[0323] (Compound number 48) N-(3-(2-((4-(4-(2-(2-((1,3-Dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0324] (Compound number 49) N-(3-(2-((4-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl) Piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide;

[0325] (Compound number 50) N-(3-(2-((4-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide;

[0326] (Compound number 51) N-(3-(2-((4-(4-((1-(2-(2,6-Dioxy Sopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl )piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0327] (Compound No. 52) N-(3-(2-((1-(1-(9-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperidine-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0328] (Compound No. 53) 3-(2-((1-(1-(9-((2-(2,6-Dioxopipette Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)piper Zin-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)-N-methylbenzamide;

[0329] (Compound number 54) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-phenylpyrrolo[2,1-f][1,2,4]triazine-2-yl )amino)-1H-pyrazole-1-yl)piperidine-1-yl)nonyl)oxy) Soindrin-1,3-dione;

[0330] (Compound number 55) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-(1-methyl-1H-pyrazole-4-yl)pyrrolo[2,1-f] [1,2,4] Triazine-2-yl)amino)-1H-pyrazole-1-yl)piper Zin-1-yl)nonyl)oxy)isoindoline-1,3-dione;

[0331] (Compound number 56) 4-((9-(4-(4-((7-(1H-indole-6-yl )pyrolo[2,1-f][1,2,4]triazine-2-yl)amino)-1H-pyrazo (Ir-1-yl)piperidine-1-yl)nonyl)oxy)-2-(2,6-dioxop Peridine-3-yl)isoindorin-1,3-dione;

[0332] (Compound number 57) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-(4-hydroxyphenyl)pyrrolo[2,1-f][1,2,4]to Riazin-2-yl)amino)-1H-pyrazole-1-yl)piperidine-1-yl) Nonyl(oxy)isoindoline-1,3-dione;

[0333] (Compound number 58) Methyl-7-(4-(2-((1-(1-(9-((2-(2,6 (-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-4-yl) C)nonyl)piperidine-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl(phenoxy)heptanate;

[0334] (Compound number 59) N-(3-(2-((4-(4-(5-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)pent (Tyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0335] (Compound number 60) N-(3-(2-((4-(4-(3-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)propyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0336] (Compound number 61) N-(3-(2-((4-(4-(7-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0337] (Compound number 62) N-(3-(2-((4-(4-(11-((2-(2,6-Geo Xopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)unde Sil)piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0338] (Compound number 63) N-(3-(2-((4-(4-(2-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)ethyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0339] (Compound number 64) N-(3-(2-((4-(4-(4-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0340] (Compound number 65) N-(3-(2-((4-(4-(6-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0341] (Compound number 66) N-(3-(2-((4-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)octyl )piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0342] (Compound number 67) N-(3-(2-((4-(4-(9-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0343] (Compound number 68) N-(3-(2-((4-(4-(2-(2-((1,3-Dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2, 1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0344] (Compound number 69) N-(3-(2-((4-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0345] (Compound number 70) N-(3-(2-((4-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0346] (Compound number 71) N-(3-(2-((6-(4-(5-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)pentyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0347] (Compound number 72) N-(3-(2-((6-(4-(3-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)propyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0348] (Compound number 73) N-(3-(2-((6-(4-(7-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0349] (Compound number 74) N-(3-(2-((6-(4-(11-((2-(2,6-Geo Xopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)unde Sil)piperazin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1 [2,4]triazine-7-yl(phenyl)methanesulfonamide;

[0350] (Compound number 75) N-(3-(2-((6-(4-(2-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)ethyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0351] (Compound number 76) N-(3-(2-((6-(4-(4-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0352] (Compound number 77) N-(3-(2-((6-(4-(6-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0353] (Compound number 78) N-(3-(2-((6-(4-(8-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)octyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0354] (Compound number 79) N-(3-(2-((6-(4-(9-((2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0355] (Compound number 80) N-(3-(2-((6-(4-(2-(2-((1,3-Dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1- f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0356] (Compound number 81) N-(3-(2-((6-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0357] (Compound number 82) N-(3-(2-((6-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide;

[0358] (Compound number 83)(2S,4R)-1-((S)-3,3-dimethyl-2-(2-( 2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1- f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1-yl) Ethoxyacetaminobutanoyl-4-hydroxy-N-(4-(4-methylthia) Zole-5-yl)benzyl)pyrroridine-2-carboxyamide;

[0359] (Compound number 84) (2S,4R)-1-((S)-3,3-dimethyl-2-(3-( 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2 ,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1- Butanoyl-4-hydroxy-N-(4 -(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxyamide;

[0360] (Compound number 85)(2S,4R)-1-((S)-3,3-dimethyl-2-(3-( 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2 ,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1- (Iyl)ethoxy)ethoxy)propanamide)butanoyl)-4-hydroxy-N-(( S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine- 2-Carboxamide;

[0361] (Compound number 86) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(4-(trifluoromethoxy)phenyl)pyrrolo[2,1-f][ [1,2,4] Triazine-2-yl)amino)pyridine-2-yl)piperazine-1-yl Pentyl oxyisoindoline-1,3-dione;

[0362] (Compound number 87) 4-((5-(4-(5-((7-(3,5-difluorophenyl )Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2- Il)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine) -3-yl)isoindoline-1,3-dione;

[0363] (Compound number 88) 4-((5-(4-(5-((7-(2-aminopyridine-5-i (Lu) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2 -yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine) (n-3-yl)isoindoline-1,3-dione;

[0364] (Compound number 89) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(Quinoline-3-yl)pirolo[2,1-f][1,2,4]tria (Zin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy C) Isoindoline-1,3-dione;

[0365] (Compound No. 90) tert-butyl 4-(3-(2-((6-(4-(5-((2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindoline-4-yl (Lu)oxy)pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)benzyl)piperazine-1-carb nitrate;

[0366] (Compound number 91)(E)-2-(2,6-dioxopiperidine-3-yl)-4-( (5-(4-(5-((7-Styrylpyrrolo[2,1-f][1,2,4]triazine- 2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy) Soindrin-1,3-dione;

[0367] (Compound No. 92) tert-butyl 4-(4-(2-((6-(4-(5-((2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindoline-4-yl (Lu)oxy)pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)-1H-pyrazole-1-yl)pi Peridine-1-carboxylate salt;

[0368] (Compound number 93) 4-((5-(4-(5-((7-(4-(dimethylamino)phen Nyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine- 2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperazine Zin-3-yl)isoindoline-1,3-dione;

[0369] (Compound number 94) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(pyridine-4-yl)pyrrolo[2,1-f][1,2,4]tri (Zin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy C) Isoindoline-1,3-dione;

[0370] (Compound number 95) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(thiazole-5-yl)pyrrolo[2,1-f][1,2,4]to (Riadin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl) Oxy)isoindoline-1,3-dione;

[0371] (Compound number 96) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole Ru-5-yl)pyrolo[2,1-f][1,2,4]triazine-2-yl)amino)pi Lysine-2-yl)piperazine-1-yl)pentyl)oxy)isoindoline-1,3 - Zeon;

[0372] (Compound number 97) 4-((5-(4-(5-((7-((3,5-difluoropheny (Lu)ethinyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pi Lysine-2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxy) Sopiperidine-3-yl)isoindorine-1,3-dione;

[0373] (Compound number 98) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-((3-methoxyphenyl)ethynyl)pyrrolo[2,1-f][1, 2,4] Triazine-2-yl)amino)aminopyridine-2-yl)piperazine-1- Il)pentyl)oxy)isoindoline-1,3-dione;

[0374] (Compound number 99)N-(3-(2-((4-(4-(2-(2-(3-(4-((4 -(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo Isoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)- 3-Oxopropoxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino) Pyrrolo[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone Amido;

[0375] (Compound number 100)N-(3-(4-(3-(2,4-dihydroxy-5-isopro Pyrphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)pheno Xy)propyl)-3-(2-(2-(4-(4-((7-(3-(methanesulfone ammonium (d)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)f Ethoxy)piperazine-1-yl)ethoxy)propanamide;

[0376] (Compound number 101) N-(2-((3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl )Phenoxy)propyl)amino)-2-oxoethyl)-3-(2-(2-(4-(4 -((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][1,2, 4] Triazine-2-yl)amino)phenyl)piperazine-1-yl)ethoxy)eth Xy)propanamide;

[0377] (Compound number 102) N-(3-(2-((4-(4-(2-(2-(3-(4-(4 -(3-(2,4-dihydroxy-5-isophenylpropyl)-5-hydroxy-4H -1,2,4-triazole-4-yl)benzyl)piperazine-1-yl)-3-oxy Sopropoxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0378] (Compound number 103) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy C-4H-1,2,4-triazole-4-yl)benzyl)piperazine-1-yl) (Tyl)piperidine-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazine -1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7- Iyl(phenyl)methanesulfonamide;

[0379] (Compound number 104) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindorin-5-yl) Methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazin (1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7 -yl)phenyl)methanesulfonamide;

[0380] (Compound number 105) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 4-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindoline-5 -yl)methyl)piperazine-1-yl)methyl)piperidine-1-yl)-3-oxo Propoxy)ethoxy)ethyl)piperazine-1)yl)phenyl)amino)pyrrolo[2 ,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0381] (Compound number 106) 2-amino-4-(2,4-dichloro-5-(2-(4-(3- (2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[ 2,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1 -yl)ethoxy)ethoxy)propanoyl)piperazine-1-yl)ethoxy)pheni (Lu)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide;

[0382] (Compound number 107)N-(3-(2-((4-(4-((4-((4-((2-(2, 4-Dihydroxy-5-isopropylbenzoate)isoindoline-5-yl)methyl) Piperazine-1-yl)methyl)benzoate)piperazine-1-yl)phenyl)amino)pi Roro[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone Mido;

[0383] (Compound number 108) N-(3-(2-((4-(4-(1-((2-(2,4-dihy) Droxy-5-isopropylbenzoate (isoindorin-5-yl)methyl)piperidine -4-carbonyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][ [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide;

[0384] (Compound number 109) 4-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-Benzenecycloundecaffeinate-8-yl)ethoxy )-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione;

[0385] (Compound number 110) 4-(3-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl)propoxy C)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione ;

[0386] (Compound number 111) 4-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-2-(2-oxopiperidine-3-yl)isoindorine-1,3 - Zeon;

[0387] (Compound number 112) 4-((6-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)hex Sil)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1, 3-Zeon;

[0388] (Compound number 113) 4-((8-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl) (Tyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1, 3-Zeon;

[0389] (Compound number 114) 4-((8-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl) (Tyl)oxy)-2-(2-oxopiperidine-3-yl)isoindoline-1,3-di on;

[0390] (Compound number 115) 4-((11-((2 1 Z,4 4 E)-4 1 H-11-oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-Pyrazole-1(1,4)-Benzenecycloundecaffeine-8-yl) (ndecyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline- 1,3-Zeon;

[0391] (Compound number 116) 4-((9-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-Pyrazola-1(1,4)-Benzenecycloundecaffeine-8-yl)nonyl )oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3- Dioneundecaffeine;

[0392] (Compound number 117) 5-(4-((1-(3-(2-(2-((2 1 Z,4 4 E)- 4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2 [4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaf (Chen-8-yl)ethoxy)ethoxy)propanoyl)piperidine-4-yl)methyl )piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)-6-full Oroisoindoline-1,3-dione;

[0393] (Compound number 118) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-N-(3-(4-(3-(2,4-dihydroxy-5-isopropyl (Phenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)phenoxy C) Propyl) Propanamide;

[0394] (Compound number 119) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-Pyrazole-1(1,4)-Benzenecycloundecaffeine-8-yl) Ethoxy)ethoxy)-N-(2-((3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl Phenoxypropyl amino-2-oxoethyl propanamide;

[0395] (Compound number 120) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropyl) (Phenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl )piperazine-1-yl)propan-1-one;

[0396] (Compound number 121) 3-(2-(2-((2 1 Z,4 4 E)-41 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((4-(4-(3-(2,4-dihydroxy-5-I (Sopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl) Benzyl piperazine-1-yl methyl piperidine-1-yl propan-1-one ;

[0397] (Compound number 122) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((2-(2,4-dihydroxy-5-isopropylbe Isoindoline-5-yl)methylpiperazine-1-yl)propane-1- on;

[0398] (Compound number 123)3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa -3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((4-((2,4-dihydroxy-5-isopropyl Ropyrubenzoyl isoindolin-5-yl methyl piperazine-1-yl methyl )piperidine-1-yl)propan-1-one;

[0399] (Compound number 124) 4-(5-(2-(4-(3-(2-(2-((2 1 Z,4 4 E )-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1 [2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclounden Caffeine-8-yl)ethoxy)ethoxy)propanoyl)piperazine-1-yl) Toxy)-2,4-dichlorophenyl)-2-amino-N-ethylthieno[2,3-d] Pyrimidine-6-carboxyamide;

[0400] (Compound number 125) ((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffeinate-8-yl)(4-((4-(( 2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindorin-5-yl )methyl)piperazine-1-yl)methyl)phenyl)methanone; and

[0401] (Compound number 126)(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazo La-1(1,4)-benzenecycloundecaffeine-8-yl)(1-((2-(2, 4-Dihydroxy-5-isopropylbenzoate)isoindoline-5-yl)methyl) Peridine-4-yl)methanone.

[0402] The pharmaceutical composition of the present invention is a 2,7-substituted pyrrolo[2,1 -f][1,2,4]triazine compounds, pharmaceutically acceptable salts thereof, solvates thereof, It contains the hydrate as an active ingredient, and a normal, non-toxic, pharmacochemically acceptable carrier. By adding reinforcing agents and excipients, etc., it becomes a conventional pharmaceutical preparation, such as tablets and capsules. Formulated as oral or parenteral formulations such as lozenges, liquids, or suspensions. It is possible.

[0403] Excipients used in the pharmaceutical composition of the present invention include sweeteners, binders, solvents, and solubilizers. , wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, It contains fragrances, etc. For example, lactose, dextrose, sucrose, mannitol. Sorbitol, cellulose, glycine, silica, talc, stearic acid, sterol, Magnesium stearate, aluminum magnesium silicate, starch, gelatin, traga Cant gum, alginic acid, sodium arginate, methylcellulose, carboxymethyl Sodium cellulose, agar, water, ethanol, polyethylene glycol, polyvinyl Lupyrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence Examples include vanilla and other aromas.

[0404] Furthermore, the dosage of the compound according to the present invention for human use depends on the patient's age, weight, sex, and administration. This can vary depending on morphology, health condition, and disease severity, and is for adult patients weighing 70 kg. When using this as a reference, the general range is 0.01 to 1,000 mg / day, and is recommended by a doctor or pharmacist. Depending on the doctor's judgment, the medication can be divided into one to several doses per day at regular intervals.

[0405] Another aspect of the present invention is any one of the aforementioned compounds, which is pharmaceutically acceptable. In a method for producing salt, its hydrate, or its solvide,

[0406] N-(3-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl) Phenyl)methanesulfonamide;

[0407] N-(3-(2-((4-(piperazine-1-yl)phenyl)amino)pyrrolo[2, 1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide;

[0408] N-(3-(2-((6-(piperazine-1-yl)pyridine-3-yl)amino)pi Roro[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone Mido;

[0409] N-(3-(2-((2-methoxy-4-(piperazine-1-yl)phenyl)amino )Pyrrolo[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfo Namido;

[0410] N-(3-(2-((1-(piperidine-4-yl)-1H-pyrazole-4-yl) Amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl)phenyl)methane Sulfonamide;

[0411] 4-((7-(4-(4-amino-1H-pyrazole-1-yl)piperidine-1-yl (L)heptyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindri n-1,3-Zeon;

[0412] 4-((5-(4-(4-aminophenyl)piperazine-1-yl)pentyl)oxy )-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione;

[0413] 3-(2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pi Roro[2,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazi 1-yl ethoxy ethoxy propanoic acid;

[0414] 4-(4-(4-(3-aminopropoxy)phenyl)-5-hydroxy-4H-1, 2,4-Triazole-3-yl)-6-isopropylbenzene-1,3-diol;

[0415] 2-amino-N-(3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl (Nyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)phenoxy) Ropil acetamide;

[0416] 4-(5-hydroxy-4-(4-(piperazine-1-ylmethyl)phenyl)-4H -1,2,4-triazole-3-yl)-6-isopropylbenzene-1,3-diole Lu;

[0417] 4-(5-hydroxy-4-(4-((4-(piperidine-4-ylmethyl)piperazi (1-yl)methyl)phenyl)-4H-1,2,4-triazole-3-yl)-6 -Isopropylbenzene-1,3-diol;

[0418] (2,4-dihydroxy-5-isopropylphenyl)(5-(piperazin-1-yl) Methyl)isoindolin-2-yl)methanone;

[0419] (2,4-dihydroxy-5-isopropylphenyl)(5-((4-(piperidine- 4-Ilmethyl)piperazine-1-yl)methyl)isoindoline-2-yl)methanone ;

[0420] 2-amino-4-(2,4-dichloro-5-(2-(piperazine-1-yl)ethoxy )phenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide;

[0421] 4-(3-isopropyl-4-(4-(1-methyl-1H-pyrazole-4-yl)- 1H-imidazole-1-yl)-1H-pyrazola[3,4-b]pyridine-1-yl) -2-((4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)benz Amido;

[0422] 4-Chloro-7-((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl) -5-(3-(4-(piperidine-4-ylmethyl)piperazine-1-yl)prop-1 -in-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine;

[0423] 4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoin Drin-5-yl)methyl)piperazine-1-yl)methyl)benzoic acid; and

[0424] 1-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindoline- 5-Il)methyl)piperidine-4-carboxylic acid;

[0425] One of the 2,7-substituted pyrolo[2,1-f][1,2, 4] A method for producing a compound is provided, which includes a step of reacting an intermediate compound of a triazine compound. ru.

[0426] On the other hand, the present invention relates to the 2,7-substituted pyrrolo represented by chemical formulas 2 and 3 [2 The characteristic lies in the method of producing [1-f][1,2,4]triazine compounds, but a representative example is The manufacturing method is as follows:

[0427] The compound having the above chemical formula has a pyrrolo[2,1-f][1,2,4]triazine skeleton. It has the characteristic of being such.

[0428] Chemical formula 2 shows a cyclization of the benzene ring at position 7 of the skeleton via a Suzuki reaction. A hydrocarbon was introduced. Next, a cyclic compound having an amine functional group was added to the second position. Substitution was carried out via the Chwald reaction. The amine functional group introduced at position 2 was linked to Linke It was synthesized by introducing the r+E3l ligase binder.

[0429] Chemical formula 3 shows a cyclization of the benzene ring at position 7 of the skeleton via the Suzuki reaction. A hydrocarbon was introduced. Subsequently, an alkyl group having a cyclizable functional group was linked. Next, an alkyl group having a cyclizable functional group was linked to the second position. The cyclic compounds having amine functional groups were substituted via the Buchwald reaction. (Numbers 2 and 7) After introducing substituents at the specified positions, the cyclic compound can be cyclized through a reaction that allows for cyclization. I synthesized them.

[0430] The present invention, as described above, will be explained in more detail based on the following examples, formulations, and experimental examples. Therefore, the following examples, formulations, and experimental examples illustrate the present invention. The scope of clarity is not limited by these factors. [Examples]

[0431] Example 1: (2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2 )-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1 ,4)-Benzenecycloundecaffeine

[0432] [ka]

[0433] Stage 1) 4-(2-chloropyrrole[2,1-f][1,2,4]triazine-7-i (Lu) Phenol production

[0434] 7-Bromo-2-chloropyrrole[2,1-f][1,2,4]triazine (1.0g) (4.3 mmol) and (4-hydroxyphenyl)boronic acid (623 mg, 4.5 mmol) (1) Dilute 1,4-dioxane in distilled water (16 / 4 mL), and add sodium carbonate (1,3 (7g, 12.9 mmol) and t-ButylXphos (0.2g, 0.47 mmol) The mixture was then exposed to nitrogen for 10 minutes, followed by the addition of Pd(PPh3)Cl2(1.45g). After adding 2.07 mmol, the mixture was stirred at 60°C for 6 hours. Once the reaction was complete, the mixture was mixed. The material was filtered using Celite, then diluted with ethyl acetate and washed with saturated brine. As a result... The separated organic layer was dried over anhydrous sodium sulfate, followed by vacuum filtration and vacuum distillation. Results The resulting residue was purified by chromatography to obtain 0.95 g of the title compound (yield: 90%). %) was obtained. MSM / z:246[M+1].

[0435] Stage 2) 7-(4-(2-bromoethoxy)phenyl)-2-chloropyrrole[2,1 -f][1,2,4] Production of triazine

[0436] 4-(2-chloropyrrole[2,1-f][1,2,4]triazine-7-yl) After diluting 4.1g of ethanol (16.69 mmol) in toluene (50 mL), add triphe Nylphosphine (6.57g, 25.0 mmol) and 2-bromoethanol (2.4 mL) (7.64 mmol) was added. After stirring for 5 minutes, azocarboxylic acid diisopropyl alcohol was added to it. The pill (1.13 mL, 5.73 mmol) was gradually added, and the mixture was stirred at 50°C. Once completed, the mixture was diluted with ethyl acetate and then washed with distilled water and saturated brine. Results and The separated organic layer was dried over anhydrous sodium sulfate, and then subjected to vacuum filtration and vacuum distillation. The resulting residue was purified by chromatography to obtain 5 g of the title compound (yield: 85%). ) was obtained. MSM / z:353[M+1].

[0437] Step 3) tert-butyl(3-(4-((7-(4-(2-bromoethoxy)phen Lu)pyrolo[2,1-f][1,2,4]triazine-2-yl)amino)-1H-pyra Manufacturing of Zole-1-yl)propyl)carbamate

[0438] 7-(4-(2-bromoethoxy)phenyl)-2-chloropyrrole[2,1-f][ [1,2,4] Triazine (1g, 2.83 mmol) diluted in 20 mL of sec-butanol. Therefore, potassium carbonate (1.2g, 8.5 mmol) and tert-butyl(3-(4-amino) -1H-pyrrole-1-yl)propyl)carbamate (0.75g, 3.11mmo l) was added. After flowing nitrogen through the mixture for 10 minutes, Pd2(dba)3(0.51g, After adding (0.57 mmol) and Xphos (0.31 g, 0.62 mmol), 80 The mixture was stirred at °C for 4 hours. Once the reaction was complete, the mixture was filtered using Celite, and then acetic acid was added. The resulting organic layer was diluted with ethyl acetate and washed with saturated brine. The resulting separated organic layer was then subjected to anhydrous sodium sulfate. After drying, the material was subjected to vacuum filtration and vacuum distillation. The resulting residue was then chromatographed. The compound was purified to obtain 0.8 g (yield: 57%). MSM / z: 557[M+1 ].

[0439] Stage 4) N-(1-(3-aminopropyl)-1H-pyrazole-4-yl)-7-( 4-(2-bromoethoxy)phenyl)pyrrolo[2,1-f][1,2,4]triazine Production of -2-amines

[0440] tert-butyl(3-(4-((7-(4-(2-bromoethoxy)phenyl)pyro Ro[2,1-f][1,2,4]triazine-2-yl)amino)-1H-pyrazole- 1-Iylpropyl)carbamate (2.1g, 3.77mmol) in DCM (50ml) Dilute with (L), and add 5 mL of 4 M hydrochloric acid-dioxane solution. Sterilize the mixture at 40°C for 4 hours. Stirring was performed. Once the reaction was complete, the mixture was diluted with dichloromethane and then sterilized with sodium bicarbonate. The mixture was neutralized to a concentration of 5 hydrogen. The resulting separated organic layer was dried with anhydrous sodium sulfate. After drying, the sample was subjected to vacuum filtration and vacuum distillation. The resulting yield was 1.53 g of the title compound (yield). 88% was used in the next reaction without further purification. MSM / z: 457[M+1].

[0441] Stage 5)(2 1 Z,4 4 E)-41 H-11-oxa-3,8-diaza-2(7,2) -Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1, 4) Production of benzenecycloundecaffeine

[0442] N-(1-(3-aminopropyl)-1H-pyrazole-4-yl)-7-(4-(2 -Bromoethoxy)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-a Dilute 0.42g of 2-ethoxymethanol (0.92 mmol) with 40mL of 2-ethoxymethanol. After adding diisopropylethylamine (1.0 mL), the mixture was stirred at 80°C for two days. Once the process is complete, purify 100 mg (29% yie) of the title compound by chromatography. ld) was obtained. ¹H NMR (400 MHz, DMSO-d6) δ 9.41 (s, ¹H) , 8.89(s, 1H), 7.97(s, 1H), 7.78-7.73(m, 2H), 7 .35-7.30(m, 2H), 7.26(s, 1H), 6.92-6.86(m, 2H) ), 4.44(m, 2H), 4.11(m, 2H), 2.82(m, 4H), 1.73( m, 2H). MSM / z:376[M+1].

