RU2820445C2 - Jak inhibitor compound and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula G, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein X₁, X₂, X₃, R₂, R₁₃, L are defined in the claims, which are JAK inhibitors. Also disclosed are pharmaceutical compositions of the compounds and use thereof in preparing a medicinal agent.

EFFECT: treating and/or preventing a JAK-mediated disease or disorder.

35 cl, 8 dwg, 60 ex

Description

Field of technology

[0001] The present disclosure relates to a class of novel compounds with pharmacological activity that can be used to inhibit Janus kinase (JAK). The present disclosure also relates to a composition containing the compound, and to the use of the compound and composition in the preparation of a medicament for the treatment and/or prevention of JAK-related diseases or disorders.

State of the art

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific sites in proteins and are broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activities caused by mutations, overexpression or misregulation, abnormal regulation or dysregulation, and over or underproduction of growth factors or cytokines are implicated in many diseases, including, but not limited to, cancer, cardiovascular disease, allergies, bronchial asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders (such as Alzheimer's disease). Inappropriate kinase activity triggers a range of biological cellular responses associated with cell growth, cell differentiation, function, cell survival, apoptosis and cell motility that are associated with the above diseases and other related diseases. As a consequence, protein kinases have become an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular tyrosine protein kinases plays an important role in cytokine signal transduction (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253).

[0003] Since the first JAK inhibitor was discovered in the early 1990s, the development of JAK inhibitors has stalled for almost 30 years. JAK is a family of intracellular non-receptor tyrosine kinases that plays an important role in the cytokine receptor signal transduction pathway through interaction with signaling protein and activator of transcription (STAT). The JAK/STAT signal transduction pathway is involved in many important biological processes, such as cell proliferation, differentiation, apoptosis, and immune regulation. Compared with other signal transmission pathways, the transmission process in this signal transmission pathway is relatively simple. Mainly, it consists of three components, namely, tyrosine kinase-associated receptor, JAK tyrosine kinase, signaling protein and STAT transcriptional activator.

[0004] Many cytokines and growth factors signal through the JAK-STAT signaling pathway, including interleukins (such as interleukins IL-2 to IL-7, IL-9, IL-10, IL-15, IL -21, etc.), GM-CSF (granulocyte-macrophage colony-stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PRL (prolactin), EPO (erythropoietin), TPO (thrombopoietin), PDGF ( platelet factors) and interferons (including IFN-α, IFN-β, IFN-γ, etc.) and so on. These cytokines and growth factors have corresponding receptors on the cell membrane. A common feature of these receptors is that the receptor itself does not have kinase activity, but its intracellular segment has a binding site for the JAK tyrosine kinase. After the receptor binds to the ligand, tyrosine residues of various target proteins are phosphorylated through activation of JAK, which binds to the receptor to carry out signal transduction from the extracellular space into the cell.

[0005] JAK is a cytoplasmic tyrosine kinase that transmits cytokine signals from membrane receptors to STAT transcription factors. As mentioned above, JAK is an abbreviation for Janus kinase in English. In Roman mythology, Janus is a two-faced deity responsible for the beginning and the end. The reason it is called Janus kinase is that JAK can phosphorylate the cytokine receptors it binds to and can also phosphorylate several signaling molecules containing specific SH2 domains. The JAK protein family includes 4 members: JAK1, JAK2, JAK3 and TYK2. They have 7 homologous JAK (JH) domains in a structure in which the JH1 domain is a kinase domain that has the function of encoding protein kinases; the JH2 domain is a “pseudo” kinase domain that regulates JH1 activity; and JH3-JH7 constitute a four-in-one domain that regulates the binding of JAK proteins to receptors.

[0006] STAT is a type of cytoplasmic protein that can bind DNA at the regulatory region of target genes and is a downstream substrate for JAK in the signal transduction cascade. Seven members of the STAT family have been discovered, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. The STAT protein can be divided into the following functional segments in a structure including an N-terminal conserved sequence, a DNA binding region, an SH3 domain, an SH2 domain, and a C-terminal transcription activating region. Of these, the segment that is most conserved in sequence and most important in function is the SH2 domain, which has the same core sequence “GTFLLRFSS” as the SH2 domain of the Src tyrosine kinase.

[0007] The JAK-STAT signal transduction pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Currently, research related to innovation in disease treatment and drug development primarily focuses on inflammatory diseases and neoplastic diseases, with inflammatory diseases predominantly including rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis and Crohn's disease; and neoplastic diseases predominantly include myelofibrosis, polycythemia vera and primary platelet hyperplasia. In addition, mutations in the JAK molecule itself can also cause acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ductal breast carcinoma and non-small cell lung cancer (NSCLC), polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic myeloid leukemia (CML), etc.

[0008] JAK is a very important drug target. JAK inhibitors developed for this target are primarily used for therapeutic drug screening for blood diseases, tumors, rheumatoid arthritis and psoriasis. JAK-1, JAK-2 and TYK-2 are expressed in cells of various tissues in the human body. JAK-3 is mainly expressed in various cells of hematopoietic tissue, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes. Studies have shown that JAK2 inhibitors are appropriate in myeloproliferative diseases (Santos et al., Blood, 2010, 115:1131; Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16:129; Atallah E. and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9:663), and JAK3 inhibitors are suitable as immunosuppressive agents (as for example in US patent No. 6313129; Borie et al., Curr. Opin. Investigational Drugs, 2003 , 4:1297).

[0009] Currently, JAK inhibitors approved by the FDA and EMA include tofacitinib, ruxolitinib and oclacitinib. JAK inhibitors in mid- to late-stage clinical trials include filgotinib, peficitinib, and so on.

[0010] Tofacitinib, a JAK3 inhibitor, was developed by Pfizer and approved by the FDA in November 2012 for the treatment of moderate to severe rheumatoid arthritis (RA) due to insufficient response to methotrexate or intolerance to methotrexate in adult patients. It is the first oral JAK inhibitor approved for the treatment of RA. Thereafter, it was approved by the Japanese PMDA (Pharmaceuticals and Medical Devices Agency) for registration in March 2013 under the trade name Xeljanz. On March 16, 2017, Pfizer China announced that the CFDA (China Food and Drug Administration) has formally approved Pfizer's application to market an oral JAK inhibitor. The drug was reported to be approved for the treatment of adult patients with moderate to severe rheumatoid arthritis who have an insufficient response to methotrexate or are intolerant to methotrexate. Currently, tofacitinib is close to approval for indications such as psoriasis, ulcerative colitis, juvenile idiopathic arthritis; and clinical trials for indications such as Crohn's disease and alopecia areata have also entered mid-to-late stages. The main side effects of tofacitinib are a serious incidence of infectious diseases and increased levels of low-density lipoprotein. The most common adverse effects are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat, and nasopharyngitis. Additionally, tofacitinib may cause side effects such as anemia and neutropenia in clinical studies.

[0011] Ruxolitinib, a JAK1 and JAK2 inhibitor, was jointly developed by Incyte and Novartis and approved by the US FDA in November 2011. It is also the first approved drug specifically for the treatment of myelofibrosis. It was approved by the EMA in August 2012 and was approved by the Japanese PMDA for registration in July 2014. This drug is marketed by Incyte in the United States under the trade name Jakafi; and it is marketed by Novartis in Europe and Japan under the trade name Jakavi. Ruxolitinib is undergoing a number of mid- and late-stage clinical trials, with indications including a range of cancers, GVHD (rejection disease), alopecia areata, allergic dermatitis, rheumatoid arthritis, vitiligo, psoriasis, etc. The most common hematologic adverse effects with ruxolitinib, with a prevalence >20%, are low platelet counts and anemia. The most common nonhematologic adverse effects with a prevalence >10% are ecchymosis, dizziness, and headache.

[0012] Olatinib, approved by the US FDA in 2013, is used to control pruritus and atopic dermatitis caused by allergic dermatitis in dogs. Olatinib is a new type of inhibitor of JAK- and JAK1-dependent cytokines. Olatinib is not only a very effective JAK1 inhibitor, but can also inhibit the functioning of JAK1-dependent cytokines in some allergic, inflammatory and pruritic reactions. It has little effect on cytokines that are not involved in JAK1 activation. Oral administration of 0.4–0.6 mg/kg olatinib twice daily is safe and effective for the treatment of pruritus caused by allergic dermatitis. During treatment, olatinib may relieve itching for up to 24 hours. In experiments, in more than 70% of experimental animals (dogs), the reaction with itching and scratching was alleviated by more than 50% on the 7th day. However, olatinib still cannot be used to treat human diseases.

[0013] Filgotinib, a JAK1 inhibitor, entered phase III clinical trials in September 2018 for the treatment of rheumatoid arthritis. Meanwhile, research on filgotinib for the treatment of ulcerative colitis and Crohn's disease is currently in phase II/III clinical trials. Filgotinib is a selective JAK1 inhibitor with IC50 values of 10 nM, 28 nM, 810 nM, and 116 nM for JAK1, JAK2, JAK3, and TYK2, respectively.

[0014] Peficitinib, a JAK1 and JAK3 inhibitor developed by Astellas, is currently in phase III clinical trials for the treatment of rheumatoid arthritis. A phase II clinical trial for the treatment of psoriasis has been completed. Peficitinib is a novel oral JAK inhibitor. Peficitinib inhibits the enzymatic activities of JAK1, JAK2, JAK3 and TYK2 with IC50 of 3.9 nM, 5.0 nM, 0.71 nM and 4.8 nM, respectively.

[0015] Although some JAK inhibitors have been approved for registration, and a large number of JAK inhibitors are still undergoing clinical trials, these JAK inhibitors are not satisfactory in terms of efficacy or safety. Thus, there is always a need for JAK inhibitors with better efficacy and/or fewer side effects.

The essence of the invention

[0016] One purpose of the present disclosure is to provide a new JAK inhibitor that is an alternative to existing JAK inhibitors so as to provide more options for the treatment of JAK-mediated diseases.

[0017] An additional object of the present disclosure is to provide a new JAK inhibitor with better efficacy and/or better safety than existing JAK inhibitors.

[0018] In accordance with a first aspect, the present invention provides a compound of formula (G) as a JAK inhibitor

or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein

L represents C=O, O=S=O, CH ₂ or a bond; And

Χ ₁ represents N or CR ₁₄ ; And

X ₂ represents N or CR ₁₅ ; And

X ₃ represents N or CR ₁₆ ; And

R ₁₄ , R ₁₅ , R ₁₆ are each independently selected from H, C _1-6 alkyl; And

R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl or C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7- membered heteroaryl or 5-11 membered bicyclic heteroalkyl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ , where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and optionally substituted with one or more substituents, each independently selected from -OH, -CN; or R ₁₇ , R ₁₈ and the N atom connected to them form a 3-14 membered ring; And

0, 1, 2, 3 or 4 R ₂ are present in formula (G) and R ₂ is selected from halogen, C _1-6 alkyl; And

R ₁ is selected from -OH, -CN, C _1-8 alkyl, C _3-7 cycloalkyl, 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ ; And

R ₄ is each independently selected from C _1-6 alkyl.

[0019] According to some preferred embodiments of the present disclosure, in formula (G), X ₁ is N. According to some preferred embodiments of the present disclosure, in formula (G), X ₂ is N. According to some preferred embodiments of the present disclosure, in formula (G), X ₃ is N. In accordance with some preferred embodiments of the present disclosure, in formula (G), X ₁ is CR ₁₄ , X ₂ is N or CR ₁₅ , and X ₃ is CR ₁₆ . According to certain preferred embodiments of the present disclosure, in formula (G), X ₁ is CR ₁₄ , X ₂ is CR ₁₅ , and X ₃ is CR ₁₆ . According to certain preferred embodiments of the present disclosure, in formula (G), X ₁ is CR ₁₄ , X ₂ is CR ₁₅ , X ₃ is CR ₁₆ , and R ₁₄ , R ₁₅ , and R ₁₆ are each independently selected from Η C _{1 -6} alkyl. According to some preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are the same. According to certain preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are CH. In accordance with some preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are N. In accordance with some preferred embodiments of the present disclosure, in formula (G) X ₁ is C(CH ₃ ). X ₂ and X ₃ represent CH. According to certain preferred embodiments of the present disclosure, in formula (G), X ₂ is C(CH ₃ ), X ₁ and X ₃ are CH. According to certain preferred embodiments of the present disclosure, in formula (G), X ₃ is C(CH ₃ ), X ₁ and X ₂ are CH. According to certain preferred embodiments of the present disclosure, in formula (G), X ₁ is N, X ₂ and X ₃ are CH. According to certain preferred embodiments of the present disclosure, in formula (G), X ₂ represents N, X ₁ and X ₃ represent CH. According to certain preferred embodiments of the present disclosure, in formula (G), X ₃ represents N, X ₁ and X ₂ represent CH.

[0020] According to certain preferred embodiments of the present disclosure, in formula (G), L is C=O, O=S=O, or CH ₂ . In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), L represents C=O. According to some particularly preferred embodiments of the present disclosure, in formula (G), L is O=S=O. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), L is CH ₂ . According to other embodiments of the present disclosure, in formula (G), L represents a bond.

[0021] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CH and L is C=O.

[0022] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CH and L is O=S=O.

[0023] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CH and L is CH ₂ .

[0024] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CH and L is a bond.

[0025] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all N and L is C=O.

[0026] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all N and L is O=S=O.

[0027] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all N and L is CH ₂ .

[0028] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all N and L is a bond.

[0029] According to certain particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CR ₁₄ wherein R ₁₄ is selected from C _1-6 alkyl and L is C=O .

[0030] According to certain particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CR ₁₄ wherein R ₁₄ is selected from C _1-6 alkyl and L is O=S =O.

[0031] According to certain particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CR ₁₄ wherein R ₁₄ is selected from C _1-6 alkyl and L is CH ₂ .

[0032] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ , X ₂ and X ₃ are all CR ₁₄ wherein R ₁₄ is selected from -C _1-6 alkyl and L is a bond.

[0033] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is C(CH ₃ ), X ₂ and X ₃ are both CH, and L is C=O.

[0034] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is C(CH ₃ ), X ₂ and X ₃ are both CH, and L is O=S=O.

[0035] According to certain particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is C(CH ₃ ), X ₂ and X ₃ are both CH, and L is CH ₂ .

[0036] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is C(CH ₃ ), X ₂ and X ₃ are both CH, and L is a bond.

[0037] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₂ is C(CH ₃ ), X ₁ and X ₃ are both CH, and L is C=O.

[0038] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₂ is C(CH ₃ ), X ₁ and X ₃ are both CH, and L is O=S=O.

[0039] According to certain particularly preferred embodiments of the present disclosure, in formula (G), X ₂ is C(CH ₃ ), X ₁ and X ₃ are both CH, and L is CH ₂ .

[0040] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₂ is C(CH ₃ ), X ₁ and X ₃ are both CH, and L is a bond.

[0041] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₃ is C(CH ₃ ), X ₁ and X ₂ are both CH, and L is C=O.

[0042] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₃ is C(CH ₃ ), X ₁ and X ₂ are both CH, and L is O=S=O.

[0043] According to certain particularly preferred embodiments of the present disclosure, in formula (G), X ₃ is C(CH ₃ ), X ₁ and X ₂ are both CH, and L is CH ₂ .

[0044] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₃ is C(CH ₃ ), X ₁ and X ₂ are both CH, and L is a bond.

[0045] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is N, X ₂ and X ₃ are both CH, and L is C=O.

[0046] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is N, X ₂ and X ₃ are both CH, and L is O=S=O.

[0047] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is N, X ₂ and X ₃ are both CH, and L is CH ₂ .

[0048] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₁ is N, X ₂ and X ₃ are both CH, and L is a bond.

[0049] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₂ represents N, X ₁ and X ₃ both represent CH, and L represents C=O.

[0050] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₂ represents N, X ₁ and X ₃ both represent CH, and L represents O=S=O.

[0051] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₂ is N, X ₁ and X ₃ are both CH, and L is CH ₂ .

[0052] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₂ represents N, X ₁ and X ₃ both represent CH, and L represents a bond.

[0053] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₃ represents N, X ₁ and X ₂ both represent CH, and L represents C=O.

[0054] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₃ is N, X ₁ and X ₂ are both CH, and L is O=S=O.

[0055] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₃ is N, X ₁ and X ₂ are both CH, and L is CH ₂ .

[0056] According to some particularly preferred embodiments of the present disclosure, in formula (G), X ₃ represents N, X ₁ and X ₂ both represent CH, and L represents a bond.

[0057] According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, or C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 membered heteroaryl, or 5-11 membered bicyclic heteroalkyl, wherein R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _3-7 heterocycloalkyl, and optionally substituted with one or more of -OH, -CN, wherein R ₁₃ is optionally substituted with 1, 2, 3 or 4 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, or C _3-7 cycloalkyl, 3-7 -membered heterocycloalkyl, C _5-7 aryl, 5-7 membered heteroaryl, and R ₁₇ and R ₁₈ as defined above, where R ₁₃ is optionally substituted with 1, 2, 3 or 4 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, or C _3-7 cycloalkyl, 4-6 -membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl and R ₁₇ and R ₁₈ as defined above, where R ₁₃ is optionally substituted with 1, 2, or 3 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-3 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl or C _1-4 alkyl and R ₁₇ and R ₁₈ are defined above, where R ₁₃ is optionally substituted with 1, 2 or 3 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(C _1-3 alkyl), -N(Η)(3-6 membered cycloalkyl), -N(Η) (4-6 membered heterocycloalkyl), -N (C _1-3 alkyl)(C _1-3 alkyl), C _3-6 cycloalkyl, 4-6 membered azacycloalkyl or oxacycloalkyl or C _1-4 alkyl; or R ₁₃ is -N(R ₁₇ )(R ₁₈ ) and R ₁₇ and R ₁₈ and the N atom connected thereto form a 4-10 membered ring (where R ₁₃ is optionally substituted with 1, 2, or 3 R ₁ ). According to certain particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, -N(H)(CH ₃ ) , -N(H)(CH ₂ CH ₃ ), -N(H)(CH ₂ CH ₂ OH), -N(H)(CH ₂ CH ₂ CN), -N(CH ₃ )(CH ₃ ), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl), pyrazinyl, pyridazinyl, pyrrolidinyl, pyrazolyl, piperidinyl, phenyl, azetidinyl, morpholinyl, piperazinyl or tetrahydropyranyl; or R ₁₃ is -N(R ₁₇ )(R ₁₈ ) and R ₁₇ and R ₁₈ and the N atom connected thereto form a 7-membered ring (where R ₁₃ is optionally substituted with 1, 2, or 3 R ₁ ) . According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is cyclopropyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is cyclobutyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is cyclopentyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents cyclohexyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents a methyl group. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents an ethyl group. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents propyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents a butyl group. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents pyrazinyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is pyridazinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents pyrrolidinyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is pyrazolyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ represents piperidinyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is phenyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is azetidinyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is morpholinyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is piperazinyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is tetrahydropyranyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is methoxy. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is ethoxy. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(CH ₂ CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(CH ₂ CH ₂ OH). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(CH ₂ CH ₂ CN). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -K(CH ₃ )(CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(cyclopropyl). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(cyclobutyl). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(H)(tetrahydrofuranyl). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is -N(R ₁₇ )(R ₁₈ ) and R ₁₇ and R ₁₈ and the N atom connected thereto form a 7-membered ring.

[0058] According to certain particularly preferred embodiments of the present disclosure, in formula (G), R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and are optionally substituted one or more of -OH, -CN. According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₇ and R ₁₈ are each independently selected from H, methyl, ethyl, propyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl and 6-membered heterocycloalkyl, and is optionally substituted with one or more of -OH and -CN. In accordance with some preferred embodiments of the present disclosure, in formula (G), R ₁₇ , R ₁₈ and the N atom connected thereto form a 4-10 membered ring. In accordance with some preferred embodiments of the present disclosure, in formula (G), R ₁₇ , R ₁₈ and the N atom connected thereto form a 7-membered ring.

[0059] According to certain particularly preferred embodiments of the present disclosure, in formula (G) L is C=O and R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, and R ₁₃ is substituted 0, 1, 2, 3 or 4 R ₁ where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and are optionally substituted by one or more of - OH, -CN, or R ₁₇ , R ₁₈ and the N atom connected to them form a 3-14-membered ring. According to certain particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(R ₁₇ )(R ₁₈ ), or C _1-6 alkoxy, wherein R ₁₇ and R ₁₈ each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 heterocycloalkyl and optionally substituted with one or more of -OH, -CN, or R ₁₇ , R ₁₈ and an N atom connected thereto, form a 3-10 membered ring. According to certain particularly preferred embodiments of the present disclosure, in formula (G) L is C=O and R ₁₃ is methoxy, ethoxy, propoxy, -N(H)(CH ₃ ), -N(H)(CH ₂ CH ₃ ), -N(H)(CH ₂ CH ₂ OH), -N(H)(CH ₂ CH ₂ CN), -N(CH ₃ )(CH ₃ ), -N(H)(cyclopropyl), -N(H) (cyclobutyl), -N(H) (tetrahydrofuranyl); or R ₁₃ is -N(R17)(R ₁₈ ) and R ₁₇ , R ₁₈ and the N atom connected to them form a 7-membered ring. According to some particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is methoxy. According to some particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is ethoxy. According to certain particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(H)(CH ₃ ). According to certain particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(H)(CH ₂ CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(H)(CH ₂ CH ₂ OH). According to some particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(H)(CH ₂ CH ₂ CN). According to certain particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(CH ₃ )(CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(H)(cyclopropyl). According to some particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(H)(cyclobutyl). According to some particularly preferred embodiments of the present disclosure, in formula (G), L is C=O and R ₁₃ is -N(H)(tetrahydrofuranyl). According to certain particularly preferred embodiments of the present disclosure, in formula (G), L represents C=O and R ₁₃ represents -N(R ₁₇ )(R ₁₈ ) and R ₁₇ , R ₁₈ and the N atom connected thereto, form a 7-membered ring.

[0060] In accordance with some particularly preferred embodiments of the present disclosure, in formula (G) one, two or three R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G) one or two R ₂ are present and R ₂ is selected from halogen and C _1-6 alkyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G) one or two R ₂ are present and R ₂ is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. In accordance with some preferred embodiments of the present disclosure, in formula (G) one or two R ₂ are present and R ₂ is selected from fluorine, chlorine, methyl, ethyl, n-propyl and isopropyl. In accordance with some preferred embodiments of the present disclosure, in formula (G) one or two R ₂ are present and R ₂ is selected from fluorine, methyl and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (G) one or two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (G) one R ₂ is present and R ₂ is selected from fluorine and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (G) two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some particularly preferred embodiments of the present disclosure, two R ₂ are present in formula (G), which are respectively fluorine and ethyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G) one R ₂ is present and R ₂ represents an ethyl group.

[0061] According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is substituted with 0, 1, 2, 3, or 4 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-8 alkyl, C _3-7 cycloalkyl, 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is substituted with 0, 1, 2, 3, or 4 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-8 alkyl, C _{3- 7} cycloalkyl, 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G) R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ and each R ₁ is independently selected -OH, -CN, C _1-8 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-6 alkyl, C _3-7 cycloalkyl, 5-7 -membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-4 alkyl, C _3-6 cycloalkyl, and 5-7 -membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R ₄ . According to certain particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from methyl, ethyl, hydroxyl, -CN, piperidinyl, morpholinyl, piperazinyl, and cyclopropyl, wherein piperidinyl, morpholinyl and piperazinyl are optionally substituted with 1, 2, 3 or 4 C _1-3 alkyls. According to certain particularly preferred embodiments of the present disclosure, in formula (G), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from methyl, ethyl, hydroxy, -CN, piperidinyl, morpholinyl, 1-methylpiperazinyl, and cyclopropyl. In accordance with some particularly preferred embodiments of the present disclosure, R ₁ is omitted from formula (G). According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ is 1-methylpiperazinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ represents methyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ represents ethyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ represents piperidinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ represents morpholinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ represents hydroxyl. According to some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ is -CN. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G), R ₁ represents cyclopropyl.

[0062] Preferred embodiments of the respective substituents mentioned in the above various preferred embodiments may be combined with each other in any manner, and various combinations thereof are within the scope of the present disclosure. In accordance with the most preferred embodiments of the present disclosure, the compound of formula (G) is each specific compound shown in Example 1 to Example 58 herein. In other words, the compound of formula (G) is selected from

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-(piperidin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-morpholinylpyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 1-methylpiperidin-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4 -methylpiperazin-1-yl)pyrazin-2-yl)ketone;

5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )phenol;

5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmetal)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole -6-yl)phenol;

4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone;

4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 3-hydroxylcyclobutyl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-3-yl)ketone;

(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-( 1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1 H-indazol- 6-yl)phenol;

4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole -2-yl)-1H-indazol-6-yl)phenol;

4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol ;

5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl) -1H-indazol-6-yl)phenol;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)ethan-1-one;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)propan-1-one;

(1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-yl)-2-methylpropan-1-one);

2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)ethan-1-one;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)-3-methylbutan-1-one;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(pyrrolidin-1-yl)ketone;

Azetidin-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(piperidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(morpholino)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(4-methylpiperazin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(4-ethylpiperazin-1-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5( 1H)-yl)ketone;

(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone;

(R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 (1H )-yl)(3-hydroxypyrrolidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxylasetidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (4-hydroxylpiperidin-1-yl)ketone;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-carboxamide;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-carboxamide;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-carboxamide;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5 -carbon yl)azetidine-3-nitrile;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5 -carbonyl)pyrrolidine-3-nitrile;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazole-5(1H)-carboxamide;

Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate ;

Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate ;

(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4 -d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)- yl)-3-hydroxypropionitrile;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5( 1H)-carboxamide;

N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-carboxamide;

N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H) -carboxamide;

N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5 (1H) -carboxamide;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (2,6-diazaspiro[3,3]heptan-2-yl)ketone;

(S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-indazole and

(R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- N-indazole.

[0063] In a compound of formula (G), if Χ ₁ , X ₂ and X ₃ are the same, the compound of formula (G) can also be represented as a compound of formula (G'):

where X represents N or CR ₁₄ and R ₁₄ , R ₁₃ , R ₁ , L and R ₂ are defined in the compound of formula (G).

[0064] In accordance with a preferred embodiment, the present invention relates to a compound of formula (G)'

or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein

X represents N or CH;

L represents C=O, O=S=O, CH ₂ or a bond; And

R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl or C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7- membered heteroaryl, or 5-11 membered bicyclic heteroalkyl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ , where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl , C _3-7 heterocycloalkyl, and is optionally substituted with one or more substituents, each independently selected from -OH, -CN; or R ₁₇ , R ₁₈ and the N atom connected to them form a 3-14 membered ring; And

0, 1, 2, 3 or 4 R ₂ are present in formula (G') and R ₂ is selected from halogen, C _1-6 alkyl;

And

R ₁ is selected from -OH, -CN, C _1-8 alkyl, C _3-7 cycloalkyl, 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ ; And

R ₄ is each independently selected from C _1-6 alkyl.

[0065] According to some preferred embodiments of the present disclosure, in formula (G') X is N. According to some more preferred embodiments of the present disclosure, in formula (G') X is CH.