[0443] Example 2: (2 1 Z,4 4 E)-8-methyl-4 1 H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffeine

[0444] [ka]

[0445] (21 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyroro [2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-be Cyanthencycloundecaffeine (0.42g, 0.92mmol) (40mg, 0.11 After diluting mmol) with dichloromethane (2.1 mL), add acetic acid (1 drop) and formaldehyde. Add (0.01 mL, 0.26 mmol) and . After stirring for 30 minutes, add sodium t After gradually adding riacetoxyborohydride (29 mg, 0.14 mmol), stir for one day. The mixture was stirred. Once the reaction was complete, the mixture was washed with saturated salt water containing dichloromethane. The result was The separated organic layer was dried over anhydrous sodium sulfate, then subjected to vacuum filtration and vacuum distillation. The residue obtained as a result was purified by chromatography to obtain 16 mg of the title compound (yield: 38%). %) was obtained. ¹H NMR (400 MHz, DMSO-d6) δ 9.41 (s, ¹H), 8.89(s, 1H), 7.97(s, 1H), 7.78-7.73(m, 2H), 7. 35-7.30(m, 2H), 7.26(s, 1H), 6.92-6.86(m, 2H) , 4.44(m, 2H), 4.11(m, 2H), 2.82(m, 4H), 2.21(s , 3H), 1.73(m, 2H). MSM / z:390[M+1].

[0446] Example 3: 1-(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7 ,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1 (1,4)-Benzenecycloundecaffeinate-8-yl)ethane-1-one

[0447] [ka]

[0448] (2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyroro [2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-be Decongestant cyclodecaffeine (40 mg, 0.11 mmol) is mixed with dichloromethane (2. After diluting to 6 mL, add acetyl chloride (0.015 mL, 0.22 mmol) and triethyl After adding the amine (0.2 mL, 0.52 mmol) at 0°C, stir at room temperature for 30 minutes. The reaction was completed, and the mixture was diluted with ethyl acetate and washed with saturated brine. The separated organic layer was dried with anhydrous sodium sulfate, followed by vacuum filtration and vacuum distillation. The results and The resulting residue was purified by chromatography to obtain 14 mg of the title compound (yield: 31%). Obtained: MSM / z:418[M+1].

[0449] Example 4: 1-(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7 ,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1 (1,4)-Benzenecycloundecaffeinate-8-yl)butan-1-one

[0450] [ka]

[0451] Using the corresponding asyl chloride, the same procedure as in Example 3 was performed to obtain the title compound. Obtained. MSM / z:446[M+1].

[0452] Example 5: (2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2 )-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1 ,4)-Benzenecycloundecaffeinate-8-yl)(4-chlorophenyl)methanone

[0453] [ka]

[0454] Using the corresponding asyl chloride, the same procedure as in Example 3 was performed to obtain the title compound. Obtained. MSM / z:514[M+1].

[0455] Example 6: (2 1 Z,4 4 E)-N-cyclohexyl-4 1 H-11-oxa-3,8 -diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4(4,1 )-Pyrazola-1(1,4)-benzenecycloundecaffeine-8-carboxamide

[0456] [ka]

[0457] (2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyroro [2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-be Nzencycloundecaffeine (40 mg, 0.11 mmol) is used in tetrahydrofuran ( Dilute to 2.6 mL, add isocyanate (32 mg, 0.22 mmol), and then at room temperature. The mixture was stirred for 30 minutes. Once the reaction was complete, the mixture was diluted with ethyl acetate and washed with saturated brine. The resulting separated organic layer was dried over anhydrous sodium sulfate, then filtered under reduced pressure and reduced pressure. The compound was distilled. The resulting residue was purified by chromatography to obtain 18 mg of the title compound. (Yield: 32%) was obtained. MSM / z: 501[M+1].

[0458] Example 7: (2 1 Z,4 4 E)-N-(3-methoxyphenyl)-4 1 H-11-Oki sa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine- 4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-carb xyamide

[0459] [ka]

[0460] The title compound was obtained by performing the same procedure as in Example 6 using a corresponding isocyanate. MSM / z:524[M+1].

[0461] Example 8: (2 1 Z,4 4 E)-N-ethyl-4 1 H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffeine-8-carboxamide

[0462] [ka]

[0463] The title compound was obtained by performing the same procedure as in Example 6 using a corresponding isocyanate. MSM / z:477[M+1].

[0464] Example 9: (2 1 Z,4 4 E)-8-(methylsulfonyl)-4 1 H-11-oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-Pyrazola-1(1,4)-benzenecycloundecaffeine

[0465] [ka]

[0466] (2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyroro [2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-be Decongestant cyclodecaffeine (40 mg, 0.11 mmol) is mixed with dichloromethane (2. After diluting to 6 mL, methanesulfonyl chloride (0.016 mL, 0.39 mmol) [The substance was added.] Once the reaction was complete, the mixture was washed with a saturated brine solution containing dichloromethane. The result was... The separated organic layer was dried over anhydrous sodium sulfate, then subjected to vacuum filtration and vacuum distillation. The residue obtained as a result was purified by chromatography to obtain 16 mg of the title compound (yield: 33%). %) was obtained. MSM / z:454[M+1].

[0467] Example 10: (2 1 Z,4 4 E)-8-((3,4-difluorophenyl)sulfonyl )-4 1H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1 [2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclounden caffeine

[0468] [ka]

[0469] Using the corresponding sulfonyl chloride, the same procedure as in Example 9 was carried out to form the title compound. I obtained an item. MSM / z:552[M+1].

[0470] Example 11: (2 1 Z,4 4 E)-8-(phenylsulfonyl)-4 1 H-11-Oki sa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine- 4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine

[0471] [ka]

[0472] Using the corresponding sulfonyl chloride, the same procedure as in Example 9 was carried out to form the title compound. I obtained something. MSM / z:516[M+1].

[0473] Example 12: (2 1 Z,4 4 E)-8-(cyclopropylsulfonyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine

[0474] [ka]

[0475] Using the corresponding sulfonyl chloride, the same procedure as in Example 9 was carried out to form the title compound. I obtained something. MSM / z:480[M+1].

[0476] Example 13: (2 1 Z,4 4 E)-8-(propylsulfonyl)-4 1 H-11-Oki sa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine- 4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine

[0477] [ka]

[0478] Using the corresponding sulfonyl chloride, the same procedure as in Example 9 was carried out to form the title compound. I obtained something. MSM / z:482[M+1].

[0479] Example 14: (2 1 Z,4 4 E)-8-((5-chlorothiophen-2-yl)sulfon Nil)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f] [1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclou Decaffeinated

[0480] [ka]

[0481] Using the corresponding sulfonyl chloride, the same procedure as in Example 9 was carried out to form the title compound. I obtained an item. MSM / z:556[M+1].

[0482] Example 15: (2 1 Z,4 4 E)-8-(cyclohexylsulfonyl)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine

[0483] [ka]

[0484] Using the corresponding sulfonyl chloride, the same procedure as in Example 9 was carried out to form the title compound. I obtained an item. MSM / z:522[M+1].

[0485] Example 16: (Z)-5-oxa-3,9,15-triazine-2(7,2)-pyrrolo [2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclopenta Big Panties - 10-on

[0486] [ka]

[0487] Stage 1) 2-chloro-7-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4 Triazine production

[0488] Using a corresponding boronic acid, the same procedure as in Step 1 of Example 1 was performed to obtain the title compound. MSM / z:275[M+1].

[0489] Stage 2) 4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl) ) Aniline production

[0490] 2-Chloro-7-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]tri Dilute din (1.2g, 4.4 mmol) in EtOH (10mL) and add tin dichloride. After adding hydrate (2.82g, 11.0 mmol), the mixture was stirred at 80°C for 3 hours. Once the reaction is complete, dilute the mixture with dichloromethane and adjust the pH to 5 with sodium bicarbonate. It was neutralized in this manner. The resulting separated organic layer was dried with anhydrous sodium sulfate, The compound was filtered under reduced pressure and distilled under reduced pressure. The resulting yield was 700 mg of the title compound (yield: 65%). It was used in the next reaction without further purification. MSM / z: 245[M+1].

[0491] Step 3) Ethyl 5-((4-(2-chloropyrrolo[2,1-f][1,2,4]tri Production of Zin-7-yl)phenyl)amino)pentanoic acid

[0492] 4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl)anili Dilute potassium carbonate (630 mg, 2.58 mmol) in acetonitrile (8.6 mL). Um (1.07g, 7.74mmol) and ethyl pentanoate (0.61mL, 3.84m) After adding (mol), the mixture was stirred at 80°C for 3 hours. Once the reaction was complete, the mixture was mixed with dichlorocellulose. The resulting organic layer was washed with a saturated brine solution containing lomethane. The separated organic layer was then dried with anhydrous sodium sulfate. After drying, the material was subjected to vacuum filtration and vacuum distillation. The resulting residue was then chromatographed. The compound was purified to obtain 800 mg (yield: 85%) of the title compound. MSM / z: 373 [M+1] .

[0493] Step 4) Ethyl 5-((4-(2-((4-(3-((tert-butoxycarbonyl) Amino)propoxy)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazi Production of phenyl(amino)pentanoic acid

[0494] Ethyl 5-((4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7 -Iyl(phenyl)amino(pentanoic acid) (90 mg, 0.23 mmol) sec-buta Dilute with 2.4 mL of Nol, add potassium carbonate (0.60 g, 0.60 mmol) and tert- Butyl (3-(4-aminophenoxy)propyl)carbamate (97 mg, 0.36 mmol) was added. After passing nitrogen through the mixture for 10 minutes, Pd2(dba)3(44 After adding (mg, 0.05 mmol) and Xphos (48 mg, 0.10 mmol), The mixture was stirred at 80°C for 4 hours. Once the reaction was complete, the mixture was filtered using Celite, The resulting organic layer was diluted with ethyl acetate and washed with saturated brine. The separated organic layer was then anhydrous sodium sulfate. After drying with um, the residue was subjected to vacuum filtration and vacuum distillation. The resulting residue was chromatographically analyzed. Purification by filtration yielded 60 mg of the title compound (yield: 42%). MSM / z: 603[M +1]

[0495] Stage 5) 5-((4-(2-((4-(3-((tert-butoxycarbonyl)amino )propoxy)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7 - Production of yl(phenyl)aminopentanoic acid

[0496] Ethyl 5-((4-(2-((4-(3-((tert-butoxycarbonyl)amino) Propoxy)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7- Iyl(phenyl)amino(pentanoic acid) (90 mg) in methanol / water (4:1, v / v) Diluted, lithium hydroxide was added at 0°C, and then stirred at room temperature. Once the reaction was complete, the diced Dilute with lolomethane, adjust the pH to 3-4 with a 1N HCl aqueous solution, and extract with dichloromethane. The resulting separated organic layer was dried over anhydrous sodium sulfate, then filtered under reduced pressure and reduced pressure. The compound was distilled under pressure. The resulting title compound was used in the next reaction without further purification. SM / z:575[M+1].

[0497] Stage 6) 5-((4-(2-((4-(3-aminopropoxy)phenyl)amino)pi Roro[2,1-f][1,2,4]triazine-7-yl)phenyl)amino)pentane Acid production

[0498] 5-((4-(2-((4-(3-((tert-butoxycarbonyl)amino)prop Xy(phenyl)amino(pyrrolo[2,1-f][1,2,4]triazine-7-yl) Phenyl(amino)pentanoic acid was added to a 4M hydrochloric acid-dioxane solution. The mixture was heated at 40°C. The mixture was stirred for 4 hours. Once the reaction was complete, the mixture was diluted with dichloromethane and sodium bicarbonate. The pH was neutralized with um to 5. The resulting separated organic layer was anhydrous sodium sulfate. After drying with um, the compound was subjected to vacuum filtration and vacuum distillation. The resulting title compound was then separately processed. It was used in the following reaction without purification. MSM / z: 475[M+1].

[0499] Stage 7)(Z)-5-oxa-3,9,15-triazine-2(7,2)-pyrrolo[2 [1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclopentadeca Manufacturing of Pan-10-ON

[0500] 5-((4-(2-((4-(3-aminopropoxy)phenyl)amino)pyrrolo[2 ,1-f][1,2,4]triazine-7-yl)phenyl)amino)pentanoic acid dimeth Dilute with ethylformamide, add diisopropylethylamine and HATU at 0°C, The mixture was stirred at room temperature for 1 hour. Once the reaction was complete, the mixture was diluted with dichloromethane and saturated with brine. The resulting organic layer was washed. After drying with anhydrous sodium sulfate, it was filtered under reduced pressure. The compound was then subjected to vacuum distillation. The resulting title compound was used in the next reaction without further purification. MSM / z:457[M+1].

[0501] Example 17: (1 4 Z,2 1 Z)-1 1 H-5-oxa-3,9-diaza-2(7,2 )-Pyrrolo[2,1-f][1,2,4]triazine-1(4,1)-pyrazola-4(1 ,4)-Benzenecyclohexadecapan-10-one

[0502] [ka]

[0503] Stage 1) tert-butyl 4-(2-chloropyrrolo[2,1-f][1,2,4]tri Preparation of azine-7-yl)-1H-pyrazole e-1-carboxylate

[0504] Using a corresponding boronic acid, the same procedure as in Step 1 of Example 1 was performed to obtain the title compound. Obtained. MSM / z:320[M+1].

[0505] Stage 2) 2-Chloro-7-(1H-pyrazole-4-yl)pyrrolo[2,1-f][1 ,2,4] Production of triazine

[0506] tert-butyl4-(2-chloropyrrolo[2,1-f][1,2,4]triazine- 7-yl)-1H-pyrazole e-1-carboxylate (500 mg, 2.38 mmol) Dilute with dichloromethane (2.3 mL), and add trifluoroacetic acid (2.3 mL) at 0°C. Afterward, the mixture was stirred at room temperature for 12 hours. Once the reaction was complete, the mixture was diluted with dichloromethane. The pH was neutralized with sodium bicarbonate to 5. As a result, the separated organic layer was free of After drying with sodium hydroxide sulfate, the material was filtered under reduced pressure and distilled under reduced pressure. The resulting title was obtained The compound was used in the next reaction without further purification. MSM / z: 220 [M+1].

[0507] Step 3) Methyl 6-(4-(2-chloropyrrolo[2,1-f][1,2,4]triazi Production of n-7-yl)-1H-pyrazole-1-yl)heptanoic acid

[0508] 4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl)anili Dilute potassium carbonate (280 mg, 1.28 mmol) in acetonitrile (2.6 mL). Um (442 mg, 3.2 mmol) and methyl hexanoate (0.35 mL, 1.92 mL) After adding (ol), the mixture was stirred at 80°C for 3 hours. Once the reaction was complete, the mixture was dichloro The resulting organic layer was washed with methane-saturated brine. The separated organic layer was then dried over anhydrous sodium sulfate. Afterward, the residue was filtered under reduced pressure and distilled under reduced pressure. The resulting residue was purified by chromatography. Prepared to obtain 200 mg (yield: 45%) of the title compound. MSM / z: 348 [M+1].

[0509] Step 4) Methyl 6-(4-(2-((4-(3-((tert-butoxycarbonyl) Mino)propoxy)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine Production of -7-yl)-1H-pyrazole-1-yl)heptanoic acid

[0510] Using the appropriate aniline, the same procedure as in step 4 of Example 16 was performed to produce the title compound. Obtained: MSM / z:578[M+1].

[0511] Stage 5)(1 4 Z,2 1 Z)-1 1 H-5-oxa-3,9-diaza-2(7,2)- Pyrrolo[2,1-f][1,2,4]triazine-1(4,1)-pyrazola-4(1,4 )-Benzencyclohexadecapan-10-one production

[0512] Using the compound produced in step 4, the same process as in step 7 is carried out in step 5 of Example 16. The title compound was obtained by performing the following procedure. MSM / z: 460[M+1].

[0513] Example 18: (1 4 Z,2 1 Z,4 4 E)-1 1 H, 4 1 H-3,8-diaza-2(7 ,2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(4,1)-dipyrazole Lacyclopentadecapan-9-on

[0514] [ka]

[0515] The title compound was obtained by performing the same procedure as in Example 17. MSM / z: 434[M+1] .

[0516] Example 19: (1 4 Z,2 1Z)-1 1 H-3-Aza-2(7,2)-Pirolo[2,1 -f][1,2,4]triazine-5(1,4)-piperazine-1(4,1)-pyrazola -4(1,4)-benzenecyclododecapan-9-one

[0517] [ka]

[0518] The title compound was obtained by performing the same procedure as in Example 17. MSM / z: 471[M+1] .

[0519] Example 20: (Z)-13-fluoro-5,17-dioxa-3,9-diaza-2(7 ,2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenz Ncycloheptadecapan-10-on

[0520] [ka]

[0521] Stage 1) 4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl Production of )-2-fluorophenol

[0522] Using a corresponding boronic acid, the same procedure as in Step 1 of Example 1 was performed to obtain the title compound. Obtained. MSM / z:264[M+1].

[0523] Step 2) Methyl 7-(4-(2-chloropyrrolo[2,1-f][1,2,4]triazi Production of 0-7-yl-2-fluorophenoxyheptanoic acid

[0524] 4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl)-2- Fluorophenol (400 mg, 1.52 mmol) in acetonitrile (5.5 mL) Dilute with potassium carbonate (570 mg, 3.8 mmol) and methylheptanoic acid (0.34 mg) After adding L (1.82 mmol), the mixture was stirred at 80°C for 3 hours. Once the reaction was complete, The mixture was washed with saturated saline solution containing dichloromethane. The resulting separated organic layer was then treated with sulfuric acid anhydrous. After drying with sodium, the residue was subjected to vacuum filtration and vacuum distillation. The resulting residue was then chromatographed. Purification by tography yielded 514 mg of the title compound (yield: 83%). MSM / z: 4 06[M+1].

[0525] Step 3) Methyl 7-(4-(2-((4-(3-((tert-butoxycarbonyl) Mino)propoxy)phenyl)amino)pyrrolo[2,1-f][1,2,4]triaz Production of in-7-yl)-2-fluorophenoxy)heptanoic acid

[0526] Using the appropriate aniline, the same procedure as in step 4 of Example 16 was performed to produce the title compound. Obtained: MSM / z:636[M+1].

[0527] Stage 4) (Z)-13-fluoro-5,17-dioxa-3,9-diaza-2(7,2 )-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenes Manufacturing of Chloheptadecapan-10-one

[0528] Using the compound produced in step 3, the same process as in step 7 was carried out in step 5 of Example 16. The title compound was obtained by performing the following procedure. MSM / z: 504[M+1].

[0529] Example 21: (2 1 Z,4 4 E)-13-fluoro-4 1H-16-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazola-1(1,4)-benzenecyclohexadecapan-9-one

[0530] [ka]

[0531] The title compound was obtained by performing the same procedure as in Example 20. MSM / z: 478[M+1] .

[0532] Example 22: (Z)-1 3 -fluoro-13-oxa-3-aza-2(7,2)-pyro [2,1-f][1,2,4]triazine-5(1,4)-piperazine-1,4(1, 4)-Dibenzenecyclotridecapan-6-one

[0533] [ka]

[0534] The title compound was obtained by performing the same procedure as in Example 20. MSM / z: 504[M+1] .

[0535] Example 23: (Z)-17-oxa-3,9-diaza-2(7,2)-pyrolo[2,1 -f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4)-gibe Nzencycloheptadekapan-10-on

[0536] [ka]

[0537] Stage 1) 4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl ) Phenol production

[0538] Using a corresponding boronic acid, the same procedure as in Step 1 of Example 1 was performed to obtain the title compound. Obtained (yield: 90%). MSM / z: 246[M+1].

[0539] Step 2) Methyl 7-(4-(2-chloropyrrolo[2,1-f][1,2,4]triazi Production of 7-yl phenoxyheptanoic acid

[0540] 4-(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl)pheno Using a meter, the title compound was obtained by performing the same procedure as in step 2 of Example 20. / z:388[M+1].

[0541] Step 3) Methyl 7-(4-(2-((4-(4-(3-((tert-butoxycabony (Lu)amino)propyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f [1,2,4] Production of Triazine-7-yl Phenoxyheptanoic Acid

[0542] Using the appropriate aniline, the same procedure as in step 4 of Example 16 was performed to produce the title compound. Obtained: MSM / z:686[M+1].

[0543] Stage 4) ((Z)-17-oxa-3,9-diaza-2(7,2)-pyrolo[2,1- f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4)-dibene Manufacturing of Zencycloheptadecapan-10-one

[0544] Using the compound produced in step 3, the same process as in step 7 was carried out in step 5 of Example 16. The title compound was obtained by performing the following procedure. MSM / z: 504[M+1].

[0545] Example 24: (Z)-13-oxa-3-aza-2(7,2)-pyrolo[2,1-f] [1,2,4]triazine-5(1,4)-piperazine-1,4(1,4)-dibenzene Cyclotripekapan-6-on

[0546] [ka]

[0547] Stage 1) tert-butyl 4-(4-((7-(4-((7-methoxy-7-oxohe Butyl(oxy)phenyl(pyrrolo[2,1-f][1,2,4]triazine-2-yl) Production of amino)phenyl)piperazine-1-carboxylate

[0548] Using the aniline corresponding to the compound produced in step 2 of Example 23, The title compound was obtained by performing the same procedure as in Step 4 of Example 16. MSM / z: 497[M+1] .

[0549] Stage 2) (Z)-13-oxa-3-aza-2(7,2)-pirolo[2,1-f][1 [2,4] Triazine-5(1,4)-piperazine-1,4(1,4)-dibenzenesic Manufacturing of Rotride DeKapan-6-ON

[0550] Using the compound produced in step 1, the same process as in step 7 is carried out in step 5 of Example 16. The title compound was obtained by performing the following procedure. MSM / z: 629[M+1].

[0551] Example 25: (2 1 Z,4 4 E)-4 1 H-11-oxa-3-aza-2(7,2)- Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidine-4(4, 1)-Pyrazola-1(1,4)-benzenecycloundecapan-6-one

[0552] [ka]

[0553] Step 1) Ethyl 5-(4-(2-chloropyrrolo[2,1-f][1,2,4]triazi Production of phenoxypentanoic acid (7-yl)

[0554] The title compound was obtained using ethyl 5-bromopentanoic acid in step 1 of Example 23. MSM / z:373[M+1].

[0555] Stage 2)(2 1 Z,4 4 E)-4 1 H-11-oxa-3-aza-2(7,2)-pyro [2,1-f][1,2,4]triazine-5(4,1)-piperidine-4(4,1) - Production of Pyrazola-1(1,4)-benzenecycloundecapan-6-one

[0556] The compound produced from step 1 above and the compound obtained by performing the same process as in step 7 in step 4 of Example 16 above. The target compound was obtained. MSM / z: 458 [M+1].

[0557] Example 26: (2 1 Z,4 4 E)-4 1 H-15-oxa-3,9-diaza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidine-4 (4,1)-pyrazola-1(1,4)-benzenecyclopentadecapan-10-one

[0558] [ka]

[0559] The title compound was obtained by performing the same procedure as in Example 25 using the appropriate aniline. MSM / z:515[M+1].

[0560] Example 27: (2 1 Z,4 4 E)-4 1 H-17-oxa-3,9-diaza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidine-4 (4,1)-pyrazola-1(1,4)-benzenecycloheptadecapan-10-one

[0561] [ka]

[0562] The title compound was obtained by performing the same procedure as in Example 25 using the appropriate aniline. MSM / z:675[M+1].

[0563] Example 28: (Z)-5,12,15-trioxa-3,9-diaza-2(7,2)- Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclo Pentadecapan-10-on

[0564] [ka]

[0565] Step 1) Ethyl 2-(2-(4-(2-chloropyrrolo[2,1-f][1,2,4] Production of riazin-7-yl phenoxyethoxy acetate

[0566] Using ethyl 2-(2-bromoethoxy)acetate, the same as in step 2 of Example 23. The process was carried out to obtain the title compound. MSM / z: 376 [M+1].

[0567] Stage 2) (Z)-5,12,15-trioxa-3,9-diaza-2(7,2)-pyro [2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclopene Manufacturing of Tadekapan-10-ON

[0568] The title compound was obtained by performing the same procedure as in Example 24 using the appropriate aniline. MSM / z:460[M+1].

[0569] Example 29: (Z)-5,17-dioxa-3,9-diaza-2(7,2)-pyrrolo[ 2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecycloheptade Kapan-10-on

[0570] [ka]

[0571] The title compound was obtained by performing the same procedure as in Example 71 using the appropriate aniline. MSM / z:486[M+1].

[0572] Example 30: (Z)-5,12-dioxa-3,9-diaza-2(7,2)-pyrrolo[ 2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclododecaf Chain

[0573] [ka]

[0574] Step 1) tert-butyl(3-(4-((7-(4-(2-bromoethoxy)phen (Lu) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenoxy) Manufacturing of propylcarbamate

[0575] Using the appropriate aniline, the same procedure as in step 3 of Example 1 was performed to obtain the title compound. Obtained. MSM / z:582[M+1].

[0576] Stage 2) (Z)-5,12-dioxa-3,9-diaza-2(7,2)-pyrolo[2, 1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclododecafe Manufacturing

[0577] The compound produced in step 1 above is diluted with dichloromethane (5 mL), and 4 M hydrochloride-dichloromethane is used. Oxane solution was added. The mixture was stirred at 40°C for 4 hours. Once the reaction was complete, the mixture Dilute with dichloromethane, neutralize with sodium bicarbonate to pH 5, and then use isopropyl The organic layer was extracted with a pyramine / chloroform (1:4, v / v) solution. The organic layer was extracted using anhydrous sodium sulfate. After drying with um, the compound was subjected to vacuum filtration and vacuum distillation. The resulting title compound was then separately processed. It was used in the next reaction without purification (yield: 88%). MSM / z: 483 [M+1]. Results The bromoamine obtained was diluted with dimethylformamide (4 mL) and diisopropyl Ethylamine (5 equivalents) was added and the mixture was stirred at 80°C for 12 hours. Once the reaction was complete, acetic acid was added. The resulting organic layer was diluted with ethyl acetate and washed with saturated brine. After drying, the title compound was purified by chromatography (yield: 29%). MSM / z:402[M+1].

[0578] Example 31: (Z)-1-(5,12-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclod Dekapan-9-il) Propane-1-on

[0579] [ka]

[0580] The compound produced from step 2 of Example 30 was diluted with tetrahydrofuran (1 ml). Then, triethylamine (3 equivalents) was added at 0°C. After that, acetyl chloride (1.2 equivalents) was added. In addition, the mixture was stirred at 0°C for 20 minutes. Once the reaction was complete, it was diluted with ethyl acetate and washed with saturated brine. The resulting organic layer was purified. After drying with anhydrous sodium sulfate, chromatography was performed. The title compound was obtained by purification using a fertilizer (yield: 57%). MSM / z: 582 [M+1].

[0581] Example 32: (Z)-5,12-dioxa-3,9-diaza-2(7,2)-pyrrolo[ 2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclododecap 0-9-yl(4-chlorophenyl)methanone

[0582] [ka]

[0583] Using the corresponding asyl chloride, the same procedure as in Example 31 was performed to obtain the title compound. The yield was 88%. MSM / z: 540[M+1].

[0584] Example 33: (2 1 Z,7Z)-5,10-dioxa-3-aza-2(7,2)-pyro [2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclodeca Pan-7-en

[0585] [ka]

[0586] Stage 1) 4-(2-((4-hydroxyphenyl)amino)pyrrolo[2,1-f][1 [2,4] Triazine-7-yl)phenol

[0587] Using the aniline corresponding to the compound produced from step 1 of Example 1, the embodiment The title compound was obtained by performing the same procedure as in step 4 of Example 1 (yield: 62%). MSM / z: 31 9[M+1].

[0588] Step 2) N,7-bis(4-(allyloxy)phenyl)pyrrolo[2,1-f][1, 2,4] Production of triazine-2-amine

[0589] 4-(2-((4-hydroxyphenyl)amino)pyrrolo[2,1-f][1,2,4 Dilute triazine-7-ylphenol in dimethylformamide (5 mL) and carbonate After adding 5 equivalents of lium and 3 equivalents of allyl bromide, the mixture was stirred at 50°C for 2 hours. Once the reaction was complete, the mixture was diluted with ethyl acetate and washed with saturated brine. The resulting organic layer was then prepared. After drying with anhydrous sodium sulfate, the title compound was obtained by chromatography ( rate: 78%). MSM / z:399[M+1].

[0590] Stage 3)(2 1 Z,7Z)-5,10-dioxa-3-aza-2(7,2)-pyrolo[ 2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclodecapane -7- Manufacturing

[0591] N,7-Bis(4-(allyloxy)phenyl)pyrrolo[2,1-f][1,2,4] Dilute triazine-2-amine in toluene (10 mL) and add Grubbs' second catalyst (10 M Add 0% and stir at 100°C for 40 hours. Once the reaction is complete, after vacuum distillation, The title compound was obtained by purification by chromatography (yield: 12%). MSM / z: 371 [M+1].

[0592] Example 34: (Z)-4 2 -Methoxy-5,12,15-trioxa-3,9-diaza -2(7,2)-Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)- Dibenzenecyclopentadecapan-10-one

[0593] [ka]

[0594] The title compound was obtained by performing the same procedure as in Example 24 using the appropriate aniline. MSM / z:490[M+1].

[0595] Example 35: (2 1 Z,4 4 E)-4 1 H-11,14-dioxa-3,8-diaza- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazo La-1(1,4)-benzenecyclotetradecapan-9-one

[0596] [ka]

[0597] Step 1) Ethyl 2-(2-(4-(2-chloropyrrolo[2,1-f][1,2,4] Production of riazin-7-yl phenoxyethoxy acetate

[0598] Using tert-butyl(3-(4-aminophenoxy)propyl)carbamate Then, the title compound was obtained by performing the same procedure as in step 2 of Example 1 (yield: 58%). MS M / z:376[M+1].

[0599] Stage 2)(2 1 Z,4 4 E)-4 1 H-11,14-dioxa-3,8-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- Production of 1(1,4)-benzenecyclotetradecapan-9-one

[0600] Using the corresponding aniline, the same process as in step 7 of Example 1 was carried out to combine the title compound. I obtained something. MSM / z:434[M+1].

[0601] Example 36: (2 1 Z,4 4 E)-4 1 H-14-oxa-3,8-diaza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1( 1,4)-Benzenecyclotetradecapan-9-one

[0602] [ka]

[0603] The title compound was obtained by performing the same procedure as in Example 25 using the appropriate aniline. MSM / z:432[M+1].

[0604] Example 37: (2 1 Z,4 4 E)-4 1 H-16-oxa-3,8-diaza-2(7, 2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1( 1,4)-Benzenecyclohexadecapan-9-one

[0605] [ka]

[0606] The title compound was obtained by performing the same procedure as in Example 24 using the appropriate aniline. MSM / z:460[M+1].

[0607] Example 38: (Z)-5,15-dioxa-3,9-diaza-2(7,2)-pyrrolo[ 2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclopentadeno Kapan-10-on

[0608] [ka]

[0609] The title compound was obtained by performing the same procedure as in Example 25 using the appropriate aniline. MSM / z:458[M+1].

[0610] Example 39: N-(3-(2-((4-(4-(5-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoiisoindoline-4-yl)oxy)pentyl) Piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide

[0611] [ka]

[0612] Stage 1: N-(3-(2-c chloropyrrolo[2,1-f][1,2,4]triazine- 7-yl)phenyl)methanesulfonamide

[0613] 7-Bromo-2-chloropyrrole[2,1-f][1,2,4]triazine (1.0g) (4.31 mmol) and (3-(methanesulfonamide)phenyl)boronic acid (972 ml) (g, 4.53 mmol) and 1,4-dioxane (28 mL) and 2.0 N sodium carbonate After dissolving in 13 mL of water, add t-ButylXphos (182 mg, 0.43 mg). (ol) was added. After passing nitrogen through the mixture for 10 minutes, Pd(PPh3)Cl2(302) After adding mg (0.43 mmol), the mixture was stirred at 60°C for 6 hours. Once the reaction was complete, the mixture was mixed. The mixture was filtered using Celite, the filtrate was diluted with ethyl acetate, and then wiped with salt water. The organic layer was dried over magnesium sulfate and concentrated. It was purified by chromatography. The standard compound (1.1 g, 86% yield) was obtained. MSM / z: 323 [M+1].

[0614] Stage 2: tert-butyl 4-(4-((7-(3-(methanesulfonamide)phen (Lu) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenyl)pi Perazine-1-carboxylate

[0615] N-(3-(2-c chloropyrrolo[2,1-f][1,2,4]triazine-7-yl) Phenyl)methanesulfonamide (1.0g, 3.11 mmol) is sec-butanol After dissolving in 17 mL of water, add calcium carbonate (1.8 g, 12.8 mmol) and tert- Butyl 4-(4-aminophenyl)piperazine-1-carboxylate (861 mg, 3.1 1 mmol) was added. After passing nitrogen through this mixed solution for 10 minutes, Pd2(dba) 3 (570 mg, 0.62 mmol) and Xphos (300 mg, 0.62 mmol) The mixture was added. The reaction mixture was stirred at 80°C for 6 hours. Once the reaction was complete, the mixture was simmered. After filtering using a filter, the filtrate was diluted with ethyl acetate and then wiped with salt water. The organic layer was then subjected to sulfuric acid. It was dried with magnesium and concentrated. The target compound (1.1) was purified by chromatography. A 7g sample was obtained with a yield of 67%. MSM / z: 564[M+1].

[0616] Stage 3: N-(3-(2-((4-(piperazine-1-yl)phenyl)amino)pyro [2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone Do

[0617] tert-butyl4-(4-((7-(3-(methanesulfonamide)phenyl)pyro Ro[2,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine Dissolve the -1-carboxylate (0.1g, 0.18 mmol) in dichloromethane (2mL) Afterward, trifluoroacetic acid (0.3 mL) was added. Once the reaction was complete, it was dried under reduced pressure. It was then used in the next reaction without purification. MSM / z: 464[M+1].

[0618] Stage 4: N-(3-(2-((4-(4-(5-((2-(2,6-dioxopiperidine (-3-yl)-1,3-dioxoindoline-4-yl)oxy)pentyl)piperazi (1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7 -yl)phenyl)methanesulfonamide

[0619] N-(3-(2-((4-(piperazine-1-yl)phenyl)amino)pyrrolo[2, 1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide(10 (0 mg, 0.22 mmol), potassium iodide (73 mg, 0.22 mmol), diiso Propylethylamine (0.12 mL, 0.66 mmol) and 4-((5-bromopene (Tyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1, Dissolve 3-dione (186 mg, 0.44 mmol) in dimethylformamide (2 mL) The reaction mixture was stirred at 60°C for 12 hours. Once the reaction was complete, the reaction mixture was acetic acid. After dilution with ethyl acetate, it was wiped with salt water. The organic layer was dried and concentrated with magnesium sulfate. The target compound (101 mg, 57% yield) was obtained by purification using matrix imaging. z:806[M+1].

[0620] Example 40: N-(3-(2-((4-(4-(3-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)propyl) Piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide

[0621] [ka]

[0622] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((5-br Romopropyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindri The experimental method is identical to that of Example 39, except that n-1,3-dione was used.

[0623] Example 41: N-(3-(2-((4-(4-(7-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)heptyl) Piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide

[0624] [ka]

[0625] In step 4 of Example 1, 4-((5-bromopentyl)oxy)-2-(2,6-dioxo Instead of piperidine-3-yl)isoindorin-1,3-dione, use 4-((5-bro Moheptyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline The experimental method is identical to that of Example 39, except that -1,3-dione was used.

[0626] Example 42: N-(3-(2-((4-(4-(11-((2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)undecyl (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Liazin-7-yl)phenyl)methanesulfonamide

[0627] [ka]

[0628] In step 4 of Example 1, 4-((5-bromopentyl)oxy)-2-(2,6-dioxo Instead of piperidine-3-yl)isoindorin-1,3-dione, use 4-((5-bro Mounddecyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindri The experimental method is identical to that of Example 39, except that n-1,3-dione was used.

[0629] Example 43: N-(3-(2-((4-(4-(2-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)ethyl) Peridine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazi (n-7-yl)phenyl)methanesulfonamide

[0630] [ka]

[0631] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((5-br Romoethyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline The experimental method is identical to that of Example 1, except that -1,3-dione was used.

[0632] Example 44: N-(3-(2-((4-(4-((4-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)butyl) Peridine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazi (n-7-yl)phenyl)methanesulfonamide

[0633] [ka]

[0634] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((5-br Romobutyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline The experimental method is identical to that of Example 39, except that -1,3-dione was used.

[0635] Example 45: N-(3-(2-((4-(4-(6-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)hexyl) Piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide

[0636] [ka]

[0637] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((5-br Romohexyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindri The experimental method is identical to that of Example 39, except that n-1,3-dione was used.

[0638] Example 46: N-(3-(2-((4-(4-(8-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)octyl) Piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide

[0639] [ka]

[0640] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((5-br Romooctyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindri The experimental method is identical to that of Example 39, except that n-1,3-dione was used.

[0641] Example 47: N-(3-(2-((4-(4-(8-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)nonyl)pi Peridine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazi (n-7-yl)phenyl)methanesulfonamide

[0642] [ka]

[0643] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((5-br Lomonol)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline The experimental method is identical to that of Example 39, except that -1,3-dione was used.

[0644] Example 48: -(3-(2-((4-(4-(2-(2-((1,3-dioxo-2- (2-Oxopiperidine-3-yl)isoindorin-4-yl)oxy)ethoxy)e (Tyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide

[0645] [ka]

[0646] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-(2-(2 -Bromoethoxy)ethoxy)-2-(2-oxopiperidine-3-yl)isoindri The experimental method is identical to that of Example 39, except that n-1,3-dione was used.

[0647] Example 49: N-(3-(2-((4-(4-(6-((1,3-dioxo-2-(2 -Oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl)pipera Zin-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine- 7-yl)phenyl)methanesulfonamide

[0648] [ka]

[0649] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((6-br Romohexyl)oxy)-2-(2-oxocyclohexyl)isoindoline-1,3- The experimental method is identical to that of Example 39, except that Zion was used.

[0650] Example 50: N-(3-(2-((4-(4-(8-((1,3-dioxo-2-(2 -Oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl)pipera Zin-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine- 7-yl)phenyl)methanesulfonamide

[0651] [ka]

[0652] In step 4 of Example 39, 4-((5-bromopentyl)oxy)-2-(2,6-dioxy Instead of sopiperidine-3-yl)isoindorin-1,3-dione, use 4-((6-br Romooctyl)oxy)-2-(2-oxocyclohexyl)isoindoline-1,3- The experimental method is identical to that of Example 39, except that Zion was used.

[0653] Example 51: N-(3-(2-((4-(4-((1-(2-(2,6-dioxopipe Lysine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)pipette Lysine-4-yl)methyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide

[0654] [ka]

[0655] N-(3-(2-((4-(piperazine-1-yl)phenyl)amino)pyrrolo[2, 1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide(10 0 mg, 0.22 mmol), 1-(2-(2,6-dioxopiperidine-3-yl)- 6-Fluoro-1,3-Dioxoisoindorin-5-yl)piperidine-4-carb Dehyde (128 mg, 0.33 mmol) and acetic acid (1 drop) in dichloromethane (2 mL) Dissolve in. Sodium triacetoxyborohydride (140 mg, 0.66 mmol) After adding the mixture, the reaction mixture was stirred at room temperature for 3 hours. Once the reaction was complete, water was added to complete the reaction. The mixture was terminated, diluted with dichloromethane, and then wiped with salt water. The organic layer was dried with magnesium sulfate. The compound was concentrated and purified by chromatography to obtain the target compound (113 mg, 62% yield). ) was obtained. MSM / z:835[M+1].

[0656] Example 52: N-(3-(2-((1-(1-(9-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)piper Zin-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f][1, [2,4] Triazine-7-yl)phenyl)methanesulfonamide

[0657] [ka]

[0658] Stage 1: 2-(2,6-dioxopiperidine-3-yl)-4-((9-(4-(4- Nitro-1H-pyrazole-1-yl)piperidine-1-yl)nonyl)oxy)iso Ndrin-1,3-zione

[0659] 4-(4-nitro-1H-pyrazole-1-yl)piperidine (1.5g, 7.61mg) (mol), potassium iodide (2.5g, 15.22 mmol), diisopropyl ethyl alcohol Min (4 mL, 22.83 mmol) and 4-((9-bromonol)oxy)-2-( 2,6-Dioxopiperidine-3-yl)isoindoline-1,3-dione (186mg) Dissolve 0.44 mmol of the solution in dimethylformamide (15 mL). Mix the reaction solution in 6 ml. The mixture was stirred at 0°C for 12 hours. Once the reaction was complete, the reaction mixture was diluted with ethyl acetate, and then the salt... The layer was wiped with water. The organic layer was dried and concentrated with magnesium sulfate. By chromatography... The target compound was obtained by purification. MSM / z: 595 [M+1].

[0660] Stage 2: 4-((9-(4-(4-amino-1H-pyrazole-1-yl)piperidine -1-yl)nonyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoyl Ndrin-1,3-zione

[0661] 2-(2,6-dioxopiperidine-3-yl)-4-((9-(4-(4-nitro- 1H-Pyrazole-1-yl)piperidine-1-yl)nonyl)oxy)isoindoline After dissolving -1,3-dione (1g, 1.68 mmol) in ethyl acetate (20 mL), Pd / C (100 mg) was added. The mixture was stirred at room temperature for one day under the pressure of a hydrogen gas-filled balloon. The reaction mixture was filtered through Celite and concentrated. The target compound was then subjected to the next reaction without purification. Used for: MSM / z:565[M+1].

[0662] Stage 3: N-(3-(2-((1-(1-(9-((2-(2,6-dioxopiperidine (-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)piperidine -4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide

[0663] In step 2 of Example 1, tert-butyl 4-(4-aminophenyl)piperazine-1-ka Instead of ruvonate, use 4-((9-(4-(4-amino-1H-pyrazole-1-yl )piperidine-1-yl)nonyl)oxy)-2-(2,6-dioxopiperidine-3- The experimental method was identical except for the use of yl)isoindoline-1,3-dione. MSM / z:851[M+1].

[0664] Example 53: 3-(2-((1-(1-(9-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)piperidine- 4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f][1,2,4 Triazine-7-yl)-N-methylbenzamide

[0665] [ka]

[0666] In Step 1 of Example 39, replace (3-(methanesulfonamide)phenyl)boronic acid Except for the use of (3-(methylcarbamoyl)phenyl)boronic acid, the experimental method They are identical.

[0667] Example 54: 2-(2,6-dioxopiperidine-3-yl)-4-((9-(4-( 4-((7-phenylpyrrolo[2,1-f][1,2,4]triazine-2-yl)amine (N)-1H-pyrazole-1-yl)piperidine-1-yl)nonyl)oxy)isoin Dorin-1,3-Zeon

[0668] [ka]

[0669] In Step 1 of Example 39, replace (3-(methanesulfonamide)phenyl)boronic acid The experimental method was identical, except for the use of phenylboronic acid.

[0670] Example 55: 2-(2,6-dioxopiperidine-3-yl)-4-((9-(4-( 4-((7-(1-methyl-1H-pyrazole-4-yl)pyrrolo[2,1-f][1, 2,4] Triazine-2-yl)amino)-1H-pyrazole-1-yl)piperidine- 1-yl)nonyl)oxy)isoindoline-1,3-dione

[0671] [ka]

[0672] In Step 1 of Example 39, replace (3-(methanesulfonamide)phenyl)boronic acid Except for the use of (1-methyl-1H-pyrazole-4-yl)boronic acid, the experimental method The law is the same.

[0673] Example 56: 4-((9-(4-(4-((7-(1H-indole-6-yl)pyro Ro[2,1-f][1,2,4]triazine-2-yl)amino)-1H-pyrazole- 1-yl)piperidine-1-yl)nonyl)oxy)-2-(2,6-dioxopiperidine (n-3-yl)isoindoline-1,3-dione

[0674] [ka]

[0675] In Step 1 of Example 39, replace (3-(methanesulfonamide)phenyl)boronic acid The experimental method was identical except for the use of (1H-indole-6-yl)boronic acid. ru.

[0676] Example 57: 2-(2,6-dioxopiperidine-3-yl)-4-((9-(4-( 4-((7-(4-hydroxyphenyl)pyrrolo[2,1-f][1,2,4]triazi (n-2-yl)amino)-1H-pyrazole-1-yl)piperidine-1-yl)nonyl )Oxy)isoindoline-1,3-dione

[0677] [ka]

[0678] In Step 1 of Example 39, replace (3-(methanesulfonamide)phenyl)boronic acid The experimental method was identical, except that (4-hydroxyphenyl)boronic acid was used.

[0679] Example 58: Methyl-7-(4-(2-((1-(1-(9-((2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)no Nyl)piperidine-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1 -f][1,2,4]triazine-7-yl(phenoxy)heptanoic acid

[0680] [ka]

[0681] In step 3 of Example 52, N-(3-(2-c chloropyrrolo[2,1-f][1,2,4] Instead of triazine-7-yl(phenyl)methanesulfonamide, use methyl-7-(4 -(2-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl)phenoxy The experimental method was identical, except for the use of heptanoic acid.

[0682] Example 59: N-(3-(2-((4-(4-(5-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoiisoindoline-4-yl)oxy)pentyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, [2,4] Triazine-7-yl)phenyl)methanesulfonamide

[0683] [ka]

[0684] In step 2 of Example 39, tert-butyl 4-(4-aminophenyl)piperazine-1- Instead of the carboxylate salt, use tert-butyl-4-(4-amino-3-methoxyphenyl The experimental method was identical, except that piperazine-1-carboxylate was used.

[0685] Example 60: N-(3-(2-((4-(4-(3-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindolin-4-yl)oxy)propyl)pipette Radin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide

[0686] [ka]

[0687] In Example 40, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0688] Example 61: N-(3-(2-((4-(4-(7-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl)pipette Radin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide

[0689] [ka]

[0690] In Example 41, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0691] Example 62: N-(3-(2-((4-(4-(11-((2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoindorin-4-yl)oxy)undecyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, [2,4] Triazine-7-yl)phenyl)methanesulfonamide

[0692] [ka]

[0693] In Example 42, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0694] Example 63: N-(3-(2-((4-(4-(2-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindolin-4-yl)oxy)ethyl)piper Zin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4 Triazine-7-yl(phenyl)methanesulfonamide

[0695] [ka]

[0696] In Example 43, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0697] Example 64: N-(3-(2-((4-(4-(4-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl)piper Zin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4 Triazine-7-yl(phenyl)methanesulfonamide

[0698] [ka]

[0699] In Example 44, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0700] Example 65: N-(3-(2-((4-(4-(6-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl)pipette Radin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide

[0701] [ka]

[0702] Example 45: tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0703] Example 66: N-(3-(2-((4-(4-(8-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)octyl)pipette Radin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide

[0704] [ka]

[0705] In Example 46, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0706] Example 67: N-(3-(2-((4-(4-(9-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)pipera Zin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4 Triazine-7-yl(phenyl)methanesulfonamide

[0707] [ka]

[0708] In Example 47, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0709] Example 68: N-(3-(2-((4-(4-(2-(2-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)ethoxy) Ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide

[0710] [ka]

[0711] In Example 48, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0712] Example 69: N-(3-(2-((4-(4-(6-((1,3-dioxo-2-(2 -Oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl)pipera Zin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4 Triazine-7-yl(phenyl)methanesulfonamide

[0713] [ka]

[0714] In Example 49, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0715] Example 70: N-(3-(2-((4-(4-(8-((1,3-dioxo-2-(2 -Oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl)pipera Zin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4 Triazine-7-yl(phenyl)methanesulfonamide

[0716] [ka]

[0717] In Example 50, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl-4-(4-amino-3-methoxyphenyl)pipera The experimental method was identical, except that din-1-carboxylate was used.

[0718] Example 71: N-(3-(2-((6-(4-(5-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)pentyl)pipette Radin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide

[0719] [ka]

[0720] In Example 51, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0721] Example 72: N-(3-(2-((6-(4-(3-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindolin-4-yl)oxy)propyl)pipette Radin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide

[0722] [ka]

[0723] In Example 40, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0724] Example 73: N-(3-(2-((6-(4-(7-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl)pipette Radin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide

[0725] [ka]

[0726] In Example 42, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0727] Example 74: N-(3-(2-((6-(4-(11-((2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoindorin-4-yl)oxy)undecyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4] Triazine-7-yl(phenyl)methanesulfonamide

[0728] [ka]

[0729] In Example 43, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0730] Example 75: N-(3-(2-((6-(4-(2-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindolin-4-yl)oxy)ethyl)piper (Din-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4]to Liazin-7-yl)phenyl)methanesulfonamide

[0731] [ka]

[0732] In Example 44, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0733] Example 76: N-(3-(2-((6-(4-(4-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl)piper (Din-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4]to Liazin-7-yl)phenyl)methanesulfonamide

[0734] [ka]

[0735] Example 45: tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0736] Example 77: N-(3-(2-((6-(4-(6-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl)pipette Radin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide

[0737] [ka]

[0738] In Example 46, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0739] Example 78: N-(3-(2-((6-(4-(8-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)octyl)pipette Radin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide

[0740] [ka]

[0741] In Example 47, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0742] Example 79: N-(3-(2-((6-(4-(9-((2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)pipera (Din-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4]to Liazin-7-yl)phenyl)methanesulfonamide

[0743] [ka]

[0744] In Example 48, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0745] Example 80: N-(3-(2-((6-(4-(2-(2-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)ethoxy) Ethyl)piperazin-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][ [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide

[0746] [ka]

[0747] In Example 49, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0748] Example 81: N-(3-(2-((6-(4-(6-((1,3-dioxo-2-(2 -Oxopiperidine-3-yl)isoindorin-4-yl)oxy)hexyl)pipera (Din-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4]to Liazin-7-yl)phenyl)methanesulfonamide

[0749] [ka]

[0750] In Example 50, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0751] Example 82: N-(3-(2-((6-(4-(8-((1,3-dioxo-2-(2 -Oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl)pipera (Din-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2,4]to Liazin-7-yl)phenyl)methanesulfonamide

[0752] [ka]

[0753] In Example 51, tert-butyl 4-(4-aminophenyl)piperazine-1-carbone Instead of the salt, use tert-butyl4-(5-aminopyridine-2-yl)piperazine- The experimental method was identical, except that 1-carboxylate salts were used.