[0066] According to certain preferred embodiments of the present disclosure, in formula (G'), L is C=O, O=S=O, or CH ₂ . In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), L represents C=O. According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is O=S=O. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), L represents CH ₂ . In accordance with other embodiments of the present disclosure, in formula (G'), L represents a bond.

[0067] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is CH and L is C=O.

[0068] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is CH and L is O=S=O.

[0069] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is CH and L is CH ₂ .

[0070] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is CH and L is a bond.

[0071] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is N and L is C=O.

[0072] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is N and L is O=S=O.

[0073] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is N and L is CH ₂ .

[0074] According to some particularly preferred embodiments of the present disclosure, in formula (G'), X is N and L is a bond.

[0075] According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, or C _3-7 cycloalkyl , 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 membered heteroaryl, or 5-11 membered bicyclic heteroalkyl, where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _{3 -7} cycloalkyl, C _3-7 heterocycloalkyl, and optionally substituted with one or more of -OH, -CN, wherein R ₁₃ is optionally substituted with 1, 2, 3 or 4 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, or C _3-7 cycloalkyl, 3- 7-membered heterocycloalkyl, C _5-7 aryl, 5-7 membered heteroaryl, and R ₁₇ and R ₁₈ as defined above, where R ₁₃ is optionally substituted with 1, 2, 3 or 4 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, or C _3-7 cycloalkyl, 4 -6-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl and R ₁₇ and R ₁₈ are defined above, where R ₁₃ is optionally substituted with 1, 2, or 3 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-3 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl , 5-6 membered heteroaryl or G _1-4 alkyl and R ₁₇ and R ₁₈ are as defined above, where R ₁₃ is optionally substituted with 1, 2, or 3 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(G _1-3 alkyl), -N(H)(3-6 membered cycloalkyl), -N(H )(4-6-membered heterocycloalkyl), -N(C _1-3 alkyl) (C _1-3 alkyl), C _1-3 alkoxy, C _3-6 cycloalkyl, 4-6-membered azacycloalkyl or oxacycloalkyl, phenyl, 5-6 membered azaaryl or C _1-4 alkyl; or R ₁₃ is -N(R ₁₇ )(R ₁₈ ) and R ₁₇ and R ₁₈ and the N atom connected thereto form a 4-10 membered ring (where R ₁₃ is optionally substituted with 1, 2, or 3 R ₁ ). According to certain particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, -N(H)(CH ₃ ), -N(H)(CH ₂ CH ₃ ), -N(H)(CH ₂ CH ₂ OH), -N(H)(CH ₂ CH ₂ CN), -N(CH ₃ )(CH ₃ ) , -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl), pyrazinyl, pyridazinyl, pyrrolidinyl, pyrazolyl, piperidinyl, phenyl, azetidinyl, morpholinyl, piperazinyl or tetrahydropyranyl; or R ₁₃ is -N(R ₁₇ )(R ₁₈ ) and R ₁₇ and R ₁₈ and the N atom connected thereto form a 7-membered ring (where R ₁₃ is optionally substituted with 1, 2, or 3 R ₁ ) . In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents cyclopropyl. According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is cyclobutyl. According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is cyclopentyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents cyclohexyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents a methyl group. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents an ethyl group. According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents propyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents a butyl group. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents pyrazinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents pyridazinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents pyrrolidinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents pyrazolyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents piperidinyl. According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is phenyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents azetidinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents morpholinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents piperazinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ represents tetrahydropyranyl. According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is methoxy. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is ethoxy. According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(CH ₃ ). According to certain particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(CH ₂ CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(CH ₂ CH ₂ OH). According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(CH ₂ CH ₂ CN). According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -n(CH ₃ )(CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(cyclopropyl). According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(cyclobutyl). According to some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(H)(tetrahydrofuranyl). According to certain particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is -N(R ₁₇ )(R ₁₈ ) and R ₁₇ and R ₁₈ and the N atom joined together form a 7-membered ring .

[0076] According to certain particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and optionally substituted with one or more substituents selected from -OH, -CN. According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₇ and R ₁₈ are each independently selected from H, methyl, ethyl, propyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl and 6-membered heterocycloalkyl and optionally substituted with one or more of -OH and -CN. In accordance with some preferred embodiments of the present disclosure, in formula (G'), R ₁₇ , R ₁₈ and the N atom connected thereto form a 4-10 membered ring. According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₇ , R ₁₈ and the N atom connected thereto form a 7-membered ring.

[0077] According to certain particularly preferred embodiments of the present disclosure, in formula (G') L is C=O and R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, and R ₁₃ substituted with 0, 1, 2, 3 or 4 R ₁ , where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and are optionally substituted with one or more of -OH, -CN, or R ₁₇ , R ₁₈ and the N atom connected to them form a 3-14 membered ring. According to certain particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(R ₁₇ )(R ₁₈ ) or C _1-6 alkoxy, wherein R ₁₇ and R ₁₈ each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 heterocycloalkyl and optionally substituted with one or more of -OH, -CN, or R ₁₇ , R ₁₈ and an N atom connected thereto, form a 3-10 membered ring. According to certain particularly preferred embodiments of the present disclosure, in formula (G') L is C=O and R ₁₃ is methoxy, ethoxy, propoxy, -N(H)(CH ₃ ), -N(H)(CH ₂ CH ₃ ), -N(H)(CH ₂ CH ₂ OH), -N(H)(CH ₂ CH ₂ CN), -N(CH ₃ )(CH ₃ ), -N(H)(cyclopropyl) , -N(H)(cyclobutyl), N(H)(tetrahydrofuranyl); or R ₁₃ is -N(R ₁₇ )(R ₁₈ ) and R ₁₇ , R ₁₈ and the N atom connected thereto form a 7-membered ring. According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is methoxy. According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is ethoxy. According to certain particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(H)(CH ₃ ). According to certain particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(H)(CH ₂ CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(H)(CH ₂ CH ₂ OH). According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(H)(CH ₂ CH ₂ CN). According to certain particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(CH ₃ )(CH ₃ ). According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(H)(cyclopropyl). According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(H)(cyclobutyl). According to some particularly preferred embodiments of the present disclosure, in formula (G'), L is C=O and R ₁₃ is -N(H)(tetrahydrofuranyl). In accordance with certain particularly preferred embodiments of the present disclosure, in formula (G') L represents C=O and R ₁₃ represents -N(R ₁₇ )(R ₁₈ ) and R ₁₇ , R ₁₈ and an N atom connected thereto , form a 7-membered ring.

[0078] In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), one, two or three R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl. According to some particularly preferred embodiments of the present disclosure, in formula (G'), 1 or two R ₂ are present and R ₂ is selected from halogen and C _1-6 alkyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), one or two R ₂ are present and R ₂ is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. In accordance with some preferred embodiments of the present disclosure, in formula (G'), one or two R ₂ are present and R ₂ is selected from fluorine, chlorine, methyl, ethyl, n-propyl and isopropyl. In accordance with some preferred embodiments of the present disclosure, in formula (G'), one or two R ₂ are present and R ₂ is selected from fluorine, methyl and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (G'), one or two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (G'), one R ₂ is present and R ₂ is selected from fluorine and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (G'), two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some particularly preferred embodiments of the present disclosure, two R ₂ are present in formula (G'), which are respectively fluorine and ethyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), one R ₂ is present and R ₂ represents an ethyl group.

[0079] According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₇ is substituted with 0, 1, 2, 3, or 4 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-8 alkyl , C _3-7 cycloalkyl, 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is substituted with 0, 1, 2, 3, or 4 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-8 alkyl, C _{3 -7} cycloalkyl, 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is substituted with 0, 1, 2, 3, or 4 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-8 alkyl, C _{3 -7} cycloalkyl and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-6 alkyl, C _3-7 cycloalkyl, 5- 7-membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R ₄ . According to certain preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from -OH, -CN, C _1-4 alkyl, C _3-6 cycloalkyl, and 5- 7-membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R ₄ . According to certain particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from methyl, ethyl, hydroxyl, -CN, piperidinyl, morpholinyl, piperazinyl, and cyclopropyl, wherein piperidinyl , morpholinyl and piperazinyl are optionally substituted with 1, 2, 3 or 4 C _1-3 alkyls. According to certain particularly preferred embodiments of the present disclosure, in formula (G'), R ₁₃ is substituted with 0 or 1 R ₁ and each R ₁ is independently selected from methyl, ethyl, hydroxy, -CN, piperidinyl, morpholinyl, 1-methylpiperazinyl, and cyclopropyl. In accordance with some particularly preferred embodiments of the present disclosure, R ₁ is not present in formula (G'). In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents 1-methylpiperazinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents methyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents ethyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents piperidinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents morpholinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents hydroxyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents -CN. In accordance with some particularly preferred embodiments of the present disclosure, in formula (G'), R ₁ represents cyclopropyl.

[0080] Preferred embodiments of the respective substituents mentioned in the above various preferred embodiments may be combined with each other in any manner, and various combinations thereof are within the scope of the present disclosure.

[0081] In a compound of formula (G'), if R ₁₃ is a ring, the compound of formula (G') may also be represented as a compound of the following formula (I):

wherein ring A is C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 member heteroaryl, which may be optionally substituted with R ₁ and L, R ₁ , R ₂ and X as defined above in a compound of formula (G').

[0082] In particular, the present invention relates to a compound of formula (I) as a JAK inhibitor:

or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein

L represents C=O, O=S=O, CH ₂ or a bond; And

X represents CH or N;

Ring A is C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 member heteroaryl;

0, 1, 2, 3 or 4 R ₁ are present in formula (I) and R ₁ is selected from C _1-8 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, wherein 3-7 membered heterocycloalkyl is optionally substituted 1, 2, 3 or 4 R ₄ ,

0, 1, 2, 3 or 4 R ₂ are present in formula (I) and R ₂ is selected from halogen, C _1-6 alkyl;

R ₄ is selected from C _1-3 alkyl.

[0083] According to certain preferred embodiments of the present disclosure, in formula (I), L is C=O, O=S=O, or CH ₂ . In accordance with some particularly preferred embodiments of the present disclosure, in formula (I) L represents C=O. According to some particularly preferred embodiments of the present disclosure, in formula (I) L is O=S=O. According to some particularly preferred embodiments of the present disclosure, in formula (I) L is CH ₂ . In accordance with other embodiments of the present disclosure, in formula (I), L represents a bond.

[0084] According to some particularly preferred embodiments of the present disclosure, in formula (I) X is CH. According to certain other embodiments of the present disclosure, in formula (I), X is N.

[0085] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is CH and L is C=O.

[0086] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is CH and L is O=S=O.

[0087] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is CH and L is CH ₂ .

[0088] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is CH and L is a bond.

[0089] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is N and L is C=O.

[0090] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is N and L is O=S=O.

[0091] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is N and L is CH ₂ .

[0092] According to some particularly preferred embodiments of the present disclosure, in formula (I), X is N and L is a bond.

[0093] According to certain preferred embodiments of the present disclosure, in formula (I), ring A is C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 member heteroaryl, wherein ring A optionally substituted with 1, 2, 3 or 4 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (I), ring A is C _5-6 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, wherein ring A is optionally substituted with 1, 2, 3 or 4 R ₁ . According to some preferred embodiments of the present disclosure, in formula (I), ring A is a 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, wherein ring A is optionally substituted with 1, 2, 3 or 4 R ₁ . According to some preferred embodiments of the present disclosure, in formula (I), ring A is 5-6 membered azacycloalkyl, phenyl, 5-6 membered azaaryl, wherein ring A is optionally substituted with 1, 2, 3 or 4 R ₁ . According to certain preferred embodiments of the present disclosure, in formula (I), ring A is pyrazinyl, pyrazolyl, piperidinyl, or phenyl, wherein ring A is optionally substituted with 1, 2, 3, or 4 R ₁ . According to some particularly preferred embodiments of the present disclosure, in formula (I), ring A is pyrazinyl. According to some particularly preferred embodiments of the present disclosure, in formula (I), ring A is pyrazolyl. According to some particularly preferred embodiments of the present disclosure, in formula (I), ring A is piperidinyl. According to some particularly preferred embodiments of the present disclosure, in formula (I), ring A is phenyl.

[0094] According to certain preferred embodiments of the present disclosure, in formula (I), R ₁ is absent or R ₁ is selected from C _1-8 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, wherein 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ . According to some preferred embodiments of the present disclosure, in formula (I) R ₁ is absent or R ₁ is selected from C _1-8 alkyl and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ₄ . In accordance with some preferred embodiments of the present disclosure, in formula (I) R ₁ is absent or R ₁ is selected from C _1-6 alkyl, 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ . In accordance with some preferred embodiments of the present disclosure, in formula (I) R ₁ is absent or R ₁ is selected from C _1-6 alkyl, 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 With _1-3 alkyls. In accordance with some preferred embodiments of the present disclosure, in formula (I) R ₁ is absent or R ₁ is selected from C _1-4 alkyl and 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 C _1-3 alkyls. In accordance with some preferred embodiments of the present disclosure, in formula (I) R ₁ is absent or R ₁ is selected from methyl, piperidinyl, morpholinyl, piperazinyl, wherein piperidinyl, morpholinyl and piperazinyl are optionally substituted with 1, 2, 3 or 4 C _1-3 alkyl in groups. In accordance with some preferred embodiments of the present disclosure, in formula (I), R ₁ is absent or R ₁ is selected from methyl, piperidinyl, morpholinyl and 1-methylpiperazinyl. In accordance with some particularly preferred embodiments of the present disclosure, R ₁ is omitted from formula (I). According to some particularly preferred embodiments of the present disclosure, in formula (I), R ₁ is 1-methylpiperazinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I), R ₁ represents methyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I), R ₁ represents piperidinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I), R ₁ represents morpholinyl.

[0095] In accordance with some particularly preferred embodiments of the present disclosure, in formula (I) one, two or three R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I) one or two R ₂ are present and R ₂ is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) one or two R ₂ are present and R ₂ is selected from fluorine, chlorine, methyl, ethyl, n-propyl and isopropyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) one or two R ₂ are present and R ₂ is selected from fluorine, methyl and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) one or two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) one R ₂ is present and R ₂ is selected from fluorine and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some particularly preferred embodiments of the present disclosure, two R ₂ are present in formula (I), which are respectively fluorine and ethyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I) one R ₂ is present and R ₂ represents an ethyl group.

[0096] Preferred embodiments of the respective substituents mentioned in the above various preferred embodiments may be combined with each other in any manner, and various combinations thereof are within the scope of the present disclosure.

[0097] In particular, the present invention relates to a compound of formula (I) as a JAK inhibitor:

or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein

L represents C=O and O=S=O;

X represents CH;

Ring A is 5-7 membered heteroaryl or C _5-7 aryl;

0, 1, 2, 3 or 4 R ₁ are present in formula (I) and R ₁ is selected from C _1-8 alkyl and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ₄ ,

1, 2 or 3 R ₂ are present in formula (I) and R ₂ is selected from halogen, C _1-6 alkyl;

R ₄ is selected from C _1-3 alkyl.

[0098] According to some preferred embodiments of the present disclosure, in formula (I), L is O=S=O. In accordance with some preferred embodiments of the present disclosure, in formula (I), L represents C=O.

[0099] In accordance with certain preferred embodiments of the present disclosure, in formula (I), ring A is a 5-6 membered heteroaryl or phenyl, wherein ring A is optionally substituted with 1, 2, 3 or 4 R ₁ . According to some preferred embodiments of the present disclosure, in formula (I), ring A is pyrazinyl, pyrazolyl, or phenyl, wherein ring A is optionally substituted with 1, 2, 3, or 4 R ₁ . According to some particularly preferred embodiments of the present disclosure, in formula (I), ring A is pyrazinyl. According to some particularly preferred embodiments of the present disclosure, in formula (I), ring A is phenyl.

[00100] According to certain preferred embodiments of the present disclosure, in formula (I), R ₁ is absent or R ₁ is selected from C _1-8 alkyl and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2 , 3 or 4 R ₄ . In accordance with some preferred embodiments of the present disclosure, in formula (I) R ₁ is absent or R ₁ is selected from C _1-6 alkyl, 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ₄ . According to some preferred embodiments of the present disclosure, in formula (I), R ₁ is absent or R ₁ is selected from C _1-6 alkyl, 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 C _1-3 alkyls. In accordance with some preferred embodiments of the present disclosure, in formula (I) R ₁ is absent or R ₁ is selected from C _1-4 alkyl and 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 With _1-3 alkyls. In accordance with some preferred embodiments of the present disclosure, in formula (I), R ₁ is absent or R ₁ is selected from methyl, piperidinyl, morpholinyl, wherein piperidinyl and morpholinyl are optionally substituted with 1, 2, 3 or 4 C _1-3 alkyl groups. In accordance with some preferred embodiments of the present disclosure, in formula (I), R ₁ is absent or R ₁ is selected from methyl, piperidinyl and morpholinyl. In accordance with some particularly preferred embodiments of the present disclosure, R ₁ is omitted from formula (I). In accordance with some particularly preferred embodiments of the present disclosure, in formula (I), R ₁ represents methyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I), R ₁ represents piperidinyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I), R ₁ represents morpholinyl.

[00101] In accordance with some particularly preferred embodiments of the present disclosure, in formula (I) one or two R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl. In accordance with some particularly preferred embodiments of the present disclosure, in formula (I) two R ₂ are present and R ₂ is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) two R ₂ are present and R ₂ is selected from fluorine, chlorine, methyl, ethyl, n-propyl and isopropyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) two R ₂ are present and R ₂ is selected from fluorine, methyl and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some preferred embodiments of the present disclosure, in formula (I) two R ₂ are present and R ₂ is selected from fluorine and ethyl. In accordance with some particularly preferred embodiments of the present disclosure, two R ₂ are present in formula (I), which are respectively fluorine and ethyl.

[00102] Preferred embodiments of the respective substituents mentioned in the above various preferred embodiments may be combined with each other in any manner, and various combinations thereof are within the scope of the present disclosure.

[00103] In accordance with a more preferred embodiment of the present disclosure, a compound of formula (I) is selected from

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-(piperidin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)--4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl )(5-morpholinylpyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 1-methylpiperidin-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4 -methylpiperazin-1-yl)pyrazin-2-yl)ketone;

5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )phenol;

5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole -6-yl)phenol;

4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone;

4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-3-yl)ketone;

4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole -2-yl)-1H-indazol-6-yl)phenol;

4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol ;

5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl) -1H-indazol-6-yl)phenol;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-e]imidazol-5-(1H)-yl )(pyrrolidin-1-yl)ketone;

Azetidin-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(piperidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-(5]imidazol-5-(1H)- yl)(morpholino)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(4-methylpiperazin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-e]imidazol-5-(1H)-yl )(4-ethylpiperazin-1-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5( 1H)-yl)ketone;

(8)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone;

(R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H )-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxylasetidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (4-hydroxypiperidin-1-yl)ketone;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-(1]imidazol- 5-carbonyl)azetidine-3-nitrile;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5 -carbonyl)pyrrolidine-3-nitrile;

(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4 -d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

(S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-indazole and

(R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-indazole.

[00104] In accordance with the most preferred embodiments of the present disclosure, the compound of formula (I) is each specific compound known in Example 1 to Example 8 in the present invention. In other words, the compound of formula (I) is selected from

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-(piperidin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-morpholinepyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone;

5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H -indazol-6-yl}phenol;

5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H -indazol-6-yl}phenol;

3-ethyl-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6 -yl}phenol;

5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )phenol and

5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole -6-yl)phenol.

[00105] For simplicity hereinafter, the term “compound represented by formula (G)” or “compound of formula (G)” or “compound of the present invention” or “compound of the present invention” also covers any optical isomer; the term "compound represented by formula (G')" or "compound of formula (G')" or "compound of the present invention" or "compound of the present invention" also covers any optical isomer; and the term “compound represented by formula (I)” or “compound of formula (I)” or “compound of the present invention” or “compound of the present invention” also covers any optical isomer.

[00106] The term "optical isomer" is mentioned if the compound contains one or more chiral centers, each chiral center may be characterized by an R configuration, or an S configuration, and the various isomers thus formed are known as an optical isomer. Optical isomers include all diastereoisomers, enantiomers, mesomers, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or chiral synthesis.

[00107] The compound of formula (G) may exist in the form of a pharmaceutically acceptable salt, for example, an acid addition salt and/or a base addition salt of the compound of formula (G). Unless otherwise noted, "pharmaceutically acceptable salt" as used herein includes the acid addition salts or base addition salts that may be present in the compound of formula (G). The compound of formula (G') may exist in the form of a pharmaceutically acceptable salt, for example, an acid addition salt and/or a base addition salt of the compound of formula (G'). Unless otherwise noted, "pharmaceutically acceptable salt" as used herein includes the acid addition salts or base addition salts that may be present in the compound of formula (G'). The compound of formula (I) may exist in the form of a pharmaceutically acceptable salt, for example, an acid addition salt and/or a base addition salt of the compound of formula (I). Unless otherwise noted, "pharmaceutically acceptable salt" as used herein includes the acid addition salts or base addition salts that may be present in the compound of formula (I).

[00108] The pharmaceutically acceptable salt of a compound of formula (G), a compound of formula (G'), and a compound of formula (I) includes their acid addition salts and base addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexaminesulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-( 4-Hydroxybenzyl)benzoate, hydrochloride/chloride, hydrobromide/bromide, iodohydrate/iodide, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthalate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate and trifluoroacetate. Suitable base addition salts are formed from bases that form non-toxic salts. Examples thereof include, without limitation: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts. It is also possible to form hemisalts of acids and bases, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described in the present invention are known to those skilled in the art.

[00109] Certain compounds of the present invention may exist in unsolvated form as well as solvated forms, including hydrated forms. In general, compounds of formula (G), compounds of formula (G') and compounds of formula (I), whether present in solvated form or unsolvated form, are included within the scope of the present invention.

[00110] Certain compounds of the present invention may exist in various crystalline or amorphous forms, and compounds of formula (G), compounds of formula (G') and compounds of formula (I) present in various forms are included within the scope of the present invention.

[00111] To avoid ambiguity, definitions of certain terms used herein are provided below. Unless otherwise noted, the meanings of the terms used herein are as follows.

[00112] The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecules are suitable for administration to humans. It is preferable that the term be approved by regulatory authorities such as the CFDA (China), EMEA (Europe), FDA (United States) and other regulatory authorities as being suitable for mammals, particularly humans.

[00113] The term "hydroxy" refers to -OH.

[00114] The term “halogen” or “halo” refers to -F, -Cl, -Br, or -I.

[00115] The term "cyano" refers to -CN.

[00116] In accordance with the present disclosure, if a plurality of substituents of a particular type are present, each substituent is independently selected from each other and such substituents may be the same or different. For example, if 2, 3, or 4 R ₁ are present, the R ₁ may be the same or different. For example, if 2, 3, or 4 R ₂ are present, the R ₂ may be the same or different. For example, if R ₁ and R ₂ are both -N(R ₉ )(R ₁₀ ), the R ₉ and R ₁₀ contained in R ₁ and R ₂ may be independently selected, i.e., R ₉ in R ₁ and R ₉ in R ₂ can be the same or different, and R ₁₀ in R ₁ and R ₁₀ in R ₂ can be the same or different. For example, if R ₁ is present and two R ₁ are both -N(R ₉ )(R ₁₀ ), R ₉ and R ₁₀ in the two R ₁ can be selected independently, i.e., R ₉ in the first R ₁ and R ₉ in the second R ₁ can be the same or different, and R ₁₀ in the first R ₁ and R ₁₀ in the second R ₁ can be the same or different. The above statement applies to R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ .

[00117] As used herein, the term “substituted” means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in a group are independently replaced by an appropriate number of substituents.

[00118] As used herein, the term “regardless” means that if the number of substituents is more than one, such substituents may be the same or different.

[00119] As used herein, the term “optional” or “optional” means that the event described in the present invention may or may not occur. For example, an "optionally substituted" group means that the group may be unsubstituted or substituted.

[00120] As used herein, the term “heteroatom” refers to oxygen (O), nitrogen (N) or S(O) _m , where m can be 0, 1 or 2, i.e., a sulfur atom S, or sulfoxide SO group, or sulfonyl group S(O) ₂ ).

[00121] As used herein, the term “alkyl” refers to saturated aliphatic hydrocarbons, including straight and branched chains. In accordance with some embodiments, the alkyl group contains 1-8, or 1-6, or 1-3 carbon atoms. For example, the term "C _1-8 alkyl" refers to a group of straight or branched chain atoms containing 1-8 carbon atoms. The term "C _1-8 alkyl" includes the terms "C _1-6 alkyl", "C ₁ -C ₃ alkyl" and "C ₁ -C ₄ alkyl" in its definition. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, etc. The alkyl group may be optionally substituted with one or more (eg, 1 to 5) suitable substituent(s).

[00122] As used herein, the term “C _3-7 cycloalkyl” refers to a cycloalkyl group containing 3-7 carbon atoms forming a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. The cycloalkyl may be optionally substituted with one or more suitable substituent(s).

[00123] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl group containing m ring-forming carbon atoms and (n-m) ring-forming heteroatoms, the heteroatoms being selected from O, S and N. For example, 3-7 membered heterocycloalkyl includes, without limitation, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine, oxepane, thiepane and azepine. Heterocycloalkyl may be optionally substituted with one or more suitable substituent(s).

[00124] As used herein, the term “C _5-7 aryl” refers to an aryl group containing an aromatic ring containing 5-7 carbon atoms, preferably phenyl.

[00125] As used herein, the term “n-membered heteroaryl” refers to a heteroaryl group containing m aromatic ring-forming carbon atoms and (n-m) aromatic ring-forming heteroatoms, the heteroatoms being selected from O, S and N. For example, 5-7 membered heteroaryl includes, but is not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole and pyridine. Heteroaryl may be optionally substituted with one or more suitable substituent(s).

[00126] As used herein, the term “alkoxy” refers to an alkyl with a single bond attached to an oxygen atom. The point of attachment of the alkoxy group to the molecule passes through the oxygen atom. Alkoxy can be described as alkyl-O-. The term "C _1-6 alkoxy" refers to a straight or branched alkoxy group containing from 1 to 6 carbon atoms. The term "C _1-6 alkoxy" includes the term "C _1-3 alkoxy" in its definition. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexoxy and the like. The alkoxy group may optionally be substituted with one or more suitable substituent(s).