[0754] Example 83: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-( 4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][ [1,2,4] Triazine-2-yl)amino)phenyl)piperazine-1-yl)ethoxy Acetaminobutanoyl-4-hydroxy-N-4-(4-methylthiazole -5-yl)benzyl)pyrroridine-2-carboxyamide

[0755] [ka]

[0756] Stage 1: Ethyl-2-(2-(4-(4-((7-(3-(methanesulfonamide) Phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenyl Piperazine-1-yl ethoxy acetate

[0757] N-(3-(2-((4-(piperazine-1-yl)phenyl)amino)pyrrolo[2, 1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide(10 (0 mg, 0.22 mmol), potassium iodide (73 mg, 0.22 mmol), diiso Propylethylamine (0.12 mL, 0.66 mmol) and ethyl-2-(2-chloromethylamine) Roethoxyacetate (73 mg, 0.44 mmol) in dimethylformamide (2 mL) It was dissolved in [a solution]. The reaction mixture was stirred at 60°C for 24 hours. Once the reaction was complete, the reaction mixture dissolved [in another solution]. The solution was diluted with ethyl acetate and then wiped with salt water. The organic layer was dried and concentrated with magnesium sulfate. The target compound (99 mg, 76% yield) was obtained by purification using chromatography. SM / z:594[M+1].

[0758] Stage 2: 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenyl)pipera Zin-1-yl)ethoxy)acetic acid

[0759] Ethyl-2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenyl)pipera Din-1-yl(ethoxy)acetate (99 mg, 0.17 mmol) is tetrahydrofurcation After dissolving in (1 mL), methanol (1 mL), and water (1 mL), LiOH-H2O( 15 mg (0.34 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After diluting the mixed solution with ethyl acetate, neutralize it with 1N hydrogen chloride solution to make a pH of 5. The organic layer was wiped with salt water. The organic layer was dried with magnesium sulfate and concentrated to obtain the target compound (92 mg, A 94% yield was obtained. It was used in the next reaction without purification. MSM / z: 566[M+1].

[0760] Stage 3: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-(4- (4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][1, 2,4] Triazine-2-yl)amino)phenyl)piperazine-1-yl)ethoxy) Acetamino)butanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5 -yl)benzyl)pyrroridine-2-carboxyamide

[0761] 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[ 2,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1 -Iyl(ethoxy)acetic acid (92 mg, 0.16 mmol), PyBOP (166 mg, 0 (0.32 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbronium Tanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl ) Pyrrolidine-2-carboxamide (103 mg, 0.24 mmol) dimethyl for After dissolving in Muamido (2 mL), diisopropylethylamine (0.1 mL, 0.48 A mmol was added. The reaction mixture was stirred at room temperature for 3 hours. Once the reaction was complete, the reaction The mixed solution was diluted with ethyl acetate and then wiped with salt water. The organic layer was dried with magnesium sulfate. The solution was concentrated. The target compound (88 mg, 56% yield) was obtained by purification using chromatography. MSM / z:978[M+1].

[0762] Example 84: (2S,4R)-1-((S)-3,3-dimethyl-2-(3-(2-( 2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1- f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1-yl) Ethoxy)Ethoxy)Propanamide)Butanoyl)-4-Hydroxy-N-(4-(4 -Methylthiazole-5-yl)benzyl)pyrroridine-2-carboxyamide

[0763] [ka]

[0764] Stage 1: tert-butyl-3-(2-(2-(4-(4-((7-(3-(methanes (Sulfonamide) Phenyl) Pyrrolo[2,1-f][1,2,4]triazine-2-yl) Amino(phenyl)piperazine-1-yl)ethoxy)ethoxy)propanoic acid

[0765] In step 1 of Example 45, instead of ethyl-2-(2-chloroethoxy)acetate, ter We used t-butyl-3-(2-(2-iodoethoxy)ethoxy)propanoic acid. Except for the exceptions, the experimental methods are identical.

[0766] Stage 2: 3-(2-(2-(4-(4-((7-(3-(methanesulfonamide)fe Nyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenyl) Piperazine-1-yl Ethoxy Ethoxy Propano Acid

[0767] Step 3 of Example 1: tert-butyl 4-(4-((7-(3-(methanesulfonamide (d)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)f Instead of phenyl)piperazine-1-carboxylate, use tert-butyl-3-(2-(2 -(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f [1,2,4] Triazine-2-yl)amino)phenyl)piperazine-1-yl) The experimental method was identical, except that toxic(ethoxy)propanoic acid was used.

[0768] Stage 3: (2S,4R)-1-((S)-3,3-dimethyl-2-(3-(2-(2- (4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f] [1,2,4] Triazine-2-yl)amino)phenyl)piperazine-1-yl)eth (Xy)ethoxy)propanamide)butanoyl)-4-hydroxy-N-(4-(4-Me) Chilthiazol-5-yl)benzyl)pyrroridine-2-carboxamide

[0769] Step 3 of Example 45: 2-(2-(4-(4-((7-(3-(methanesulfonamide )phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phen Instead of (nyl)piperazin-1-yl)ethoxy)acetic acid, use 3-(2-(2-(4-(4 -((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][1,2, 4] Triazine-2-yl)amino)phenyl)piperazine-1-yl)ethoxy)eth The experimental method was identical, except that xy)propanoic acid was used.

[0770] Example 85: (2S,4R)-1-((S)-3,3-dimethyl-2-(3-(2-( 2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1- f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1-yl) Ethoxy)Ethoxy)Propanamide)Butanoyl)-4-Hydroxy-N-((S)- 1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-ca Luboxiamid

[0771] [ka]

[0772] In step 3 of Example 84, (2S,4R)-1-((S)-2-amino-3,3-dimethyl Butanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl Instead of (2S,4R)-1-((S)-2 -amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4- (4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxylate The experimental method was identical, except for the use of mido.

[0773] Example 86: 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-( 5-((7-(4-(trifluoromethoxy)phenyl)pyrrolo[2,1-f][1,2 ,4]Triadin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pe Isoindoline-1,3-dione (Isoindoline-1,3-dione)

[0774] [ka]

[0775] Stage 1) 2-bromo-7-(4-(trifluoromethoxy)phenyl)pyrrolo[2,1 -f][1,2,4]triazine

[0776] In Step 1 of Example 39, (3-(methanesulfonamide)phenyl)boronic acid (972m (4-(trifluoromethoxy)phenyl)borone (instead of g, 4.53 mmol) The experimental method was identical except for the use of acid. MSM / z: 359 [M+1].

[0777] Stage 2) 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-(5- Nitropyridine-2-yl)piperazine-1-yl)pentyl)oxy)isoindoline -1,3- Zeon's production

[0778] 1-(5-nitropyridine-2-yl)piperazine (1 equivalent), 4-((5-bromope (Ixyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1 ,3-dione (1.2 equivalents), potassium iodide (1 equivalent), diisopropylethylamine (2.5 equivalents) was dissolved in dimethylformamide. The reaction mixture was stirred at 65°C for 2 hours. The reaction was completed, then diluted with ethyl acetate and wiped with salt water. The result was separated. The organic layer was dried over anhydrous sodium sulfate, then subjected to vacuum filtration and vacuum distillation. The result obtained was The residue was purified by chromatography to obtain the title compound. MSM / z: 550[M+ 1].

[0779] Stage 3) 4-((5-(4-(4-aminophenyl)piperazine-1-yl)pentyl )oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3- Zeon's production

[0780] 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-(5-nitropi Lysine-2-yl)piperazine-1-yl)pentyl)oxy)isoindoline-1,3 - Dione (1 equivalent), ammonium chloride (10 equivalents), iron powder (10 equivalents) in tetrahydro It was dissolved in furan / methanol / water (4:2:1). The reaction mixture was incubated at 80°C for 1 hour. Stirring was maintained throughout. Once the reaction was complete, the solution was diluted with ethyl acetate, then with sodium bicarbonate solution, and finally with salt water. It was wiped. The resulting separated organic layer was dried with anhydrous sodium sulfate and then filtered under reduced pressure. Distillation was performed under supervolt and vacuum conditions. MSM / z: 520 [M+1].

[0781] Stage 4) 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-(5- ((7-(4-(trifluoromethoxy)phenyl)pyrrolo[2,1-f][1,2,4 Triazine-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pench Isoindoline-1,3-dione (Oxy)

[0782] 2-Chloro-7-(4-(trifluoromethoxy)phenyl)pyrrolo[2,1-f][ Dissolve triazine (1,2,4) in sec-butanol / toluene (1:1) Afterwards, calcium carbonate (4 equivalents) and 4-((5-(4-(4-aminophenyl)piperazi (1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine-3-yl) Soindorin-1,3-dione (1 equivalent) was added. Nitrogen was added to this mixed solution for 10 minutes. After flushing, Pd2(dba)3 (0.1 equivalent) and Xphos (0.1 equivalent) were added. The reaction mixture was stirred at 85°C for 6 hours. Once the reaction was complete, the mixture was removed using Celite. After filtration, the filtrate was diluted with ethyl acetate and then wiped with salt water. The organic layer was magnesium sulfate. It was dried and concentrated. The title compound was obtained by chromatography. MSM / z :798[M+1].

[0783] Example 87: 4-((5-(4-(5-((7-(3,5-difluorophenyl)pyro [2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2-yl) Piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine-3- Isoindoline-1,3-dione

[0784] [ka]

[0785] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid The experimental method was identical, except that (3,5-difluorophenyl)boronic acid was used. Yes, it exists. MSM / z:750[M+1].

[0786] Example 88: 4-((5-(4-(5-((7-(2-aminopyridine-5-yl)py Roro[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2-yl )piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine-3 -Isoindoline-1,3-dione

[0787] [ka]

[0788] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid The experimental method was the same, except that (2-aminopyrimidine-5-yl)boronic acid was used. It is one. MSM / z:731[M+1].

[0789] Example 89: 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-( 5-((7-(Quinoline-3-yl)pyrrolo[2,1-f][1,2,4]triazine- 2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy) Soindrin-1,3-dione

[0790] [ka]

[0791] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid The experimental method was identical except for the use of quinoline-3-ylboronic acid. MSM / z:765[M+1].

[0792] Example 90: tert-butyl 4-(3-(2-((6-(4-(5-((2-(2, 6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-4-yl) Xy(pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)benzyl)piperazine-1-carboxylate

[0793] [ka]

[0794] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxa Except for the use of borolan-2-yl)benzyl)piperazine-1-carboxylate The experimental method is identical. MSM / z: 913[M+1].

[0795] Example 91: (E)-2-(2,6-dioxopiperidine-3-yl)-4-((5- (4-(5-((7-Styrylpyrrolo[2,1-f][1,2,4]triazine-2-i (L)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy)isoin Dorin-1,3-Zeon

[0796] [ka]

[0797] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid The experimental method was identical, except that tert-butyl(E)-styrylboronic acid was used. It is. MSM / z:740[M+1].

[0798] Example 92: tert-butyl 4-(4-(2-((6-(4-(5-((2-(2, 6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-4-yl) Xy(pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)-1H-pyrazole-1-yl)piperidine n-1-carboxylate salt

[0799] [ka]

[0800] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa Bororan-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylate Aside from the use of certain components, the experimental method was identical. MSM / z: 888[M+1].

[0801] Example 93: 4-((5-(4-(5-((7-(4-(dimethylamino)phenyl) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2-yl) (Lu)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine- 3-Isoindoline-1,3-dione

[0802] [ka]

[0803] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabolol) The experimental method was identical except for the use of ran-2-yl aniline. MSM / z :757[M+1].

[0804] Example 94: 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-( 5-((7-(pyridine-4-yl)pyrrolo[2,1-f][1,2,4]triazine- 2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy) Soindrin-1,3-dione

[0805] [ka]

[0806] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid The experimental method was identical, except that pyridine-4-ylboronic acid was used. MSM / z:715[M+1].

[0807] Example 95: 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-( 5-((7-(thiazole-5-yl)pyrrolo[2,1-f][1,2,4]triazi (-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy Isoindoline-1,3-dione

[0808] [ka]

[0809] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid , 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The experimental method was identical except for the use of iazole. MSM / z:721[M+ 1].

[0810] Example 96: 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-( 5-((7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5 -yl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine -2-yl)piperazine-1-yl)pentyl)oxy)isoindoline-1,3-diol hmm

[0811] [ka]

[0812] In Step 1 of Example 86, replace (4-(trifluoromethoxy)phenyl)boronic acid , 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetrameth Except for the use of ru-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Therefore, the experimental method is identical. MSM / z: 788[M+1].

[0813] Example 97: 4-((5-(4-(5-((7-((3,5-difluorophenyl) Thinyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine -2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopipe Lysine-3-yl)isoindorin-1,3-dione

[0814] [ka]

[0815] Stage 1) 2-Chloro-7-((3,5-difluorophenyl)ethynyl)pyrrolo[2, [1-f][1,2,4] Production of triazine

[0816] 7-Bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine (1 equivalent), 1-Ethynyl-3,5-difluorobenzene (1.5 equivalents), copper iodide (0.1 equivalents), Diisopropylamine (3 equivalents), PdCl2(Ph3)2 (0.1 equivalents) sec - Pig It was dissolved in ethanol / toluene (1:1). After flowing nitrogen through this reaction mixture for 10 minutes, The mixture was stirred at 85°C for 6 hours. Once the reaction was complete, the mixture was filtered using Celite, and then filtered again. The peroxide was diluted with ethyl acetate and then wiped with salt water. The organic layer was dried over magnesium sulfate and concentrated. The title compound was obtained by purification using chromatography. MSM / z: 290[M+ 1].

[0817] Stage 2) 4-((5-(4-(5-((7-((3,5-difluorophenyl)ethyn (Lu) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2 -yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine) Production of (n-3-yl)isoindoline-1,3-dione

[0818] In step 4 of Example 86, 2-chloro-7-(4-(trifluoromethoxy)phenyl) Instead of lol[2,1-f][1,2,4]triazine, use 2-chloro-7-((3,5 -Difluorophenyl)ethynyl)pyrrolo[2,1-f][1,2,4]triazine is used Except for the use of [specific material], the experimental method is identical to that of Step 4 in Example 86. MSM / z:774[ [M+1].

[0819] Example 98: 2-(2,6-dioxopiperidine-3-yl)-4-((5-(4-( 5-((7-((3-methoxyphenyl)ethynyl)pyrrolo[2,1-f][1,2,4 Triazine-2-yl)amino)aminopyridine-2-yl)piperazine-1-yl) Pentyl(oxy)isoindoline-1,3-dione

[0820] [ka]

[0821] In Example 97, instead of 1-ethynyl-3,5-difluorobenzene, 1-ethynyl- The experimental method was identical except for the use of 3-methoxybenzene. MSM / z:67 8[M+1].

[0822] Example 99: N-(3-(2-((4-(4-(2-(2-(3-(4-((4-(2 -(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoiisoy (Piperidin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-ol Xopropoxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino)pyrrolo [2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide

[0823] [ka]

[0824] 3-(2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pi Roro[2,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazi 1-yl ethoxypropanoic acid (60 mg, 0.10 mmol), ED CI (56 mg, 0.29 mmol), HOAt (40 mg, 0.29 mmol) After dissolving in ethylformamide (2 mL), add diisopropylethylamine (0.08 mL) , 0.49 mmol) was added. After stirring the reaction mixture at room temperature for 30 minutes, 2-(2, 6-Dioxopiperidine-3-yl)-5-fluoro-6-(4-(piperidine-4-yl) (Methyl)piperazin-1-yl)isoindoline-1,3-dione (50mg, 0.1 After adding 1 mmol), the mixture was stirred at 50°C for 6 hours. Once the reaction was complete, the reaction mixture solution was used. After diluting with dichloromethane, it was wiped with salt water. The organic layer was dried and concentrated with magnesium sulfate. The title compound was obtained by purification using chromatography. MSM / z: 1064[M +1]

[0825] Example 100: N-(3-(4-(3-(2,4-dihydroxy-5-isopropyl Phenoxy)-5-hydroxy-4H-1,2,4-triazole-4-yl) Propyl)-3-(2-(2-(4-(4-((7-(3-(methanesulfonamide) Phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenyl Piperazine-1-yl Ethoxy Ethoxy Propanamide

[0826] [ka]

[0827] Step 1) Production of t-butyl(3-(4-nitrophenoxy)propyl)carbamate

[0828] 4-nitrophenol (4g, 28.75 mmol) and t-butyl (3-bromopropyl Carbamate (8.22g, 34.505mmol) and acetonitrile 9.6mg After dissolving in L, potassium carbonate (7.95g, 57.51 mmol) was added. Reaction solution The mixture was stirred at 80°C for 20 hours. Once the reaction was complete, the mixture was filtered using Celite. The filtrate was diluted with ethyl acetate and then wiped with salt water. The organic layer was dried with sodium sulfate and concentrated. It shrunk. It was used in the next reaction without purification. MSM / z: 297[M+1].

[0829] Step 2) Production of t-butyl(3-(4-aminophenoxy)propyl)carbamate

[0830] t-Butyl(3-(4-nitrophenoxy)propyl)carbamate (6g, 22. After dissolving 53 mmol) in acetonitrile (45 mL), Pd / C (10% wt, 600 mg was added. The mixture was stirred under hydrogen pressure for 12 hours. Once the reaction was complete, the mixture was separated. After filtering with a light, the title compound (4.01g) was purified by chromatography. A yield of 67% was obtained. MSM / z: 267[M+1].

[0831] Step 3) t-butyl(3-(4-(2,4-dihydroxy-5-isopropylphenyl Manufacturing of thioamide phenoxypropyl carbamate

[0832] 2,4-Dihydroxy-5-isopropylbenzodithioic acid (3.4g, 14.9mmo) l) Dissolve in 12 mL of N,N-dimethylformamide, then add sodium bicarbonate (3. (78g, 44.97 mmol) and sodium chloroacetate (2.6g, 22.48 mmol) ) and were added at 0°C. t-Butyl(3-(4-aminophenoxy)propyl)carbamine Dissolve the salt (972 mg, 4.53 mmol) in 12 mL of N,N-dimethylformamide. After adding the solution dropwise, the mixture was stirred at 70°C for 2 hours. Once the reaction was complete, the reaction solution was diluted with ethyl acetate. Afterward, it was wiped with salt water. The organic layer was dried and concentrated with sodium sulfate. Chromatography The title compound (5.2 g, 75% yield) was obtained by purification using the following method. ¹H NMR (400M) Hz, DMSO-d6)δ11.41(s, 1H), 11.27(s, 1H), 10.0 7(s, 1H), 7.78(s, 1H), 7.59-7.51(m, 2H), 7.01- 6.90(m, 3H), 6.40(s, 1H), 3.98(t, 3.13-3.01(m) , 3H), 1.83(p, 2H), 1.38(s, 9H), 1.16(d, 6H). M.S. M / z:461[M+1].

[0833] Step 4) tert-butyl(3-(4-(7-hydroxy-6-isopropyl-2-o Xo-4-thioxo-2H-benzo[e][1,3]oxazine-3(4H)-yl) Manufacturing of phenoxypropyl carbamate

[0834] 2,4-Dihydroxy-5-isopropylbenzodithioic acid (5.1g, 11.01mm) After dissolving (ol) in 22 mL of tetrahydrofuran, carbonyldiimidazole (3.5 7g (22.02 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Once complete, the reaction solution was diluted with ethyl acetate and then wiped with salt water. The organic layer was treated with sodium sulfate. It was dried and concentrated. It was used in the next reaction without purification. MSM / z: 487 [M+1].

[0835] Step 5) t-butyl(3-(4-(3-(2,4-dihydroxy-5-isopropyl Phenoxy)-5-hydroxy-4H-1,2,4-triazole-4-yl) Manufacturing of propylcarbamate

[0836] tert-butyl(3-(4-(7-hydroxy-6-isopropyl-2-oxo-4 -Thioxo-2H-benzo[e][1,3]oxazine-3(4H)-yl)phenoxy )Propyl)carbamate (5.6g, 11.50mmol) mixed with anhydrous ethanol (57 After dissolving it in mL, add hydrazine hydrate (1.15 g, 22.995 mmol). The reaction was completed, and the reaction solution was diluted with ethyl acetate and then wiped with salt water. The organic layer was sodium sulfate. The compound was dried with thorium and concentrated. It was purified by chromatography to obtain the title compound (3.86). g, 69% yield was obtained. ¹H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.56(s, 1H), 9.38(s, 1H), 7.14-7.03(m , 2H), 6.95-6.85(m, 3H), 6.80(s, 1H), 6.25(s, 1 H), 3.94(t, 2H), 3.12-2.87(m, 3H), 1.80(p, 2H) , 1.37(s, 9H), 0.98(d, 6H). MSM / z:485[M+1].

[0837] Step 6) 4-(4-(4-(3-aminopropoxy)phenyl)-5-hydroxy-4 H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol Manufacturing of

[0838] t-butyl(3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl) -5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)propyl Dissolve carbamate (2.75g, 6.19mmol) in dichloromethane (30mL). Add 27 mL of 4 M HCl 1,4-dioxane at 0°C. Stir at room temperature for 4 hours. Mixed. Once the reaction was complete, it was dried under reduced pressure. Used in the next reaction without purification. 1H NMR (400MHz, DMSO-d6) δ11.88(s, 1H), 9.65(s, 1 H), 9.41(s, 1H), 7.95(s, 3H), 7.14-7.05(m, 2H) , 6.98-6.87(m, 2H), 6.83(s, 1H), 6.28(s, 1H), 4 .03(t, 2H), 3.06-2.86(m, 3H), 1.99(p, 2H), 0.9 9(d, 6H). MSM / z:385[M+1].

[0839] Step 7) N-(3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl )-5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)prop (L)-3-(2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl )Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)phenyl)pipe Radin-1-yl Ethoxy Ethoxy Propanamide

[0840] In Example 99, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-( 4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3- Instead of dione, 2-amino-N-(3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl The experimental method was identical except for the use of phenoxypropyl acetamide. MSM / z:991[M+1].

[0841] Example 101: N-(2-((3-(4-(3-(2,4-dihydroxy-5-isopropyl Ropyrphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl) (Noxy)propyl)amino)-2-oxoethyl)-3-(2-(2-(4-(4-(( 7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][1,2,4]t Liazin-2-yl)amino)phenyl)piperazin-1-yl)ethoxy)ethoxy) Propanamide

[0842] [ka]

[0843] Step 1) tert-butyl(2-((3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl Phenoxypropyl amino-2-oxaethyl carbamate

[0844] 4-(4-(4-(3-aminopropoxy)phenyl)-5-hydroxy-4H-1, 2,4-Triazole-3-yl)-6-isopropylbenzene-1,3-diol(5 (00 mg, 1.10 mmol), (t-butoxycarbonyl)glycine (175 mg, 1. Dissolve 51 mmol) in dimethylformamide (3.7 mL), then infuse with diisopropyl alcohol at 0°C. Pyrethylamine (0.76 mL, 4.39 mmol) was gradually added dropwise. The reaction mixture solution was then prepared. The mixture was stirred at room temperature for 1 hour. Once the reaction was complete, it was diluted with dichloromethane and wiped with salt water. The resulting separated organic layer was dried with anhydrous sodium sulfate, then filtered under reduced pressure and steamed under reduced pressure. The mixture was then purified by chromatography, yielding 495 mg of the title compound. (Yield: 83%) was obtained. MSM / z: 542[M+1].

[0845] Stage 2) 2-amino-N-(3-(4-(3-(2,4-dihydroxy-5-isopropyl Pyrphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)pheno Xypropyl acetamide

[0846] 2-amino-N-(3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl (Nyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)phenoxy) Dissolve acetamide (495 mg) in 5 mL of dichloromethane, then steep at 0°C in a 4 M solution. A 5 mL hydrochloric acid-dioxane solution was gradually added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction was completed, and the title compound was obtained by vacuum distillation. MSM / z: 442[M+1 ].

[0847] Step 3) N-(2-((3-(4-(3-(2,4-dihydroxy-5-isopropyl Phenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)phenoxy )propyl)amino)-2-oxoethyl)-3-(2-(2-(4-(4-((7-( 3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][1,2,4]triazi (-2-yl)amino)phenyl)piperazine-1-yl)ethoxy)ethoxy)propane Namido

[0848] In Example 99, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-( 4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3- Instead of dione, 2-amino-N-(3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl The experimental method was identical except for the use of phenoxypropyl acetamide. MSM / z:1048[M+1].

[0849] Example 102: N-(3-(2-((4-(4-(2-(2-(3-(4-(4-(3 -(2,4-dihydroxy-5-isophenylpropyl)-5-hydroxy-4H-1, 2,4-Triazole-4-yl)benzyl)piperazine-1-yl)-3-oxopro Poxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide

[0850] [ka]

[0851] Step 1) 4-(5-hydroxy-4-(4-(piperazine-1-ylmethyl)phenyl )-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3 - Diol production

[0852] Step 3 of Example 100: t-butyl(3-(4-aminophenoxy)propyl)carb Instead of t-butyl 4-(4-aminobutyrate (972 mg, 4.53 mmol)), The experimental method was identical except for the use of (nzyl)piperazine-1-carboxylate. MSM / z:410[M+1].

[0853] Stage 2) N-(3-(2-((4-(4-(2-(2-(3-(4-(4-(3-(2 ,4-dihydroxy-5-isophenylpropyl)-5-hydroxy-4H-1,2,4 -Triazole-4-yl)benzyl)piperazine-1-yl)-3-oxopropoxy )Ethoxy)ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide

[0854] In Example 99, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-( 4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3- Instead of dione, use 4-(5-hydroxy-4-(4-(piperazine-1-ylmethyl) Phenyl)-4H-1,2,4-triazole-3-yl)-6-isopropylbenzene The experimental method was identical except for the use of -1,3-diol. MSM / z:101 6[M+1].

[0855] Example 103: N-(3-(2-((4-(4-(2-(2-(3-(4-((4-( 4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4 H-1,2,4-triazol-4-yl)benzyl)piperazine-1-yl)methyl) Piperidine-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazine-1- (yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl) Phenyl)methanesulfonamide

[0856] [ka]

[0857] Step 1) 4-(5-hydroxy-4-(4-((4-(piperidine-4-ylmethyl) Piperazine-1-yl(methyl)phenyl)-4H-1,2,4-triazole-3-yl Production of (L)-6-isopropylbenzene-1,3-diol

[0858] 4-(5-hydroxy-4-(4-(piperazine-1-ylmethyl)phenyl)-4H -1,2,4-triazole-3-yl)-6-isopropylbenzene-1,3-diole (300mg, 0.73mmol), tert-butyl4-formylpiperidine-1- Carboxylate (312 mg, 1.47 mmol), acetic acid (4 mg, 0.07 mmol) Dilute with dichloroethylene (5 mL) and at 0°C, sodium triacetoxyborohydride (3 (0.9 mg, 1.47 mmol) was gradually added dropwise. The reaction mixture was stirred at room temperature for 6 hours. Once the reaction was complete, the mixture was diluted with dichloromethane and neutralized with sodium bicarbonate. The resulting separated organic layer was dried over anhydrous sodium sulfate, followed by vacuum filtration and vacuum distillation. The compound was purified by chromatography to obtain the title compound (360 mg, 67% yield). MSM / z:609[M+1].

[0859] Step 2) 4-(5-hydroxy-4-(4-((4-(piperidine-4-ylmethyl) Piperazine-1-yl(methyl)phenyl)-4H-1,2,4-triazole-3-yl (Lu)-6-isopropylbenzene-1,3-diol (360 mg) in dichloromethane 4 After dissolving in mL, 4 mL of 4 M hydrochloric acid-dioxane solution was gradually added dropwise at 0°C. The mixed solution was stirred at room temperature for 1 hour. Once the reaction was complete, the title compound was obtained by vacuum distillation. MSM / z:509[M+1].

[0860] Stage 3) N-(3-(2-((4-(4-(2-(2-(3-(4-((4-(4-( 3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazole-4-yl)benzyl)piperazine-1-yl)methyl)piper (Zin-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazin-1-yl) Phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl)phenyl Methanesulfonamide

[0861] In Example 99, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-( 4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3- Instead of dione, use 4-(5-hydroxy-4-(4-((4-(piperidine-4-yl Methyl)piperazin-1-yl)methyl)phenyl)-4H-1,2,4-triazole Except for the use of -3-yl)-6-isopropylbenzene-1,3-diol, The testing method is the same. MSM / z:1113[M+1].

[0862] Example 104: N-(3-(2-((4-(4-(2-(2-(3-(4-((2-( 2,4-Dihydroxy-5-isopropylbenzoate)isoindorin-5-yl)methyl Piperazine-1-yl-3-oxopropoxy-ethoxy-ethyl-piperazine-1 -yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl )phenyl)methanesulfonamide

[0863] [ka]

[0864] Step 1) 1-(2,4-dihydroxy-5-isopropylphenyl)ethane-1-one Manufacturing

[0865] 4-Isopropylbenzene-1,3-diol (121 mg, 0.80 mmol) After adding 0.6 mL of boron fluoride diethyl etherate, acetic acid (48 mg) was added at room temperature. (0.80 Mol) was added. The reaction mixture was stirred at 90°C for 4 hours. Then, an aqueous sodium acetate solution was added and the mixture was vigorously stirred for 2.5 hours, after which it was filtered to obtain the result. The solid was dried to obtain the title compound. MSM / z: 195 [M+1].

[0866] Stage 2) 1-(2,4-bis(benzyloxyl)-5-isopropylphenyl)ethanol n-1-on

[0867] 1-(2,4-dihydroxy-5-isopropylphenyl)ethane-1-one (115 (mg, 0.59 mmol), benzyl bromide (236 mg, 1.38 mmol), potassium carbonate Acetonitrile (2 mL) was added to um (204 mg, 1.48 mmol). The reaction mixture was then mixed. The mixture was stirred at 80°C for 12 hours. Once the reaction was complete, acetonitrile was distilled under reduced pressure. Next, water was added, and the resulting solid was filtered and dried. Then, hexane was added. The title compound was obtained by wiping with [a specific tool / method]. MSM / z: 375 [M+1].

[0868] Step 3) 2,4-Bis(benzyloxy)-5-isopropylbenzoic acid

[0869] 1-(2,4-bis(benzyloxyl)-5-isopropylphenyl)ethane-1- On (1.5g, 4.01 mmol), sodium hydroxide aqueous solution (1.60g, 40.1 Dissolve 0 mmol) in 1,4-dioxane (15 mL) / water (15 mL), then add bromine ( 0.04 mL (0.80 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. Mix. Once the reaction is complete, adjust the pH to 2 using an aqueous hydrogen chloride solution and remove the resulting solid. The compound was filtered, washed with water, and dried to obtain the title compound. ¹H NMR (300 MHz) DMSO-d6)δ7.57(s, 1H), 7.55-7.28(m, 10H), 6.8 9(s, 1H), 5.20(s, 4H), 3.24-3.13(m, 1H), 1.18- 1.13(m, 6H). MSM / z:377[M+1].

[0870] Stage 4) (2,4-bis(benzyloxy)-5-isopropylphenyl)(5-bro Manufacturing of Moisoindolin-2-yl)methanone

[0871] 2,4-Bis(benzyloxy)-5-isopropylbenzoic acid (138 mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (140 mg, 0.73 mmol), hydroxybenzotriazole (100 mg, 0.74 mmol) Dissolve (ol) in dimethylformamide (1.5 mL). Allow the reaction mixture to stand at room temperature for 10 minutes. After stirring, add diisopropylethylamine (0.260 mL, 1) to the reaction mixture at 0°C. Add 0.47 mmol) and slowly add 5-bromoisoindoline (95 mg, 0.4 mmol). The mixture was added to each of the following. The reaction mixture was stirred at room temperature for 8 hours. Once the reaction was complete, the reaction mixture was stirred. After diluting with ethyl acetate, the mixture was wiped with salt water. The organic layer was dried and concentrated with magnesium sulfate. The title compound (205 mg, 64% yield) was obtained by purification using chromatography. H NMR (300MHz, DMSO-d6) δ7.64-7.18(m, 13H), 7 .10(s, 1H), 6.96(s, 1H), 5.19(s, 4H), 4.76(d, J =13.9, 2H), 4.51(d, J=16.3, 2H), 3.27-3.16(m, 1H), 1.16(s, 3H), 1.14(s, 3H). MSM / z:556[M+H] .

[0872] Step 5) Potassium benzyl 4-(methyltrifluoroborate)piperazine-1-carboxylate Production of um salts

[0873] Benzylpiperazine-1-carboxylate (100 mg, 0.45 mmol) and potassium (Bromomethyl)trifluoroboric acid (90 mg, 0.45 mmol) and tetrahydro After dissolving in furan (1.5 mL), the mixed solution was stirred at 80°C for 12 hours. The reaction was complete. After that, the reaction mixture was cooled and then concentrated. Acetone and After adding potassium carbonate and stirring for 30 minutes, the mixture was filtered through Celite and then concentrated to form the title. A compound (116 mg, 76% yield) was obtained. MSM / z: 301 [MK].

[0874] Step 6) Benzyl 4-((2-(2,4-bis(benzyloxy)-5-isopropyl Preparation of Benzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate

[0875] (2,4-bis(benzyloxy)-5-isopropylphenyl)(5-bromoisopropylphenyl) (Methyl-2-yl)methanone (100 mg, 0.18 mmol) and benzyl-4-(methicone) (Trifluoroboric acid)piperazine-1-carboxylate potassium salt (61 mg, 0.18 mg) (mol), XPhos (5 mg, 0.011 mmol), Cesium carbonate (176 mg, 0 Place 0.54 mmol) in a reaction vessel and, under a nitrogen environment, add palladium acetate (1.2 mg, 0.0 A mixture of 0.54 mmol) and tetrahydrofuran (0.9 mL) / water (0.1 mL) Added. The reaction mixture was stirred at 80°C for 12 hours. Once the reaction was complete, the mixture was simmered. After filtering using a filter, the filtrate was diluted with ethyl acetate and then wiped with salt water. The organic layer was sulfurized. It was dried and concentrated with magnesium oxide. Purified by chromatography to obtain the title compound (1 0.7 mg (84% yield) was obtained. MSM / z: 710 [M+H].

[0876] Step 7) (2,4-dihydroxy-5-isopropylphenyl) (5-(piperazine- Manufacturing of 1-ylmethyl)isoindoline-2-yl)methanone hydrochloride

[0877] Benzyl 4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl Isoindoline-5-yl)methyl)piperazine-1-carboxylate (100mg, (0.25 mmol) and palladium hydroxide (20 mg) adsorbed on carbon are combined in a tetrahydro After dissolving in a furan (1 mL) / methanol (1 mL) mixed solution, pressurize with hydrogen and then 1 The mixture was stirred for 2 hours. Once the reaction was complete, the mixture was filtered using Celite, and the resulting filtrate was then extracted. The concentrate was concentrated. The concentrated filtrate was diluted with ethyl acetate, then 1N hydrochloric acid solution was added, and the solution was filtered. The solid was wiped twice with ethyl acetate to obtain the title compound (80 mg, 74% yield). 1H NMR (300MHz, DMSO-d6) δ10.08(s, 1H), 7.35-7.1 4(m, 3H), 7.04(s, 1H), 6.39(s, 1H), 4.76(s, 4H) , 3.40(s, 2H), 3.15-3.03(m, 1H), 2.71-2.62(m, 4H), 2.26(s, 4H), 1.16(s, 3H), 1.14(s, 3H). MSM / z:396[M+H].

[0878] Stage 8) N-(3-(2-((4-(4-(2-(2-(3-(4-((2-(2,4 -Dihydroxy-5-isopropylbenzoate)isoindoline-5-yl)methyl)pipette Radin-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazin-1-yl )phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl Nyl)methanesulfonamide

[0879] In Example 99, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-( 4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3- Instead of dione, (2,4-dihydroxy-5-isopropylphenyl)(5-(pipe Except for the use of radin-1-ylmethyl)isoindolin-2-yl)methanone, The experimental method is identical. MSM / z: 1002[M+1].

[0880] Example 105: N-(3-(2-((4-(4-(2-(2-(3-(4-((4-( (2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindorin-5-yl )methyl)piperazine-1-yl)methyl)piperidine-1-yl)-3-oxopropone Xy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1- f][1,2,4]triazine-7-yl(phenyl)methanesulfonamide

[0881] [ka]

[0882] In Example 99, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-( 4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3- Instead of dione, (2,4-dihydroxy-5-isopropylphenyl)(5-((4 -(piperidine-4-ylmethyl)piperazine-1-yl)methyl)isoindoline-2 The experimental method was identical except for the use of yl(methanone). MSM / z:1099 [M+1].

[0883] Example 106: 2-amino-4-(2,4-dichloro-5-(2-(4-(3-(2- (2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1 -f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1-yl )Ethoxy)Ethoxy)Propanoyl)Piperadin-1-yl)Ethoxy)Phenyl)- N-ethylthieno[2,3-d]pyrimidine-6-carboxamide

[0884] [ka]

[0885] Step 1) Preparation of N-(2,4-dichloro-5-hydroxyphenyl)acetamide

[0886] N-(3-hydroxyphenyl)acetamide (8g, 52.9mmol) is mixed with acetic acid (1 Diluted with 00 mL, then at room temperature, thionyl chloride (1.0 M in MC, 111 mL, 11 1 mmol was gradually added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 8 hours. Once the reaction was complete, ice water was added, and the resulting solid was filtered and washed with water. 5 The compound was dried at 0°C to obtain a yellow title compound (92% yield).

[0887] Step 2) N-(5-(benzyloxy)-2,4-dichlorophenyl)acetamide manufacturing

[0888] N-(2,4-dichloro-5-hydroxyphenyl)acetamide (10g, 45.4 mmol), potassium carbonate (7.27 g, 52.7 mmol) in acetonitrile (100 After dilution with (mL), benzyl bromide (7.765g, 45.4 mmol) was gradually added dropwise. The reaction mixture was stirred at 80°C for 3 hours. Once the reaction was complete, it was diluted with dichloromethane. The area was wiped with salt water, sodium hydroxide solution, and ammonium solution. As a result, separation was observed. The organic layer was dried over anhydrous sodium sulfate, and then the title compound was obtained by vacuum filtration and vacuum distillation. A yield of 95% was obtained.

[0889] Stage 3) 5-(benzyloxy)-2,4-dichloroaniline

[0890] N-(5-(benzyloxy)-2,4-dichlorophenyl)acetamide is methanol Dissolved in (100 mL) water (100 mL) and saturated hydrochloric acid (15 g, 0.15 mol). The reaction mixture was stirred at 60°C for 12 hours. Once the reaction was complete, the product was obtained by vacuum distillation. The solid was filtered. It was wiped with water and dried at 50°C to obtain the title compound (yield: 85%).

[0891] Step 4) Production of 1-(benzyloxyl)-2,4-dichloro-5-iodobenzene

[0892] Hydrogen chloride (60 mL, 6 M) is converted to 5-(benzyloxy)-2,4-dichloroaniline

[0893] (16.2g, 60 mmol) was gradually added dropwise to acetic acid (240 mL). Sodium nitrite A 40 mL aqueous solution of um (4.8 g, 69 mmol) was gradually added dropwise at 5°C. The reaction was mixed. After stirring the solution at the same temperature for 30 minutes, potassium iodide (20 gg, 120 mmol), Add 4g of porcini (16 mmol) and 200mL of water dropwise. The reaction mixture was then heated at the same temperature. Stirring was continued for 90 minutes. Once the reaction was complete, it was diluted with dichloromethane, water, and sodium thiosulfate. The wiping was performed in the following order: aqueous solution, sodium hydroxide solution, water, and salt water. As a result, the separated [unclear] After drying the chamber with anhydrous sodium sulfate, the title compound was obtained by vacuum filtration and vacuum distillation (yield 90% was obtained.

[0894] Step 5) Ethyl 2-amino-4-(5-(benzyloxy)-2,4-dichlorophenic (Lu) Thieno[2,3-d]pyrimidine-6-carboxylate

[0895] 1-(benzyloxyl)-2,4-dichloro-5-iodobenzene (20.6g, 5 4 mmol), bis(pinacolic acid) viboron (14.5 g, 57 mmol), potassium Dilute muacetoxide (16g, 163mmol) with 50mL of dimethylformamide, then add vinegar. Palladium(II) acid (450 mg, cat.) was added. The reaction mixture was heated at 90°C for 1 The mixture was stirred for 8 hours. Once the reaction was complete, it was diluted with ethyl acetate and wiped with salt water. As a result... The separated organic layer was dried over anhydrous sodium sulfate, then subjected to vacuum filtration and vacuum distillation to obtain the title. A compound was obtained: 2-amino-4-chlorothieno[2,3-d]pyrimidine-6-carbone. Ethyl acid ester (12.85 g, 50 mmol), potassium phosphate aqueous solution (40 mL, Add 2M ( ) and dilute with 1,4-dioxane (160 mL). Palladium(II) acetate ( 450 mg (cat.) was added, and the reaction mixture was stirred at 100°C for 3 hours. The reaction was complete. Once formed, it was diluted with ethyl acetate and wiped with salt water. The resulting separated organic layer was then subjected to anhydrous sulfur dioxide. After drying with sodium acid, the residue was subjected to vacuum filtration and vacuum distillation. The resulting residue was chloro. The title compound (yield: 45%) was obtained by purification using matrix imaging.

[0896] Step 6) 2-amino-4-(5-(benzyloxyl)-2,4-dichlorophenyl) -N-ethylthieno[2,3-d]pyrimidine-6-carboxamide

[0897] Ethyl 2-amino-4-(5-(benzyloxy)-2,4-dichlorophenyl) No[2,3-d]pyrimidine-6-carboxylate (500 mg, 1.05 mmol) Dissolve in trahydrofuran (4 mL) / methanol (4 mL) / water (4 mL), then add water. Lithium oxide (88 mg, 2.00 mmol) was added. Once the reaction was complete, ethyl acetate was added. The mixture was diluted with water and wiped with a 1N hydrogen chloride solution. The resulting separated organic layer was anhydrous sodium sulfate. After drying with thorium, the title compound was obtained by vacuum filtration and vacuum distillation. HATU(798) (mg, 2.10 mmol), diisopropylethylamine (0.55 mL, 3.15 mg) Add ethylamine (145 mg, 3.15 ol) and stir at room temperature for 30 minutes. Then add ethylamine (145 mg, 3.15 ol) and stir. mmol was gradually added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Once the reaction was complete... Then, it was diluted with ethyl acetate and wiped with salt water. The resulting separated organic layer was anhydrous sodium sulfate. After drying with aluminium, the residue was subjected to vacuum filtration and vacuum distillation. The resulting residue was then chromatographed. The title compound (50%) was obtained by purification using a Raffy filter.

[0898] Step 7) 2-amino-4-(2,4-dichloro-5-hydroxyphenyl)-N-eth Lucieno[2,3-d]pyrimidine-6-carboxamide

[0899] 2-amino-4-(5-(benzyloxyl)-2,4-dichlorophenyl)-N-E Chilchieno[2,3-d]pyrimidine-6-carboxamide (280 mg, 0.59 mg) After dissolving (mol) in 3 mL of dichloromethane, a boron trichloride solution (1 M dichloromethane) is prepared. 3 mL of lomethane was gradually added at -78°C. The reaction mixture was stirred at room temperature for 3 hours. Once the reaction is complete, distill under reduced pressure, dilute with ethyl acetate, and then add sodium acetate aqueous solution and salt water in that order. The resulting organic layer was washed. After drying with anhydrous sodium sulfate, it was filtered under reduced pressure. The compound was obtained by perspiration and vacuum distillation, followed by the use of hexane to produce a solid, and then filtered.

[0900] Step 8) tert-butyl 4-(2-(5-(2-amino-6-(ethylcarbamoyl )thieno[2,3-d]pyrimidine-4-yl)-2,4-dichlorophenoxy)ethyl ) piperazine-1-carboxylate

[0901] 2-amino-4-(2,4-dichloro-5-hydroxyphenyl)-N-ethylthieno [2,3-d] Pyrimidine-6-carboxamide (500 mg, 1.05 mmol (8 (8 mg, 0.23 mmol), triphenylphosphine (91 mg, 0.35 mmol) tert-butyl-4-(2-hydroxyethyl)piperazine-1 carboxylate (65 (mg, 0.28 mmol) was dissolved in 10 mL of tetrahydrofuran. Then, DEAD The mixture was gradually added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. Once the reaction was complete, acetic acid was added. The solution was diluted with ethyl acetate, then washed with ammonium chloride solution and then salt water. As a result, the following separation was achieved. The resulting organic layer was dried over anhydrous sodium sulfate, then subjected to vacuum filtration and vacuum distillation. The resulting residue was purified by chromatography to obtain the title compound (55%).

[0902] Step 9) 2-amino-4-(2,4-dichloro-5-(2-(piperazine-1-yl) Ethoxy)phenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxya Mido

[0903] tert-butyl 4-(2-(5-(2-amino-6-(ethylcarbamoyl)thieno [2,3-d]pyrimidine-4-yl)-2,4-dichlorophenoxy)ethyl)piper Dissolve 300 mg of din-1-carboxylate in 4 mL of ethyl acetate, then add 4N aqueous chloride solution. Four mL of 1,4-dioxane solution was gradually added dropwise. The reaction mixture was stirred at room temperature for four hours. Once the reaction was complete, the title compound (95%) was obtained by vacuum distillation.

[0904] Step 10) 2-amino-4-(2,4-dichloro-5-(2-(4-(3-(2-(2 -(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f [1,2,4] Triazine-2-yl)amino)phenyl)piperazine-1-yl) Toxy)ethoxy)propanoyl)piperazin-1-yl)ethoxy)phenyl)-N- Ethylthieno[2,3-d]pyrimidine-6-carboxamide

[0905] In Example 99, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-( 4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3- Instead of dione, use 2-amino-4-(2,4-dichloro-5-(2-(piperazine-1 -yl)ethoxy)phenyl)-N-ethylthieno[2,3-d]pyrimidine-6-cal The experimental method was identical except for the use of boxiamid. MSM / z:1048[M +1]

[0906] Example 107: N-(3-(2-((4-(4-((4-((4-((2-(2,4- Hydroxy-5-isopropylbenzoate (isoindorin-5-yl)methyl)piperazi (Piperadin-1-yl)methyl)benzoate)piperazine-1-yl)phenyl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide

[0907] [ka]

[0908] Step 1) Methyl 4-((4-((2-(2,4-bis(benzyloxy)-5-isopropyl Ropyrubenzoyl isoindolin-5-yl methyl piperazine-1-yl methyl ) Production of benzoic acid

[0909] In steps 5-6 of Example 104, instead of benzylpiperazine-1-carboxylate, methyl The experimental method was identical except for the use of 4-(piperazine-1-ylmethyl)benzoic acid. It is. MSM / z:724[M+1].

[0910] Stage 2) 4-((4-((2-(2,4-bis(benzyloxy)-5-isopropyl Benzoyl)isoindolin-5-yl)methyl)piperazine-1-yl)methyl)benzoyl Aromatic acid

[0911] The experimental procedure is identical to that of Step 3 in Example 108. MSM / z: 709 [M+1].

[0912] Stage 3) 4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoic acid) Production of isoindolin-5-yl)methyl)piperazine-1-yl)methyl)benzoic acid

[0913] The experimental procedure is identical to that of Step 4 in Example 108. MSM / z: 530 [M+1].

[0914] Stage 4) N-(3-(2-((4-(4-((4-((4-((2-(2,4-dihydro Xy-5-isopropylbenzoate)isoindorin-5-yl)methyl)piperazine-1 -yl)methyl)benzoate)piperazine-1-yl)phenyl)amino)pyrrolo[2,1 -f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide

[0915] 4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoin (50 mg, 0.5 mg) dilin-5-yl methyl piperazine-1-yl methyl benzoic acid 09mmol), EDCI (54mg, 0.28mmol), HOAt (37mg, 0. After dissolving 29 mmol) in dimethylformamide (2 mL), diisopropylethyl Amine (0.08 mL, 0.45 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After mixing, N-(3-(2-((4-(piperazine-1-yl)phenyl)amino)pyro [2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone After adding (46 mg, 0.10 mmol), the mixture was stirred at 50°C for 6 hours. The reaction was completed. Then, the reaction mixture was diluted with dichloromethane and wiped with salt water. The organic layer was then treated with magnesium sulfate. The solution was dried with citric acid and concentrated. The title compound was obtained by purification using chromatography. (MS) M / z:976[M+1].

[0916] Example 108: N-(3-(2-((4-(4-(1-((2-(2,4-dihydrox C-5-isopropylbenzoate)isoindorin-5-yl)methyl)piperidine-4- Carbonyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2 ,4]Triadin-7-yl)phenyl)methanesulfonamide

[0917] [ka]

[0918] Step 1) Methyl 1-(methyltrifluoroboric acid)piperidine-4-carboxylic acid potassium Production of humic acid

[0919] Methylpiperidine-4-carboxylate (100 mg, 0.70 mmol) and potassium ( Bromomethyl)trifluoroboric acid (141 mg, 0.70 mmol) and tetrahydro After dissolving in furan (2 mL), the mixed solution was stirred at 80°C for 12 hours. The reaction was complete. Afterward, the reaction mixture was cooled and then concentrated. Acetone and carbonic acid were added to the concentrated reaction mixture. After adding potassium and stirring for 30 minutes, filter through Celite and concentrate to obtain the target compound. (109 mg, 59% yield) was obtained. MSM / z: 224 [MK].