[00127] As used herein, a range of numerical values that refers to the number of substituents, the number of carbon atoms, or the number of ring members is a numbering of all integers in the range, and the range is only a simplified representation thereof. For example:

"1-4 substituent(s)" means 1, 2, 3 or 4 substituent(s);

"1-3 substituent(s)" means 1, 2 or 3 substituents);

"3-12 membered ring" means a 3, 4, 5, 6, 7, 8,9, 10, 11 or 12 membered ring;

"3-14 membered ring" means a 3, 4, 5, 6, 7, 8, 9, 10, I, 12, 13 or 14 membered ring;

"3-8 membered ring" means a 3, 4, 5, 6, 7 or 8 membered ring;

"1-12 carbons" or "C _1-12 " means 1 (C ₁ ), 2 (C ₂ ), 3 (C ₃ ), 4 (C ₄ ), 5 (C ₅ ), 6 (C ₆ ) , 7 (C ₇ ), 8 (C ₈ ), 9 (C ₉ ), 10 (C ₁₀ ), 11 (C ₁₁ ) or 12 (C ₁₂ ) carbon atoms;

"1-6 carbons" or " _C1-6 " means 1 ( _C1 ), 2 ( _C2 ), 3 ( _C3 ), 4 ( _C4 ), 5 ( _C5 ) or 6 carbon atoms;

“1-4 carbon atoms” or “C _1-4 ” 1 (C ₁ ), 2 (C ₂ ), 3 (C ₃ ), 4 (C ₄ ) carbon atoms;

"2-6 carbons" or " _C2-6 " means 2 ( _C2 ), 3 ( _C3 ), 4 ( _C4 ), 5 ( _C5 ) or 6 ( _C6 ) carbon atoms;

"C _3-8 " means 3 (C ₃ ), 4 (C ₄ ), 5 (C ₅ ), 6 (C ₆ ), 7 (C ₇ ), 8 (C ₈ ) carbon atoms; And

"3-8 ring members" means 3, 4, 5, 6, 7 or 8 ring members.

[00128] Thus, the numerical range associated with the number of substituents, the number of carbon atoms, or the number of ring members is also covered by any of its subranges, and each range is also considered to be disclosed in the present invention.

[00129] In accordance with a second aspect, the present disclosure relates to a pharmaceutical composition containing the above or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[00130] The pharmaceutical compositions of the present invention can be formulated in suitable dosage forms for oral, topical (including, without limitation, topical application, spray, and the like), parenteral (including subcutaneous, intramuscular, intradermal and intravenous), bronchial or nasal administration if necessary. Preferably, the pharmaceutical compositions of the present invention may be formulated in suitable dosage forms for oral or external use. More preferably, the pharmaceutical compositions of the present invention can be formulated in suitable dosage forms for oral administration.

[00131] When using a solid carrier, the drug may be tabletted, placed in a hard gelatin capsule in the form of a powder or pellet, or in the form of a lozenge or lozenge. The solid carrier may contain conventional auxiliaries such as binders, fillers, tabletting agents, disintegrants, wetting agents, and the like. If necessary, the tablet can be coated with a film using traditional methods. When using a liquid carrier, the preparation may be in the form of a syrup, emulsion, paste, soft gelatin capsule, sterile injectable vehicle, aqueous or non-aqueous liquid suspension, or may be a dry product for dissolution in water or other suitable carrier medium prior to use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous carrier vehicles (including edible oils), preservatives, and flavoring and/or coloring agents. For parenteral administration, the carrier medium will typically comprise sterile water, at least in large part, although saline solutions, glucose solutions, and the like can be used. Injectable suspensions may also be used, in which case conventional suspending agents may be used. Traditional preservatives, buffers, etc. may also be added to parenteral dosage forms. Pharmaceutical compositions are prepared by conventional techniques suitable for the desired preparation containing suitable amounts of the active ingredient, namely a compound of formula (G), a compound of formula (G') or a compound of formula (I) in accordance with the present invention.

[00132] Compositions suitable for parenteral injection may

contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for conversion into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters , such as ethyl oleate.

[00133] Such compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It may be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be due to the use of absorption delaying agents, such as aluminum monostearate and gelatin.

[00134] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert standard excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) excipients or dry diluents such as, for example, starches, lactose, sucrose, glucose , mannitol and silicic acid; (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum; (c) moisturizing agents such as, for example, glycerin; (d) disintegrants such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (f) dissolution retarding agents such as, for example, paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (h) absorbents such as, for example, kaolin and bentonite clay; and (i) lubricants such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof.

[00135] Solid compositions of this type can also be used as fillers in soft and hard gelatin capsules for filling with excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00136] Solid dosage forms, such as tablets, dragees, capsules, pills and granules, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents and may also be of such a composition that they can release the active compound or compounds in a delayed manner in a specific part of the intestine. Examples of encapsulating compositions that can be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, optionally with one or more of the above excipients.

[00137] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of such substances, etc.

[00138] In addition to such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and aromatic agents.

[00139] Suspensions, in addition to the active ingredients, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters of sorbitan, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar or gum tragacanth, or mixtures of such substances and so on.

[00140] Dosage forms for topical application of the compound of the present invention include pastes, powders, sprays and inhalants. The active component is mixed under sterile conditions with a physiologically acceptable vehicle and any preservatives, buffers or propellants, if necessary. Ophthalmic compositions, ophthalmic ointments, powders and solutions are also provided within the scope of the present invention.

[00141] A dosage form for external use of a compound of the present disclosure may be in the form of a water-in-oil (w/o) or oil-in-water (o/w) emulsion, in a multiemulsion form such as a water-in-water form. oil-in-water (w/o/w) or oil-in-water-oil (o/w/o) emulsion, or in the form of an aqueous dispersion or lipid dispersion, gel or aerosol.

[00142] A dosage form for external use of a compound of the present disclosure may contain additives and auxiliaries such as emulsifiers, thickeners, gelling agents, water fixatives, lyophilizers, stabilizers, colors, flavors and preservatives. Suitable emulsifiers include stearic acid, triethanolamine and PEG-40 stearate. Suitable thickeners include glyceryl monostearate and PEG600. Suitable preservatives include propylparaben and chlorocresol. Suitable lyophilizing additives include dimethicone and polydimethylcyclosilocean. Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol 600.

[00143] A topical dosage form of a compound of the present disclosure may include pastes, lotions, gels, emulsions, microemulsions, sprays, transdermal patches, and the like, which may be applied topically for the treatment of atopic dermatitis, eczema, psoriasis, and scleroderma, itching, vitiligo, hair loss and other skin diseases. In particular, the external dosage form of the compound of the present disclosure are pastes that can be applied topically for the treatment of skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo and hair loss, and other skin diseases.

[00144] The amount of a compound of formula (G), a compound of formula (G'), or a compound of formula (I) in a pharmaceutical composition or dosage form can be appropriately determined by those skilled in the art as necessary. For example, a compound of formula (G), a compound of formula (G'), or a compound of formula (I) may be provided in a pharmaceutical composition or dosage form in a therapeutically effective amount.

[00145] In accordance with a third aspect, the present disclosure provides the use of a compound as described above, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a composition as described above, in the preparation of a medicament for the treatment and/or prevention of JAK-related diseases or violations.

[00146] "JAK-related diseases or disorders" include, but are not limited to, the following:

arthritis, including rheumatoid arthritis, juvenile arthritis and psoriatic arthritis;

autoimmune diseases or disorders, including autoimmune disorders in one organ or one cell type, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, pernicious anemia with autoimmune atrophic gastritis, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulonephritis, autoimmune disorders including systemic autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, Negren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic scleroderma, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid) and other B-cell (humoral) or T-cell autoimmune diseases (including Cogan's syndrome), ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I diabetes mellitus, or juvenile diabetes mellitus, or thyroiditis;

cancer or tumor, including digestive/gastrointestinal cancer, colorectal cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast cancer, ovarian cancer, prostate cancer glands, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral melanoma and metastatic melanoma) , Kaposi's sarcoma, myeloma (including multiple myeloma), myeloproliferative disorders, proliferative diabetic retinopathy or disorders associated with angiogenesis (including solid tumors);

diabetes mellitus, including type I diabetes mellitus or complications of diabetes mellitus;

ocular diseases, disorders or conditions, including autoimmune ocular diseases, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis and lens uveitis associated with Behçet's disease), keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoplakia, mucosal pemphigoid ocular membranes, Moran's ulcer, scleritis, ocular symptoms of Graves' disease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye syndrome), bullous lesions, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis or neovascularization of the eye;

inflammation, allergies or bowel conditions, including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis or mastocytosis;

neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative disease caused by cerebral ischemia or traumatic injury, stroke, glutamate neurotoxicity or hypoxia; ischemia-reperfusion injury in stroke, myocardial ischemia, renal ischemia, myocardial infarction, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation;

skin diseases, conditions or disorders, including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other itchy conditions, vitiligo, hair loss;

allergies, including mammalian allergic dermatitis (including equine allergic diseases such as insect bite allergies), summer eczema, Culex itching syndrome (sweet itch), emphysema, inflammatory airway disease, recurrent airway obstruction airway hyperresponsiveness or chronic obstructive pulmonary disease;

bronchial asthma and other obstructive airway diseases, including chronic or refractory bronchial asthma, advanced bronchial asthma, bronchitis, bronchial asthma, allergic bronchial asthma, endogenous form of bronchial asthma, exogenous form of bronchial asthma or dust bronchial asthma; And

graft rejection, including islet cell graft rejection, bone marrow graft rejection, graft-versus-host disease, organ graft and cellular graft rejection (eg, bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islets, kidney, limbs, liver, lung, muscle, myoblasts, nerve, pancreas, skin, small intestine or trachea) or xenotransplantation.

[00147] In accordance with a fourth aspect, the present invention provides a method of treating JAK-related diseases or disorders, the method comprising administering a therapeutically effective amount of a compound as described above, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a composition as described above for patients in need. The patient is preferably a mammal and, more preferably, a human patient. The route of administration may be oral, topical (including, but not limited to, topical application, spraying, and the like), parenteral (including subcutaneous, intramuscular, cortical, and intravenous) administration, bronchial administration, or nasal administration. The administration is preferably oral or local. More preferably, administration is oral.

[00148] Surprisingly, the compound of the present disclosure has demonstrated excellent efficacy as a JAK kinase inhibitor in experiments, superior to existing JAK kinase inhibitors such as filgotinib, and potentially having good safety.

[00149] Preferably, the present disclosure relates to the following embodiments:

1. Compound of formula (G)

or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein

L represents C=O, O=S=O, CH ₂ or a bond; And

Χ ₁ represents N or CR ₁₄ ; And

X ₂ represents N or CR ₁₅ ; And

X ₃ represents N or CR ₁₆ ; And

R ₁₄ , R ₁₅ , R ₁₆ are each independently selected from H, C _1-6 alkyl, and

R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl or C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7- membered heteroaryl or 5-11 membered bicyclic heteroalkyl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ , where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and they are optionally substituted with one or more substituents, each independently selected from -OH, -CN,; or R ₁₇ , R ₁₈ and the N atom connected to them form a 3-14 membered ring; And

0, 1, 2, 3 or 4 R ₂ are present in formula (G) and R ₂ is selected from halogen, C _1-6 alkyl;

And

R ₁ is selected from -OH, -CN, C _1-8 alkyl, C _3-7 cycloalkyl, 3-10 membered heterocycloalkyl, wherein 3-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ ; And

R ₄ is each independently selected C _1-6 alkyl.

2. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ represents N.

3. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₂ represents N.

4. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₃ represents N.

5. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is CR ₁₄ , X ₂ is N or CR ₁₅ and X ₃ is CR ₁₆ .

6. The compound, or its optical isomer, or its pharmaceutically acceptable salt according to claim 1, where X ₁ , X ₂ and X ₃ are the same.

7. The compound, or its optical isomer, or its pharmaceutically acceptable salt according to claim 6, where X ₁ , X ₂ and X ₃ represent CH.

8. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. -7, where L represents C=O, O=S=O or CH ₂ .

9. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of paragraphs. 1-7, where R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, - C _1-6 alkyl or C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 membered heteroaryl, or 5-11 membered bicyclic heteroalkyl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl , C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and optionally substituted with one or more of -OH, -CN.

10. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl , 5-7 membered heteroaryl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ .

11. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 -membered heteroaryl and R ₁₃ is substituted with 0, 1, 2 or 3 R ₁ .

12. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, wherein R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 heterocycloalkyl and are optionally substituted by one or more of -OH, -CN.

13. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₇ , R ₁₈ and the N atom connected to them form a 4-10-membered ring.

14. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where L is C=O and R ₁₃ is -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ , where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl and are optionally substituted with one or more of -OH, -CN, or R ₁₇ , R ₁₈ and an N atom , connected to them, form a 3-14-membered ring.

15. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, wherein 1, 2 or 3 R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl.

16. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 11, wherein 1 or 2 R ₂ are present and R ₂ is selected from halogen and C _1-6 alkyl.

17. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₃ is substituted with 0 or 1 R ₁ and R ₁ is selected from -OH, C _1-6 alkyl, 5-7 membered heterocycloalkyl and C _3-7 cycloalkyl, wherein 5-7 membered heterocycloalkyl is optionally substituted with 1 , 2, 3 or 4 C _1-3 alkyls.

18. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, wherein the compound is selected from the group consisting of:

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-(piperidin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-morpholinylpyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 1-methylpiperidin-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4 -methylpiperazin-1-yl)pyrazin-2-yl)ketone;

5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )phenol;

5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole -6-yl)phenol;

4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4^]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol ;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone;

4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-indazol-6-yl)-5-ethyl-2- fluorophenol;

Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone;

(2-(6-(2-ethyl-5-φτop-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 3-hydroxylcyclobutyl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-4-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-3-yl)ketone;

(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-( 1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6 -yl)phenol;

4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol;

5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-(1] imidazol-2-yl)-1H-indazol-6-yl)phenol;

4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol ;

5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl) -1H-indazol-6-yl)phenol;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)ethan-1-one;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) - yl)propan-1-one;

(1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-e]imidazol-5-(1H )-yl)-2-methylpropan-1-one);

2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)ethan-1-one;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)-3-methylbutan-1-one;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(pyrrolidin-1 yl)ketone;

Azetidin-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(piperidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(morpholino)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(4-methylpiperazin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(4-ethylpiperazin-1-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-e] imidazol-5(1H)-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5( 1H)-yl)ketone;

(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone;

(R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H )-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxylasetidin-1-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (4-hydroxylpiperidin-1-yl)ketone;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-(1]imidazol-5-( 1H)-carboxamide;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-carboxamide;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-e]imidazol- 5(1H)-carboxamide;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5 -carbonyl)azetidine-3-nitrile;

1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5 -carbonyl)pyrrolidine-3-nitrile;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazole-5(1H)-carboxamide;

Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate ;

Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate ;

(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4 -d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;

3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)- yl)-3-hydroxypropionitrile;

2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-(1]imidazol-5 (1H)-carboxamide;

N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-carboxamide;

N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H) -carboxamide;

N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imvdazol-5(1H) -carboxamide;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (2,6-diazaspiro[3,3]heptan-2-yl)ketone;

(S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-indazole and

(R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-indazole.

19. A pharmaceutical composition for the treatment and/or prevention of a JAK-mediated disease or disorder, containing a compound or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims. 1-18 in a therapeutically effective amount and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

20. Use of a compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-18 or the pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment and/or prevention of a JAK-mediated disease or disorder.

21. The use of claim 20, wherein the JAK-mediated disease or disorder is selected from the group consisting of arthritis, autoimmune diseases or disorders, cancer or tumor, diabetes, eye diseases, disorders or conditions, inflammation, allergies or bowel conditions, neurodegenerative diseases , skin diseases, conditions or disorders, allergies, asthma and other obstructive airway diseases and transplant rejection.

22. Compound of formula (I)

or an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

Where

L represents C=O, O=S=O, CH ₂ or a bond; And

X represents CH or N;

ring A is C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 member heteroaryl;

0, 1, 2, 3 or 4 R ₁ are present in formula (I) and R ₁ is selected from C _1-8 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, wherein 3-7 membered heterocycloalkyl is optionally substituted 1, 2, 3 or 4 R ₄ ,

0, 1, 2, 3 or 4 R ₂ are present in formula (I) and R ₂ is selected from C _1-6 alkyl halogen;

R ₄ is selected from C _1-3 alkyl.

23. The compound, or its optical isomer, or its pharmaceutically acceptable salt according to claim 22, where L represents C=O, O=S=O or CH ₂ .

24. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 22, wherein X represents CH.

25. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, where ring A is a 5-6 membered heteroaryl or phenyl.

26. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, wherein 0 or 1 R ₁ is present and R ₁ is selected from C _1-6 alkyl and 5-7 membered heterocycloalkyl, wherein the 5-7 member heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 C _1-3 alkyls .

27. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, wherein 1 or 2 R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl.

28. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, where

L represents C=O and O=S=O; X represents CH;

ring A is 5-7 membered heteroaryl or C _5-7 aryl;

0, 1, 2, 3 or 4 R ₁ are present and R ₁ is selected from C _1-8 alkyl and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ₄ .

1, 2 or 3 R ₂ are present and R ₂ is selected from halogen;

R ₄ is selected from C _1-3 alkyl.

29. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 28, wherein ring A is a 5-6 membered heteroaryl or phenyl.

30. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 28, wherein 0 or 1 R ₁ is present and R ₁ is selected from C _1-6 alkyl and 5-7 membered heterocycloalkyl, wherein 5-7 membered the heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 C _1-3 alkyls.

31. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 28, wherein 1 or 2 R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl.

32. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof, according to any one of paragraphs. 22-24, wherein the compound is selected from the group consisting of:

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-(piperidin-1-yl)pyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-morpholinepyrazin-2-yl)ketone;

(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone;

5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H -indazol-6-yl}phenol;

5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H -indazol-6-yl}phenol;

3-ethyl-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6 -yl}phenol;

5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )phenol and

5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole -6-yl)phenol.

33. A pharmaceutical composition for the treatment and/or prevention of a JAK-mediated disease or disorder, containing a compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims. 22-32 in a therapeutically effective amount and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

34. Use of a compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-32 or the pharmaceutical composition according to claim 33 in the manufacture of a medicament for the treatment and/or prevention of a JAK-mediated disease or disorder.

35. The use of claim 34, wherein the JAK-mediated disease or disorder is selected from the group consisting of arthritis, autoimmune diseases or disorders, cancer or tumor, diabetes, eye diseases, disorders or conditions, inflammation, allergies or bowel conditions, neurodegenerative diseases , skin diseases, conditions or disorders, allergies, asthma and other obstructive airway diseases and transplant rejection.

[00150] The present invention will be further illustrated and described below in conjunction with drawings and specific examples.

Brief description of drawings

[00151] In FIG. Figure 1 shows the NMR spectrum for compound MDI-2.

[00152] In FIG. Figure 2 shows the NMR spectrum for compound MDI-201.

[00153] In FIG. Figure 3 shows the NMR spectrum for compound MDI-202.

[00154] In FIG. Figure 4 shows the NMR spectrum for compound MDI-206.

[00155] In FIG. Figure 5 shows the IC50 curve of JAK1 experiments for MDI-201, MDI-202 and MD1-206, in which filgotinib was used as a positive control.

[00156] In FIG. Figure 6 shows the IC50 curve for JAK2 experiments for MDI-201, MDI-202 and MDI-206, in which filgotinib was used as a positive control.

[00157] In FIG. Figure 7 shows the IC50 curve of JAK3 experiments for MDI-201, MDI-202 and MDI-206, in which filgotinib was used as a positive control.

[00158] In FIG. Figure 8 shows the IC50 curve for TYK2 experiments for MDI-201, MDI-202 and MDI-206, in which filgotinib was used as a positive control.

EXAMPLES

[00159] Compounds of formula (G), compounds of formula (G'), or compounds of formula (I) of the present disclosure can be synthesized by various methods known to those skilled in the art of organic synthesis. The following specific examples provide some illustrative methods for synthesizing compounds of formula (G), compounds of formula (G'), or compounds of formula (I), and such methods are well known in the art of synthetic chemistry. It will be appreciated that, with respect to the exemplary embodiments of the present application, those skilled in the art can appropriately select reagents, reaction conditions, and protecting groups to easily formulate other synthetic routes for compounds of formula (G), formula (C'), or formula (I).

[00160] The present disclosure is further described below along with examples. However, such examples do not limit the scope of the present disclosure.

[00161] Example 1:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 (1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone (MDI-2)

[00162] Route for synthesizing target compound 8 (i.e., MDI-2):

[00163] Synthetic route for intermediate 10

[00164] Synthetic route for intermediate 16

[00165] Synthetic route for intermediate 20

Synthesis method:

[00166] Synthesis of intermediate 1: 6-bromo-1H-indazole-3-formaldehyde

[00167] Sodium nitrite (14.00 g, 200 mmol) was dissolved in 75 ml DMF and 100 ml water, and then cooled to 0°C. Under nitrogen protection, 3N HCl (23 mL, 68.9 mmol) was slowly added dropwise and after addition the reaction was carried out for 10 minutes. At 0°C, 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35 ml) was slowly added dropwise to the reaction solution. After the dropwise addition was completed, the reaction was continued at room temperature overnight. The resulting mixture was extracted with ethyl acetate 3 times and then the organic phases were combined, washed 3 times with water, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 1 in 83.6% yield.

[00168] ¹ H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.80 (d, J=4.0 Hz , 1H), 7.52 (dd, J=8.0 Hz, J=4.0 Hz, 1H).

[00169] Synthesis of intermediate 2: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-formaldehyde

[00170] Intermediate 1 (1.56 g, 6.93 mmol) was dissolved in dry tetrahydrofuran and then cooled to 0°C. Sodium hydride (0.33 g, 8.32 mmol) was added slowly and the reaction was carried out at room temperature for 1 hour and then cooled to 0°C. Thereafter, 2-(trimethylsilyl)ethoxymethyl chloride (1.73 g, 10.40 mmol) was added dropwise and the reaction was carried out at room temperature overnight. The reaction was quenched by adding water. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 2 in 49.2% yield.

[00171] ¹ H NMR (400 MHz, CDCl3) δ 10.25 (s, IH), 8.22 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.88 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 7.52 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 5.81 (s, 2H), 3 .63-3.58 (m, 2H), 0.97-0.93 (m, 2H), 0.04 (s, 9H).

[00172] Synthesis of Intermediate 16: Tert-Butyl 3,4-diaminopyrrolidinyl-1-carboxylate

[00173] 1. Synthesis of intermediate 11: Tert-butyl-2,5-dihydro-1H-pyrrole-1-carboxylate

[00174] 3-Pyrroline (10.0 g, 0.15 mol) was dissolved in 400 ml of dichloromethane and triethylamine (40.6 ml, 0.29 mol) and then cooled to 0°C. (Boc) _2O (37.9 g, 0.17 mol) was added slowly. The reaction was carried out at room temperature overnight. Water was added and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water three times, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 11 in 91.0% yield.

[00175] 2. Synthesis of intermediate 12: Tert-butyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

[00176] Intermediate 11 (24.5 g, 0.15 mol) was dissolved in 450 ml of dichloromethane and then cooled to 0°C. M-chloroperbenzoic acid (37.5 g, 0.22 mol) was added slowly in separate portions. The reaction was carried out at room temperature overnight. Saturated sodium thiosulfate (40 ml) was then added and then stirred for 30 minutes. The aqueous phase was extracted twice with dichloromethane, washed with saturated potassium carbonate solution, water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column yielding intermediate 12 in 84.9% yield.

[00177] ¹ H NMR (400 MHz, CDCl3) δ 3.85 (d, J=12.0 Hz, 1H), 3.77 (d, J=12.0 Hz, 1H), 3.69-3 .67 (m, 2H), 3.36-3.30 (m, 2H), 1.45 (s, 9H).

[00178] 3. Synthesis of intermediate 13: Tert-butyl-3-azido-4-hydroxylpyrrolidinyl-1-carboxylate

[00179] Intermediate 12 (20.8 g, 0.12 mol) was dissolved in 150 ml of 1,4-dioxane and 50 ml of water, and then sodium azide (24.0 g, 0.37 mol) was added. The mixture was heated to 106°C and reacted for 18 hours, then cooled to room temperature, and then 100 ml of saturated saline was added. The resulting mixture was extracted with dichloromethane (250 ml x 4) and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give intermediate 13 in 100% yield.

[00180] ¹ H NMR (400 MHz, CDCl3) δ 4.27-4.24 (m, 1H), 3.94 (s, IH), 3.73-3.59 (m, 2H), 3, 41-3.36 (m, 2H), 1.47 (s, 9H).

[00181] 4. Synthesis of Intermediate 14: Tert-Butyl-3-azido-4-((methanesulfonyl)oxy)pyrrolidinyl-1-carboxylate

[00182] Intermediate 13 (28.0 g, 0.12 mol) was dissolved in 350 ml of dichloromethane and triethylamine (37.3 g, 0.37 mol) and cooled to 0°C, and then methanesulfonyl chloride was added slowly dropwise ( 16.9 g, 0.15 mol). After addition, the reaction was carried out at room temperature for 2 hours, the reaction was quenched with water and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated to give intermediate 14 in 98.0% yield.

[00183] 5. Synthesis of Intermediate 15: Tert-Butyl 3,4-diazidopyrrolidinyl-1-carboxylate

[00184] Intermediate 14 (36.9 g, 0.12 mol) was dissolved in 250 ml DMF to which sodium azide (23.5 g, 0.36 mol) was added. The mixture was heated to 90°C, reacted for 2 days and cooled to room temperature, and then 750 ml of water was added. The resulting mixture was extracted with butyl tert-butyl ether (400 mL x 4) and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and purified on a silica gel column to give intermediate 15 in 62.2% yield.

[00185] 6. Synthesis of Intermediate 16: Tert-Butyl 3,4-diaminopyrrolidinyl-1-carboxylate

[00186] Intermediate 15 (18.9 g, 0.08 mol) was dissolved in 200 ml methanol and 10% Pd/C was added where it was replaced with hydrogen 3 times. The mixture was heated to 40°C and the reaction was carried out for 2 days. The resulting mixture was filtered and concentrated to give intermediate 16 in 78% yield.

[00187] ¹ H NMR (400 MHz, CDCl3) δ 3.51-3.49 (m, 2H), 3.40-3.36 (m, 2H), 3.21-3.11 (m, 2H ), 1.47 (s, 9H).

[00188] Synthesis of Intermediate 3: Tert-Butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)3,4,6,6a-tetrahydropyrrolo [3,4-d]imidazole-5(1H)-carboxylate

[00189] Intermediate 2 (1.56 g, 6.93 mmol) and tert-butyl-3,4-diaminopyrroline-1-carboxylate (1.56 g, 6.93 mmol) were dissolved in 5 ml hexafluoroisopropanol and heated to 40°C for 2 days. The resulting mixture was concentrated and purified on a silica gel column to give intermediate 3 in 54.7% yield.

[00190] Synthesis of Intermediate 4: Tert-Butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)4,6-dihydropyrrolo[3, 4-d]imidazole-5(1H)-carboxylate

[00191] Oxalyl chloride (0.53 g, 4.20 mmol) was dissolved in dry dichloromethane 15 ml and cooled to -78°C under nitrogen protection. DMSO (0.61 g, 7.84 mmol) was added dropwise slowly. After addition was complete, the mixture was allowed to react for 30 minutes. Intermediate 3 (1.00 g, 1.87 mmol) in dichloromethane was added slowly dropwise. After adding dropwise, the mixture was allowed to react for 30 minutes. Dry triethylamine (1.89 g, 18.66 mmol) was added slowly dropwise and the mixture was allowed to react for 10 minutes. The temperature was slowly increased and the reaction was carried out at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride and the resulting mixture was extracted twice with dichloromethane and the organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 4 in 36.3% yield.

[00192] ¹ H NMR (400 MHz, CDCl3) δ 8.36 (d, J=4.0 Hz, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.44 (dd , J=8.0 Hz, J=4.0 Hz, 1H), 5.69 (s, 2H), 4.64-4.52 (m, 4H), 3.67-3.56 (m, 2H), 1.56 (s, 9H), 0.95-0.89 (m, 2H), 0.03 (s, 9H).