[0920] Step 2) Methyl 1-((2-(2,4-bis(benzyloxy)-5-isopropylbe Production of (nzoyl)isoindoline-5-yl)methyl)piperidine-4-carboxylate

[0921] (2,4-bis(benzyloxy)-5-isopropylphenyl)(5-bromoisopropylphenyl) (Methyl-2-yl)methanone (100 mg, 0.18 mmol) and methyl-1-(methyl Trifluoroboric acid) piperidine-4-carboxylate potassium salt (47 mg, 0.18 mm) (ol), XPhos (5 mg, 0.011 mmol), Cesium carbonate (176 mg, 0. Place 54 mmol) in a reaction vessel and add palladium acetate (1.2 mg, 0.00) under nitrogen conditions. Add a mixture of 54 mmol of tetrahydrofuran (0.9 mL) and water (0.1 mL). The reaction mixture was stirred at 80°C for 12 hours. Once the reaction was complete, the mixture was turned into Celite. After filtering using [a specific method], the filtrate was diluted with ethyl acetate and then wiped with salt water. The organic layer was then treated with sulfuric acid. It was dried with magnesium and concentrated. The target compound (49) was purified by chromatography. mg (43% yield) was obtained. MSM / z: 633 [M+H].

[0922] Stage 3) 1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl Production of isoindoline-5-yl methylpiperidine-4 carboxylate

[0923] Methyl 1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl Isoindolin-5-yl(methyl)piperidine-4-carboxylate (660 mg, 1 (0.0 mmol) in water (1 mL) / tetrahydrofuran (4 mL) / methanol (2 mL) After dissolving in the mixed solution, the lithium hydroxide hydrate (130 mg, 3.1 mmol) was heated at 0°C. It was added. After stirring the reaction mixture at room temperature for 2 hours, the reaction was completed and the solution was concentrated. After diluting the reduced reaction mixture with water and dichloromethane, a 1N hydrochloric acid solution was used to dissolve the reaction mixture. The solution was gradually added until its pH reached 4. The mixed solution was extracted three times with dichloromethane. The mixture was collected, dried with sodium sulfate, and concentrated to obtain the target compound (590 mg, 92% yield). Obtained: MSM / z 619[M+H].

[0924] Stage 4) 1-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoin Production of dorin-5-yl)methyl)piperidine-4-carboxylate

[0925] Benzyl 1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl Isoindoline-5-yl)methyl)piperidine-4-carboxylate (155 mg, (0.25 mmol) and palladium hydroxide (20 mg) adsorbed on carbon are combined in a tetrahydro After dissolving in a furan (1 mL) / methanol (1 mL) mixed solution, pressurize with hydrogen and then 1 The mixture was stirred for 2 hours. Once the reaction was complete, the mixture was filtered using Celite, and the resulting filtrate was then extracted. The solution was concentrated to obtain the target compound (81 mg, 74% yield). MSM / z 439[M+H] .

[0926] Stage 5) N-(3-(2-((4-(4-(1-((2-(2,4-dihydroxy-5 -Isopropylbenzoic acid)isoindolin-5-yl)methyl)piperidine-4-carb Nyl)piperazin-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide

[0927] In Example 107, 4-((4-((2-(2,4-dihydroxy-5-isopropylbenzo Isoindolin-5-yl methyl piperazine-1-yl methyl benzoic acid Instead, 1-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoin Except for the use of dorin-5-yl)methyl)piperidine-4-carboxylate, the experiment The method is the same. MSM / z 885[M+H].

[0928] Example 109: 4-(2-(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-dia Za-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pi Lazora-1(1,4)-benzenecycloundecaffei-8-yl)ethoxy)-2- (2,6-Dioxopiperidine-3-yl)isoindorin-1,3-dione

[0929] [ka]

[0930] (2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyroro [2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-be Cyanthencycloundecaffeine (83 mg, 0.22 mmol), potassium iodide (21 9 mg, 0.66 mmol), diisopropylethylamine (0.12 mL, 0.66 mL) mol) and 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3- Isoindoline-1,3-dione (167 mg, 0.44 mmol) is dimethylform Dissolve in Muamido (2 mL). Stir the reaction mixture at 60°C for 12 hours. The reaction is complete. The reaction mixture was then diluted with ethyl acetate and wiped with salt water. The organic layer was magnesium sulfate. It was dried and concentrated. Purified by chromatography to obtain the title compound (75 mg, 51%). Yield obtained: MSM / z: 676[M+1].

[0931] Example 110: 4-(3-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-di Aza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4(4,1)- Pyrazola-1(1,4)-benzenecycloundecaffeinate-8-yl)propoxy)- 2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione

[0932] [ka]

[0933] In Example 109, 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3) - Instead of isoindoline-1,3-dione (167 mg, 0.44 mmol) , 4-(3-bromopropoxy)-2-(2,6-dioxopiperidine-3-yl)iso The experimental method was identical except for the use of indoline-1,3-dione. MSM / z :690[M+1].

[0934] Example 111: 4-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-Benzenecycloundecaffeinate-8-yl)ethoxy )Ethoxy)-2-(2-oxopiperidine-3-yl)isoindorine-1,3-diol hmm

[0935] [ka]

[0936] In Example 109, 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3) - Instead of isoindoline-1,3-dione (167 mg, 0.44 mmol) , 4-(2-(2-bromoethoxy)ethoxy)-2-(2-oxopiperidine-3- The experimental method is identical except for the use of isoindoline-1,3-dione. SM / z:706[M+1].

[0937] Example 112: 4-((6-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)hexyl) Oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-di on

[0938] [ka]

[0939] In Example 109, 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3) - Instead of isoindoline-1,3-dione (167 mg, 0.44 mmol) , 4-((6-bromohexyl)oxy)-2-(2,6-dioxopiperidine-3- The experimental method is identical except for the use of isoindoline-1,3-dione. SM / z:732[M+1].

[0940] Example 113: 4-((8-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)octyl) Oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-di on

[0941] [ka]

[0942] In Example 109, 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3) - Instead of isoindoline-1,3-dione (167 mg, 0.44 mmol) , 4-((8-bromooctyl)oxy)-2-(2,6-dioxopiperidine-3- The experimental method is identical except for the use of isoindoline-1,3-dione. SM / z:690[M+1].

[0943] Example 114: 4-((8-((2 1 Z,4 4 E)-41 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)octyl) Oxy)-2-(2-oxopiperidine-3-yl)isoindorin-1,3-dione

[0944] [ka]

[0945] In Example 109, 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3) - Instead of isoindoline-1,3-dione (167 mg, 0.44 mmol) , 4-((8-bromooctyl)oxy)-2-(2-oxopiperidine-3-yl) The experimental method was identical except for the use of soindoline-1,3-dione. MSM / z:746[M+1].

[0946] Example 115: 4-((11-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8 -diaza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4(4,1 )-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)undecaffeine (L)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3 - Zeon

[0947] [ka]

[0948] In Example 109, 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3) - Instead of isoindoline-1,3-dione (167 mg, 0.44 mmol) , 4-((11-bromoundecyl)oxy)-2-(2,6-dioxopiperidine-3 The experimental method was identical except for the use of -yl)isoindoline-1,3-dione. MSM / z:802[M+1].

[0949] Example 116: 4-((9-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl)nonyl)oxy C)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione Undecaffeinated

[0950] [ka]

[0951] In Example 109, 4-(2-bromoethoxy)-2-(2,6-dioxopiperidine-3) - Instead of isoindoline-1,3-dione (167 mg, 0.44 mmol) , 4-((9-bromononyl)oxy)-2-(2,6-dioxopiperidine-3-yl The experimental method was identical except for the use of isoindoline-1,3-dione. MS M / z:774[M+1].

[0952] Example 117: 5-(4-((1-(3-(2-(2-((2 1 Z,4 4 E)-4 1 H -11-oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine -8-yl)ethoxy)ethoxy)propanoyl)piperidine-4-yl)methyl)piperidine Radin-1-yl)-2-(2,6-dioxopiperidine-3-yl)-6-fluoroyl Soindrin-1,3-dione

[0953] [ka]

[0954] Stage 1) t-butyl 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-Pyrazole-1(1,4)-Benzenecycloundecaffeine-8-yl) Production of Toxyethoxypropanoic Acid

[0955] N(2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyro [2,1-f][1,2,4]triazine-4(4,1)-pyrazole-1(1,4) -Benzenecycloundecaffeine (83 mg, 0.22 mmol), potassium iodide ( 73 mg, 0.22 mmol), diisopropylethylamine (0.12 mL, 0.66 mmol) and t-butyl 3-(2-(2-iodoethoxy)ethoxy)propanoic acid (1 51 mg (0.44 mmol) was dissolved in dimethylformamide (2 mL). The reaction mixture was then prepared. The solution was stirred at 60°C for 24 hours. Once the reaction was complete, the reaction mixture was diluted with ethyl acetate. Afterward, it was wiped with salt water. The organic layer was dried and concentrated with magnesium sulfate. Chromatography The title compound (66 mg, 51% yield) was purified using the following method. MSM / z: 592[M +1]

[0956] Stage 2) 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-di Aza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4(4,1)- Pyrazole-1(1,4)-benzenecycloundecaffeinate-8-yl)ethoxy) Toxypropanoic acid

[0957] t-butyl3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)ethoxy) Ethoxypropanoic acid (90 mg, 0.17 mmol) mixed with tetrahydrofuran (1 mL) After dissolving in methanol (1 mL) and water (1 mL), LiOH-H2O (15 mg, 0 0.34 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After diluting with ethyl acetate, neutralize with a 1N hydrogen chloride solution to create a pH of 5, then wipe with salt water. The organic layer was dried over magnesium sulfate and concentrated to obtain the title compound (92 mg, 94% yield). The result was obtained. It was used in the next reaction without purification. MSM / z: 536[M+1].

[0958] Stage 3) 5-(4-((1-(3-(2-(2-((21 Z,4 4 E)-4 1 H-11 -oxa-3,8-diaza-2(7,2)-pirolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecane-8-yl) Ethoxy)Ethoxy)Propanoyl)Piperidin-4-yl)Methyl)Piperazine-1- (Iyl)-2-(2,6-dioxopiperidine-3-yl)-6-fluoroisoindoline -1,3- Zeon's production

[0959] 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2 (7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazole Lu-1(1,4)-benzenecycloundecaffeinate-8-yl)ethoxy)ethoxy) Propanic acid (55 mg, 0.10 mmol), EDCI (56 mg, 0.29 mmol) Dissolve HOAt (40 mg, 0.29 mmol) in dimethylformamide (2 mL) Afterward, diisopropylethylamine (0.08 mL, 0.49 mmol) was added. After stirring the mixed solution at room temperature for 30 minutes, 2-(2,6-dioxopiperidine-3-yl) -5-fluoro-6-(4-(piperidine-4-ylmethyl)piperazine-1-yl) After adding soindoline-1,3-dione (50 mg, 0.11 mmol), at 50°C The mixture was stirred for 6 hours. Once the reaction was complete, the reaction mixture was diluted with dichloromethane and then with salt water. The sample was wiped clean. The organic layer was dried and concentrated over magnesium sulfate. It was then purified by chromatography. The title compound was obtained. MSM / z: 976[M+1].

[0960] Example 118: 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3, 8-diaza-2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4, 1)-pyrazole-1(1,4)-benzenecycloundecaphen-8-yl)ethoxy )ethoxy)-N-(3-(4-(3-(2,4-dihydroxy-5-isopropylphen yl)-5-hydroxy-4H-1,2,4-triazol-4-yl)phenoxy)pro pyl)propanamide

[0961] [Chemical Structure]

[0962] In Example 117, except that 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6- (4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3 -dione was replaced with 4-(4-(4-(3-aminopropoxy)phenyl)-5-hydr oxy-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1 ,3-diol, the experimental method was the same. MSM / z: 903 [M + 1].

[0963] Example 119: 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3, 8-diaza-2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4, 1)-pyrazole-1(1,4)-benzenecycloundecaphen-8-yl)ethoxy yl)ethoxy)-N-(2-((3-(4-(3-(2,4-dihydroxy-5-isop Ropyrphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl) Noxypropylamino-2-oxoethylpropanamide

[0964] [ka]

[0965] In Example 117, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6- (4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3 -Instead of dione, 2-amino-N-(3-(4-(3-(2,4-dihydroxy-5 (-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-I The experimental method was identical except for the use of phenoxypropyl acetamide. MSM / z:960[M+1].

[0966] Example 120: 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-Benzenecycloundecaffeinate-8-yl)ethoxy )Ethoxy)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropyl phenyl (Nyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)benzyl)pipette Radin-1-yl)propane-1-one

[0967] [ka]

[0968] In Example 117, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6- (4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3 -Instead of dione, 4-(5-hydroxy-4-(4-(piperazine-1-ylmethyl )phenyl)-4H-1,2,4-triazole-3-yl)-6-isopropylbenzyl The experimental method was identical except for the use of n-1,3-diol. MSM / z:92 8[M+1].

[0969] Example 121: 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-Benzenecycloundecaffeinate-8-yl)ethoxy )Ethoxy)-1-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropyl) Pyrphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)benzyl Piperazine-1-yl Methylpiperidine-1-yl Propan-1-one

[0970] [ka]

[0971] In Example 117, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6- (4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3 -Instead of dione, 4-(5-hydroxy-4-(4-((4-(piperidine-4-i (Methyl)piperazin-1-yl)methyl)phenyl)-4H-1,2,4-triazole Except for using 3-(2-(2-((2 The experimental method is the same. MS M / z: 1025 [M+1].

[0972] Example 122: 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3, 8-diaza-2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4, 1)-pyrazola-1(1,4)-benzene cycloundecaphane-8-yl)ethoxy )ethoxy)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl yl)isoindolin-5-yl)methyl)piperazin-1-yl)propan-1-one

[0973]

Chemical Structure

[0974] In Example 117, except for using (2,4-dihydroxy-5-isopropylphenyl)(5-(piperazin-1-ylmethyl)isoindolin-2-yl)methanone instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6- (4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3 -dione, the experimental method is the same. MS M / z: 914 [M+1].

[0975] Example 123: Except for using 3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3, 8-diaza-2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4, 1)-pyrazola-1(1,4)-benzene cycloundecaphane-8-yl)ethoxy )Ethoxy)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropyl Benzoyl)isoindolin-5-yl)methyl)piperazine-1-yl)methyl)piperazine Lysine-1-yl)propan-1-one

[0976] [ka]

[0977] In Example 117, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6- (4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3 - Instead of dione, (2,4-dihydroxy-5-isopropylphenyl)(5-(( 4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)isoindoline- The experimental method was identical except for the use of 2-yl(methanone). MSM / z:101 1[M+1].

[0978] Example 124: 4-(5-(2-(4-(3-(2-(2-((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2, 4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffe In-8-yl)ethoxy)ethoxy)propanoyl)piperazine-1-yl)ethoxy )-2,4-dichlorophenyl)-2-amino-N-ethylthieno[2,3-d]pyrim Zin-6-carboxamide

[0979] [ka]

[0980] In Example 117, 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6- (4-(piperidine-4-ylmethyl)piperazine-1-yl)isoindoline-1,3 -Instead of dione, 2-amino-4-(2,4-dichloro-5-(2-(piperazine- 1-yl)ethoxy)phenyl)-N-ethylthieno[2,3-d]pyrimidine-6-ca The experimental method was identical except for the use of ruboxyamide. MSM / z:1014[ [M+1].

[0981] Example 125: ((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- 1(1,4)-Benzenecycloundecaffei-8-yl)(4-((4-((2-( 2,4-Dihydroxy-5-isopropylbenzoyl)isoindorin-5-yl)meth Piperazine-1-yl Methylphenyl Methanone

[0982] [ka]

[0983] 4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoin (50 mg, 0.5 mg) dilin-5-yl methyl piperazine-1-yl methyl benzoic acid 09mmol), EDCI (54mg, 0.28mmol), HOAt (37mg, 0. After dissolving 29 mmol) in dimethylformamide (2 mL), diisopropylethyl Amine (0.08 mL, 0.45 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After mixing, (2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2(7,2) -Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola-1(1, 4) After adding benzenecycloundecaffeine (38 mg, 0.10 mmol), The mixture was stirred at 50°C for 6 hours. Once the reaction was complete, the reaction mixture was diluted with dichloromethane. The mixture was wiped with salt water. The organic layer was dried and concentrated with magnesium sulfate. Chromatography method The title compound was obtained by purification using a standard method. MSM / z: 888[M+1].

[0984] Example 126: ((2 1 Z,4 4 E)-4 1 H-11-oxa-3,8-diaza-2( 7,2)-Pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- 1(1,4)-Benzenecycloundecaffeine-8-yl)(1-((2-(2,4- Dihydroxy-5-isopropylbenzoate (isoindorin-5-yl)methyl)piper (Zin-4-yl)methanone

[0985] [ka]

[0986] In Example 125, 4-((4-((2-(2,4-dihydroxy-5-isopropylbenzo Isoindolin-5-yl methyl piperazine-1-yl methyl benzoic acid Instead, 1-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoin Except for the use of dorin-5-yl)methyl)piperidine-4-carboxylate, the experiment The method is the same. MSM / z:796[M+1].

[0987] The structures and LC-MS results of Examples 1 to 126 are summarized in the table below. be.

[0988] [Table 1]

[0989] [Table 2]

[0990] [Table 3]

[0991] [Table 4]

[0992] [Table 5]

[0993] [Table 6]

[0994] [Table 7]

[0995] [Table 8]

[0996] [Table 9]

[0997] [Table 10]

[0998] [Table 11]

[0999] [Table 12]

[1000] [Table 13]

[1001] [Table 14]

[1002] [Table 15]

[1003] [Table 16]

[1004] On the other hand, the novel compound represented by chemical formula 1 according to the present invention can take various forms depending on the purpose. It can be formulated as follows. Next, the compound represented by chemical formula 1 according to the present invention is used as the active ingredient. This document illustrates several formulation methods for incorporating the substance, and the present invention is not limited thereto. It's not something that can be done.

[1005] [Examples of formulations]

[1006] Formulation example 1: Tablet (direct pressurization)

[1007] After sieving 5.0 mg of the active ingredient, 14.1 mg of lactose and crospovidone USN F 0.8 mg and magnesium stearate 0.1 mg are mixed and pressurized to form tablets. Ta.

[1008] Formulation example 2: Tablets (wet assembly)

[1009] After sieving 5.0 mg of the active ingredient, it was mixed with 16.0 mg of lactose and 4.0 mg of starch. Dissolve 0.3 mg of polysorbate 80 in pure water, then add an appropriate amount of this solution. After that, it was atomized. After drying, the atomized material was sieved, and then colloidal silicon dioxide 2.7 It was mixed with mg and 2.0 mg of magnesium stearate. The granules were then compressed to form tablets.

[1010] Formulation example 3: Powder and capsules

[1011] After sieving 5.0 mg of the active ingredient, 14.8 mg of lactose and polyvinylpyrrolidone were added. Mix 10.0 mg of [unclear] with 0.2 mg of magnesium stearate. The mixture was then packaged in an appropriate container. The mixture was then used to fill hard No. 5 gelatin capsules.

[1012] Formulation example 4: Injectable drug

[1013] It contains 100 mg of the active ingredient, as well as 180 mg of mannitol and Na2 An injectable preparation was manufactured containing 26 mg of HPO412H2O and 2974 mg of distilled water.

[1014] [Example of experiment]

[1015] Experimental Example 1: Measurement of enzyme activity in cancer cells

[1016] Dispense 3000 cells into each well of a 96-well plate. Cell stabilization. After the reaction, the compound was continuously diluted by 1 / 3 and treated to 0.5% DMSO, then cultured for 72 hours. To nourish. If cell titerglo is treated, Lucifer will only appear if ATP is present. -ase breaks down luciferin and releases luminescence. Envision the luminescence value. Measurements were taken using a Perkinelmer instrument. Based on the measured luminescence values, further details were developed. The concentration of the compound that causes cell death was calculated to determine the GI50 value.

[1017] The experimental results were the same as those shown in Table 1 below. Activity levels were indicated on a three-point scale.

[1018] A:IC 50 <1μM

[1019] B: 1μM≦IC 50 <10μM

[1020] C:IC 50 ≥10 μM

[1021] [Table 17]

[1022] Experimental Example 2. Measurement of enzyme activity in Ba / F3 cells

[1023] Dispense 3000 cells into each well of a 96-well plate. Cell stabilization. After the reaction, the compound was continuously diluted by 1 / 3 and treated to 0.5% DMSO, then cultured for 72 hours. To nourish. If cell titerglo is treated, Lucifer will only appear if ATP is present. -ase breaks down luciferin and releases luminescence. Envision the luminescence value. Measurements were taken using a Perkinelmer instrument. Based on the measured luminescence values, further details were developed. The concentration of the compound that causes cell death was calculated to determine the GI50 value.

[1024] The experimental results were the same as those shown in Table 2 below. Activity levels were expressed in three stages.

[1025] A:IC 50 <1μM

[1026] B: 1μM≦IC 50 <10μM

[1027] C:IC 50 ≥10 μM

[1028] [Table 18]

[1029] Experimental Example 3. Measurement of Target Protein Resolution in Cancer Cells

[1030] 1x10 per well of a 6-well plate 6 Dispense individual cells. Dispense the compound. The samples are treated according to concentration and incubated for 24 hours. After cell lysis, proceed with the BCA assay. The protein quantification was carried out using laemmli sample buffer (red Add (ucing) and boil at 99°C for 5 minutes to prepare the sample for Western blot. To manufacture.

[1031] The sample is loaded onto the acrylamide gel and electrophoresis is performed, Transfers proteins to the membrane via ansfer. 5% skim milk After stirring for 30 minutes to prevent nonspecific binding between antibody and protein, 1 Mix the antibody solution diluted 1:1000 with the membrane at 4°C for 10 hours. By washing the S / T buffer membrane three times for 5 minutes each, the membrane Removes primary antibodies that are not bound to HRP (horse radish pe). A solution of a secondary antibody with roxidase attached, diluted to 1:10000, and membra Stir the ne at room temperature for 1 hour. Stir the TBS / T buffer membrane for 5 minutes. Wash the membrane multiple times to remove any unbound secondary antibodies. Process the ECL solution. Afterward, chemiluminescence was measured via LAS.

[1032] The experimental results were the same as those shown in Figure 1.