[00193] Synthesis of Intermediate 5: Tert-Butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl )ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[00194] Intermediate 4 (110 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran and cooled to 0°C. Sodium hydride (12.3 mg, 0.31 mmol) was added and allowed to react at room temperature for 30 minutes. The mixture was cooled to 0°C. 2-(trimethylsilyl)ethoxymethyl chloride (41.2 mg, 0.25 mmol) was added slowly dropwise and allowed to react at room temperature for 4 hours. The reaction was quenched with water and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 5 in 73.1% yield.

[00195] ¹ H NMR (400 MHz, CDCl3) δ 8.41-8.36 (m, 1H), 7.79 (s, 1H), 7.44 (dd, J =8.0 Hz, J= 4.0 Hz, 1H), 5.94 (d, J=12.0 Hz, 2H), 5.73 (s, 2H), 4.65-4.52 (m, 4H), 3.63- 3.57 (m, 4H), 1.56 (s, 9H), 0.96-0.91 (m, 4H), 0.03 (s, 18H).

[00196] Synthesis of intermediate 10: 5-(piperidin-1-yl)pyrazin-2-carboxylic acid

[00197] 1. Synthesis of Intermediate 9: Methyl 5-(piperidin-1-yl)pyrazin-2-carboxylate

[00198] Methyl 5-chloropyrazine-2-carboxylate (1.72 g, 10 mmol) was dissolved in 10 ml DMF and N,N-diisopropylethylamine (4.3 ml, 25.0 mmol) and piperidine hydrochloride (1, 45 g, 12.0 mmol). The mixture was stirred overnight at room temperature. Water was added while stirring vigorously. The solid precipitated, filtered and the filter cake was washed with water and dried to give intermediate 9 in 80.0% yield.

[00199] 2. Synthesis of intermediate 10: 5-(piperidin-1-yl)pyrazin-2-carboxylic acid

[00200] Intermediate 9 (430 mg, 1.95 mmol) was dissolved in 20 ml of tetrahydrofuran and 20 ml of water, to which lithium hydroxide (163 mg, 3.88 mmol) was added. The reaction was carried out at room temperature for 4 hours. The mixture was concentrated by distilling off tetrahydrofuran under reduced pressure and the pH was adjusted to 4 with 1 N HCl. The solid precipitated, filtered and the filter cake was washed with water and dried to give intermediate 10 in 91.5% yield.

[00201] 'H NMR (400 MHz, CDC13) δ 8.84 (s, 1H), 8.02 (s, 1H), 3.76-3.73 (m, 4H), 1.78-1, 65 (m, 6H).

[00202] Synthesis of intermediate 6: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

[00203] Intermediate 10 (34.3 mg, 0.17 mmol) and N,N-diisopropylethylamine (58.2 mg, 0.45 mmol) were dissolved in DMF, HATU (85.7 mg, 0.22 mmol) was added ) and the reaction was carried out at room temperature for 10 minutes. Intermediate 5 (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane to which 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF and then slowly added to the previous reaction solution. This was left to react overnight at room temperature. The reaction was quenched with water and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 6 in 57.3% yield.

[00204] ¹ H NMR (400 MHz, CDCl3) δ 8.87 (d, J=8.0 Hz, 1H), 8.41-8.37 (m, 1H), 8.09-8.04 ( m, 1H), 7.80 (s, 1H), 7.44-7.41 (m, 1H), 5.96 (s, 2H), 5.75 (d, J=8.0 Hz, 2H ), 5.28 (s, 1H), 5.19 (s, 1H), 4.99 (s, 1H), 4.91 (s, 1H), 3.74-3.68 (m, 4H) , 3.67-3.64 (m, 2H), 3.63-3.59 (m, 2H), 1.71-1.68 (m, 6H), 0.95-0.91 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

[00205] Synthesis of intermediate 20: (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy) ethyl)trimethylsilane

[00206] 1. Synthesis of intermediate 17: 5-ethyl-2-fluorophenol

[00207] 5-Bromo-2-fluorophenol (200.0 mg, 1.05 mmol) and bis(tri-tert-butylphosphorus)palladium (10.7 mg, 0.02 mmol) were dissolved in 10 ml THF. The atmosphere was replaced with nitrogen, which was repeated 3 times. The temperature was lowered to 10-20°C. A 1 mol/L diethylzinc solution (2.3 mL, 2.30 mmol) was added dropwise. After addition was complete, the temperature was raised to 50°C. This was left to react overnight and the temperature was cooled to 0°C. The reaction was quenched with water and filtered using celite. The celite layer was washed with ethyl acetate. The resulting filtrate was extracted with ethyl acetate and the organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After drying, this was concentrated and separated by column chromatography to give an oily liquid in 65.1% yield.

[00208] ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.97 (d, J=8.0 Hz, 1H), 6.85 (d, J=12.0 Hz, 1H), 6.69- 6.65 (m, 1H), 2.91-2.55 (m, 2H), 1.21 (t, J=8.0 Hz, 3H).

[00209] 2. Synthesis of intermediate 18: 4-bromo-5-ethyl-2fluorophenol

[00210] Intermediate 17 (200.1 mg, 1.43 mmol) was dissolved in 6 ml of acetonitrile to which CuBr ₂ (957.5 mg, 4.29 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water, extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. This was concentrated and separated by column chromatography to give a colorless oil, yield: 78.1%.

[00211] ¹ H NMR (400 MHz, CDCl3) δ7.25 (d, J=12.0 Hz, 1H), 6.89 (d, J=12.0 Hz, 1H), 2.99-2, 93 (m, 2H), 1.19 (t, J=12.0 Hz, 3H).

[00212] 3. Synthesis of intermediate 19: 2-((4-bromo-5-ethyl-2-fluorophenoxy)methoxy)ethyl)trimethylsilane

[00213] Intermediate 18 (220.0 mg, 1.00 mmol) was dissolved in 6 ml DCM, DIPEA (130.5 mg, 1.10 mmol) was added and the temperature was lowered to 0°C. SEMCl (168.2 mg, 1.10 mmol) was added dropwise at 0°C. After addition, the temperature was raised to room temperature and the mixture was allowed to react for 8 hours. The reaction was quenched with water and extracted with DCM. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. This was concentrated to give a colorless oil, crude yield: 99.1%.

[00214] ¹ H NMR (400 MHz, CDCl3) δ7.26 (d, J=12.0 Hz, 1H), 6.89 (d, J=12.0 Hz, 1H), 5.24 (s, 2H) 3.82-3.78 (m, 2H) 2.97-2.92 (m, 2H), 1.19 (t, J=12.0 Hz, 3H), 0.98 -0.94 (m, 2H), 0.01 (s, 9H).

[00215] 4. Synthesis of intermediate 20: (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy) methoxy)ethyl)trimethylsilane

[00216] Compound 19 (280.0 mg, 0.80 mmol), pinacolborate (206.1 mg, 0.80 mmol), Pd(dppf)Cl ₂ (59.2 mg, 0.08 mmol) and KOAc ( 237.5 mg, 2.40 mmol) was dissolved in 1,4-dioxane (6 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C and it was left to react overnight. After completion of the reaction, it was quenched with water, extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. This was concentrated and separated by column chromatography to give a colorless oil, yield: 56.2%.

[00217] ¹ H NMR (400 MHz, CDCl3) δ7.48 (d, J=12.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 5.28 (s, 2H), 3.82-3.78 (m, 2H) 2.89-2.83 (m, 2H), 1.35 (s, 12H), 1.17 (t, J=8.0 Hz, 3H), 0.98-0.94 (m, 2H), 0.01 (s, 9H).

[00218] Synthesis of intermediate 7: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-( piperidin-1-yl)pyrazin-2-yl)ketone

[00219] Intermediate 6 (65.0 mg, 0.09 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (40.9 mg, 0.10 mmol), Pd(dppf)Cl ₂ (6.3 mg, 0.01 mmol) and potassium phosphate (25.3 mg , 0.26 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the mixture was extracted 2 times with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 7 in 52.8% yield.

[00220] ¹ H NMR (400 MHz, CDCl3) δ 8.87 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.54 (dd, J=8.0 Hz, J =20.0 Hz, 1H), 8.10 (dd, J=8.0 Hz, 1H), 7.48 (s, IH), 7.27 (s, 1H), 7.20 (d, J =8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, IH), 6.00 (s, 2H), 5.79 (d, J=4.0 Hz, 2H), 5.35 (s, 2H), 5.33 (s, IH), 5.29 (s, 1H), 5.20 (s, 1H), 5.01 (s, 1H), 3.91 (t , J=8.0 Hz, J=20.0 Hz, 2H), 3.76-3.74 (m, 4H), 3.64-3.62 (m, 4H), 2.58 (t, J=8.0 Hz, J=16.0 Hz, 2H), 1.74 -1.72 (m, 6H), 1.10-1.06 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H), 0.04 (s, 9H), 0.03 (s, 9H).

[00221] Synthesis of compound 8 (i.e., MDI-2): (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)--4,6 -dihydropyrrolo[3,4-d]imidazol-5(IH)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

[00222] Intermediate 7 (43.0 mg, 0.05 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The resulting solid was dissolved in 1 ml of methanol, the pH value was adjusted to 8-9 using sodium bicarbonate solution, and then the resulting mixture was extracted 4 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and purified on a preparation plate to obtain 4.5 mg of the final product in 18.0% yield.

[00223] ¹ H NMR (400 MHz, MeOD-d4) δ 8.67 (s, 1H), 8.28 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.21 (s, 1H), 7.40 (s, 1H), 7.18 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.96-6.89 (m, 2H) , 5.14 (s, 2H), 4.82 (s, 2H), 3.76-3.73 (m, 4H), 2.58 (dd, J=12.0 Hz, J=8.0 Hz, 2H), 1.76-1.66 (m, 6H), 1.10 (t, J=8.0 Hz, 3H).

[00224] Example 2: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone (MDI-201)

[00225] Synthesis route for MDI-201:

[00226] Synthesis method:

[00227] Synthesis of intermediate MDI-201-1: Methyl 5-morpholinepyrazine-2-carboxylate

[00228] Methyl 5-chloropyrazine-2-carboxylate (1.5 g, 8.7 mmol) was dissolved in 10 ml DMF and N,N-diisopropylethylamine (3.0 ml, 17.4 mmol) and morpholine (0 .91 g, 10.4 mmol). The mixture was stirred overnight at room temperature. Water was added with vigorous stirring and the solid precipitated and filtered. The resulting filter cake was washed with water and dried to obtain intermediate MDI-201-1 in 72.2% yield.

[00229] Synthesis of intermediate MDI-201-2: 5-morpholinepyrazine-2-carboxylic acid

[00230] Intermediate MDI-201-1 (1.4 g, 6.27 mmol) was dissolved in 20 ml tetrahydrofuran and 20 ml water, lithium hydroxide (0.32 g, 7.53 mmol) was added and the reaction was carried out at room temperature for 4 hours. The reaction mixture was concentrated by distilling off tetrahydrofuran under reduced pressure and the pH was adjusted to 4 with 1 N HCl. The solid precipitated and filtered. The resulting filter cake was washed with water and dried to obtain intermediate MDI-201-2 in 99.1% yield.

[00231] ¹ H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.04 (s, 1H), 3.88-3.86 (m, 4H), 3.80-3, 77 (m, 4H).

[00232] Synthesis of intermediate MDI-201-3: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

[00233] Intermediate MDI-201-2 (27.4 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in DMF to which HATU (67.8 mg) was added , 0.18 mmol). This was left to react at room temperature for 10 minutes. Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF and then slowly added to the previous reaction solution. This was left to react at room temperature overnight and water was added to quench the reaction. The mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MD1-201-3 in 47.8% yield.

[00234] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (d, J=8.0 Hz, 1H), 8.44-8.36 (m, 1H), 8.10 (d, J =8.0 Hz, 1H), 7.80 (s, 1H), 7.46-7.41 (m, 1H), 5.96 (s, 2H), 5.74 (d, J=4, 0 Hz, 2H), 5.27 (s, 1H), 5.19 (s, 1H), 5.00 (s, 1H), 4.92 (s, 1H), 3.90-3.88 ( m, 4H), 3.75-3.72 (m, 4H), 3.64-3.58 (m, 4H), 0.96-0.89 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

[00235] Synthesis of intermediate MDI-201-4: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl )ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-morpholinepyrazin-2-yl)ketone

[00236] Intermediate MDI-201-3 (43.0 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.2 mg, 0.17 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-201-4 in 40.9% yield.

[00237] ¹ H NMR (400 MHz, CDCl3) δ 8.91 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 8.52 (dd, J=8.0 Hz, J =16.0 Hz, 1H), 8.10 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.49 (s, 1H), 7.27 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.00 (s, 2H), 5.79 (d, J=4 .0 Hz, 2H), 5.35 (s, 2H), 5.29 (s, 1H), 5.20 (s, 1H), 5.02 (s, 1H), 4.94 (s, 1H ), 3.91-3.86 (m, 6H), 3.76-3.72 (m, 4H), 3.65-3.61 (m, 4H), 2.58 (t, J=8 .0 Hz, 2H), 1.10-1.03 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H), 0.04 (s, 9H) , 0.03 (s, 9H).

[00238] Synthesis of MDI-201: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

[00239] Intermediate MDI-201-4 (22.0 mg, 0.02 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The resulting solid was dissolved in 1 ml of methanol, and 2 ml of concentrated aqueous ammonia was added to it. The resulting mixture was concentrated to a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was purified on a preparation plate to obtain 8 mg of the final product, with a yield of 61.9%.

[00240] ¹ H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 9.89 (s, 1H), 8.66 (d, J=4.0 Hz, 1H), 8 ,38-8.33 (m, 2H), 7.42 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 5.05 (s, 2H), 4.72 (s, 2H), 3.76-3.74 (m, 4H), 3.71-3.68 (m, 4H), 2.52 (dd, J=12.0 Hz, J=4.0 Hz, 2H), 1.05 (t, J=8.0 Hz, 3H ).

[00241] Example 3: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone (MDI-202)

[00242] Synthesis route for MDI-202:

[00243] Synthesis method:

[00244] Synthesis of intermediate MDI-202-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

[00245] The intermediate 1-methyl-1H-pyrazole-4-carboxylic acid (16.5 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in DMF, where HATU (67.8 mg, 0.18 mmol) was added. This was left to react at room temperature for 10 minutes. Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF and then slowly added to the previous reaction solution. This was left to react at room temperature overnight and water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-202-1 in 41.3% yield.

[00246] ¹ H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 2H ), 7.81(s, 1H), 7.45 (d, J=8.0 Hz, 1H), 5.96 (s, 2H), 5.75 (s, 2H), 5.02-4 .85 (m, 4H), 4.01 (s, 3H), 3.64-3.59 (m, 4H), 0.97-0.91 (m, 4H), 0.03 (s, 9H ), 0.02 (s, 9H).

[00247] Synthesis of intermediate MDI-202-2: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl )ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone

[00248] Intermediate MDI-202-1 (33 mg, 0.05 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (23.3 mg, 0.06 mmol), Pd(dppf)Cl ₂ (3.6 mg, 0.005 mmol) and potassium phosphate (31.3 mg , 0.15 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times and the mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-202-2 in 85.0% yield.

[00249] ¹ H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 2H), 7.49 (s , 1H), 7.20 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.00 (s , 2H), 5.79 (s, 2H), 5.35 (s, 2H), 5.04-4.87 (m, 4H), 4.01 (s, 3H), 3.91 (t, J=8.0 Hz, J=20.0 Hz, 2H), 3.67-3.61 (m, 4H), 2.58 (d, J=8.0 Hz, 2H), 1.11- 1.07 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H), 0.03 (s, 9H), 0.02 (s, 9H).

[00250] Synthesis of MDI-202: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

[00251] Intermediate MDI-202-2 (36.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol, and 2 ml of concentrated aqueous ammonia was added to it. The mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was purified on a preparation plate to obtain 5.0 mg of the final product with a yield of 25.4%.

[00252] ¹ H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 12.87 (s, 1H), 9.89 (s, 1H), 8.35 (d, J= 8.0 Hz, 2H), 7.94 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.06 (d, J= 12.0 Hz, 1H), 6.95 (d, J=12.0 Hz, 1H), 4.89(s, 2H), 4.67 (s, 2H), 3.92 (s, 3H) , 2.51-2.48 (m, 2H), 1.05 (t, J=8.0 Hz, 3H).

[00253] Example 4: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)(1-methylpiperidin-4-yl)ketone (MDI-203)

[00254] MDI-203 may also be referred to as 5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4 -d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

[00255] Synthesis route for MDI-203:

[00256] Synthesis method:

[00257] Synthesis of intermediate MDI-203-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

[00258] 1-Methylpiperidine-4-carboxylic acid (18.6 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in DMF, to which HATU (67.8 mg, 0.18 mmol). This was left to react at room temperature for 10 minutes. Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness (removing trifluoroacetic acid), which was repeated 3 times. The resulting residue was then dissolved in DMF, which was slowly added to the previous reaction solution. This was left to react at room temperature overnight. Water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-203-1 in 40.2% yield.

[00259] ¹ H NMR (400 MHz, CDl3) δ8.29-8.22 (m, 1H), 7.76 (s, 1H), 7.41-7.26 (m, 1H), 5.85 (s, 2H), 5.69 (s, 2H), 4.88-4.59 (m, 4H), 3.63-3.54 (m, 6H), 3.21-2.81 (m , 5H), 2.28-2.01 (m, 4H), 0.93-0.83 (m, 5H), 0.03 (s, 9H), 0.02 (s, 9H).

[00260] Synthesis of intermediate MDI-203-2: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl )ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 1-methylpiperidin-4-yl)ketone

[00261] Intermediate MDI-203-1 (41.29 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.2 mg, 0.17 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-203-2 in 40.9% yield.

[00262] ¹ H NMR (400 MHz, CDCl3) δ8.50-8.44 (m, 1H), 7.49 (s, 1H), 7.22 (dd, J=12.0 Hz, 2H), 7.04 (d, J=12.0 Hz, 1H), 5.98 (d, J=12.0 Hz, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.84-4.69 (m, 4H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 3.38-3.30 (m, 2H ), 2.91-2.54 (m, 5H), 2.13-2.05 (m, 4H), 1.10-1.01 (m, 5H), 0.97-0.89 (m , 3H), 0.03 (s, 9H), 0.02 (s, 18H).

[00263] Synthesis of compound MDI-203: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H ,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

[00264] Intermediate MDI-203-2 (26.4 mg, 0.03 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol, and 2 ml of aqueous concentrated ammonia was added to it. This was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness (removing ammonia water), which was repeated 3 times. After separation, 5.0 mg of the final product was obtained in a yield of 34.2%.

[00265] ¹ H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 9.87 (s, 1H), 9.24 (s, 1H), 8.32 (d, J= 8.0 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.03 (d, J=12.0 Hz, 1H), 6 .96 (d, J=12.0 Hz, 1H), 4.80 (s, 2H), 4.48 (s, 2H), 3.04-3.01 (m, 2H), 2.79 ( s, 3H), 2.55-2.51 (m, 2H), 2.05-1.99 (m, 3H), 1.85-1.78 (m, 2H), 1.01-0, 98 (m, 3H). The two H signals were masked by the water peak (δ=3.37).

[00266] Example 5: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone (MDI-204)

[00267] MDI-204 may also be referred to as 5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazine-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4 -d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

[00268] Synthesis route for MDI-204:

[00269] Synthesis method:

[00270] Synthesis of intermediate MDI-204-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

[00271] 5-(4-methylpiperazin-1-yl)pyrazin-2-carboxylic acid (28.9 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in DMF to which HATU (67.8 mg, 0.18 mmol) was added. This was left to react at room temperature for 10 minutes. Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilylethoxy)methyl)-4, 6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added, the reaction mixture was stirred at room temperature for 30. minutes and concentrated to obtain a residue. The residue was dissolved in dichloromethane and concentrated to dryness (removing trifluoroacetic acid), which was repeated 3 times. The resulting residue was then dissolved in DMF, which was slowly added to the previous reaction solution. This was left to react at room temperature overnight. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-204-1 in 43% yield.

[00272] ¹ H NMR (400 MHz, CDCl3) δ8.86-8.84 (m, 1H), 8.41-8.33 (m, 1H), 8.07-8.05 (m, 1H) , 7.76 (d, J=4.0 Hz, 1H), 7.42-7.38 (m, 1H), 5.92 (s, 2H), 5.70 (d, J=4.0 Hz, 2H), 5.23-4.88(m, 4H), 3.77-3.65 (m, 4H), 3.61-3.55 (m, 4H), 2.55 (t, J=4.0 Hz, 4H), 2.37 (s, 3H), 0.94-0.83 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

[00273] Synthesis of intermediate MDI-204-2: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl )ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

[00274] Intermediate MDI-204-1 (46.0 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl ₂ (4.2 mg, 0.006 mmol) and potassium phosphate (36, 2 mg, 0.17 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-204-2 in 47.2% yield.

[00275] ^1H NMR (400 MHz, CDCl3) δ8.86-8.84 (m, 1H), 8.51-8.43 (m, 1H), 8.08-8.06 (m, 1H) , 7.45 (d, J=4.0 Hz, 1H), 7.26-7.23 (m, IH), 7.21-7.14 (m, 1H), 7.02 (d, J =8.0 Hz, 1H), 5.97 (s, 2H), 5.75(d, J=4.0 Hz, 2H), 5.32 (s, 2H), 5.25-5.16 (m, 2H), 4.99-4.90 (m, 2H), 3.87-3.83 (m, 2H), 3.77-3.74 (m, 4H), 3.63-3 .56 (m, 4H), 2.56-2.51 (m, 6H), 2.37 (s, 3H), 1.07-1.01 (m, 3H), 0.99-0.88 (m, 6H), 0.03 (s, 9H), -0.07(s, 9H), -0.09 (s, 9H).

[00276] Synthesis of compound MDI-204: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H ,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

[00277] Intermediate MDI-204-2 (28.7 mg, 0.03 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The resulting solid was dissolved in 1 ml of methanol, and 2 ml of concentrated aqueous ammonia was added to it. This was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness (removing ammonia water), which was repeated 3 times. After separation, 4.0 mg of the final product was obtained with a yield of 23.51%.

[00278] ¹ H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.79 (d, J=16.0 Hz, 1H), 9.85 (s, 1H), 8 .62 (s, 1H), 8.36 (s, 1H), 8.34-8.30 (m, 1H),7.40 (s, 1H), 7.14-7.10 (m, 1H ), 7.03 (d, J=12.0 Hz, 1H), 6.92 (d, J=12.0 Hz, 1H), 5.08-4.65 (m, 4H), 2.55 -2.49 (m, 6H), 2.24 (s, 3H), 2.03-1.97 (m, 4H), 1.04-1.02 (m, 3H).

[00279] Example 6: (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl )(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone (MDI-205)

[00280] MDI-205 may also be referred to as 3-ethyl-4-{3-[5-(4-methylpiperazine-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazole -2-yl]-1H-indazol-6-yl}phenol.

[00281] Synthesis route for MDI-205:

[00282] Synthesis method:

[00283] Synthesis of intermediate MDI-205-1: 4-benzyloxy-2-ethyliodobenzene

[00284] 3-ethyl-4-iodophenol (200 mg, 0.81 mmol), benzyl bromide (165.5 mg, 0.97 mmol) and potassium carbonate (222.9 mg, 1.61 mmol) were dissolved in DMF. This was left to react at room temperature for two hours. Water was added and the resulting mixture was extracted twice with EA. The organic phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 250 mg of a colorless oil in 91.7% yield.

[00285] ¹ H NMR (400 MHz, CDCl3) δ7.70 (d, J=8.0 Hz, 1H), 7.46-7.36(m, 5H), 6.92 (d, J=4 .0 Hz, 1H), 6.57 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 5.06 (s, 2H), 2.72 (dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.22 (t, J=8.0 Hz, 3H).

[00286] Synthesis of intermediate MDI-205-2: (2-(4-(phenoxy)-2-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[00287] MDI-205-1 (250.0 mg, 0.74 mmol), pinacolborate (225.1 mg, 0.89 mmol), Pd(dppf)Cl ₂ (54.0 mg, 0.07 mmol) and KOAc (217.6 mg, 2.22 mmol) were dissolved in 1,4-dioxane (10 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C and reacted overnight. After completion of the reaction, it was quenched with water, extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. This was concentrated and separated by column chromatography to give a colorless oil in 70% yield.

[00288] ¹ H NMR (400 MHz, CDCl3) δ 7.77 (d, J=8.0 Hz, IH), 7.47-7.34 (m, 5H), 6.86-6.80 ( m, 2H), 5.11 (s, 2H), 2.93 (dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.35 (s, 12H), 1.21 ( t, J=8.0 Hz, 3H).

[00289] Synthesis of compound MDI-205-3: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl )ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

[00290] Intermediate 5-(4-methylpiperazin-1-yl)pyrazin-2-carboxylic acid (64.2 mg, 0.29 mmol) and N,N-diisopropylethylamine (93.2 mg, 0.72 mmol) dissolved in DMF to which HATU (109.7 mg, 0.29 mmol) was added. This was left to react at room temperature for 10 minutes. Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilylethoxy)methyl)-4, 6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (160.0 mg, 0.24 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature. for 30 minutes and concentrated to obtain a residue. The residue was dissolved in dichloromethane and concentrated to dryness (removing trifluoroacetic acid), which was repeated 3 times. The resulting residue was then dissolved in DMF, which was slowly added to the previous reaction solution. This was left to react at room temperature throughout. overnight, water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate, the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-205-3 in 49 yield. .2%.

[00291] ¹ H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=4.0 Hz 1H), 8.42 (dd, J=8.0 Hz, J= 20.0 Hz 1H), 8.10 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.80 (s, 1H), 7.41-7.46 (m, 1H) , 5.96 (s, 2H), 5.74 (d, J=4.0 Hz, 2H), 5.27 (s, IH), 5.19 (s, 1H), 4.99 (s, 1H), 4.91 (s, 1H), 3.80-3.78 (m, 4H), 3.63-3.59 (m, 4H), 2.59-2.56 (m, 4H) , 2.40 (s, 3H), 0.97-0.91(m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

[00292] Synthesis of compound MDI-205-4: (2-(6-(4-(phenoxy)-2-ethyl-phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3 -yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl) pyrazin-2-yl)ketone

[00293] Intermediate MDI-205-3 (91.0 mg, 0.12 mmol), Intermediate MDI-205-2 (48.1 mg, 0.14 mmol), Pd(PPh ₃ ) ₄ (13, 6 mg, 0.01 mmol) and potassium phosphate (75.4 mg, 0.36 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted 2 times with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-205-4 in 44.1% yield.

[00294] ¹ H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=4.0 Hz 1H), 8.46 (dd, J=4.0 Hz, J= 8.0 Hz 1H), 8.11 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.52-7.31 (m, 6H), 7.27-7.22 ( m, 2H), 7.00 (d, J=4.0 Hz, 1H), 6.91 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.00 (s, 2H), 5.77 (d, J=4.0 Hz, 2H), 5.20 (s, 1H), 5.19 (s, IH), 5.15 (s, 2H), 5.01 ( s, IH), 4.93 (s, IH), 3.81-3.77 (m, 4H), 3.65-3.61 (m, 4H), 2.92-2.57 (m, 6H), 2.40 (s, 3H), 1.10 (t, J=8.0 Hz, 3H), 0.95-0.9 1(m, 4H), 0.03(s, 9H) , 0.02(s, 9H).