Claims

1. The 2,7-substituted pyrrolo[2,1-f][1,2,4]tri represented by the chemical formula 1 below. Azine compounds, their pharmaceutically acceptable salts, their hydrates or solvates: 【Chemistry 1】 In the aforementioned chemical formula 1, R １ , R ２ and R ３ These are, independently, hydrogen; hydroxyl group; halogen group; and C. １ -C １３ Alkyl group; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclic group; C ３ -C １０ Hete Rosicyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-NR ８ R ９ ); Ni Tro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); ester group (-C(O ) OR ８ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide Group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group (-S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ ); and A and B are each independently C ６ -C １０ Aryl group; C ３ -C １０ Cyclyl group; C ３ -C １０ heteroaryl group; or C ３ -C １０ Heterocyclyl group; R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen; hydroxyl group; halogen group; and C. １ -C １３ Alkyl alkyl group; C １ -C ６ Haloalkyl; C １ -C ６ Alkoxy group; C ３ -C １ ０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl) ； Amino group (-NR ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR ８ ); Nitori L group (-CN); sulfonamide group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group (-S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ );in can be, L ａ is hydrogen; hydroxyl group; halogen group; C １ -C １３ Alkyl alkyl group; -Z ａ - Q ３ - E; or -Z ａ - Q １ -M; and the aforementioned -Z ａ - Q １ -M, where M is L ｂ ga-Z ｂ - Q ２ When Q ２ It is connected to form a ring, L ｂ is hydrogen; hydroxyl group; halogen group; C １ -C １３ Alkyl alkyl group; C １ -C ６ Al Coxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ alkyl); amino group (-NR ８ R ９ ); nitro group (-N(O) ２ ); amide Group (-(C=O)NR ８ R ９ ); carboxylic acid group (-C(O)OH); ester group (-C( O) OR ８ ); nitrile group (-CN); sulfonamide group (-NHS(O) ２ R ８ );vinegar Rufid group (-SR ８ ); Sulfone group (-S(O) ２ R ８ ); Or -Z ｂ -Q ２ ; dea , the aforementioned -Z ｂ - Q ２ So, Q ２ is, L ａ ga-Z ａ - Q １ -When M is present, it is connected to M and forms a ring Forming, Said Z ａ or Z ｂ These may exist independently or not exist at all, Z ａ or Z ｂ but In some cases, Z ａ or Z ｂ These are independently -O-, -CO-, -COO-, and -C ｎ H ｎ＋２ -、-O(C ｎ H ｎ＋２ )-、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ＋２ )O (C ｍ H ｍ＋２ ) -, -C ３ -C １０ cyclyl group -; or -C ３ -C １０ Heterocycline It is a lu group; The aforementioned Q １ Q ２ and Q ３ Each of them is independently -C ｎ H ｎ＋２ -, -O(C) ｎ H ｎ＋２ )-、-(OC ２ H ４ ) ｎ -、-(C ２ H ４ O) ｎ -、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ＋２ )CO-、-NR ８ (C ｎ H ｎ＋２ )-、-(NR ８ C ２ H ４ ) ｎ -、-(C ２ H ４ NR ８ ) ｎ -、-(C ｎ H ｎ＋２ )NR ８ -、-(C ｎ H ｎ＋２ )O(C ｍ H ｍ＋ ２ ) -, -( C ｎ H ｎ＋２ )O(C ｍ H ｍ＋２ ) CO-, -C ３ -C １０ cyclyl group -; or -C ３ -C １０ It is a heterocyclyl group; The aforementioned Q ４ It may or may not exist, and if it does exist, -C ｎ H ｎ＋２ -, -C ｎ H ｎ - or -C ｎ H ｎ－２ - and The aforementioned M is -O-, -CO-, -COO-, -C ２ H ２ -, -C ｎ H ｎ＋２ -, -O( C ｎ H ｎ＋２ )-、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ＋２ )O(C ｍ H ｍ＋２ )- ,-NR ８ -;-NR ８ CH ２ -;-NHR ８ -;-NR ８ C(O)-;-NR ８ C(O) )O-;-C(O)NR ８ -;-NR ８ C(O)NR ８ -;-NC(O)R ８ -;-NS (O) ２ R8-;-S(O) ２ -;-NR ８ S(O) ２ -; and -S(O) ２ NR ８ -; And, The aforementioned n and m are each independent integers between 0 and 15. The aforementioned E is, 【Chemistry 2】 or 【Transformation 3】 And, The aforementioned X ２ , X ３ and X ４ These are, independently, hydrogen; halogen group; and C. １ -C １３ Alki group; C １ -C ６ Haloalkyl; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-N R ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); Carbonara Acid group (-C(O)OH); Ester group (-C(O)OR ８ ); nitrile group (-CN); Sulfonamide group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group ( -S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ ); and The aforementioned X １ Is it present or absent, and if present, X １ is, -CR ８ R ９ -, -O- or -NR ８ - and The aforementioned Y １ , Y ２ , Y ３ and Y ４ Each of them is independently C ６ -C １０ Aryl group; C ３ - C １０ heteroaryl group; C ３ -C １０ cyclyl group; or C ３ -C １０ heterocycline It is the base; The aforementioned R ８ and R ９ Each is independently hydrogen; C １ -C ６ Alkyl alkyl group; C １ -C ６ Al Kenyl group; C １ -C ６ Alkynyl group; C ６ -C １０ Aryl group; C ３ -C １０ Heterozygous ants group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; or R ８ R ９ N, O, S, NH, C=N, C=O, -NHC( O)-, -NHC(O)NH-, -NHS(O) ２ -, or SO ２ at least one of It can contain any species, including hydrogen and C. １ -C １３ alkyl group, C ６ -C １０ Aryl group, C ３ -C １０ Among heteroaryl groups, hydroxyl groups, halide groups, and cyano groups, at least Each of them forms a 3- to 7-membered saturated ring which can be arbitrarily substituted by one type. Said C １ -C ６ Alkoxy group, C １ -C １３ Alkyl or C ３ -C １０ cyclyl group is hydrogen; hydroxyl group; halogen group; C １ -C １３ Alkyl alkyl group; C １ -C ６ Alkoxy Group; amino group (-NR ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)N R ８ R ９ ); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR ８ ); Ni Tolyl group (-CN); Urea group (-NR ８ (C=O)NR ９ -); sulfonamide group (- NHS (O) ２ -); sulfide group (-S-); sulfone group (-S(O) ２ -); phospho Lyl group (-P(O)R ８ R ９ ); C ６ -C １０ Aryl group; C ３ -C １０ Heteroaryl Base; and C ３ -C １０ Includes one or more substituents selected from the group consisting of heterocyclyl groups; fruit, Said C ６ -C １０ Aryl group, C ３ -C １０ heteroaryl group or C ３ -C １０ Hete The rosicyl group consists of hydrogen; a hydroxyl group; a halogen group; and a carbonyl group (-(C=O)R). ８ R ９ ); halogen or C ３ -C １０ C substituted or unsubstituted with heterocyclyl groups １ -C ３ a Luchyl group; halogen or C ３ -C １０ C substituted or unsubstituted with heterocyclyl groups １ -C ３ Alkoxy group; C ６ -C １０ Phenoxy; amino group (-NR ８ R ９ ); amide group (-( C=O)NR ８ R ９ ); C ６ -C １０ Aryl group; C ３ -C １０ Heteroaryl group and C ３ -C １０ comprising one or more substituents selected from the group consisting of heterocyclyl groups; Said C ３ -C １０ Heteroaryl group and C ３ -C １０ The heterocyclyl group is N, O, and It contains one or more heteroatoms selected from the group consisting of S.

2. A and B are each independently furan, benzofuran, pyrrole, indole, and cyanoacrylate. Ofen, benzothiophene, imidazole, benzimidazole, purine, pyrazole Indazole, oxazole, benzoxazole, thiazole, benzothiazole Lu, benzene, naphthalene, anthracene, pyridine, quinoline, pyrazine, quinoxali n, acridine, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine or Triazine, represented by chemical formula 1 as described in claim 1, 2,7-substituted pyrrolo[2 ,1-f[1,2,4]triazine compounds, their pharmaceutically acceptable salts, and their hydrates or its solvent.

3. A and B are each independently benzene, pyrazole, pyridine, indazole, These are pyrimidines, quinolines, or thiazoles. The aforementioned R １ , R ２ and R ３ These are, independently, hydrogen, halogen group, and C. １ -C １３ Alki C group or C ３ -C １０ The cyclyl group is represented by 2,7 ​​represented by chemical formula 1 as described in claim 1. - Substituted pyrrolo[2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable Salts, their hydrates, or their solvates.

4. The aforementioned R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen; hydroxyl group; and halogen group. ;-NHCH ３ ;-NHM3;--GENH)CH ３ ;-OCH ３ ;-OC ２ H ５ ;また Ha-OC ６ H １２ COOCH ３ ; which is the 2,7- represented by chemical formula 1 as described in claim 1. Substituted pyrrolo[2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable Salts, their hydrates, or their solvates.

5. The aforementioned compound is represented by the following chemical formula 2, 【Chemistry 4】 In the aforementioned chemical formula 2, R １ , R ２ and R ３ These are, independently, hydrogen; hydroxyl group; halogen group; and C. １ -C １３ Alkyl alkyl group; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Hete Rosicyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-NR ８ R ９ ); Ni Tro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); ester group (-C(O ) OR ８ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide Group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group (-S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ ); and A and B are each independently C ６ -C １０ Aryl group; C ３ -C １０ Cyclyl group; C ３ -C １０ heteroaryl group; or C ３ -C １０ Heterocyclyl group; R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen; hydroxyl group; halogen group; and C. １ -C １３ Alkyl alkyl group; C １ -C ６ Haloalkyl; C １ -C ６ Alkoxy group; C ３ -C １ ０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl) ; Amino group (-NR ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR ８ ); Nitori L group (-CN); sulfonamide group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group (-S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ );in can be, L ｂ is hydrogen; hydroxyl group; halogen group; C １ -C １３ Alkyl alkyl group; C １ -C ６ Al Coxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-NR ８ R ９ ); Nitro group (-N(O) ２ ); amide Group (-(C=O)NR ８ R ９ ); carboxylic acid group (-C(O)OH); ester group (-C( O) OR ８ ); nitrile group (-CN); sulfonamide group (-NHS(O) ２ R ８ );vinegar Rufid group (-SR) ８ ); or sulfone group (-S(O) ２ R ８ ); and Said Z ａ Is there, or is there not, Z ａ If Z ａ is -O-, -CO-, -COO- 、-C ｎ H ｎ＋２ -、-O(C ｎ H ｎ＋２ )-、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ ＋２ )O(C ｍ H ｍ＋２ ) -, -C ３ -C １０ cyclyl group -; or -C ３ -C １０ Hete The rosicyl group is -; The aforementioned Q ３ is, -C ｎ H ｎ＋２ -, -O(C) ｎ H ｎ＋２ )-,-(OC ２ H ４ ) n-, - (C ２ H ４ O) ｎ -、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ＋２ )CO-、-NR ８ ( C ｎ H ｎ＋２ )-、-(NR ８ C ２ H ４ )n-、-(C ２ H ４ NR ８ ) ｎ -、-(C ｎ H ｎ＋２ )NR ８ -、-(C ｎ H ｎ＋２ )O(C ｍ H ｍ＋２ )-、-(C ｎ H ｎ＋２ )O( C ｍ H ｍ＋２ ) CO-, -C ３ -C １０ cyclyl group -; or -C ３ -C １０ Heterocycline The lyl group is -; The aforementioned Q ４ It may or may not exist, and if it does exist, -C ｎ H ｎ＋２ -, -C ｎ H ｎ - or -C ｎ H ｎ－２ - and The aforementioned n and m are each independent integers between 0 and 15. The aforementioned E is, 【Transformation 5】 or 【Transformation 6】 And, The aforementioned X ２ , X ３ and X ４ These are, independently, hydrogen; halogen group; and C. １ -C １３ Alki group; C １ -C ６ Haloalkyl; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-N R ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); Carbonara Acid group (-C(O)OH); Ester group (-C(O)OR ８ ); nitrile group (-CN); Sulfonamide group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group ( -S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ ); and The aforementioned X １ Is it present or absent, and if present, X １ is, -CR ８ R ９ -, -O- or -NR ８ - and The aforementioned Y １ , Y ２ , Y ３ and Y ４ Each of them is independently C ６ -C １０ Aryl group; C ３ - C １０ heteroaryl group; C ３ -C １０ cyclyl group; or C ３ -C １０ heterocycline It is the base; The aforementioned R ８ and R ９ Each is independently hydrogen; C １ -C ６ Alkyl alkyl group; C １ -C ６ Al Kenyl group; C １ -C ６ Alkynyl group; C ６ -C １０ Aryl group; C ３ -C １０ Heterozygous ants group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; or R ８ R ９ N, O, S, NH, C=N, C=O, -NHC( O)-, -NHC(O)NH-, -NHS(O) ２ -, or SO ２ at least one of It can contain any species, including hydrogen and C. １ -C １３ alkyl group, C ６ -C １０ Aryl group, C ３ -C １０ Among heteroaryl groups, hydroxyl groups, halide groups, and cyano groups, at least Each of them forms a 3- to 7-membered saturated ring which can be arbitrarily substituted by one type. Said C １ -C ６ Alkoxy group, C １ -C １３ Alkyl or C ３ -C １０ cyclyl group is hydrogen; hydroxyl group; halogen group; C １ -C １３ Alkyl alkyl group; C １ -C ６ Alkoxy Group; amino group (-NR ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)N R ８ R ９ ); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR ８ ); Ni Tolyl group (-CN); Urea group (-NR ８ (C=O)NR ９ -); sulfonamide group (- NHS (O) ２ -); sulfide group (-S-); sulfone group (-S(O) ２ -); phospho Lyl group (-P(O)R ８ R ９ ); C ６ -C １０ Aryl group; C ３ -C １０ Heteroaryl Base; and C ３ -C １０ Includes one or more substituents selected from the group consisting of heterocyclyl groups; fruit, Said C ６ -C １０ Aryl group, C ３ -C １０ heteroaryl group or C ３ -C １０ Hete The rosicyl group consists of hydrogen; a hydroxyl group; a halogen group; and a carbonyl group (-(C=O)R). ８ R ９ ); halogen or C ３ -C １０ C substituted or unsubstituted with heterocyclyl groups １ -C ３ a Luchyl group; halogen or C ３ -C １０ C substituted or unsubstituted with heterocyclyl groups １ -C ３ Alkoxy group; C ６ -C １０ Phenoxy; amino group (-NR ８ R ９ ); amide group (-( C=O)NR ８ R ９ ); C ６ -C １０ Aryl group; C ３ -C １０ Heteroaryl group and C ３ -C １０ comprising one or more substituents selected from the group consisting of heterocyclyl groups; Said C ３ -C １０ Heteroaryl group and C ３ -C １０ The heterocyclyl group is N, O, and The chemical formula according to claim 1, comprising one or more heteroatoms selected from the group consisting of bi and S. A 2,7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by, The pharmaceutically acceptable salt thereof, its hydrate, or its solvate.

6. In the aforementioned chemical formula 2, A and B are each independently benzene, pyrazole, pyridine, indazole, These are pyrimidines, quinolines, or thiazoles. The aforementioned R １ , R ２ and R ３ These are, independently, hydrogen, halogen group, and C. １ -C １３ Alki C group or C ３ -C １０ It is a cyclyl group, The aforementioned R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen; hydroxyl group; and halogen group. ;-NHCH ３ ;-NHMs;-CO(NH)CH ３ ;-OCH ３ ;-OC ２ H ５ ; Also Ha-OC ６ H １２ COOCH ３ ; And, The aforementioned Y １ teeth, 【Transformation 7】 And, Y ａ and Y ｂ These are, independently, hydrogen; halogen group; and C. １ -C １３ Alkyl alkyl group; C １ -C ６ Haloalkyl; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-NR ８ R ９ ) ; Nitro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); carboxylic acid group (- C(O)OH); ester group (-C(O)OR ８ ); nitrile group (-CN); sulfone group Mido group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group (-S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ ); and Y ｃ and Y ｄ These are independently -O-, -CO-, -COO-, and -C ｎ H ｎ＋２ - 、-O(C ｎ H ｎ＋２ )-、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ＋２ )O(C ｍ H ｍ ＋２ ) -, -C ３ -C １０ cyclyl group -; or -C ３ -C １０ Heterocyclyl group -; can be, Y ｅ C ６ -C １０ Aryl group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterozygous ants C group; or C ３ -C １０ A heterocyclyl group; represented by chemical formula 1 as described in claim 5. The 2,7-substituted pyrrolo[2,1-f][1,2,4]triazine compound, A pharmaceutically acceptable salt, its hydrate, or its solvide.

7. In the aforementioned chemical formula 2, E １ 、E ２ 、E ３ 、E ４ 、E ５ 、E ６ 、E ７ 、E ８ 、E ９ 、E １０ 、E １１ , E １２ , E １３ , E １４ or E １５ That is, 【Transformation 8】 The 2,7-substituted pyrrolo[2,1-f][1, 2,4] Triazine compounds, pharmaceutically acceptable salts thereof, hydrates thereof or their solvates 。

8. The aforementioned compound is represented by the following chemical formula 3, 【Chemistry 9】 In the aforementioned chemical formula 3, R １ , R ２ and R ３ These are, independently, hydrogen; hydroxyl group; halogen group; and C. １ -C １３ Alkyl alkyl group; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Hete Rosicyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-NR ８ R ９ ); Ni Tro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); ester group (-C(O ) OR ８ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); sulfonamide Group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group (-S(O) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ ); and A and B are each independently C ６ -C １０ Aryl group; C ３ -C １０ Cyclyl group; C ３ -C １０ heteroaryl group; or C ３ -C １０ Heterocyclyl group; R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen; hydroxyl group; halogen group; and C. １ -C １３ Alkyl alkyl group; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclyl group; C ３ -C １ ０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-NR ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); carboxylic acid group ( -C(O)OH); ester group (-C(O)OR ８ ); nitrile group (-CN); sulfone Amide group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group (-S(O ) ２ R ８ ); or phosphoryl group (-P(O)R ８ R ９ ); and Said Z ａ or Z ｂ These may exist independently or not exist at all, Z ａ or Z ｂ but In some cases, Z ａ or Z ｂ These are independently -O-, -CO-, -COO-, and -C ｎ H ｎ＋２ -、-O(C ｎ H ｎ＋２ )-、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ＋２ )O (C ｍ H ｍ＋２ ) -, -C ３ -C １０ cyclyl group -; or -C ３ -C １０ Heterocycline It is a lu group; The aforementioned Q １ and Q ２ Each of them is independently -C ｎ H ｎ＋２ -, -O(C) ｎ H ｎ＋２ ) - -(OC ２ H ４ ) ｎ -、-(C ２ H ４ O) ｎ -、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ ＋２ )CO-、-NR ８ (C ｎ H ｎ＋２ )-、-(NR ８ C ２ H ４ ) ｎ -、-(C ２ H ４ NR ８ ) ｎ -、-(C ｎ H ｎ＋２ )NR ８ -、-(C ｎ H ｎ＋２ )O(C ｍ H ｍ＋２ )- , - (C ｎ H ｎ＋２ )O(C ｍ H ｍ＋２ ) CO-, -C ３ -C １０ Cyclyl group -; or -C ３ -C １０ It is a heterocyclyl group; The aforementioned M is -O-, -CO-, -COO-, -C ２ H ２ -, -C ｎ H ｎ＋２ -, -O( C ｎ H ｎ＋２ )-、-(C ｎ H ｎ＋２ )O-、-(C ｎ H ｎ＋２ )O(C ｍ H ｍ＋２ )- ,-NR ８ -;-NR ８ CH ２ -;-NHR ８ -;-NR ８ C(O)-;-NR ８ C(O) )O-;-C(O)NR ８ -;-NR ８ C(O)NR ８ -;-NC(O)R ８ -;-NS (O) ２ R ８ -;-S(O) ２ -;-NR ８ S(O) ２ -; and -S(O) ２ NR ８ -; And, The aforementioned E is, 【Chemistry 10】 or 【Chemistry 11】 And, The aforementioned X ２ , X ３ and X ４ These are, independently, hydrogen; halogen group; and C. １ -C １３ Alki group; C １ -C ６ Haloalkyl; C １ -C ６ Alkoxy group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; -C(O)-(C １ -C １３ Alkyl group; amino group (-N R ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)NR ８ R ９ ); Carbonara phosphoric acid group (-C(O)OH); ester group (-C(O)OR ８ ); nitrile group (-CN); Sulfonamide group (-NHS(O) ２ R ８ ); sulfide group (-SR ８ ); sulfone group ( -S(O) ２ R ８ ); or a phosphoryl group (-P(O)R ８ R ９ ); and The aforementioned X １ Is it present or absent, and if present, X １ is, -CR ８ R ９ -, -O- or -NR ８ - and The aforementioned Y １ , Y ２ , Y ３ and Y ４ Each of them is independently C ６ -C １０ Aryl group; C ３ - C １０ heteroaryl group; C ３ -C １０ cyclyl group; or C ３ -C １０ heterocycline It is the base; The aforementioned R ８ and R ９ Each is independently hydrogen; C １ -C ６ Alkyl alkyl group; C １ -C ６ Al Kenyl group; C １ -C ６ Alkynyl group; C ６ -C １０ Aryl group; C ３ -C １０ Heterozygous ants group; C ３ -C １０ Cyclyl group; C ３ -C １０ Heterocyclyl group; or R ８ R ９ N, O, S, NH, C=N, C=O, -NHC( O)-, -NHC(O)NH-, -NHS(O) ２ -, or SO ２ at least one of It can contain any species, including hydrogen and C. １ -C １３ alkyl group, C ６ -C １０ Aryl group, C ３ -C １０ Among heteroaryl groups, hydroxyl groups, halide groups, and cyano groups, at least Each of them forms a 3- to 7-membered saturated ring which can be arbitrarily substituted by one type. Said C １ -C ６ Alkoxy group, C １ -C １３ Alkyl or C ３ -C １０ cyclyl group is hydrogen; hydroxyl group; halogen group; C １ -C １３ Alkyl alkyl group; C １ -C ６ Alkoxy Group; amino group (-NR ８ R ９ ); Nitro group (-N(O) ２ ); amide group (-(C=O)N R ８ R ９ ); Carboxylic acid group (-C(O)OH); Ester group (-C(O)OR ８ ); Ni Tolyl group (-CN); Urea group (-NR ８ (C=O)NR ９ -); sulfonamide group (- NHS(O) ２ -); sulfide group (-S-); sulfone group (-S(O) ２ -); phospho Lyl group (-P(O)R ８ R ９ ); C ６ -C １０ Aryl group; C ３ -C １０ Heteroaryl Base; and C ３ -C １０ Includes one or more substituents selected from the group consisting of heterocyclyl groups; fruit, Said C ６ -C １０ Aryl group, C ３ -C １０ heteroaryl group or C ３ -C １０ Hete The rosicyl group consists of hydrogen; a hydroxyl group; a halogen group; and a carbonyl group (-(C=O)R). ８ R ９ ); halogen or C ３ -C １０ C substituted or unsubstituted with heterocyclyl groups １ -C ３ a Luchyl group; halogen or C ３ -C １０ C substituted or unsubstituted with heterocyclyl groups １ -C ３ Alkoxy group; C ６ -C １０ Phenoxy; amino group (-NR ８ R ９ ); amide group (-( C=O)NR ８ R ９ ); C ６ -C １０ Aryl group; C ３ -C １０ Heteroaryl group and C ３ -C １０ comprising one or more substituents selected from the group consisting of heterocyclyl groups; Said C ３ -C １０ Heteroaryl group and C ３ -C １０ The heterocyclyl group is N, O, and The chemical formula according to claim 1, comprising one or more heteroatoms selected from the group consisting of bi and S. A 2,7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by, The pharmaceutically acceptable salt thereof, its hydrate, or its solvate.

9. In the aforementioned chemical formula 3, A and B are each independently benzene, pyrazole, pyridine, indazole, These are pyrimidines, quinolines, or thiazoles. The aforementioned R １ , R ２ and R ３ These are, independently, hydrogen, halogen group, and C. １ -C １３ Alki C group or C ３ -C １０ It is a cyclyl group, The aforementioned R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen; hydroxyl group; and halogen group. ;-NHCH ３ ;-NHM3;--GENH)CH ３ ;-OCH ３ ;-OC ２ H ５ ;また Ha-OC ６ H １２ COOCH ３ ; which is the 2,7- represented by chemical formula 1 as described in claim 8. Substituted pyrrolo[2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable Salts, their hydrates, or their solvates.

10. In the aforementioned chemical formula 3, E １ 、E ２ 、E ３ 、E ４ 、E ５ 、E ６ 、E ７ 、E ８ 、E ９ 、E １０ 、E １１ , E １２ , E １３ , E １４ or E １５ That is, 【Chemistry 12】 The 2,7-substituted pyrrolo[2,1-f][1, 2,4] Triazine compounds, pharmaceutically acceptable salts thereof, hydrates thereof or their solvates 。