[00295] Synthesis of compound MDI-205-5: (2-(6-(2-ethyl-4-hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl )ketone

[00296] Intermediate MDI-205-4 (47.0 mg, 0.05 mmol) was dissolved in 10 ml of methanol and 5 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. This was left to react at room temperature overnight. The carbon-supported palladium was filtered off and the filtrate was concentrated to give intermediate MDI-205-5 in 78.0% yield, which was used immediately in the next step.

[00297] Synthesis of compound MDI-205: (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H )-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

[00298] Intermediate MDI-205-5 (33.0 mg, 0.04 mmol) was dissolved in 4 ml of methanol and 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness (removing hydrochloric acid), which was repeated 3 times. The resulting product was dissolved in 1 ml of methanol and 2 ml of aqueous ammonia was added to neutralize it, and the resulting mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness (removing aqueous ammonia), which was repeated 2 times. The resulting product was purified on a preparation plate to obtain 6.2 mg of product with a yield of 27.7%.

[00299] ¹ H NMR (400 MHz, MeOD-d4) δ 8.72 (d, J=4.0 Hz, IH), 8.28 (dd, J=4.0 Hz, J=8.0 Hz , 2H), 7.40 (s, 1H), 7.18 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H ), 6.80 (d, J=4.0 Hz, 1H), 6.72-6.69 (m, 1H), 5.17 (s, 2H), 4.85 (s, 2H), 3 ,83-3.81 (m, 4H), 2.97-2.94 (m, 4H), 2.90 (dd, J=4.0 Hz, J=8.0 Hz, 2H), 2, 43 (s, 3H), 1.10 (t, J=8.0 Hz, 3H).

[00300] Example 7: 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H -indazol-6-yl)phenol (MDI-206)

[00301] Synthesis route for MDI-206:

[00302] Synthesis method:

[00303] Synthesis of intermediate MDI-206-1: (6-bromo-3-(5-(benzenesulfonyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3 ,4-(1]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[00304] Tert-butyl-2-(6-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue (removing trifluoroacetic acid). The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml DCM and Et ₃ N (0.08 ml, 0.59 mmol), cooled to 0° C. and benzenesulfonyl chloride (28.6 mg, 0.16 mmol) was added slowly. This was left to react at room temperature for 2 hours and water was added to quench the reaction. The resulting mixture was extracted twice with DCM and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-206-1 in 41.4% yield.

[00305] ¹ H NMR (400 MHz, CDC13) δ 8.32 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.77 (s , 1H), 7.62-7.55 (m, 3H), 7.42 (d, J=8.0 Hz, 1H), 5.85 (s, 2H), 5.70 (s, 2H) , 4.66-4.58(m, 4H), 3.59-3.51 (m, 4H), 0.94-0.87 (m, 4H), 0.03 (s, 18H).

[00306] Synthesis of intermediate MDI-206-2: (6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)-3-(5-benzenesulfonyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -indazole

[00307] Intermediate MDI-206-1 (53.0 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (35.8 mg, 0.09 mmol), Pd(dppf)Cl ₂ (5.5 mg, 0.008 mmol) and potassium phosphate (47, 9 mg, 0.23 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-206-2 in 74.3% yield.

[00308] ¹ H NMR (400 MHz, CDCl3) δ 8.42 (d, J=8.0 Hz, IH), 7.96-7.94 (m, 2H), 7.62-7.57 ( m, 3H), 7.46 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.04 ( d, J=12.0 Hz, 1H), 5.89 (s, 2H), 5.75 (s, 2H), 5.34 (s, 2H), 4.67-4.60 (m, 4H ), 3.90-3.86 (m, 2H), 3.62-3.51 (m, 4H), 2.58 (dd, J=8.0 Hz, J=16.0 Hz, 2H) , 1.09-1.05 (m, 3H), 0.93-0.88 (m, 6H), 0.06 (s, 9H), 0.03 (s, 9H), 0.02 (s , 9H).

[00309] Synthesis of MDI-206: 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-(1]imidazol-2- yl)-1H-indazol-6-yl)phenol

[00310] Intermediate MDI-206-2 (50.0 mg, 0.06 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The resulting solid was dissolved in 1 ml of methanol and the pH was adjusted to 8-9 using sodium bicarbonate solution. The resulting mixture was extracted 4 times with dichloromethane and the organic phases were combined, dried over anhydrous sodium sulfate and purified on a preparation plate to obtain 13 mg of the final product with a yield of 46.2%.

[00311] ¹ H NMR (400 MHz, MeOD-d4) δ 8.22 (d, J=8.0 Hz, 1H), 7.98-7.96 (m, 2H), 7.69-7, 65 (m, 3H), 7.4l(s, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.96-6.89 (m, 2H), 4.61-4 .52 (m, 4H), 2.57 (dd, J=16.0 Hz, J=8.0 Hz, 2H), 1.08 (t, J=8.0 Hz, 3H).

[00312] Example 8: 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2- yl)-1H-indazol-6-yl)phenol (MDI-207)

[00313] Synthesis route for MDI-207:

[00314] Synthesis method:

[00315] Synthesis of intermediate MDI-207-1: (6-bromo-3-(5-(pyrazin-2-ylmethyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6 -tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[00316] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (47.0 mg, 0.07 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added and saturated sodium bicarbonate solution was used to adjust the pH to 9. The resulting mixture was extracted with DCM. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting solid was dissolved in 1,2-dichloroethane to which 2-pyrazinecarboxaldehyde (30.6 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 1 hour, to which sodium triacetyl borohydride (60.0 mg, 0.28 mmol) was added. This was left to react at room temperature for 4 hours and water was added to quench the reaction. The resulting mixture was extracted with DCM twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by a silica gel column to give the product MDI-207-1 in 49.5% yield.

[00317] ¹ H NMR (400 MHz, CDCl3) δ 8.81 (d, J=4.0 Hz, 1H), 8.60 (dd, J=8.0 Hz, J=4.0 Hz, 1H ), 8.54 (d, J=4.0 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.77 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.88 (s, 2H), 5.72 (s, 2H), 4.28 (s, 2H), 4.12 (dd, J=4.0 Hz, J=12.0 Hz, 4H), 3.62-3.55 (m, 4H), 0.96-0.87 (m, 4H), 0 .03(s, 9H), 0.02(s, 9H).

[00318] Synthesis of intermediate MDI-207-2: (6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(5-(pyrazin-2- ylmethyl)1-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indazole

[00319] Intermediate MDI-207-1 (20.0 mg, 0.03 mmol), intermediate (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (14.5 mg, 0.04 mmol), Pd(dppf)Cl ₂ (2.3 mg, 0.003 mmol) and potassium phosphate ( 19.4 mg, 0.09 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice, the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-207-2 in 93.0% yield.

[00320] ¹ H NMR (400 MHz, CDCl3) δ 8.82 (d, J=4.0 Hz, 1H), 8.60 (dd, J=8.0 Hz, J=4.0 Hz, 1H ), 8.54 (d, J=4.0 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.47 (d, J=4.0 Hz, 1H), 7.23 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 5.92 (s, 2H), 5.77 (s, 2H), 5.34 (s, 2H), 4.30 (s, 2H), 4.13 (dd, J=4 ,0 Hz, J=12.0 Hz, 4H), 3.88-3.86 (m, 2H), 3.63-3.58 (m, 4H), 2.57 (d, J=8, 0 Hz, 2H), 1.07 (t, J=8.0 Hz, 3H), 0.92-0.90 (m, 6H), 0.06 (s, 9H), 0.03 (s, 9H), 0.02 (s, 9H).

[00321] Synthesis of MDI-207: 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole -2-yl)-1H-indazol-6-yl)phenol

[00322] Intermediate MDI-207-2 (24.0 mg, 0.03 mmol) was dissolved in 4 ml of methanol, to which 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting product was dissolved in 1 ml of methanol and 2 ml of aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 2 times. The resulting product was purified on a preparation plate to obtain 8 mg of product with a yield of 61.8%.

[00323] ¹ H NMR (400 MHz, MeOD-d4) δ 8.80 (d, J=4.0 Hz, 1H), 8.65 (dd, J=4.0 Hz, J=4.0 Hz , 1H), 8.56 (d, J=4.0 Hz, 1H), 8.26 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 7.41 (d, J =4.0 Hz, 1H), 7.17(dd, J=12.0 Hz, J=4.0 Hz, 1H), 6.91- 6.89(m, 2H), 4.30 (s , 2H), 4.07 (s, 4H), 2.56 (dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.07 (t, J=8.0 Hz, 3H ).

[00324] Example 9: 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)- 5-ethyl-2-fluorophenol (MDI-208)

[00325] Synthesis route for MDI-208:

[00326] Synthesis method:

[00327] Synthesis of intermediate MDI-208-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate, tert-butyl

[00328] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (500.0 mg, 0.75 mmol), 2-(4-benzyloxy-2-ethyl-5-fluorophenyl-4, 4,5,5-tetramethyl-1,3,2-dioxaborane (401.9 mg, 1.13 mmol), Pd(PPh ₃ ) ₄ (86.9 mg, 0.08 mmol) and potassium phosphate (478, 9 mg, 2.26 mmol) was dissolved in 1,4-dioxane (30 ml) and water (6 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to. At room temperature, water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-208-1 in 85% yield. 1%.

[00329] ¹ NMR (400 MHz, CDCl3) δ 8.50-8.45 (m, 1H), 7.53-7.37 (m, 6H), 7.26 (d, J=8.0 Hz , 1H), 7.06 (d, J=8.0 Hz, 1H), 6.99 (d, J=12.0 Hz, 1H), 5.97 (d, J=8.0 Hz, 2H ), 5.77 (s, 2H), 5.23 (s, 2H), 4.67-4.54 (m, 4H), 3.65-3.59 (m, 4H), 2.55 ( d, J=8.0 Hz, 2H), 1.57 (s, 9H), 1.05 (t, J=8.0 Hz, 3H), 0.95-0.89 (m, 4H), 0.02(s, 9H), 0.01(s, 9H).

[00330] Synthesis of intermediate MDI-208-2: (6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-3-(5-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[00331] Tert-butyl-2-(6-(4-(phenoxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl) -1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80.0 mg, 0.10 mmol) was dissolved in 5 ml dichloromethane to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added and saturated sodium bicarbonate solution was used to adjust the pH to 9. The resulting mixture was extracted with DCM, the organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting solid was dissolved in 2 ml DMF and Et ₃ N (0.1 ml) and bromomethylcyclopropane (27.0 mg, 0.20 mmol) was added. The mixture was heated to 60°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted with EA, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by a silica gel column to give MDI-208-2 in 33.5% yield.

[00332] ¹ H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.0 Hz, 1H), 7.53-7.37 (m, 6H), 7.23 (dd, J= 8.0 Hz, J=4.0 Hz, 1H), 7.06 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 6.98 (d, J=8.0 Hz , 1H), 5.94 (d, J=4.0 Hz, 2H), 5.76 (s, 2H), 5.23 (s, 2H), 4.13 (d, J=36.0 Hz , 4H), 3.67-3.58 (m, 4H), 2.80 (d, J=8.0 Hz, 2H), 2.55 (dd, J=12.0 Hz, J=8, 0 Hz, 2H), 2.32-2.22 (m, 1H), l.06 (t, J=8.0 Hz, 3H), 0.92-0.90 (m, 4H), 0, 63 (d, J=8.0 Hz, 2H), 0.27 (d, J=4.0 Hz, 2H), 0.03 (s, 9H), 0.02 (s, 9H).

[00333] Synthesis of compound MDI-208: 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6- yl)-5-ethyl-2-fluorophenol

[00334] Intermediate MDI-208-2 (28.0 mg, 0.04 mmol) was dissolved in 10 ml of methanol and 5 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. The mixture was heated to 40°C and reacted overnight, filtered to remove palladium on a carbon carrier and concentrated. The resulting solid was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added to it. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting product was dissolved in 1 ml of methanol and 2 ml of aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness (removing aqueous ammonia), which was repeated 2 times. The resulting product was purified on a preparation plate to obtain 2 mg of product with a yield of 13.1%.

[00335] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.97-6.89 (m, 2H), 4.02 (s, 4H), 2.80 (d, J= 8.0 Hz, 2H), 2.59-2.53 (m, 2H), 1.10 (m, 4H), 0.66-0.61 (m, 2H), 0.30-0.27 (m, 2H).

[00336] Example 10: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H ,6H)-yl)ketone (MDI-209)

[00337] Synthesis route for MDI-209:

[00338] Synthesis method:

[00339] Synthesis of intermediate MDI-209-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(cyclopropyl)ketone

[00340] Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of DCM, to which triethylamine (24.3 mg, 0.24 mmol) was added. The temperature was lowered to 0°C and cyclopropylformyl chloride (18.8 mg, 0.18 mmol) was added slowly dropwise. Once the dropwise addition was complete, the reaction was warmed to room temperature and allowed to react for 1-2 hours. Water was added to quench the reaction and the liquids were separated. The organic phase was dried over sodium sulfate and concentrated by column chromatography to obtain MDI-209-1 in 45% yield.

[00341] ¹ H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=17.8 Hz, J=8.6 Hz, 1H), 7.80-7.79 (m, 1H), 7 .41 (d, J=8.6 Hz, 1H), 5.97-5.92 (m, 2H), 5.71 (d, J=2.4 Hz, 2H), 4.96-4, 66 (m, 4H), 3.62-3.54 (m, 4H), 1.78-1.67 (m, 1H), 1.10-1.07 (m, 2H), 0.94- 0.84 (m, 6H), -0.05 (s, 9H), -0.08 (s, 9H).

[00342] Synthesis of intermediate MDI-209-2: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-( trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(lH,4H,6H)-yl) ketone

[00343] Intermediate MDI-209-1 (50.5 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl) trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl ₂ (5.9 mg, 0.008 mmol) and potassium phosphate (50, 9 mg, 0.24 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-209-2 in 76.1% yield.

[00344] ¹ H NMR (400 MHz, CDCl3) δ 8.50-8.43 (m, 1H), 7.46-7.45 (m, 1H), 7.25-7.22 (m, 1H ), 7.16 (d, J=8.0 Hz, 1H), 7.02 (d, J=12.0 Hz, IH), 5.99-5.94 (m, 2H), 5.76 (s, 2H), 5.32 (s, 2H), 4.98-4.67 (m, 4H), 3.88-3.84 (m, 2H), 3.64-3.55 (m , 4H), 2.57-2.51 (m, 2H), 1.79-1.68 (m, 1H), 1.07-1.02 (m, 6H), 0.95-0.87 (m, 5H), 0.03 (s, 9H), -0.06-0.08 (m, 18H).

[00345] Synthesis of compound MDI-209: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)ketone

[00346] Intermediate MDI-209-2 (50 mg, 0.06 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol, and 2 ml of concentrated aqueous ammonia was added to it. The mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was purified on a preparation plate to obtain 10.0 mg of the final product with a yield of 38.1%.

[00347] ¹ H NMR (400 MHz, MeOD-d4) δ 8.28 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (dd, J=8, 4 Hz, J=1.4 Hz, 1H), 6.98 (d, J=12.0 Hz, 1H), 6.92 (d, J=12.0 Hz, 1H), 4.95 (s , 2H), 4.65 (s, 2H), 2.59-2.53 (m, 2H), 1.98-1.89 (m, 1H), 1.08 (t, J=8.0 Hz, 3H), 1.02-1.00 (m, 2H), 0.98-0.92 (m, 2H).

[00348] Example 11: 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl) -5-ethyl-2-fluorophenol (MDI-210)

[00349] Synthesis route for MDI-210:

[00350] Synthesis method:

[00351] Synthesis of intermediate MDI-210-1: (6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-3-(5-(cyclobutylmethyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[00352] Tert-butyl-2-(6-(4-(phenoxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl) -1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80.0 mg, 0.10 mmol) was dissolved in 5 ml dichloromethane to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added and saturated sodium bicarbonate was used to adjust the pH to 9. The resulting mixture was extracted with DCM, washed with water and brine, dried over sodium sulfate and concentrated. The resulting solid was dissolved in 3 ml DMF and then DIPEA (126.8 mg, 0.98 mmol) and bromomethylcyclobutane (29.3 mg, 0.20 mmol) were added. The mixture was heated to 60°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted with EA, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by a silica gel column to give MDI-210-1 in 35.1% yield.

[00353] ¹ H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.53-7.51 (m, 2H), 7 .46-7.37 (m, 4H), 7.23(dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.06(d, J=12.0 Hz, 1H) , 6.98 (d, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.76 (s, 2H), 5.22 (s, 2H), 4.02 (s, 2H), 3.94 (s, 2H), 3.65-3.56 (m, 4H), 2.93(d, J=8.0 Hz, 2H), 2.98-2.94 (m , 1H), 2.57 (dd, J=16.0 Hz, J=8.0 Hz, 2H), 2.21-2.14 (m, 2H), 1.97-1.67 (m, 4H), 1.06 (t, J=8.0 Hz, 3H), 0.94-0.89 (m, 4H), 0.02 (s, 18H).

[00354] Synthesis of compound MDI-210: 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6- yl)-5-ethyl-2-fluorophenol

[00355] Intermediate MDI-210-1 (35.0 mg, 0.05 mmol) was dissolved in 10 ml of methanol and 5 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. The mixture was heated to 40°C and reacted overnight, filtered to remove palladium on a carbon carrier and concentrated. The resulting solid was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added to it. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting product was dissolved with 1 ml of methanol and 2 ml of concentrated aqueous ammonia was added to neutralize it, and the resulting mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 2 times. The resulting product was purified on a preparation plate to obtain 4 mg of product with a yield of 20.7%.

[00356] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.97-6.89 (m, 2H), 3.98 (s, 4H), 3.00(d, J= 8.0 Hz, 2H), 2.72-2.98 (m, 1H), 2.59-2.53 (m, 2H), 2.21-2.18 (m, 2H), 1.89 -1.85 (m, 4H), 1.07 (t, J=8.0 Hz, 3H).

[00357] Example 12: Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H ,6H)-yl)ketone (MDI-211)

[00358] Synthesis route for MDI-211:

[00359] Synthesis method:

[00360] Synthesis of intermediate MDI-211-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(cyclobutyl)ketone

[00361] Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of DCM, to which triethylamine (24.3 mg, 0.24 mmol) was added. The temperature was lowered to 0°C and cyclobutylcarbonyl chloride (21.3 mg, 0.18 mmol) was added slowly dropwise. Once the dropwise addition was complete, the reaction was warmed to room temperature and allowed to react for 1-2 hours. Water was added to quench the reaction and the liquids were separated. The organic phase was dried over sodium sulfate and concentrated by column chromatography to give MDI-211-1 in 43% yield.

[00362] ¹ H NMR (400 MHz, CDCl3) δ 8.39-8.31 (m, 1H), 7.77-7.76 (m, 1H), 7.42-7.38 (m, 1H ), 5.92-5.89 (m, 2H), 5.71-5.70 (m, 2H), 4.73-4.57 (m, 4H), 3.60-3.54 (m , 4H), 3.37-3.27 (m, 1H), 2.46-2.39 (m, 2H), 2.34-2.20 (m, 3H), 2.10-1.93 (m, 3H), 0.93-0.88 (m, 4H), -0.05 (s, 9H), -0.09 (s, 9H).

[00363] Synthesis of intermediate MDI-211-2: cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-( trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone

[00364] Intermediate MDI-211-1 (51.6 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl) trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl ₂ (5.9 mg, 0.008 mmol) and potassium phosphate (50, 9 mg, 0.24 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-211-2 in 75.2% yield.

[00365] ¹ H NMR (400 MHz, CDCl3) δ 8.49-8.42 (m, 1H), 7.47-7.45 (m, 1H), 7.25-7.22 (m, 1H ), 7.16 (d, J=8.0 Hz, IH), 7.02 (d, J=12.0 Hz, 1H), 5.96-5.93 (m, 2H), 5.75 (s, 2H), 5.32 (s, 2H), 4.75-4.58(m, 4H), 3.88-3.83 (m, 2H)), 3.63-3.55 ( m, 4H), 3.38-3.28 (m, 1H), 2.57-2.51 (m, 2H), 2.48-2.20 (m, 4H), 2.06-2, 00 (m, 1H), 1.96-1.92 (m, 1H), 1.08-1.05 (m, 3H), 0.93-0.85 (m, 6H), 0.03 ( s, 9H), -0.06-0.08 (m, 18H).

[00366] Synthesis of compound MDI-211: cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5( 1H,4H,6H)-yl)ketone

[00367] Intermediate MDI-211-2 (45 mg, 0.054 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol, 2 ml of concentrated aqueous ammonia was added and the mixture was concentrated to leave a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was separated on a preparation plate to obtain 8.2 mg of the final product with a yield of 34.2%.

[00368] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H) 7.17 (dd, J=8.4 , 1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.68-4.63 (m, 4H), 3.54-3 .46 (m, 1H), 2.57-2.53 (m, 2H), 2.43-2.26 (m, 4H), 2.16-2.04 (m, 1H), 1.98 -1.89 (m, 1H), 1.08 (t, J=8.0 Hz, 3H).

[00369] Example 13: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H, 6H)-yl)(3-hydroxylcyclobutyl)ketone (MDI-213)

[00370] Synthesis route for MDI-213:

[00371] Synthesis method:

[00372] Synthesis of intermediate MDI-213-1: (3-(benzyloxy)cyclobutyl)(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl) -1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone

[00373] The intermediate 3-benzyloxycyclobutanecarboxylic acid (44.6 mg, 0.22 mmol) and N,N-diisopropylethylamine (69.9 mg, 0.54 mmol) was dissolved in DMF to which HATU (82.3 mg, 0.22 mmol). The mixture was reacted at room temperature for 10 minutes. Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (120.0 mg, 0.18 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF and then slowly added to the previous reaction solution. This was left to react at room temperature overnight and water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-213-1 in 35.3% yield.

[00374] ¹ H NMR (400 MHz, CDCl3) δ 8.41 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.80-7.78 (m, 1H), 7 ,43-7.31 (m, 6H), 5.94 (d, J=12.0 Hz, 2H), 5.73 (d, J=4.0 Hz, 2H), 4.76-4, 61 (m, 4H), 4.49 (s, 2H), 4.10-4.04 (m, 1H), 3.63-3.57 (m, 4H)), 2.80-2.78 (m, 1H), 2.58-2.53 (m, 2H), 2.46-2.41 (m, 2H), 0.96-0.90 (m, 4H), 0.02 (s , 9H), -0.03 (s, 9H).

[00375] Synthesis of intermediate MDI-213-2: (3-(benzyloxy)cyclobutyl)(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl) -1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H ,4H,6H)-yl)ketone

[00376] Intermediate MDI-213-1 (48.0 mg, 0.06 mmol), Intermediate MDI-10-2 (30.4 mg, 0.08 mmol), Pd(dppf)Cl2 (4.7 mg, 0.01 mmol) and potassium phosphate (40.6 mg, 0.19 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added, the resulting mixture was extracted 2 times with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-213-2 in 71.5% yield.

[00377] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.49-7.48 (m, IH), 7 ,38-7.32 (m, 5H), 7.28-7.24 (m, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05 (d, J=12 ,0 Hz, IH), 5.99 (d, J=12.0 Hz, 2H), 5.78 (d, J=4.0 Hz, 2H), 5.34 (s, 2H), 4, 78-4.62 (m, 4H), 4.50 (s, 2H), 4.12-4.05 (m, 1H), 3.90-3.86 (m, 2H), 3.66- 3.58 (m, 4H),2.80-2.78 (m, 1H), 2.59-2.54 (m, 4H), 2.46-2.44 (m, 2H), 1, 10-1.05 (m, 3H), 0.95-0.90 (m, 6H), 0.06 (s, 9H), -0.04 (s, 18H).

[00378] Synthesis of intermediate MDI-213-3: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-( trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) (3-hydroxylcyclobutyl)ketone

[00379] Intermediate MDI-213-2 (43.0 mg, 0.05 mmol) was dissolved in 10 ml of methanol and 5 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. React the mixture overnight at room temperature, filter off the palladium on a carbon carrier, and concentrate to give intermediate MDI-213-3, which is used immediately in the next step.

[00380] Synthesis of compound MDI-213: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H ,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone

[00381] Intermediate MDI-213-3 (36.1 mg, 0.05 mmol) was dissolved in 4 ml of methanol and 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting product was dissolved in 1 ml of methanol and 2 ml of aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 2 times. The resulting product was purified on a preparation plate to obtain 4 mg of product with a yield of 16.4%.

[00382] ¹ H NMR (400 MHz, MeOD-d4) δ 8.28 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43-7.42 (m, 1H) , 7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.97-6.89 (m, 2H), 4.72-4.62 (m, 4H), 4.23-4.20 (m, 1H), 2.95-2.91 (m, 1H), 2.93-2.53 (m, 4H), 2.26-2.18 (m, 2H ), 1.10 (t, J=8.0 Hz, 3H).

[00383] Example 14: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H, 4H,6H)-yl)(pyridazin-4-yl)ketone (MDI-214)

[00384] Synthesis route for MDI-214:

[00385] Synthesis method:

[00386] Synthesis of intermediate MDI-214-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone

[00387] Tert-butal-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (45 mg, 0.06 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml DMF, and then pyridazine-4-carboxylic acid (9 mg, 0.07 mmol), HATU (32 mg, 0.08 mmol) and DIPEA (0.05 ml, 0.30 mmol) were added. . This was left to react at room temperature for 16 hours and water was added to quench the reaction. The mixture was extracted twice with EA and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 23 mg of intermediate MDI-214-1 in 51.2% yield.

[00388] ¹ H NMR (400 MHz, CDCl3) δ 9.45-9.50 (m, 2H), 8.34 (dd, J=38.3 Hz, J=8.6 Hz, 1H), 7 .79 (t, J=1.9 Hz, 1H), 7.69-7.66 (m, 1H), 7.45-7.41 (m, 1H), 5.92 (d, J=31 .9 Hz, 2H), 5.72 (d, J=5.3 Hz, 2H), 4.95-4.93 (m, 2H), 4.68-4.66 (m, 2H), 3 .65-3.54 (m, 4H), 1.08-0.77 (m, 4H), 0.05-0.13 (m, 18H).

[00389] Synthesis of intermediate MDI-214-2: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-( trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)- yl)(pyridazin-4-yl)ketone

[00390] Intermediate MDI-214-1 (23 mg, 0.03 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (20 mg, 0.05 mmol), Pd(dppf)Cl ₂ (3 mg, 0.003 mmol) and potassium phosphate (22 mg, 0.10 mmol) dissolved in 1,4-dioxane (5 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted for 16 hours and cooled to room temperature. Water was added and the resulting mixture was extracted 2 times with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 25 mg of intermediate MDI-214-2 in 84% yield. 7%.

[00391] ¹ NMR (400 MHz, CDCl3) δ 9.46-9.42 (m, 2H), 8.62-8.31 (m, 1H), 7.71-7.67 (m, 1H) , 7.51-7.47 (m, 1H), 7.25 (dd, J=8.4, 1.3 Hz, 1H), 7.18 (dd, J=8.4, 4.0 Hz , 1H), 7.03 (dd, J=11.6, 6.0 Hz, 1H), 5.96 (d, J=31.6 Hz, 2H), 5.78 (d, J=5, 2 Hz, 2H), 5.34 (d, J=2.7 Hz, 2H), 5.02-4.95 (m, 2H), 4.71-4.67 (m, 2H), 3, 90-3.86 (m, 2H), 3.66-3.62 (m, 4H), 2.57-2.54 (m, 2H), 1.14-0.81 (m, 9H), 0.06 (d, J=2.1 Hz, 9H), -0.04 (dd, J=12.1 Hz, J=8.6 Hz, 18H).

[00392] Synthesis of MDI-214: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5-( 1H,4H,6H)-yl)(pyridazin-4-yl)ketone

[00393] Intermediate MDI-214-2 (25 mg, 0.03 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, 1 ml of aqueous ammonia was added, and then the mixture was concentrated and purified on a preparation plate to obtain 4 mg of the final product with a yield of 29.4%.

[00394] ¹ H NMR (400 MHz, MeOD-d4) δ 9.48 (dd, J=2.3, J=1.3 Hz, 1H), 9.42 (dd, J=5.2, J =1.3 Hz, 1H), 8.26 (s, 1H), 8.02 (dd, J=5.3, J=2.2 Hz, 1H), 7.43 (d, J=1, 1 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.93 (dd, J=19.7, J=10.4 Hz, 2H), 4.90 (s, 2H), 4.73 (s, 2H), 2.55 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

[00395] Example 15: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H, 4H,6H)-yl)(pyridazin-3-yl)ketone (MDI-215)

[00396] Synthesis route for MDI-215:

[00397] Synthesis method:

[00398] Synthesis of intermediate MDI-215-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-( trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone

[00399] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane and 2 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 10 ml DMF, and then pyridazine-3-carboxylic acid (45 mg, 0.36 mmol), HATU (164 mg, 0.43 mmol) and DIPEA (0.18 ml, 1.08 mmol) were added. . This was left to react at room temperature for 16 hours and water was added to quench the reaction. The resulting mixture was extracted twice with EA and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 98 mg of intermediate MDI-215-1 in 49.2% yield.

[00400] ¹ H NMR (400 MHz, CDCl3) δ 9.35-9.30 (m, IH), 8.40 (dd, J=19.4 Hz, J=8.6 Hz, 1H), 8 .25 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.79 (dd, J=3.1, J=1.5 Hz, 1H), 7.72-7, 68 (m, 1H), 7.46-7.43 (m, 1H), 5.95 (d, J=21.7 Hz, 2H), 5.73 (d, J=3.2 Hz, 2H ), 5.40-5.24 (m, 2H), 5.06-4.98 (m, 2H), 3.66-3.56 (m, 4H), 0.98-0.87 (m , 4H), 0.00-0.05 (m, 9H), -0.09 (s, 9H).

[00401] Synthesis of intermediate MDI-215-2: (2-(6-(2-ztyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-( trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)- yl)(pyridazin-3-yl)ketone

[00402] Intermediate MDI-215-1 (98 mg, 0.15 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (100 mg, 0.25 mmol), Pd(dppf)Cl ₂ (15 mg, 0.015 mmol) and potassium phosphate (PO mg, 0.50 mmol) dissolved in 1,4-dioxane (25 ml) and water (5 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted for 16 hours and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 97 mg of intermediate MDI-215-2 in 77.1 yield %.

[00403] ¹ H NMR (400 MHz, CDCl3) δ 9.33-9.32 (d, J=4.0 Hz, 1H), 8.52-8.48 (m, 1H), 8.26- 8.21 (m, 1H), 7.71-7.69 (m, 1H), 7.48 (dd, J=2.8 Hz, J=1.2 Hz, 1H), 7.26 (dd , J=8.4 Hz, J=1.3 Hz, 1H), 7.18 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 (dd, J=11 .6 Hz, J=4.2 Hz, 1H), 5.99 (d, J=22.2 Hz, 2H), 5.78 (d, J=3.0 Hz, 2H), 5.40 ( d, J=2.4 Hz, 1H), 5.34 (s, 2H), 5.25 (t, J=2.1 Hz, 1H), 5.08-4.99 (m, 2H), 3.90-3.88 (m, 2H), 3.67-3.58 (m, 4H), 2.56 (q, J=7.5 Hz, 2H), 1.10-0.77 ( m, 9H), 0.06 (d, J=1.2 Hz, 9H), -0.01 --0.10 (m, 18H).

[00404] Synthesis of compound MDI-215: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5- (1H,4H,6H)-yl)(pyridazin-3-yl)ketone

[00405] Intermediate MDI-215-2 (97 mg, 0.11 mmol) was dissolved in methanol (10 ml), to which concentrated hydrochloric acid (5 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, 1 ml of aqueous ammonia was added and the mixture was concentrated and purified on a preparation plate to obtain 10 mg of the final product with a yield of 18.9%.

[00406] ¹ H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 12.83 (d, J=33.0 Hz, 1H), 9.85 (s, 1H), 9 .39 (dd, J=5.0 Hz, J=1.7 Hz, 1H), 8.37-8.31 (m, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.5 Hz, J=5.0 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J=8.1 Hz, 1H), 7.03 (d, J= 11.9 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 4.84-4.45 (m, 4H), 2.49 (q, J=7.5 Hz, 2H), 1.02 (t, J=7.5 Hz, 3H).

[00407] Example 16: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d ]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)ketone (MDI-216)

[00408] Synthesis route for MDI-216:

[00409] Synthesis method:

[00410] Synthesis of intermediate MDI-216-1: 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-( (2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

[00411] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (500 mg, 0.75 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborane (401 mg, 1.13 mmol), Pd(dppf)Cl ₂ (75 mg, 0.075 mmol) and potassium phosphate (495 mg, 2.25 mmol ) was dissolved in 1,4-dioxane (30 ml) and water (6 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted for 16 hours and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column. The purified product was dissolved in 25 ml of dichloromethane and 5 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was purified by a silica gel column to obtain 210 mg of intermediate MDI-216-1 in 39.2% yield.

[00412] ¹ H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.3 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 7.49-7 .37 (m, 5H), 7.25 (d, J=8.4 Hz, 1H), 7.23-6.96 (m, 2H), 5.93 (s, 2H), 5.77 ( s, 2H), 5.23 (s, 2H), 4.21 (d, J=35.1 Hz, 4H), 3.66-3.52 (m, 4H), 2.54 (q, J =7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), -0, 05 (d, J=3.4 Hz, 9H).

[00413] Synthesis of intermediate MDI-216-2: (S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3- (benzyloxy)pyrrolidin-1-yl)ketone

[00414] Triphosgene (25.8 mg, 0.09 mmol) was dissolved in 5 ml of tetrahydrofuran and intermediate MDI-216-1 (80 mg, 0.09 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0°C . The mixture was stirred at room temperature for 10 minutes and (S)-3-(benzyloxy)pyrrolidine (31.9 mg, 0.18 mmol) in tetrahydrofuran was added. The mixture was stirred at room temperature for 5 minutes and water was added. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 71 mg of intermediate MDI-216-2 in 86.1% yield.

[00415] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.42 ( m, 3H), 7.39-7.29 (m, 6H), 7.24 (dd, J=8.4 Hz, J=4.0 Hz,1H), 7.07-6.97 (m , 2H), 5.95 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.92-4.88 (m, 2H), 4.76-4, 69 (m, 2H), 4.60 (s, 2H), 4.23 (s, 1H), 3.76-3.70 (m, 2H), 3.66-3.58 (m, 6H) , 2.54 (q, J=7.5 Hz, 2H), 2.15-2.13 (m, 1H), 2.06-2.02 (m, 1H), 1.05 (t, J =7.5 Hz, 3H), 0.95-0.91 (m, 4H), -0.01-0.11 (m, 18H).

[00416] Synthesis of compound MDI-216: (8)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3, 4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

[00417] Intermediate MDI-216-2 (83 mg, 0.11 mmol) was dissolved in methanol (10 ml), to which 10 mg Pd/C and concentrated hydrochloric acid (5 ml) were added. The mixture was heated to 50°C, reacted for 6 hours, filtered and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, 1 ml of aqueous ammonia was added, and then the mixture was concentrated and purified on a preparation plate to obtain 8 mg of the final product with a yield of 15.2%.

[00418] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.81-4.61 (m, 4H), 4.46-4.44 (m, 1H ), 3.79-3.69 (m, 2H), 3.50-3.43 (m, 2H), 2.56 (q, J=7.5 Hz, 2H), 2.09-1, 99 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

[00419] Example 17: 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl) -1H-indazol-6-yl)phenol (MDI-217)

[00420] Synthesis route for MDI-217:

[00421] Synthesis method:

[00422] Synthesis of intermediate MDI-217-1: 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1, 4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

[00423] Tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (65.0 mg, 0 .08 mmol) was dissolved in 5 ml of dichloromethane and 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added, the pH was adjusted to 9 with saturated sodium bicarbonate and the resulting mixture was extracted with DCM, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting solid was dissolved in 1,2-dichloroethane and 4-hydroxycyclohexanone (17.4 mg, 0.15 mmol) was added, which was stirred at room temperature for 1 hour. And then sodium triacetyl borohydride (32.3 mg, 0.15 mmol) was added and this was left to react at room temperature for 3 hours. Water was added to quench the reaction and the resulting mixture was extracted with DCM twice, the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by a silica gel column to give the product MDI-217-1 in 38.2% yield. .

[00424] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.44 (s, 1H), 7.22 (dd , J=8.0 Hz, J=4.0 Hz, 1H), 7.02-6.95 (m, 2H), 5.93 (d, J=4.0 Hz, 2H), 5.77 (d, J=4.0 Hz, 2H), 4.27-4.07 (m, 4H), 3.76-3.74 (m, 1H), 3.65-3.56 (m, 4H ), 2.76-2.74 (m, 1H), 2.55-2.49 (m, 2H), 2.11-2.03 (m, 3H), 1.88-1.86 (m , 2H), 1.74-1.66 (m, 3H), 1.08 (t, J=4.0 Hz, 3H), 0.94-0.89 (m, 4H), 0.02 ( s, 9H), -0.05 (s, 9H).

[00425] Synthesis of MDI-217: 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2 -yl)-1H-indazol-6-yl)phenol

[00426] Intermediate MDI-217-1 (21.0 mg, 0.03 mmol) was dissolved in 4 ml of methanol and 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. 1 ml of methanol was added to the resulting residue, 2 ml of concentrated aqueous ammonia was added to neutralize it, and the mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 2 times. The resulting residue was purified on a preparation plate to obtain 5.3 mg of product in 39.5% yield.

[00427] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43-7.42 (m, 1H) , 7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.96-6.88 (m, 2H), 3.98 (s, 4H), 3.93 ( m, 1H), 2.74-2.72 (m, 1H), 2.58 (q, J=8.0 Hz, 2H), 2.04-2.05 (m, 1H), 1.90 -1.80 (m, 5H), 1.64-1.62 (m, 2H), 1.10 (t, J=8.0 Hz, J=16.0 Hz, 3H).

[00428] Example 18: 4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)- 5-ethyl-2-fluorophenol (MDI-218)

[00429] Synthesis route for MDI-218:

[00430] Synthesis method:

[00431] Synthesis of intermediate MDI-218-1: 6-bromo-3-(5-(cyclopropanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[00432] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated, quenched with sodium bicarbonate and extracted twice with dichloromethane. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting compound was dissolved in 5 ml of DCM and Et ₃ N (0.08 ml, 0.59 mmol) and cooled to 0°C. Cyclopropylsulfonyl chloride (22.4 mg, 0.16 mmol) was added slowly. This was left to react at room temperature for 2 hours and water was added to quench the reaction. The resulting mixture was extracted with DCM twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-218-1 in 36.0% yield.

[00433] ¹ H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.0 Hz, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.43 (d , J=8.0 Hz, 1H), 5.91 (s, 2H), 5.73 (s, 2H), 4.75-4.74 (m, 2H), 4.66-4.65 ( m, 2H), 3.63-3.58 (m, 4H), 2.50-2.44 (m, 1H), 1.33-1.31 (m, 2H), 1.06-1, 02 (m, 2H), 0.96-0.91 (m, 4H), 0.00-0.05 (m, 18H).

[00434] Synthesis of intermediate MDI-218-2: 3-(5-cyclopropanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d] imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazole

[00435] Intermediate MDI-218-1 (36.0 mg, 0.05 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (25.5 mg, 0.06 mmol), Pd(dppf)Cl ₂ (3.9 mg, 0.005 mmol) and potassium phosphate (34, 2 mg, 0.16 mmol) was dissolved in 1,4-dioxane (6 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-218-2, 70.0% yield. .

[00436] ¹ H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26 (d, J=7.9 Hz , 1H), 7.18 (d, J=8.0 Hz, 1H), 7.04 (d, J=12.0 Hz, IH), 5.95 (s, 2H), 5.78 (s , 2H), 5.34 (s, 2H), 4.76 (s, 2H), 4.68 (s, 2H), 3.88 (t, J=8.0 Hz, 2H), 3.68 -3.57 (m, 4H), 2.56 (q, J=7.6 Hz, 2H), 2.24 (t, J=7.7 Hz, 1H), 1.12-0.86 ( m, 13H), -0.01-0.06 (m, 27H).

[00437] Synthesis of compound MDI-218: 4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6- yl)-5-ethyl-2-fluorophenol

[00438] Intermediate MDI-218-2 (36.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol and the pH was adjusted to 8-9 with sodium bicarbonate and the resulting mixture was extracted 4 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate and purified on a preparation plate to obtain 16 mg of final product in 81.4% yield.

[00439] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (dd, J=8, 0 Hz, J=4.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.65 (s, 4H), 2.76-2 .99 (m, 1H), 2.90-2.51 (m, 2H), 1.20-1.18 (m, 2H), 1.10-1.06 (m, 5H).

[00440] Example 19: 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)- 5-ethyl-2-fluorophenol (MDI-219)

[00441] Synthesis route for MDI-219:

[00442] Synthesis method

[00443] Synthesis of intermediate MDI-219-1: 6-bromo-3-(5-(cyclobutylsulfonyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3, 4-d]imidazol-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[00444] Tert-butal-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting compound was dissolved in 5 ml of DCM and Et ₃ N (0.08 ml, 0.59 mmol) and cooled to 0°C. Cyclobutylsulfonyl chloride (24.6 mg, 0.16 mmol) was added slowly. This was left to react at room temperature for 2 hours and water was added to quench the reaction. The resulting mixture was extracted with DCM twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-219-1 in 32.1% yield.

[00445] ¹ H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.43 (d, J=8 Hz, 1H ), 5.92 (d, J=4.0 Hz, 2H), 5.73 (s, 2H), 4.70 (s, 2H), 4.60 (s, 2H), 4.03-3 .95 (m, 1H), 3.65-3.56 (m, 4H), 2.75-2.94 (m, 2H), 2.37-2.30 (m, 2H), 2.11 -2.04 (m, 2H), 0.95-0.90 (m, 4H), 0.00-0.05 (m, 18H).

[00446] Synthesis of intermediate MDI-219-2: 3-(5-(cyclobutylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d ]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -indazole

[00447] Intermediate MDI-219-1 (33.0 mg, 0.05 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (22.9 mg, 0.06 mmol), Pd(dppf)Cl ₂ (3.5 mg, 0.005 mmol) and potassium phosphate (30, 2 mg, 0.14 mmol) was dissolved in 1,4-dioxane (6 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-219-2 in 73.5% yield.

[00448] ¹ H NMR (400 MHz, CDCl3) δ 8.45 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26 (dd, J=8.3 Hz , J=1.3 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.07-7.02 (m, 1H), 5.93 (s, 2H), 5 .77 (s, 2H), 5.34 (s, 2H), 4.74-4.70 (m, 2H), 4.64-4.60 (m, 2H), 4.00-3.98 (m, 1H), 3.91-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.75-2.96 (m, 2H), 2.58-2 .54 (m, 2H), 2.11-2.02 (m, 4H), 1.10-1.04 (m, 3H), 1.01-0.96 (m, 6H), -0. 02-0.05 (m, 27N).

[00449] Synthesis of compound MDI-219: 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6- yl)-5-ethyl-2-fluorophenol

[00450] Intermediate MDI-219-2 (31.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml methanol and the pH was adjusted to 8-9 with sodium bicarbonate. The resulting mixture was extracted with dichloromethane 4 times and the organic phases were combined, dried over anhydrous sodium sulfate and purified on a preparation plate to obtain 12 mg of the final product with a yield of 65.7%.

[00451] ¹ H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17 (dd, J=8.4 Hz , J=1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.60 (s, 4H), 4.26-4.18 (m , 1H), 2.98-2.52 (m, 4H), 2.40-2.31 (m, 2H), 2.13-2.02 (m, 2H), 1.08 (t, J =7.5 Hz, 3H).

[00452] Example 20: 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)- 5-ethyl-2-fluorophenol (MDI-220)

[00453] MDI-220 synthesis route:

[00454] Synthesis method:

[00455] Synthesis of intermediate compound MSh-220-1: 6-bromo-3-(5-(cyclopentylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrole[3 ,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[00456] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting compound was dissolved in 5 ml of DCM and Et ₃ N (0.08 ml, 0.59 mmol) and cooled to 0°C. Cyclopentylsulfonyl chloride (26.8 mg, 0.16 mmol) was added slowly and allowed to react at room temperature for 2 hours. And then water was added to quench the reaction. The resulting mixture was extracted with DCM twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-220-1 in 38.1% yield.

[00457] ¹ H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.43 (dd, J=8.0 Hz , J=1.6 Hz, 1H), 5.90 (s, 2H)), 5.73 (s, 2H), 4.78-4.72 (m, 2H), 4.68-4.62 (m, 2H), 4.33 (t, J=8.0 Hz, 1H), 3.63-3.57(m, 4H), 2.14-2.03 (m, 4H), 1, 75-1.56 (m, 4H), 0.96-0.90 (m, 4H), -0.02-0.05 (m, 18H).

[00458] Synthesis of intermediate MDI-220-2: 3-(5-(cyclopentylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d ]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -indazole

[00459] Intermediate MDI-220-1 (40 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.3 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.5 mg, 0.17 mmol) was dissolved in 1,4-dioxane (6 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-220-2 in 62.9% yield.

[00460] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26 (dd, J=8.0 Hz , J=1.2 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.04 (d, J=12.0 Hz, 1H), 5.94 (s, 2H ), 5.78 (s, 2H), 5.34 (s, 2H), 4.80-4.75 (m, 2H), 4.70-4.65 (m, 2H), 4.33 ( t, J=8.0 Hz, 1H), 3.82-3.80 (m, 2H), 3.73-3.58 (m, 4H), 2.58-2.53 (m, 2H) , 2.18-2.05 (m, 4H), 1.79-1.58 (m, 4H), 1.11-1.04 (m, 3H), 0.93-0.90 (m, 6H), -0.02-0.06 (m, 27H).

[00461] Synthesis of compound MDI-220: 4-(3-(5-(cyclopentylsulfonyl)-1D5,6 hhetrahydropyrrolo[3,4-fimidazol-2-yl)-1H-indazol-6-yl)-5-ethyl- 2-fluorophenol

[00462] Intermediate MDI-220-2 (32.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol and the pH was adjusted to 8-9 with sodium bicarbonate. The resulting mixture was extracted 4 times with dichloromethane and the organic phases were combined, dried over anhydrous sodium sulfate and purified on a preparation plate to obtain 10 mg of the final product with a yield of 55.8%.

[00463] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.43 (s, 1H), 7.17 (dd, J=8.0 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.65 (s, 4H ), 3.91-3.83 (m, 1H), 2.58-2.52 (m, 2H), 2.13-2.03 (m, 4H), 1.89-1.78 (m , 2H), 1.75-1.64 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

[00464] Example 21: 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-221)

[00465] Synthesis route for MDI-221:

Synthesis method:

[00466] Synthesis of intermediate 21: Tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

[00467] Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (39.8 mg, 0.06 mmol), intermediate (2-((5-ethyl-2-fluoro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)C12 ( 4.2 mg, 0.006 mmol) and potassium phosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate 21 in 78% yield.

[00468] ¹ H NMR (400 MHz, CDCl3) δ8.46 (dd, J=12.0 Hz, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.24-7, 21 (m,1H), 7.15 (d, J=8.0 Hz, 1H), 7.01 (d, J=12.0 Hz, 1H), 5.93 (d, J=12.0 Hz, 2H), 5.75 (s, 2H), 5.31 (s, 2H), 4.65-4.50 (m, 4H), 3.88-3.84 (m, 2H), 3 .63-3.55 (m, 4H), 2.57-2.51 (m, 2H), 1.54 (s, 9H), 1.07-1.03 (m, 3H), 0.90 -0.85 (m, 4H), 0.03 (s, 9H), -0.07 (s, 18H).

[00469] Synthesis of intermediate 22: 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

[00470] Intermediate tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indazol-3-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(lH)-carboxylate (40 mg, 0.046 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was purified by a silica gel column to give intermediate 22 in 43% yield.

[00471] ¹ H NMR (400 MHz, CDCl3) δ 8.44 (d, J=8.0 Hz, 1H), 7.20 (dd, J=8.3 Hz, J=1.4 Hz, 1H ), 6.95 (dd, J=20.0 Hz, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.47 (s, 2H), 4.26-4.16 (m, 4H), 3.64-3.55 (m, 4H), 2.53-2.47 (m, 2H), 1.04 (t, J=8.0 Hz, 3H), 0. 92-0.86 (m, 4H), -0.07 (s, 9H), -0.08 (s, 9H).

[00472] Synthesis of intermediate MDI-221-1:5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol- 6-yl)phenol

[00473] 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (40 mg, 0.064 mmol) and 1-methyl-1H-pyrazole-4-formaldehyde (8.5 mg, 0.077 mmol ) was dissolved in 5 ml of 1,2-dichloroethane. This was left to react at room temperature for 10 minutes. The reaction mixture was cooled to 0°C and sodium triacetoxyborohydride (26.9 mg, 0.128 mmol) was added. After addition was completed, the mixture was warmed to room temperature and reacted for 1-2 hours. After completion of the reaction, water was added to quench the reaction, the resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-221-1, 43.4% yield.

[00474] ¹ H NMR (400 MHz, CDCl3) δ 8.41 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J=4.0 Hz , 2H), 7.19-7.16 (m, 1H), 6.93 (dd, J=24.0 Hz, J=12.0 Hz, 2H), 5.87 (s, 2H), 5 .73 (s, 2H), 4.01-3.98 (m, 4H), 3.95 (s, 2H), 3.91 (s, 3H), 3.62-3.52 (m, 4H ), 2.51-2.45 (m, 2H), 1.01 (t, J=6.0 Hz, 3H), 0.91-0.85 (m, 4H), -0.08 (s , 9H), -0.09 (s, 9H).

[00475] Synthesis of compound MDI-221: 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6- tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

[00476] Intermediate MDI-221-1 (28 mg, 0.039 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol and 2 ml of concentrated aqueous ammonia was added and concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was purified on a preparation plate to obtain 5.0 mg of the final product with a yield of 28%.

[00477] ¹ H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7 .42 (s, 1H), 7.16 (dd, J=8.4 Hz, J=l.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz , 2H), 4.03-3.96 (m, 6H), 3.92 (s, 3H), 2.58-2.53 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

[00478] Example 22: 4-(3-(5-cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5- ethyl-2-fluorophenol (MDI-224)

[00479] Synthesis route for MDI-224:

[00480] Synthesis method:

[00481] Synthesis of intermediate MDI-224-1: 4-(3-(5-(cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3, 4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

[00482] 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo [3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (31.2 mg, 0.05 mmol) and cyclopentanone (5.1 mg, 0.06 mmol) were dissolved in 5 ml 1,2-dichloroethane. This was left to react at room temperature for 10 minutes. The reaction mixture was cooled to 0°C and sodium triacetoxyborohydride (21 mg, 0.1 mmol) was added. After addition was completed, the mixture was warmed to room temperature and reacted for 1-2 hours. After completion of the reaction, water was added to quench the reaction, the resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-221-1 in 56.8% yield.

[00483] ¹ H NMR (400 MHz, CDCl3) δ 8.40 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.16 (dd, J=8.3 Hz , J=1.4 Hz, 1H), 6.93 (dd, J=24.0 Hz, J=12.0 Hz, 2H), 5.89 (s, 2H), 5.73 (s, 2H ), 4.08 (s, 2H), 3.99 (s, 2H), 3.62-3.55(m, 4H), 3.22-3.19 (m, 1H), 2.50- 2.45 (m, 2H), 1.98-1.89 (m, 2H), 1.84-1.75 (m, 2H), 1.70-1.56 (m, 4H), 1, 01 (t, J=8.0 Hz, 3H), 0.91-0.86 (m, 4H), -0.08 (s, 9H), -0.09 (s, 9H).

[00484] Synthesis of MDI-224: 4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )-5-ethyl-2-fluorophenol

[00485] Intermediate MDI-224-1 (25 mg, 0.036 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (5 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in methanol, 2 ml of concentrated aqueous ammonia was added and the mixture was concentrated to leave a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was purified on a preparation plate to obtain 7.0 mg of the final product with a yield of 45.1%.

[00486] ¹ H NMR (400 MHz, MeOD-d4) δ 8.26(d, J=8.0 Hz, 1H), 7.42(s, 1H),7.17 (d, J=8, 0 Hz, 1H),6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H),4.05-3.94 (m, 4H), 3.27-3.25 ( m, 1H), 2.59-2.54 (m, 2H), 2.08-2.01 (m, 2H), l.87-l.79(m, 2H), 1.73-1, 56 (m,4H), 1.08 (t, J=8.0 Hz, 3H).

[00487] Example 23: 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d] imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-225)

[00488] Synthesis route for MDI-225:

[00489] Synthesis method:

[00490] Synthesis of intermediate MDI-225-1: 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1,4,5,6-tetrahydropyrrolo[3,4-fimidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

[00491] 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5 ,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (60 mg, 0.096 mmol) was dissolved in 5 ml of 1,2-dichloroethane and tetrahydropyrone (14 mg, 0.14 mmol). The mixture was stirred at room temperature for 5 minutes and sodium triacetyl borohydride (41 mg, 0.19 mmol) was added. This was left to react at room temperature for 2 hours and water was added to quench the reaction. The resulting mixture was extracted twice with DCM and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-225-1 in 51.4% yield.

[00492] ¹ H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.20 (dd, J=8.0 Hz , J=1.4 Hz, 1H), 6.96 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 5.93 (s, 2H), 5.76 (s, 2H ), 4.08 (s, 4H), 4.00 (s, 2H), 3.66-3.56 (m, 4H), 3.55-3.47 (m, 2H), 2.95- 2.86 (m, 1H), 2.54-2.46 (m, 2H), 1.99-1.90 (m, 2H), 1.80-1.71 (m, 2H), 1, 04 (t, J=8.0 Hz, 3H), 0.95-0.87 (m, 4H), -0.03-0.08 (m, 18H).