11. The aforementioned compound is characterized by being selected from the group consisting of compound numbers 1 to 126 listed below. The 2,7-substituted pyrrolo[2,1-f][] represented by chemical formula 1 as described in claim 1. [1,2,4] Triazine compounds, pharmaceutically acceptable salts thereof, hydrates thereof, or solvents thereof monster: (Compound number 1) (2 １ Z, 4 ４ E)-4 １ H-11-oxa-3,8-diaza-2( 7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola- 1(1,4)-benzenecycloundecaffeine; (Compound number 2) ((2 １ Z, 4 ４ E)-8-methyl-4 １ H-11-oxa-3,8 -diaza-2(7,2)-pyroro[2,1-f][1,2,4]triazine-4(4,1 )-pyrazola-1(1,4)-benzenecycloundecaffeine; (Compound number 3) 1-((2 １ Z, 4 ４ E)-4 １ H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffei-8-yl)ethane-1-one; (Compound number 4) 1-((2 １ Z, 4 ４ E)-4 １ H-11-oxa-3,8-diaza -2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1)-pyra Zola-1(1,4)-benzenecycloundecaffeinate-8-yl)butan-1-one; (Compound number 5) ((2 １ Z, 4 ４ E)-4 １ H-11-oxa-3,8-diaza-2 (7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola -1(1,4)-benzenecycloundecaffei-8-yl)(4-chlorophenyl) Metanon; (Compound number 6) (2 １ Z, 4 ４ E)-N-cyclohexyl-4 １ H-11-Oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-carboxy Amido; (Compound number 7) (2 １ Z, 4 ４ E)-N-(3-methoxyphenyl)-4 １ H-11 -Oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8- Carboxamide; (Compound number 8) (2 １ Z, 4 ４ E)-N-ethyl-4 １ H-11-oxa-3,8- diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4,1) -Pyrazola-1(1,4)-benzenecycloundecaffeine-8-carboxamide; (Compound number 9) (2 １ Z, 4 ４ E)-8-(methylsulfonyl)-4 １ H-11-O Xa-3,8-diaza-2(7,2)-pyrrolo[2,1-f][1,2,4]triazine -4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine; (Compound number 10) (2 １ Z, 4 ４ E)-8-((3,4-difluorophenyl)sulfur Honil) - 4 １ H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f [1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclo Undecaffeinated; (Compound number 11) (2 １ Z, 4 ４ E)-8-(phenylsulfonyl)-4 １ H-11 -Oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine; (Compound number 12) (2 １ Z, 4 ４ E)-8-(cyclopropylsulfonyl)-4 １ H -11-oxa-3,8-diaza-2(7,2)-pyroro[2,1-f][1,2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine ； (Compound number 13) (2 １ Z, 4 ４ E)-8-(propylsulfonyl)-4 １ H-11 -Oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]tria Zin-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine; (Compound number 14) (2 １ Z, 4 ４ E)-8-((5-chlorothiophen-2-yl) Sulfonyl)-4 １ H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1 -f][1,2,4]triazine-4(4,1)-pyrazola-1(1,4)-benzenes Undecaffeinated; (Compound number 15) (2 １ Z, 4 ４ E)-8-(cyclohexylsulfonyl)-4 １ H -11-oxa-3,8-diaza-2(7,2)-pyroro[2,1-f][1,2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine ； (Compound No. 16) (Z)-5-oxa-3,9,15-triazine-2(7,2)- Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclo Pentadecapan-10-on; (Compound number 17) (1 ４ Z, 2 １ Z)-1 １ H-5-oxa-3,9-diaza-2( 7,2)-pyrolo[2,1-f][1,2,4]triazine-1(4,1)-pyrazola- 4(1,4)-benzenecyclohexadecapan-10-one; (Compound number 18) (1 ４ Z, 2 １ Z, 4 ４ E)-1 １ H, 4 １ H-3,8-diather 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-1,4(4,1)-di Pyrazolacyclopentadecapan-9-one; (Compound number 19) (1 ４ Z, 2 １ Z)-1 １ H-3-Aza-2(7,2)-Pirolo[ 2,1-f][1,2,4]triazine-5(1,4)-piperazine-1(4,1)-pi Lazola-4(1,4)-benzenecyclododecapan-9-one; (Compound No. 20) (Z)-13-fluoro-5,17-dioxa-3,9-diaza- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-di Benzenecycloheptadecapan-10-one; (Compound number 21) (2 １ Z, 4 ４ E)-13-Fluoro-4 １ H-16-oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazola-1(1,4)-benzenecyclohexadecapan-9-one; (Compound No. 22) (Z)-1 ３ -Fluoro-13-oxa-3-aza-2(7,2) -Pyrrolo[2,1-f][1,2,4]triazine-5(1,4)-piperazine-1,4 (1,4)-dibenzenecyclotridecapan-6-one; (Compound No. 23) (Z)-17-oxa-3,9-diaza-2(7,2)-pyrrolo[ 2,1-f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4) -Dibenzenecycloheptadecapan-10-one; (Compound No. 24) (Z)-13-oxa-3-aza-2(7,2)-pyrrolo[2,1 -f][1,2,4]triazine-5(1,4)-piperazine-1,4(1,4)-gibe Nzencyclotridecapan-6-one; (Compound number 25) (2 １ Z, 4 ４ E)-4 １ H-11-oxa-3-aza-2(7, 2) -Pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecapan-6-one; (Compound number 26) (2 １ Z, 4 ４ E)-4 １ H-15-oxa-3,9-diaza-2 (7,2)-pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidi n-4(4,1)-pyrazola-1(1,4)-benzenecyclopentadecapane-10-o hmm; (Compound number 27) (2 １ Z, 4 ４ E)-4 １ H-17-oxa-3,9-diaza-2 (7,2)-pyrrolo[2,1-f][1,2,4]triazine-5(4,1)-piperidi n-4(4,1)-pyrazola-1(1,4)-benzenecycloheptadecapan-10-o hmm; (Compound No. 28) (Z)-5,12,15-trioxa-3,9-diaza-2(7, 2) -Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzene Cyclopentadecapane-10-one; (Compound No. 29) (Z)-5,17-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclo Ptadecapan-10-on; (Compound No. 30) (Z)-5,12-dioxa-3,9-diaza-2(7,2)-pi lol[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclod Decaffeinated; (Compound No. 31) (Z)-1-(5,12-dioxa-3,9-diaza-2(7,2 )-pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenes Clododecapan-9-yl)propan-1-one; (Compound No. 32) (Z)-5,12-dioxa-3,9-diaza-2(7,2)-pi lol[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclod Decapan-9-yl(4-chlorophenyl)methanone; (Compound number 33) (2 １ Z,7Z)-5,10-dioxa-3-aza-2(7,2) -Pyrrolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenesic Rodekapan - 7-yen; (Compound No. 34) (Z)-4 ２ -Methoxy-5,12,15-trioxa-3,9- Diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-1,4(1, 4) -Dibenzenecyclopentadecapan-10-one; (Compound number 35) (2 １ Z, 4 ４ E)-4 １ H-11,14-dioxa-3,8-di Aza-2(7,2)-pirolo[2,1-f][1,2,4]triazine-4(4,1)- Pyrazola-1(1,4)-benzenecyclotetradekapan-9-one; (Compound number 36) (2 １ Z, 4 ４ E)-4 １ H-14-oxa-3,8-diaza-2 (7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola -1(1,4)-benzenecyclotetradecapan-9-one; (Compound number 37) (2 １ Z, 4 ４ E)-4 １ H-16-oxa-3,8-diaza-2 (7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazola -1(1,4)-benzenecyclohexadecapan-9-one; (Compound No. 38) (Z)-5,15-dioxa-3,9-diaza-2(7,2)-pi Rolo[2,1-f][1,2,4]triazine-1,4(1,4)-dibenzenecyclopept Ntadekapan-10-on; (Compound number 39) N-(3-(2-((4-(4-(5-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)pent (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 40) N-(3-(2-((4-(4-(3-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)pro Pyr)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 41) N-(3-(2-((4-(4-(7-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)hep (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 42) N-(3-(2-((4-(4-(11-((2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy) (ndecyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2, 4) Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 43) N-(3-(2-((4-(4-(2-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)eth (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Liazin-7-yl)phenyl)methanesulfonamide; (Compound number 44) N-(3-(2-((4-(4-(4-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)buty (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Liazin-7-yl)phenyl)methanesulfonamide; (Compound number 45) N-(3-(2-((4-(4-(6-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)hex Sil)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 46) N-(3-(2-((4-(4-(8-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy) oc (Tyl)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4] Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 47) N-(3-(2-((4-(4-(8-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)noni (Lu)piperidine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]t Liazin-7-yl)phenyl)methanesulfonamide; (Compound number 48) N-(3-(2-((4-(4-(2-(2-((1,3-dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 49) N-(3-(2-((4-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindoline-4-yl)oxy)hexyl) Piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide; (Compound number 50) N-(3-(2-((4-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]tri Zin-7-yl)phenyl)methanesulfonamide; (Compound number 51) N-(3-(2-((4-(4-((1-(2-(2,6-dioxy Sopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl )piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide; (Compound number 52) N-(3-(2-((1-(1-(9-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperidine-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 53) 3-(2-((1-(1-(9-((2-(2,6-dioxopipette Lysine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl)piper (Zin-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)-N-methylbenzamide; (Compound number 54) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-phenylpyrrolo[2,1-f][1,2,4]triazine-2-yl (amino)-1H-pyrazole-1-yl)piperidine-1-yl)nonyl)oxy) Soindrin-1,3-dione; (Compound number 55) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-(1-methyl-1H-pyrazole-4-yl)pyrrolo[2,1-f] [1,2,4] Triazine-2-yl)amino)-1H-pyrazole-1-yl)piper Zin-1-yl)nonyl)oxy)isoindoline-1,3-dione; (Compound number 56) 4-((9-(4-(4-((7-(1H-indole-6-yl ) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)-1H-pyrazo (I-1-yl)piperidine-1-yl)nonyl)oxy)-2-(2,6-dioxop Peridine-3-yl)isoindoline-1,3-dione; (Compound number 57) 2-(2,6-dioxopiperidine-3-yl)-4-((9-( 4-(4-((7-(4-hydroxyphenyl)pyrrolo[2,1-f][1,2,4]to (Riadin-2-yl)amino)-1H-pyrazole-1-yl)piperidine-1-yl) Nonyl(oxy)isoindoline-1,3-dione; (Compound number 58) Methyl-7-(4-(2-((1-(1-(9-((2-(2,6 (-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-4-yl)Oxy (C)nonyl)piperidine-4-yl)-1H-pyrazole-4-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl(phenoxy)heptanate; (Compound number 59) N-(3-(2-((4-(4-(5-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)pent (Tyl)piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 60) N-(3-(2-((4-(4-(3-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)propyl )piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 ,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 61) N-(3-(2-((4-(4-(7-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl )piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 ,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 62) N-(3-(2-((4-(4-(11-((2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)unde Sil)piperazin-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f] [1,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 63) N-(3-(2-((4-(4-(2-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)ethyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 64) N-(3-(2-((4-(4-(4-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 65) N-(3-(2-((4-(4-(6-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl )piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 ,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 66) N-(3-(2-((4-(4-(8-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)octyl )piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1 ,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 67) N-(3-(2-((4-(4-(9-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 68) N-(3-(2-((4-(4-(2-(2-((1,3-dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazine-1-yl)-2-methoxyphenyl)amino(pyrrolo[2, 1-f[1,2,4]triazine-7-yl)phenyl)methanesulfonamide; (Compound number 69) N-(3-(2-((4-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindoline-4-yl)oxy)hexyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 70) N-(3-(2-((4-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)-2-methoxyphenyl)amino)pyrrolo[2,1-f][1, 2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 71) N-(3-(2-((6-(4-(5-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)pentyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 72) N-(3-(2-((6-(4-(3-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)propyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 73) N-(3-(2-((6-(4-(7-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)heptyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 74) N-(3-(2-((6-(4-(11-((2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)unde Sil)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1 ,2,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 75) N-(3-(2-((6-(4-(2-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)ethyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4) Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 76) N-(3-(2-((6-(4-(4-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)butyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4) Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 77) N-(3-(2-((6-(4-(6-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)hexyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 78) N-(3-(2-((6-(4-(8-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindorin-4-yl)oxy)octyl )piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2 ,4] Triazine-7-yl)phenyl)methanesulfonamide; (Compound number 79) N-(3-(2-((6-(4-(9-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoindoline-4-yl)oxy)nonyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4) Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 80) N-(3-(2-((6-(4-(2-(2-((1,3-dioxy So-2-(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)eth Xy(ethyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1- f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide; (Compound number 81) N-(3-(2-((6-(4-(6-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindoline-4-yl)oxy)hexyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4) Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 82) N-(3-(2-((6-(4-(8-((1,3-dioxo-2 -(2-oxopiperidine-3-yl)isoindorin-4-yl)oxy)octyl) Piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[2,1-f][1,2, 4) Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 83) (2S,4R)-1-((S)-3,3-dimethyl-2-(2-( 2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1- f) [1,2,4]triazine-2-yl)amino)phenyl)piperazine-1-yl) Ethoxyacetaminobutanoyl-4-hydroxy-N-(4-(4-methylthia) Zole-5-yl)benzyl)pyrroridine-2-carboxamide; (Compound number 84) (2S,4R)-1-((S)-3,3-dimethyl-2-(3-( 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2 ,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1- (Iyl)ethoxy)ethoxy)propanamide)butanoyl)-4-hydroxy-N-(4 -(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide; (Compound number 85) (2S,4R)-1-((S)-3,3-dimethyl-2-(3-( 2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[2 ,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1- (yl)ethoxy)ethoxy)propanamide)butanoyl)-4-hydroxy-N-(( S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine- 2-Carboxamide; (Compound number 86) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(4-(trifluoromethoxy)phenyl)pyrrolo[2,1-f][ 1,2,4] Triazine-2-yl)amino)pyridine-2-yl)piperazine-1-yl) Pentyl oxyisoindoline-1,3-dione; (Compound number 87) 4-((5-(4-(5-((7-(3,5-difluorophenyl ) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2- Iyl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine) -3-yl)isoindoline-1,3-dione; (Compound number 88) 4-((5-(4-(5-((7-(2-aminopyridine-5-i (Lu) Pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine-2 -yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidine (n-3-yl)isoindoline-1,3-dione; (Compound number 89) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(Quinoline-3-yl)pirolo[2,1-f][1,2,4]tri (Din-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy C) Isoindoline-1,3-dione; (Compound number 90) tert-butyl 4-(3-(2-((6-(4-(5-((2- (2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-4-yl (Lu)oxy)pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)benzyl)piperazine-1-carb nitrate; (Compound number 91) (E)-2-(2,6-dioxopiperidine-3-yl)-4-( (5-(4-(5-((7-styrylpyrrolo[2,1-f][1,2,4]triazine- 2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy) Soindrin-1,3-dione; (Compound number 92) tert-butyl 4-(4-(2-((6-(4-(5-((2- (2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-4-yl (Lu)oxy)pentyl)piperazine-1-yl)pyridine-3-yl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)-1H-pyrazole-1-yl) Peridine-1-carboxylate salt; (Compound number 93) 4-((5-(4-(5-((7-(4-(dimethylamino)phen Nyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)pyridine- 2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxopiperazine) (Zin-3-yl)isoindoline-1,3-dione; (Compound number 94) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(pyridine-4-yl)pyrrolo[2,1-f][1,2,4]tri (Din-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl)oxy C) Isoindoline-1,3-dione; (Compound number 95) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(thiazole-5-yl)pyrrolo[2,1-f][1,2,4]to (Riadin-2-yl)amino)pyridine-2-yl)piperazine-1-yl)pentyl) Oxy)isoindoline-1,3-dione; (Compound number 96) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Lu-5-yl)pyrolo[2,1-f][1,2,4]triazine-2-yl)amino)pi Lysine-2-yl)piperazine-1-yl)pentyl)oxy)isoindoline-1,3 - Zeon; (Compound number 97) 4-((5-(4-(5-((7-((3,5-difluoropheny (Lu) Ethinyl) Pyrrolo[2,1-f][1,2,4] Triazine-2-yl) Amino) P Lysine-2-yl)piperazine-1-yl)pentyl)oxy)-2-(2,6-dioxy) Sopiperidine-3-yl)isoindoline-1,3-dione; (Compound number 98) 2-(2,6-dioxopiperidine-3-yl)-4-((5-( 4-(5-((7-((3-methoxyphenyl)ethynyl)pyrrolo[2,1-f][1, 2,4] Triazine-2-yl)amino)aminopyridine-2-yl)piperazine-1- Il)pentyl)oxy)isoindoline-1,3-dione; (Compound number 99) N-(3-(2-((4-(4-(2-(2-(3-(4-((4 -(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo Isoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)- 3-Oxopropoxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino) Pyrrolo[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfone Amido; (Compound No. 100) N-(3-(4-(3-(2,4-dihydroxy-5-isopropyl Pyrphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)pheno Xy(propyl)-3-(2-(2-(4-(4-((7-(3-(methanesulfone ammonium (d)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)f Ethoxy)piperazine-1-yl)ethoxy)propanamide; (Compound number 101) N-(2-((3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl )Phenoxy)propyl)amino)-2-oxoethyl)-3-(2-(2-(4-(4 - ((7-(3-(methanesulfonamide)phenyl)pyrrolo[2,1-f][1,2, 4) Triazine-2-yl)amino)phenyl)piperazine-1-yl)ethoxy)eth Xy)propanamide; (Compound number 102) N-(3-(2-((4-(4-(2-(2-(3-(4-(4 -(3-(2,4-dihydroxy-5-isophenylpropyl)-5-hydroxy-4H -1,2,4-triazole-4-yl)benzyl)piperazine-1-yl)-3-oxy Sopropoxy)ethoxy)ethyl)piperazine-1-yl)phenyl)amino)pyrrolo[ 2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonamide; (Compound number 103) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydrox C-4H-1,2,4-triazole-4-yl)benzyl)piperazine-1-yl) (Tyl)piperidine-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazine -1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7- Iyl(phenyl)methanesulfonamide; (Compound number 104) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindorin-5-yl) Methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)piperazin (1-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7 -yl)phenyl)methanesulfonamide; (Compound number 105) N-(3-(2-((4-(4-(2-(2-(3-(4-(( 4-((2-(2,4-dihydroxy-5-isopropylbenzoic acid)isoindoline-5 -yl)methyl)piperazine-1-yl)methyl)piperidine-1-yl)-3-oxo Propoxy)ethoxy)ethyl)piperazine-1)yl)phenyl)amino)pyrrolo[2 ,1-f[1,2,4]triazine-7-yl)phenyl)methanesulfonamide; (Compound number 106) 2-amino-4-(2,4-dichloro-5-(2-(4-(3- (2-(2-(4-(4-((7-(3-(methanesulfonamide)phenyl)pyrrolo[ 2,1-f][1,2,4]triazine-2-yl)amino)phenyl)piperazine-1 -yl)ethoxy)ethoxy)propanoyl)piperazine-1-yl)ethoxy)pheni (Lu)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide; (Compound number 107) N-(3-(2-((4-(4-(4-((4-((2-(2, 4-Dihydroxy-5-isopropylbenzoic acid (isoindorin-5-yl)methyl) Piperazine-1-yl)methyl)benzoate)piperazine-1-yl)phenyl)amino)pi Roro[2,1-f][1,2,4]triazine-7-yl)phenyl)methanesulfonate Mido; (Compound number 108) N-(3-(2-((4-(4-(1-((2-(2,4-dihy Droxy-5-isopropylbenzoate)isoindorin-5-yl)methyl)piperidine -4-carbonyl)piperazine-1-yl)phenyl)amino)pyrrolo[2,1-f][ 1,2,4] Triazine-7-yl(phenyl)methanesulfonamide; (Compound number 109) 4-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa-3, 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-benzenecycloundecaffeinate-8-yl)ethoxy )-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; (Compound number 110) 4-(3-((2 １ Z, 4 ４ E)-4 １ H-11-oxa-3, 8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4, 1)-Pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl)propoxy C)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione ； (Compound number 111) 4-(2-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa -3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-2-(2-oxopiperidine-3-yl)isoindoline-1,3 - Zeon; (Compound number 112) 4-((6-((2 １ Z, 4 ４ E)-4 １ H-11-Oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl)hex Sil)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1, 3 - Zeon; (Compound number 113) 4-((8-((2 １ Z, 4 ４ E)-4 １ H-11-Oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl) (Cyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1, 3 - Zeon; (Compound number 114) 4-((8-((2 １ Z, 4 ４ E)-4 １ H-11-Oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazole-1(1,4)-benzenecycloundecaffeine-8-yl) (Tyl)oxy)-2-(2-oxopiperidine-3-yl)isoindoline-1,3-di on; (Compound number 115) 4-((11-((2 １ Z, 4 ４ E)-4 １ H-11-Oxa- 3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4( 4,1)-Pyrazole-1(1,4)-Benzenecycloundecaffeine-8-yl) (ndecyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline- 1.3-Zeon; (Compound number 116) 4-((9-((2 １ Z, 4 ４ E)-4 １ H-11-Oxa-3 ,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4(4 ,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl)nonyl )oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3- Dioneundecaffeine; (Compound No. 117) 5-(4-((1-(3-(2-(2-((2 １ Z, 4 ４ E) - 4 １ H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2 ,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecycloundecaf (Chen-8-yl)ethoxy)ethoxy)propanoyl)piperidine-4-yl)methyl )piperazine-1-yl)-2-(2,6-dioxopiperidine-3-yl)-6-full Oroisoindoline-1,3-dione; (Compound number 118) 3-(2-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa -3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-N-(3-(4-(3-(2,4-dihydroxy-5-isopropyl (Phenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)phenoxy C) Propyl) Propanamide; (Compound number 119) 3-(2-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa -3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazole-1(1,4)-benzenecycloundecaffeinate-8-yl) Ethoxy)Ethoxy)-N-(2-((3-(4-(3-(2,4-dihydroxy-5- Isopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl ) Phenoxypropyl amino-2-oxoethyl propanamide; (Compound number 120) 3-(2-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa -3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropyl) (Phenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl)benzyl )piperazine-1-yl)propan-1-one; (Compound number 121) 3-(2-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa -3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((4-(4-(3-(2,4-dihydroxy-5-I (Sopropylphenyl)-5-hydroxy-4H-1,2,4-triazole-4-yl) Benzyl piperazine-1-yl methyl piperidine-1-yl propan-1-one ； (Compound number 122) 3-(2-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa -3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((2-(2,4-dihydroxy-5-isopropylbe Isoindoline-5-yl)methylpiperazine-1-yl)propane-1- on; (Compound number 123) 3-(2-(2-((2 １ Z, 4 ４ E)-4 １ H-11-oxa -3,8-diaza-2(7,2)-pyrolo[2,1-f][1,2,4]triazine-4 (4,1)-pyrazola-1(1,4)-benzenecycloundecaffeine-8-yl) Toxy)ethoxy)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropyl) Ropilbenzoyl isoindolin-5-yl methyl piperazine-1-yl methyl )piperidine-1-yl)propan-1-one; (Compound No. 124) 4-(5-(2-(4-(3-(2-(2-((2 １ Z, 4 ４ E )-4 １ H-11-oxa-3,8-diaza-2(7,2)-pyrolo[2,1-f][1 [2,4] Triazine-4(4,1)-pyrazola-1(1,4)-benzenecyclounden Caffeine-8-yl)ethoxy)ethoxy)propanoyl)piperazine-1-yl) Toxy)-2,4-dichlorophenyl)-2-amino-N-ethylthieno[2,3-d] Pyrimidine-6-carboxamide; (Compound number 125) (2 １ Z, 4 ４ E)-4 １ H-11-oxa-3,8-diather- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazo Ra-1(1,4)-benzenecycloundecaffeine-8-yl)(4-((4-((2 - (2,4-dihydroxy-5-isopropylbenzoyl)isoindorin-5-yl) Methyl)piperazine-1-yl)methyl)phenyl)methanone; and (Compound number 126) (2 １ Z, 4 ４ E)-4 １ H-11-oxa-3,8-diather- 2(7,2)-pyrrolo[2,1-f][1,2,4]triazine-4(4,1)-pyrazo La-1(1,4)-benzenecycloundecaffeine-8-yl)(1-((2-(2, 4-Dihydroxy-5-isopropylbenzoic acid (isoindorin-5-yl)methyl) Peridine-4-yl)methanone.

12. The aforementioned pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, and glycosides. Malic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, Deulic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxy Maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, Selected from the group consisting of tansulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. A 2,7-substituted substance represented by chemical formula 1 according to claim 1, which is an inorganic acid or an organic acid salt. Pyrrolo[2,1-f][1,2,4]triazine compounds, their pharmaceutically acceptable salts, The hydrate or its solvate.

13. The compound described in any one of claims 1 to 12 is included as an active ingredient. A pharmaceutical composition for the prevention, reduction, or treatment of cancer.

14. The aforementioned cancer is a disease induced by abnormal cell growth due to protein kinase activity. The pharmaceutical composition for the prevention, reduction, or treatment of cancer as described in claim 13.

15. The aforementioned compound exhibits an inhibitory activity of 80% or more against protein kinases at a concentration of 1 μM. A pharmaceutical composition for the prevention, reduction, or treatment of cancer as described in item 13.

16. The aforementioned protein kinases are ABL1, ABL2, ALK, ARK5, and Aurora. A, Aurora B, Aurora C, AXL, BLK, BMX, BRK, c-Ki t, c-MER, c-Src, CAMK2a, CAMK2d, CDK16, CDK17, CDK18, CDK2 / cyclin A, CDK2 / cyclin O, CDK4 / c cyclin D1, CDK4 / cyclin D2, CDK4 / cyclin D3, C DK6 / cyclin D1, CDK6 / cyclin D3, CDK7 / cyclin H, CDK9 / cyclin K, CDK9 / cyclin T1, CDK9 / cyc lin T2, CK2a, CK2a2, CLK1, CLK2, CLK4, DAPK1, D APK2, DDR1, DDR2, DRAK1, DYRK1 / DYRK1A, DYRK1B , DYRK3, EPHA1, EPHA2, EPHA4, EPHA5, EPHA6, EPH A7, EPHB1, EPHB2, ERBB4 / HER4, ERK7 / MAPK15, ER N2 / IRE2, FAK / PTK2, FER, FES / FPS, FGFR1, FGFR2 , FGFR3, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GLK / MAP4K3, GSK3a, HIPK2, HIPK3, HIPK4, HPK1 / MAP4K1, IGF1R, IKKe / IKBKE , IR, IRAK1, IRR / INSRR, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LCK, LIMK 1, LIMK2, LRRK2, LYN, LYN B, MAK, MARK1, MARK2 / PAR-1Ba, MARK3, MARK4, MAST3, MEKK2, MELK, MLC K2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / M AP3K11, MUSK, MYLK4, NEK1, NEK2, NEK5, NEK9, p7 0S6K / RPS6KB1, PAK4, PAK5, PAK6, PDGFRa, PDGFR b, PHKg1, PHKg2, PKAcb, PKCa, PKCb2, PKCg, PKCm u / PRKD1, PKCnu / PRKD3, PKD2 / PRKD2, PKN1 / PRK1 , PLK4 / SAK, PRKX, PYK2, RET, ROS / ROS1, RSK2, RS K3, RSK4, SIK1, SIK2, SLK / STK2, SNARK / NUAK2, S TK16, STK22D / TSSK1, STK33, STK38 / NDR1, STK38 L / NDR2, STK39 / STLK3, SYK, TBK1, TEC, TIE2 / TEK , TLK2, TNK1, TRKA, TRKB, TRKC, TYK2, TYRO3 / SKY , ULK1, ULK2, ULK3, WEE1, YES / YES1, YSK4 / MAP3K The cancer prognosis according to claim 15, wherein one or more of 19 and ZIPK / DAPK3 Pharmaceutical compositions for prevention, reduction, or treatment.

17. The protein kinase is one of CDK, NEK, Wee1, and GCN2. The above is the pharmaceutical composition for the prevention, reduction, or treatment of cancer as described in claim 15.

18. The aforementioned diseases include stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, and breast cancer. sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer , sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, myelodysplastic syndrome, etc. A group consisting of blood cancers, lymphomas such as Hodgkin's disease and non-Hodgkin's lymphoma, and fibroadenomas. A pharmaceutical composition for the prevention, reduction, or treatment of cancer according to claim 14, which is a disease selected from the above.

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