[00493] Synthesis of MDI-225: 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4 -d]imidazol-2-yl)-1H-indazol-6-yl)phenol

[00494] Intermediate MDI-225-1 (35.0 mg, 0.05 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol and the pH was adjusted to 8-9 with sodium bicarbonate. The resulting mixture was extracted 4 times with dichloromethane and the organic phases were combined, dried over anhydrous sodium sulfate and purified on a preparation plate to obtain 12 mg of the final product with a yield of 64.1%.

[00495] ¹ H NMR (400 MHz, MeOD-d4) δ 8.26 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 7.42 (s, 1H), 7.16 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.07-3.99 (m, 6H), 3.52-3.49 (m, 2H), 2.95-2.90 (m, 1H), 2.58-2.53 (m, 2H), 2.00-1 .97 (m, 2H), 1.69-1.59 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

[00496] Example 24: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5-(1H)-yl)ethan-1-one (MDI-226)

[00497] Synthesis route for MDI-226:

[00498] Synthesis method:

[00499] Synthesis of intermediate MDI-226-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

[00500] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane and 2 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting compound was dissolved in 10 ml DCM and Et3N (0.16 ml, 1.18 mmol) was added. The mixture was cooled to 0°C and acetyl chloride (25.0 mg, 0.32 mmol) was added slowly. This was left to react at room temperature for 2 hours and water was added to quench the reaction. The resulting mixture was extracted with DCM twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-226-1 in 54.8% yield.

[00501] ¹ H NMR (400 MHz, chloroform-d) 6 8.36-8.29 (m, 1H), 7.78-7.77 (m, 1H), 7.42-7.39 (m , 1H), 5.93-5.88 (m, 2H), 5.71 (d, J=4 Hz, 2H), 4.76-4.73 (m, 2H), 4.67-4, 63 (m, 2H), 3.61-3.54 (m, 4H), 2.20 (s, 3H), 0.94-0.88 (m, 4H)), -0.03-0, 09 (m, 18H).

[00502] Synthesis of intermediate MDI-226-2: 1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-yl)ethan-1-one

[00503] Intermediate MD1-226-1 (100 mg, 0.16 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (78.3 mg, 0.20 mmol), Pd(dppf)C12 (12.0 mg, 0.016 mmol) and potassium phosphate (104.8 mg, 0.49 mmol) was dissolved in 1,4-dioxane (12 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-226-2 in 76.2% yield.

[00504] ¹ H NMR (400 MHz, chloroform-d) δ 8.52-8.45 (m, 1H), 7.49 (s, 1H), 7.27-7.25 (m, 1H), 7.18 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H) 6.00-5.95 (m, 2H), 5.78 (s, 2H), 5 .34 (s, 2H), 4.80-4.77 (m, 2H), 4.71-4.69 (m, 2H), 3.90-3.86 (m, 2H), 3.66 -3.58 (m, 4H), 2.59-2.54 (m, 2H), 2.22 (d, J=8 Hz, 3H), 1.10-1.06 (m, 3H), 1.03-0.91 (m, 6H), -0.02-0.06 (m, 27H).

[00505] Synthesis of compound MDI-226: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazol-5-(1H)-yl)ethan-1-one

[00506] Intermediate MDI-226-2 (100 mg, 0.13 mmol) was dissolved in methanol (5 ml), to which concentrated hydrochloric acid (2.5 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol and the pH value was adjusted to 8-9 with aqueous ammonia. The resulting mixture was concentrated and purified by a silica gel column to obtain 5 mg of the final product with a yield of 9.8%.

[00507] ¹ H NMR (400 MHz, methanol-d4) δ 8.28 (d, J=8 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8 Hz, 1H ), 6.94 (dd, J=22, 10 Hz, 2H), 4.79 (s, 2H), 4.65 (s, 2H), 2.59-2.53 (m, 2H), 2 .23 (s, 3H), 1.08 (t, J=7.5 Hz, 3H).

[00508] Example 25: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5-(1H)-yl)propan-1-one (MDI-227)

[00509] Synthesis route for MDI-227:

[00510] Synthesis method:

[00511] Synthesis of intermediate MDI-227-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2 -(trimethylsilyl)zoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one

[00512] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-l-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane and 2 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting compound was dissolved in 10 ml DCM and Et3N (0.16 ml, 1.18 mmol) and cooled to 0°C. Propionyl chloride (29 mg, 0.32 mmol) was added slowly. This was left to react at room temperature for 2 hours and water was added to quench the reaction. The resulting mixture was extracted with DCM twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-227-1 in 53.5% yield.

[00513] ¹ H NMR (400 MHz, chloroform-d) 6 8.39-8.32 (m, 1H), 7.77-7.76 (m, 1H), 7.42-7.38 (m , 1H), 5.93-5.89 (m, 2H), 5.71 (d, J=4 Hz, 2H), 4.76-4.70 (m, 2H), 4.65-4, 63 (m, 2H), 3.61-3.55 (m, 4H), 2.46-2.40 (m, 2H), 1.25-1.23 (m, 3H), 0.93- 0.89 (m, 4H), -0.05-0.08 (m, 18H).

[00514] Synthesis of intermediate MDI-227-2: 1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-yl)propan-1-one

[00515] Intermediate MD1-227-1 (100 mg, 0.16 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (76.5 mg, 0.19 mmol), Pd(dppf)C12 (11.8 mg, 0.016 mmol) and potassium phosphate (102.4 mg, 0.48 mmol) was dissolved in 1,4-dioxane (12 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-227-2 in 76.7% yield.

[00516] ¹ H NMR (400 MHz, chloroform-d) δ 8.52-8.45 (m, 1H), 7.48 (d, J=4 Hz, 1H), 7.28-7.25 ( m, 1H), 7.18 (d, J=8 Hz, 1H), 7.04 (d, J=12 Hz, 1H), 5.98 (d, J=12 Hz, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.78 (s, 2H), 4.69-4.68 (m, 2H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.59-2.54 (m, 2H), 2.49-2.40 (m, 2H), 1.31-1.26 (m, 5H ), 1.10-1.05 (m, 3H), 0.96-0.91 (m, 4H), -0.02-0.05 (m, 27H).

[00517] Synthesis of compound MDI-227: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazol-5-(1H)-yl)propan-1-one

[00518] Intermediate MDI-227-2 (100 mg, 0.12 mmol) was dissolved in methanol (5 ml), to which concentrated hydrochloric acid (2.5 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol and the pH was adjusted to 8-9 using aqueous ammonia. The resulting mixture was concentrated and purified by a silica gel column to obtain 18 mg of the final product with a yield of 34.8%.

[00519] ¹ H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.80 (s, 1H), 9.85 (s, 1H), 8.33 (d, J= 8 Hz, 1H), 7.40 (s, 1H), 7.12 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H), 6.92 (d, J =12 Hz, 1H), 4.73-4.58 (m, 2H), 4.50-4.42 (m, 2H), 2.50-2.47 (m, 2H), 2.43- 2.37 (m, 2H), 1.08-1.01 (m, 6H).

[00520] Example 26: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5-(1H)-yl)-2-methylpropan-1-one (MDI-228)

[00521] Synthesis route for MDI-228:

[00522] Synthesis method:

[00523] Synthesis of intermediate MDI-228-1: (1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one)

[00524] Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml DCM and then triethylamine (24.3 mg, 0.24 mmol) was added. The temperature was lowered to 0°C and isobutyryl chloride (19.2 mg, 0.18 mmol) was added slowly dropwise. After the dropwise addition was completed, the mixture was warmed to room temperature and reacted for 1-2 hours. Water was added to the reaction mixture to quench the reaction. The liquids were separated and the organic phase was dried over sodium sulfate and concentrated by column chromatography to give MDI-228-1 in 58.7% yield.

[00525] ¹ H NMR (400 MHz, CDCl3) ¹ H NMR (400 MHz, CDCl3) δ 8.39-8.32 (m, 1H), 7.77-7.76 (m, 1H), 7, 42-7.38 (m, 1H), 5.92-5.89 (m, 2H), 5.71-5.69 (m, 2H), 4.83-4.64 (m, 4H), 3.63-3.55 (m, 4H), 2.81-2.70 (m, 1H), 1.22 (d, J=8 Hz, 6H), 0.98-0.86 (m, 4H), -0.05-0.08 (m, 18H).

[00526] Synthesis of intermediate MDI-228-2: 1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-fimidazol-5-(1H)- yl)-2-methylpropan-1-one

[00527] Intermediate MDI-228-1 (50.65 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl ₂ (5.9 mg, 0.008 mmol) and potassium phosphate (50, 9 mg, 0.24 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-228-2 in 77.5% yield.

[00528] ¹ H NMR (400 MHz, CDCl3) δ 8.49-8.42 (m, 1H), 7.46-7.45 (m, 1H), 7.25-7.22 (m, 1H ), 7.16 (d, J=8 Hz, 1H), 7.02 (d, J=12 Hz, 1H), 5.97-5.92 (m, 2H), 5.76(s, 2H ), 5.32 (s, 2H), 4.83-4.67 (m, 4H), 3.88-3.84 (m, 2H), 3.64-3.56 (m, 4H), 2.82-2.73 (m, 1H), 2.57-2.51 (m, 2H), 1.22 (d, J=8 Hz, 6H), 1.08-0.99 (m, 5H), 0.93-0.88 (m, 4H), 0.03 (s, 9H), -0.06-0.07 (m, 18H).

[00529] Synthesis of compound MDI-228: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazol-5-(1H)-yl)-2-methylpropan-1-one

[00530] Intermediate MDI-228-2 (50 mg, 0.061 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol, 2 ml of concentrated aqueous ammonia was added and the mixture was concentrated to leave a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was purified on a preparation plate to obtain 15 mg of the final product with a yield of 57.0%.

[00531] ¹ H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17 (d, J=8 Hz , 1H), 6.93 (dd, J=20, 12 Hz, 2H), 4.83-4.59 (m, 4H), 2.94-2.90 (m, 1H), 2.58- 2.52 (m, 2H), 1.22 (d, J=8.0 Hz, 6H), 1.08 (t, J=8.0 Hz, 3H).

[00532] Example 27: 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4 -d]imidazol-5-(1H)-yl)ethan-1-one (MDI-229)

[00533] Synthesis route for MDI-229:

[00534] Synthesis method

[00535] Synthesis of intermediate MDI-229-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-cyclopropylethan-1-one

[00536] 2-Cyclopropylacetic acid (14.5 mg, 0.14 mmol) and N,N-diisopropylethylamine (46.6 mg, 0.36 mmol) were dissolved in DMF and HATU (54.9 mg, 0.14 mmol) was added mmol). This was left to react at room temperature for 10 minutes. Intermediate tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80.0 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF and then slowly added to the previous reaction solution. This was left to react at room temperature overnight and water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MD1-229-1 in 57.8% yield.

[00537] ¹ H NMR (400 MHz, CDCl3) δ 8.40 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.80 (s, 1H), 7.44-7 .41 (m, 1H), 5.92 (s, 2H), 5.74 (s, 2H), 4.78-4.66 (m, 4H), 3.63-3.58 (m, 4H ), 2.39-2.35 (m, 2H), 2.04 (s, 1H), 0.96-0.91 (m, 4H), 0.66 (d, J=8.0 Hz, 2H), 0.27 (d, J=4.0 Hz, 2H), 0.02 (s, 18H).

[00538] Synthesis of intermediate MDI-229-2: 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5-(1H)-yl)ethan-1-one

[00539] Intermediate MDI-229-1 (45.0 mg, 0.07 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (33.1 mg, 0.08 mmol), Pd(dppf)C12 (5.1 mg, 0.007 mmol) and potassium phosphate (44.3 mg, 0.21 mmol) was dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-229-1 in 55.0% yield.

[00540] ¹ H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=8.0 Hz, J=16.0 Hz, 1H), 7.49 (s, 1H), 7.27 (s , 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 5.96 (s, 2H), 5.78 (s , 2H), 5.34 (s, 2H), 4.79-4.66 (m, 4H), 3.88 (t, J=8.0 Hz, 2H), 3.66-3.58 ( m, 4H), 2.59-2.54 (m, 2H), 2.39-2.36 (m, 2H), 2.06-2.04 (m, 1H), 1.05 (t, J=8.0 Hz, 3H), 0.96-0.91 (m, 6H), 0.66-0.63 (m, 2H), 0.28-0.26 (m, 2H), 0 .06-0.05 (m, 27 H).

[00541] Synthesis of compound MDI-229: 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[ 3,4-d]imidazol-5-(1H)-yl)ethan-1-one

[00542] Intermediate MD1-229-4 was dissolved in 4 ml of methanol and 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved with 1 ml of methanol and 2 ml of aqueous ammonia was added to neutralize it, and the resulting mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated twice, thereby obtaining 3.8 mg of product with a yield of 12.2%.

[00543] ¹ H NMR (400 MHz, MeOD-d4) δ 8.29 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.19-7.17 (m, 1H), 6.98-6.90 (m, 2H), 4.73-4.61 (m, 4H), 2.59-2.53 (m, 2H), 2.46 (d, J= 8.0 Hz, 2H), 1.17 (m, 1H), 1.08 (t, J=8.0 Hz, 3H), 0.64-0.59 (m, 2H), 0.30- 0.26 (m, 2H).

[00544] Example 28: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5-(1H)-yl)-3-methylbutan-1-one (MDI-230)

[00545] Synthesis route for MDI-230:

[00546] Synthesis method:

[00547] Synthesis of intermediate MDI-230-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

[00548] Tert-butyl-2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of dichloromethane and triethylamine (0.08 ml, 0.59 mmol) and cooled to 0°C. 3-Methylbutyryl chloride (36.6 mg, 0.30 mmol) was added slowly. This was left to react at room temperature for 2 hours and water was added to quench the reaction. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 64 mg of intermediate MDI-230-1 in 65.8% yield.

[00549] ¹ H NMR (400 MHz, CDCl3) δ 8.42-8.35 (m, 1H), 7.80-7.79 (m, 1H), 7.45-7.41 (m, 1H ), 5.96-5.91 (m, 2H), 5.74-5.73 (m, 2H), 4.78-4.69 (m, 4H), 3.67-3.58 (m , 4H), 2.31-2.22 (m, 3H), 1.08-1.05 (m, 6H), 0.97-0.90 (m, 4H), -0.02-0, 05 (m, 18N).

[00550] Synthesis of intermediate MDI-230-2: 1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-yl)-3-methylbutan-1-one

[00551] Intermediate MDI-230-1 (98 mg, 0.15 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (64 mg, 0.10 mmol), Pd(dppf)C12 (10 mg, 0.01 mmol) and potassium phosphate (70 mg, 0.30 mmol ) was dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted for 16 hours and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 50 mg of intermediate MDI-230-2 in 59.7 yield %.

[00552] ¹ H NMR (400 MHz, CDCl3) δ 8.52-8.45 (m, 1H), 7.49 (s, 1H), 7.25 (d, J=2.8 Hz, 1H) , 7.18 (d, J=8.6 Hz, 1H), 7.04 (d, J=11.8 Hz, 1H), 5.98 (d, J=15.6 Hz, 2H), 5 .78 (s, 2H), 5.36 (s, 2H), 4.78-4.72 (m, 4H), 3.91-3.86 (m, 2H), 3.66-3.59 (m, 4H), 2.90-2.56 (m, 2H), 2.32-2.30 (m, 3H), 1.11-1.01 (m, 6H), 0.99-0 .89 (m, 7H), 0.03 (s, 9H), -0.03-0.05 (m, 18H).

[00553] Synthesis of compound MDI-230: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

[00554] Intermediate MDI-230-2 (50 mg, 0.06 mmol) was dissolved in methanol (6 ml), to which concentrated hydrochloric acid (3 ml) was added. This was heated to 50°C and left to react for 6 hours. The reaction mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness (removing hydrochloric acid), which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of aqueous ammonia was added. The mixture was then concentrated and filtered, and the filtrate was concentrated and purified on a preparation plate to obtain 15 mg of the final product with a yield of 55.9%.

^1H NMR (400 MHz, MeOD-d4) 6 8.29-8.26 (m, 1H), 7.43 (s, 1H), 7.19-7.16 (m, 1H), 6.97 -6.89 (m, 2H), 4.75-4.70 (m, 4H), 2.56 (q, J=7.5 Hz, 2H), 2.36 (m, 2H), 2, 29-2.20 (m, 1H), 1.10-1.05 (m, 9H).

[00555] Example 29: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)(pyrrolidin-1-yl)ketone (MDI-231)

[00556] Synthesis route for MDI-231:

[00557] Synthesis method:

[00558] Synthesis of intermediate MDI-231-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl) ketone

[00559] Triphosgene (64.4 mg, 0.21 mmol) was dissolved in 15 ml of dichloromethane to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl )-1H-indazole (150 mg, 0.21 mmol) in dichloromethane (5 ml) at 0°C, and then triethylamine (63.6 mg, 0.63 mmol) was added. The mixture was stirred at room temperature for 5 minutes and pyrrolidine (29.8 mg, 0.42 mmol) in dichloromethane was added. The resulting mixture was stirred at room temperature for 10 minutes and water was added. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 140 mg of intermediate MDI-231-1 in 82.4% yield.

[00560] ¹ H NMR (400 MHz, CDCl3) 6 8.48 (d, J=8 Hz, 1H), 7.53-7.38 (m, 6H), 7.22 (d, J=8 Hz, 1H ), 7.03 (d, J=12 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 ( s, 2H), 4.81 (s, 2H), 4.67 (s, 2H), 3.66-3.59 (m, 4H), 3.53-3.51 (m, 4H), 2 .56-2.52 (m, 2H), 1.93-1.88 (m, 4H), 1.03 (t, J=8 Hz, 3H), 0.93 -0.87 (m, 4H ), -0.05-0.09 (m, 18H).

[00561] Synthesis of MDI-231: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone

[00562] Intermediate MDI-231-1 (140 mg, 0.173 mmol) was dissolved in methanol (6 ml), to which 15 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50°C, reacted for 6 hours, filtered and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol and 1 ml of ammonia was added. The resulting mixture was concentrated and purified on a preparation plate to obtain 21 mg of the final product with a yield of 26.3%.

[00563] 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 12.99 (s, 1H), 9.83 (s, 1H), 8.31 (d, J=8 Hz, 1H), 7.39 (s, 1H), 7.11 (d, J=8 Hz, 1H), 7.02 (d, J=12 Hz, 1H), 6.91 (d, J= 12 Hz, 1H), 4.57-4.56 (m, 2H), 4.49-4.48 (m, 2H), 3.32-3.31 (m, 4H), 2.48-2 .44 (m, 2H), 1.85-1.79 (m, 4H), 1.02 (t, J=7 Hz, 3H).

[00564] Example 30: Azetidin-1-yl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazol-5-(1H)-yl)ketone (MDI-232)

[00565] Synthesis route for MDI-232:

[00566] Synthesis method:

[00567] Synthesis of intermediate MDI-232-1: Azetidin-1-yl(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]im idazol-5-(1H)-yl)ketone

[00568] Triphosgene (49.1 mg, 0.165 mmol) was dissolved in 15 ml of tetrahydrofuran to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-( trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H -indazole (118 mg, 0.165 mmol) in tetrahydrofuran (5 ml) at 0°C, and then triethylamine (50.0 mg, 0.495 mmol) was added. The mixture was stirred at room temperature for 5 minutes and azetidine (18.8 mg, 0.330 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 105 mg of intermediate MD1-232-1 in 79.8 yield %.

[00569] ¹ H NMR (400 MHz, CDCl3) δ 8.52 (d, J=8.3 Hz, 1H), 7.58-7.55 (m, 2H), 7.52-7.40 ( m, 4H), 7.30-7.28 (m, 1H), 7.11-7.01 (m, 2H), 5.82 (s, 2H), 5.43 (s, 2H), 5 .27 (s, 2H), 4.78-4.61 (m, 4H), 4.22-4.19 (m, 4H), 3.70-3.56 (m, 4H), 2.92 (q, J=7.5 Hz, 2H), 2.41-2.36 (m, 2H), 1.03 (t, J=7.5 Hz, 3H), 0.99-0.94 ( m, 4H), 0.07 (d, J=2.7 Hz, 18H).

[00570] Synthesis of compound MDI-232: Azetidin-1-yl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3 ,4-d]imidazol-5-(1H)-yl)ketone

[00571] Intermediate MDI-232-1 (105 mg, 0.132 mmol) was dissolved in methanol (6 ml), to which 11 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50°C, reacted for 6 hours, filtered and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol and 1 ml of ammonia was added. The resulting mixture was concentrated and purified on a preparation plate to obtain 25 mg of the final product with a yield of 42.9%.

[00572] ¹ H NMR (400 MHz, MeOD-d4) δ 8.29 (dd, J=8.4 Hz, J=4.0 Hz, 1H), 7.43 (s, 1H), 7.19 -7.16 (m, 1H), 6.97-6.90 (m, 2H), 4.62-4.53 (m, 4H), 3.69-3.66 (m, 2H), 3 .43-3.40 (m, 2H), 2.54 (q, J=7.5 Hz, 2H), 2.09-2.02 (m, 2H), 1.06 (t, J=7 .5 Hz, 3H).

[00573] Example 31: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)(piperidin-1-yl)ketone (MDI-233)

[00574] Synthesis route for MDI-233:

[00575] Synthesis method:

[00576] Synthesis of intermediate MDI-233-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl) ketone

[00577] Triphosgene (54.1 mg, 0.182 mmol) was dissolved in 5 ml of tetrahydrofuran to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-( trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H -indazole (130 mg, 0.182 mmol) in tetrahydrofuran (5 ml) at 0°C, and then triethylamine (55.2 mg, 0.550 mmol) was added. The mixture was stirred at room temperature for 5 minutes and piperidine hydrochloride (44.4 mg, 0.364 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 105 mg of intermediate MDI-233-1 in 66.6 yield %.

[00578] ¹ H NMR (400 MHz, CDCl3) δ 8.44 (d, J=8.3 Hz, 1H), 7.50-7.48 (m, 2H), 7.44-7.35 ( m, 4H), 7.23-7.20 (m, 1H), 7.04-6.94 (m, 2H), 5.93 (s, 2H), 5.74 (s, 2H), 5 .20 (s, 2H), 4.69 (d, J=54.8 Hz, 4H), 3.64-3.56 (m, 4H), 3.31 (s, 4H), 2.54 ( q, J=7.5 Hz, 2H), 1.64 (s, 6H), 1.03 (t, J=7.5 Hz, 3H), 0.93-0.86 (m, 4H), -0.07 (d, J=2.7 Hz, 18H).

[00579] Synthesis of MDI-233: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5-(1H)-yl)(piperidin-1-yl)ketone

[00580] Intermediate MDI-233-1 (100 mg, 0.121 mmol) was dissolved in methanol (6 ml), to which 10 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50°C, reacted for 6 hours, filtered and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol and 1 ml of ammonia was added. The resulting mixture was concentrated and purified on a preparation plate to obtain 33 mg of the final product with a yield of 57.3%.

[00581] ¹ H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.16-7.14 (m, 1H), 6.95-6.87 (m, 2H), 4.83-4.65 (m, 4H), 3.35-3.33 (m, 4H), 2.54 (q, J= 7.5 Hz, 2H), 1.67-1.65 (m, 6H), 1.06 (t, J=7.5 Hz, 3H).

[00582] Example 32: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)(morpholino)ketone (MDI-234)

[00583] Synthesis route for MDI-234:

[00584] Synthesis method:

[00585] Synthesis of intermediate MDI-234-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone

[00586] Triphosgene (54.1 mg, 0.182 mmol) was dissolved in 5 ml of tetrahydrofuran to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-( trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4^]imidazol-2-yl)-1H- indazole (130 mg, 0.182 mmol) in tetrahydrofuran (5 ml) at 0°C, and then triethylamine (55.1 mg, 0.546 mmol) was added. The mixture was stirred at room temperature for 5 minutes and morpholine (31.7 mg, 0.364 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 120 mg of intermediate compound MDI-234-1, with a yield of 79.7%.

[00587] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35 (m, 4H), 7.26-7.23 (m, 1H), 7.06-6.97 (m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.68 (d, J=54.8 Hz, 4H), 3.80-3.78 (m, 3H), 3.67-3.59 (m, 4H) , 3.43-3.40 (m, 3H), 3.27-3.21 (m, 6H), 2.54 (q, J=7.5 Hz, 2H), 1.05 (t, J =7.5 Hz, 3H), 0.96-0.89 (m, 4H), -0.04 (d, J=2.7 Hz, 18H).

[00588] Synthesis of MDI-234: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5-(1H)-yl)(morpholino)ketone

[00589] Intermediate MD1-234-1 (120 mg, 0.145 mmol) was dissolved in methanol (6 ml), to which 12 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50°C, reacted for 6 hours, filtered and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol and 1 ml of ammonia was added. The resulting mixture was concentrated and purified on a preparation plate to obtain 42 mg of the final product with a yield of 60.9%.

[00590] ¹ H NMR (400 MHz, MeOD-d4) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.19-7.16 (m, 1H), 6.97-6.90 (m, 2H), 4.71-4.66 (m, 4H), 3.78-3.75 (m, 4H), 3.41-3.39 ( m, 4H), 2.54 (q, J=7.5 Hz, 2H), 1.06 (t, J=7.5 Hz, 3H).

[00591] Example 33: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)(4-methylpiperazin-1-yl)ketone (MDI-235)

[00592] Synthesis route for MDI-235:

[00593] Synthesis method:

[00594] Synthesis of intermediate MDI-235-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1- yl)ketone

[00595] Triphosgene (8.3 mg, 0.028 mmol) was dissolved in 5 ml of tetrahydrofuran to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-( trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H -indazole (20 mg, 0.028 mmol) in tetrahydrofuran (5 ml) at 0°C, and then triethylamine (8.5 mg, 0.084 mmol) was added. The mixture was stirred at room temperature for 5 minutes and 1-methylpiperazine (5.60 mg, 0.056 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 20 mg of intermediate MDI-235-1 in 85.1 yield %.

[00596] ¹ H NMR (400 MHz, CDCl3) δ 8.44 (d, J=8.3 Hz, 1H), 7.50-7.48 (m, 2H), 7.44-7.33 ( m, 4H), 7.23-7.21 (m, 1H), 7.04-6.94 (m, 2H), 5.93 (s, 2H), 5.75 (s, 2H), 5 .20 (s, 2H), 4.70 (d, J=54.8 Hz, 4H), 3.64-3.56 (m, 4H), 3.43-3.41 (m, 4H), 2.56-2.49 (m, 6H), 2.34 (s, 3H), 1.03 (t, J=7.5 Hz, 3H), 0.93-0.86 (m, 4H) , -0.07(d, J=2.7 Hz, 18H).

[00597] Synthesis of MDI-235: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)ketone

[00598] Intermediate MDI-235-1 (20 mg, 0.024 mmol) was dissolved in methanol (6 ml), to which 5 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50°C, reacted for 6 hours, filtered and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol and 1 ml of ammonia was added. The resulting mixture was concentrated and purified on a preparation plate to obtain 3 mg of the final product with a yield of 14.8%.

[00599] ¹ H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.16-7.14 (m, 1H), 6.95-6.87 (m, 2H), 4.83-4.66 (m, 4H), 3.44-3.41 (m, 4H), 2.56-2.51 ( m, 6H), 2.35 (s, 3H), 1.06 (t, J=7.5 Hz, 3H).

[00600] Example 34: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)(4-ethylpiperazin-1-yl)ketone (MDI-236)

[00601] Synthesis route for MDI-236:

[00602] Synthesis method:

[00603] Synthesis of intermediate MDI-236-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1- yl)ketone

[00604] Triphosgene (54.07 mg, 0.182 mmol) was dissolved in 15 ml of dichloromethane to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-Indazole (20 mg, 0.028 mmol) in dichloromethane (5 ml) at 0°C, and then triethylamine (55.2 mg, 0.55 mmol) was added. The mixture was stirred at room temperature for 5 minutes and 1-ethylpiperazine (41.5 mg, 0.364 mmol) in dichloromethane was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 100 mg of intermediate MDI-236-1 in 64.3 yield %.

[00605] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=8 Hz, 1H), 8.28 (s, 1H), 7.50-7.33 (m, 5H), 7.22 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 5.93 (s, 2H) , 5.74 (s, 2H), 5.20 (s, 2H), 4.77 (s, 2H), 4.63 (s, 2H), 3.63-3.61 (m, 4H), 3.43-3.42 (m, 4H), 2.53-2.46 (m, 8H), 1.03 (t, J=6 Hz, 3H), 0.93-0.86 (m, 7H), -0.06 - -0.08 (m, 18H).

[00606] Synthesis of MDI-236: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)ketone

[00607] Intermediate MDI-236-1 (100 mg, 0.117 mmol) was dissolved in methanol (10 ml), to which 10 mg Pd/C was added and concentrated hydrochloric acid (5 ml) was added dropwise. The mixture was heated to 50°C, reacted for 6 hours, filtered and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol and 1 ml of ammonia was added. The resulting mixture was concentrated and purified on a preparation plate to obtain 21 mg of the final product with a yield of 35.6%.

[00608] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8 Hz, 1H), 7.43 (s, 1H), 7.17 (d, J=8 Hz, 1H ), 6.96 (d, J=12 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 4.75-4.60 (m, 4H), 3.48-3.44 (m, 4H), 2.91-2.48 (m, 8H), 1.17 (t, 7=8 Hz, 3H), 1.08 (t, J=8 Hz, 3H).

[00609] Example 35: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[00609] 3,4-d]imidazol-5(1H)-yl)ketone (MDI-237)

[00610] Synthesis route for MDI-237:

[00611] Synthesis method:

[00612] Synthesis of intermediate MDI-237-1: 6-bromo-1H-pyrazolo[4,3-b]pyridine-3-formaldehyde

[00613] Sodium nitrite (2.81 g, 40.72 mmol) was dissolved in 12 ml DMF and 16 ml water and cooled to 0°C. Under nitrogen protection, 2N HCl (17.7 mL, 35.4 mmol) was slowly added dropwise and after addition was complete, the reaction was continued for 10 minutes. At 0°C, 6-bromo-4-azaindole (1.0 g, 5.08 mmol) in DMF (8 ml) was slowly added dropwise to the reaction solution. After addition was complete, it was left to react at room temperature overnight. After completion of the reaction, 50 ml of water was added to the reaction mixture. The resulting mixture was stirred at room temperature for 0.5 hour and suction filtered to obtain 580 mg of intermediate MDI-237-1 in 50.5% yield.

[00614] ¹ H NMR (400 MHz, DMSO) δ 14.52 (s, 1H), 10.27 (s, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H).

[00615] Synthesis of intermediate MDI-237-2: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-formaldehyde

[00616] Intermediate MDI-237-1 (250 mg, 1.11 mmol) was dissolved in 5 ml DMF and then cooled to 0°C. NaH (60%) (53.1 mg, 1.33 mmol) was added in separate portions at 0°C. After addition was complete, the mixture was allowed to react for 30 minutes and then SEMCl (276.6 mg, 1.66 mmol) was added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction temperature was raised to room temperature. After completion of the reaction, it was quenched with water and the resulting mixture was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated by column chromatography to obtain 157.4 mg of intermediate MDI-237-2 in 39.9% yield.

[00617] ¹ H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.39 (d, J=2.0 Hz , 1H), 6.14 (s, 2H), 3.69-3.65 (m, 2H), 0.98-0.92 (m, 2H), -0.03 (s, 9H).

[00618] Synthesis of intermediate MDI-237-3: 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy) methyl)-2H-pyrazolo[4,3-b]pyridine-3-formaldehyde

[00619] Intermediate MDI-237-2 (176 mg, 0.49 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (196 mg, 0.49 mmol), Pd(dppf)Cl2 (36.1 mg, 0.05 mmol) and potassium carbonate (205 mg, 1. 48 mmol) was dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted overnight and cooled to room temperature. Water was added, the resulting mixture was extracted with ethyl acetate twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 169.5 mg of intermediate MDI-237-3 in 62% yield. 7%.

[00620] ¹ H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.76 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0 Hz , 1H), 7.21 (d, J=8.3 Hz, 1H), 7.02 (d, J=11.3 Hz, 1H), 6.19 (s, 2H), 5.33 (s , 2H), 3.88-3.83 (m, 2H), 3.72-3.69 (m, 2H), 2.59-2.53 (m, 2H), 1.10 (t, J =8.0 Hz, 3H), 1.02-0.94 (m, 4H), 0.03 (s, 9H), -0.03 (s, 9H).

[00621] Synthesis of intermediate MDI-237-4: tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-(( 2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)- carboxylate

[00622] Intermediate MDI-237-3 (170 mg, 0.31 mmol) and tert-butyl-3,4-diaminopyrroline-1-carboxylate (69.0 mg, 0.34 mmol) were dissolved in 10 ml tert- butanol, to which I ₂ (98.8 mg, 0.39 mmol) and K ₂ CO ₃ (129 mg, 0.93 mmol) were added. The mixture was heated to 70°C and reacted for 3 hours. After completion of the reaction, aqueous sodium thiosulfate was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 150 mg of intermediate MDI-237-4 in 66.2% yield.

[00623] ¹ H NMR (400 MHz, CDCl3) δ 8.54 (d, J=1.9 Hz, 1H), 7.99 (d, J=1.9 Hz, 1H), 7.20 (d , J=8.3 Hz, 1H), 7.01 (d, J=11.3 Hz, 1H), 6.60-6.20 (m, 2H), 5.33 (s, 2H), 5 .00-4.87 (m, 1H), 4.58-4.46 (m, 1H), 3.88-3.83 (m, 2H), 3.79-3.64 (m, 6H) , 2.58-2.52 (m, 2H), 1.57 (s, 9H), 1.09 (t, J=8.0 Hz, 3H), 1.02-0.96 (m, 4H ), 0.03 (s, 9H), -0.03 (s, 9H).

[00624] Synthesis of intermediate MDI-237-5: Tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-(( 2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

[00625] Intermediate MDI-237-4 (100 mg, 0.14 mmol) and 2-iodoylbenzoic acid (77.0 mg, 0.28 mmol) were dissolved in 10 ml DMSO, heated to 45°C and reacted in within 5 hours. After completion of the reaction, the reaction was quenched with aqueous sodium thiosulfate. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 75.0 mg of intermediate MDI-237-5 in 75.2% yield. .

[00626] ¹ H NMR (400 MHz, CDCl3) δ 11.78 (d, J=8.8 Hz, 1H), 8.52-8.50 (m, 1H), 7.99-7.98 ( m, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.03 (d, J=11.3 Hz, 1H), 6.44 (s, 2H), 5.33 ( s, 2H), 4.66-4.51 (m, 4H), 3.88-3.79 (m, 4H), 2.90-2.54 (m, 2H), 1.54 (s, 9H), 1.11 (t, J=8.0 Hz, ZN), 1.03-0.98 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H) .

[00627] Synthesis of intermediate MDI-237-6: tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-(( 2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4 -d]imidazole-5(1H)-carboxylate

[00628] Intermediate MDI-237-5 (20.0 mg, 0.03 mmol) was dissolved in 10 ml THF, the temperature was lowered to 0°C and then NaH (60%) (1.2 mg, 0.03) was added mmol). The reaction mixture was stirred for 0.5 hours. SEMCl (5.1 mg, 0.03 mmol) was added to the mixture, which was warmed to room temperature and stirred for 1 hour. After completion of the reaction, water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 15.0 mg of intermediate MDI-237-6 in 63.5% yield. .

[00629] ¹ H NMR (400 MHz, CDCl3) δ 8.54 (d, J=2.0 Hz, 1H), 8.00 (t, J=2.1 Hz, 1H), 7.20 (d , J=8.3 Hz, 1H), 7.03 (d, J=11.4 Hz, 1H), 6.13 (d, J=4.5 Hz, 2H), 5.57 (d, J =3.7 Hz, 2H), 5.33 (s, 2H), 4.66-4.50 (m, 4H), 3.88-3.84 (m, 2H), 3.75-3, 64 (m, 2H), 3.43-3.38 (m, 2H), 2.90-2.54 (m, 2H), 1.54 (s, 9H), 1.11 (t, J= 8.0 Hz, 3H), 1.02-0.98 (m, 2H), 0.93-0.88 (m, 2H), 0.82-0.77 (m, 2H), 0.03 (s, 9H), -0.03 (s, 9H), -0.06 (s, 9H).

[00630] Synthesis of intermediate MDI-237-7: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2- (trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d ]imidazol-5(1H)-yl)ketone

[00631] Intermediate MDI-237-6 (30.0 mg, 0.04 mmol) was dissolved in 10 ml DCM to which zinc bromide (31.6 mg, 0.14 mmol) was added. The mixture was stirred for 5 hours and water was added to the reaction mixture to quench the reaction. The resulting mixture was extracted twice with DCM and the organic phases were combined, washed with aqueous ammonia, then washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was dissolved in 10 ml DCM to which DIPEA (5.4 mg, 0.04 mmol) was added and the mixture was then cooled to 0°C. Cyclopropylformyl chloride (4.4 mg, 0.04 mmol) was then added dropwise. After addition was completed, the temperature was raised to room temperature for reaction. After completion of the reaction, water was added to quench the reaction and the resulting mixture was extracted twice with DCM and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain 23.0 mg of crude MDI-237-7, which was used immediately in next reaction. The yield of crude substance was 79.6%.

[00632] Synthesis of compound MDI-237: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6 -dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[00633] Intermediate MD1-237-7 (23.0 mg, 0.03 mmol) was dissolved in 4 ml MeOH to which 2 ml concentrated hydrochloric acid was added. After addition, the temperature was raised to 50°C for reaction. After 6 hours of reaction, the temperature was lowered to room temperature, and the reaction solvent was evaporated by concentration under reduced pressure. After this, 4 ml of methanol and 0.5 ml of aqueous ammonia were added. After concentration, the residue was subjected to thin layer chromatography to obtain 3.2 mg of white solid MDI-237 in 26.5% yield.

[00634] ¹ H NMR (400 MHz, DMSO) δ 13.60 (s, 1H), 12.90-12.48 (m, 1H), 10.02 (s, 1H), 8.53 (d, J=1.6 Hz, 1H), 7.95 (s, 1H), 7.16 (d, J=11.8 Hz, 1H), 6.98 (d, J=9.1 Hz, 1H) , 4.91-4.41 (m, 4H), 2.51-2.47 (m, 2H), 1.96-1.84 (m, 1H), 1.03 (t, J=8, 0 Hz, 3H), 0.87-0.80 (m, 4H). LC-MS m/z (ESI) [M+H]+ calculated value for C ₂₃ H ₂₂ FN ₆ O ₂ : 433.2; measured value: 433.2.

[00635] Example 36: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazol-5(1H)-yl)ketone (MDI-239)

[00636] Synthesis route for MDI-239:

[00637] Synthesis method:

[00638] Synthesis of intermediate MDI-239-1: 6-bromo-4-methyl-1H-indazole-3-formaldehyde

[00639] Sodium nitrite (1.05 g, 15.2 mmol) was dissolved in 5 ml DMF and 5 ml water and cooled to 0°C. Under nitrogen protection, 3 N HC1 (4.5 ml, 13, 3 mmol) and the reaction was completed dropwise over 10 minutes. At 0°C, 6-bromo-4-methyl-1H-indole (400 mg, 1.90 mmol) in DMF (20 ml) was slowly added dropwise to the reaction solution. After completion of the dropwise addition, it was left to react at room temperature overnight. The mixture was extracted with ethyl acetate 3 times and the organic phases were combined, washed 3 times with water, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 388 mg of intermediate MDI-239-1 in 84.3% yield. .

[00640] ¹ H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 10.24 (s, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 2.90 (s, 3H).

[00641] Synthesis of intermediate MDI-239-2: 6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-formaldehyde

[00642] Intermediate MDI-239-1 (388 mg, 1.62 mmol) was dissolved in 25 ml of dry tetrahydrofuran and cooled to 0°C. Sodium hydride (60%) (117 mg, 4.86 mmol) was added slowly and the mixture was stirred for 10 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (540 mg, 3.24 mmol) was added slowly dropwise and the reaction was carried out at room temperature for 1 hour. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 371 mg of intermediate MD1-239-2, yielding 61.9%.

[00643] ¹ H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.68 (s, 1H), 7.30 (s, 1H), 5.78 (s, 2H), 3 .61-3.57 (m, 2H), 2.89 (s, 3H), 0.96-0.89 (m, 2H), -0.02 (s, 9H).

[00644] Synthesis of intermediate MDI-239-3: tert-butyl-2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)- 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[00645] Intermediate MDI-239-2 (371 mg, 1.00 mmol) and tert-butyl 3,4-diaminopyrroline-1-carboxylate (242 mg, 1.20 mmol) were dissolved in 10 ml tert-butanol, and then iodine (317 mg, 1.25 mmol) and potassium carbonate (414 mg, 3.00 mmol) were added and the reaction was carried out at 70°C for 3 hours. The reaction was quenched by adding saturated aqueous sodium thiosulfate and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 330 mg of intermediate MDI-239-3 in 60.0% yield.

[00646] ¹ H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.20 (s, 1H), 5.68 (s, 2H), 4.77-4.66 (m, 2H), 3.77-3.60 (m, 4H), 3.57-3.53 (m, 2H), 2.89 (s, 3H), 1.46 (s, 9H), 0.94 -0.89 (m, 2H), -0.02 (s, 9H).

[00647] Synthesis of intermediate MDI-239-4: tert-butyl-2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)- 4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[00648] MDI-239-3 (330 mg, 0.60 mmol) was dissolved in 15 ml DMSO and IBX (252 mg, 0.90 mmol) was added. This was left to react at 50°C for 16 hours. The reaction was quenched by adding water and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 240 mg of intermediate MDI-239-4 in 73.0% yield.

[00649] ¹ H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.19 (s, 1H), 5.67 (s, 2H), 4.62-4.50 (m, 4H), 3.67-3.54 (m, 2H), 2.98 (d, J=7.2 Hz, 3H), 1.55 (s, 9H), 0.98-0.89 (m , 2H), -0.03 (s, 9H).

[00650] Synthesis of intermediate MDI-239-5: tert-butyl-2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

[00651] Intermediate MDI-239-4 (145 mg, 0.26 mmol) was dissolved in 15 ml of dry tetrahydrofuran and cooled to 0°C. Sodium hydride (60%) (19.0 mg, 0.79 mmol) was added slowly and the mixture was stirred for 10 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (86.7 mg, 0.52 mmol) was added slowly dropwise. After addition, the reaction was carried out at room temperature for 1 hour. The reaction was quenched by adding water, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 148 mg of intermediate MDI-239-5 in 84% yield. .0%.

[00652] ¹ H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.17 (s, 1H), 5.73 (s, 2H), 5.44 (d, J=4, 7 Hz, 2H), 4.65-4.51 (m, 4H), 3.61-3.57 (m, 2H), 3.38 -3.34 (m, 2H), 2.54 (d , J=5.8 Hz, 3H), 1.56 (s, 9H), 0.97-0.88 (m, 4H), -0.02 (s, 9H), -0.11 (s, 9H).

[00653] Synthesis of intermediate MDI-239-6: (2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-( (2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(cyclopropyl)ketone

[00654] Intermediate MDI-239-5 (148 mg, 0.22 mmol) was dissolved in 15 ml of dichloromethane and zinc bromide (197 mg, 0.87 mmol) was added. The mixture was stirred at 25°C for 4 hours, and 10 ml of aqueous ammonia was added to the reaction solution. After separation of the liquid, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. The concentrate was dissolved in 10 ml of dichloromethane and triethylamine (66.8 mg, 0.66 mmol) and cooled to 0°C. Cyclopropionyl chloride (46.0 mg, 0.44 mmol) was added slowly and this was allowed to react at room temperature for 1 hour. The reaction was quenched by adding water. The resulting mixture was extracted with dichloromethane twice and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give intermediate MDI-239-6 94 mg in 65.8% yield.

[00655] ¹ H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.20 (s, 1H), 5.75 (s, 2H), 5.48 (d, J=15, 8 Hz, 2H), 5.00-4.69 (m, 4H), 3.63-3.59 (m, 2H), 3.46-3.34 (m, 2H), 2.57 (d , J=7.7 Hz, 3H), 2.09-2.05 (m, 1H), 1.09-1.00 (m, 4H), 0.98-0.89 (m, 4H), 0.00-0.05 (m, 18H).

[00656] Synthesis of intermediate MDI-239-7: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-4-methyl-1- ((2-trimethylsilanyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5( 1H)-yl)ketone

[00657] Intermediate MDI-239-6 (40.0 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (36.8 mg, 0.09 mmol), tetrakistriphenylphosphine palladium (6.9 mg, 0.01 mmol) and potassium phosphate (39.4 mg , 0.19 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted for 16 hours and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 27.3 mg of intermediate MDI-239-7 in a yield of 52 ,9%.

[00658] ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.06-6.92 (m, 2H ), 5.79 (d, J=7.0 Hz, 2H), 5.53 (d, J=14.4 Hz, 2H), 5.33 (d, J=5.3 Hz, 2H), 5.00-4.69 (m, 4H), 3.90-3.86 (m, 2H), 3.64-3.58 (m, 2H), 3.42-3.37 (m, 2H ), 2.94-2.56 (m, 5H), 2.06-2.03 (m, 1H), 1.13-1.07 (m, 4H), 1.05-1.01 (m , 3H), 0.95-0.89 (m, 6H), 0.02 (s, 9H), -0.03-0.12 (m, 18H).

[00659] Synthesis of compound MDI-239: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3 ,4-d]imidazol-5(1H)-yl)ketone

[00660] Intermediate MDI-239-7 (27.3 mg, 0.03 mmol) was dissolved in methanol (6 ml), to which concentrated hydrochloric acid (3 ml) was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol and 1 ml of aqueous ammonia was added. The mixture was concentrated and filtered. The resulting filtrate was concentrated and purified on a preparation plate to obtain 5.1 mg of the final product with a yield of 34.7%.

[00661] ¹ H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 6.95-6.88 (m, 3H), 4.96 (s, 2H), 4.66 (s, 2H), 2.93 (s, 3H), 2.55 (q, J=7.5 Hz, 2H), 1.98-1.92 (m, 1H), 1.07 (t, J=7 .5 Hz, 3H), 1.04-0.92 (m.4H).

[00662] Example 37: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3 ,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone (MDI-240)

[00663] MDI-240 synthesis path

[00664] Synthesis method:

[00665] Synthesis of intermediate MDI-240-1: tert-butyl-2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4-methyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

[00666] Tert-butyl-2-(6-bromo-4-methyl-1-(((2-(trimethylsilanyl)ethoxy)methyl)-1H-ind azol-3-yl)-1-(((2- (trimethylsilanyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (60.0 mg, 0.09 mmol), 2-(4-(benzyloxy)-2 -ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (47.2 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (10.4 mg, 0.01 mmol) and potassium phosphate (55.9 mg, 0.26 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C. react for 16 hours and cool to room temperature. Water was added, the resulting mixture was extracted 2 times with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 63.2. mg of intermediate MDI-240-1 in 86.7% yield.

[00667] ¹ H NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.4 Hz, 2H), 7.46-7.34 (m, 4H), 7.03-6.96 ( m, 3H), 5.77 (s, 2H), 5.50 (d, J=4.1 Hz, 2H), 5.22 (s, 2H), 4.67-4.53 (m, 4H ), 3.64-3.60 (m, 2H), 3.40-3.35 (m, 2H), 2.59-2.51 (m, 5H), 1.56 (s, 9H), 1.06 (t, J=7.5 Hz, 3H), 0.98-0.89 (m, 4H), -0.04 (s, 9H), -0.12 (s, 9H).

[00668] Synthesis of intermediate MDI-240-2: (S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4-methyl-1-((2-(trimethylsilyl )ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone

[00669] Intermediate MDI-240-1 (63.2 mg, 0.08 mmol) was dissolved in 10 ml of dichloromethane and zinc bromide (68.7 mg, 0.31 mmol) was added. The mixture was stirred at 25°C for 4 hours, and 6 ml of aqueous ammonia was added to the reaction solution. After separation of the liquid, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. The concentrate was dissolved in 8 ml of dichloromethane at 0°C, triphosgene (22.5 mg, 0.08 mmol) was added and triethylamine (76.7 mg, 0.76 mmol) was added slowly dropwise. The mixture was stirred at room temperature for 10 minutes and (S)-pyrrolidinebutan-3-ol (13.2 mg, 0.15 mmol) in dichloromethane was added. The mixture was stirred at room temperature for 20 minutes. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 44.0 mg of intermediate MDI-240-2 in 68% yield. ,9%.

[00670] ¹ H NMR (400 MHz, CDCl3) δ 7.51 (d, J=7.0 Hz, 2H), 7.45-7.34 (m, 4H), 7.03-6.95 ( m, 3H), 5.77 (s, 2H), 5.49 (s, 2H), 5.22 (s, 2H), 4.76-4.53 (m, 4H), 4.46-4 .44 (m, 1H), 3.64-3.54 (m, 4H), 3.44-3.33 (m, 4H), 2.57-2.51 (m, 5H), 2.06 -1.90 (m, 2H), 1.05 (t, J=7.5 Hz, 3H), 1.00-0.88 (m, 4H), -0.04 (s, 9H), - 0.13 (s, 9H).

[00671] Synthesis of compound MDI-240: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6- Dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

[00672] MDI-240-2 (44.0 mg, 0.05 mmol) was dissolved in 6 ml of methanol, to which 5 mg of 10% carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the resulting mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of methanol and 3 ml of concentrated hydrochloric acid was added. The mixture was allowed to react for 7 hours at 50°C and the mixture was concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified on a preparation plate to obtain 5.7 mg of the final product with a yield of 22.3%.

[00673] ¹ H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 6.95-6.88 (m, 3H), 4.85-4.82 (m, 2H), 4, 62-4.59 (m, 2H), 4.46-4.45 (m, 1H), 3.79-3.69 (m, 2H), 3.64-3.57 (m, 1H), 3.46-3.42 (m, 1H), 2.91 (s, 3H), 2.56 (q, J=7.5 Hz, 2H), 2.09-1.98 (m, 2H) , 1.07 (t, J=7.5 Hz, 3H).

[00674] Example 38: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[00674] 3,4-Nimidazol-5(1H)-yl)ketone (MDI-242)

[00675] Synthesis route for MDI-242:

[00676] Synthesis method:

[00677] Synthesis of intermediate MDI-242-1: 6-bromo-1H-pyrazolo[4,3-c]pyridine-3-formaldehyde

[00678] Sodium nitrite (1.68 g, 24.4 mmol) was dissolved in 15 ml DMF and 15 ml water and 3 N HCl (7.1 ml, 21.3 mmol) was added at 0° C. The mixture was stirred for 10 minutes and 6-bromo-1H-pyrrolo[3,2-c]pyridine (600 mg, 3.04 mmol) in DMF (15 ml) was added dropwise at 0°C. This was left to react at room temperature for 30 minutes and react at 50°C for 3 hours. The resulting mixture was extracted 3 times with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 350 mg of intermediate MDI-242-1 in 50.9% yield.

[00679] ¹ H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 9.25 (s, 1H), 7.88 (s. 1H).

[00680] Synthesis of intermediate MDI-242-2: tert-butyl-2-(6-bromo-1H-pyrazolo[4,3-c]pyridin-3-yl)-3a,4,6,6a-tetrahydropyrrolo[00680] 3,4-d]imidazole-5(1H)-carboxylate

[00681] Intermediate MDI-242-1 (350 mg, 1.55 mmol) was dissolved in 15 ml tert-butanol and then tert-butyl 3,4-diaminopyrrolidine-1-carboxylate (3734 mg, 1.86 mmol), potassium carbonate (775 mg, 5.57 mmol) and iodine (590 mg, 2.32 mmol). The mixture was stirred at 60°C for 3 hours and aqueous saturated sodium thiosulfate was added. The resulting mixture was extracted 3 times with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 240 mg of intermediate MDI-242-2 in 38.1% yield.

[00682] ¹ H NMR (400 MHz, CDCl3) δ 9.29 (d, J=0.9 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 5.00-4 .95 (m, 1H), 4.52-4.49 (m, 1H), 3.77-3.70 (m, 3H), 3.57-3.53 (m, 1H), 1.42 (s, 9H).

[00683] Synthesis of intermediate MDI-242-3: Tert-butyl-2-(6-bromo-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazole-5(1H)-carboxylate

[00684] Intermediate MDI-242-2 (240 mg, 0.59 mmol) was dissolved in 15 ml DMSO and IBX (330 mg, 1.18 mmol) was added. The mixture was stirred overnight at 45°C and extracted 3 times with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 100 mg of intermediate MDI-242-3 in 41.9% yield.

[00685] ¹ H NMR (400 MHz, CDCl3) δ 9.46 (d, J=6.1 Hz, 1H), 7.78 (s, 1H), 4.65-4.53 (m, 4H) , 1.54 (s, 9H).

[00686] Synthesis of intermediate MDI-242-4: Tert-butyl-2-(6-bromo-1H-pyrazolo[4,3-c]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy )methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[00687] Intermediate MDI-242-3 (100 mg, 0.25 mmol) was dissolved in 15 ml THF and cooled to 0°C. NaH (60%) (21.7 mg, 0.54 mmol) was added and the mixture was stirred at 0°C for 20 minutes. SEM-C1 (103 mg, 0.62 mmol) was then added. This was left to react for 2 hours. The resulting mixture was extracted 3 times with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 100 mg of intermediate MDI-242-4 in 75.7% yield.

[00688] ¹ H NMR (400 MHz, CDCl3) δ 9.53-9.51 (m, 1H), 7.77 (d, J=1.2 Hz, 1H), 5.85 (d, J= 7.2 Hz, 2H), 4.65-4.52 (m, 4H), 3.66-3.61 (m, 2H), 1.54 (s, 9H), 0.90-0.86 (m, 2H), -0.02 (s, 9H).

[00689] Synthesis of intermediate MDI-242-5: (2-(6-bromo-1H-pyrazolo[4,3-c]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(cyclopropyl)ketone

[00690] Intermediate MDI-242-4 (100 mg, 0.19 mmol) was dissolved in 5 ml dichloromethane and zinc bromide (168 mg, 0.75 mmol) was added. The mixture was stirred at room temperature for 4 hours and aqueous ammonia was added. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting compound was dissolved in 5 ml of dichloromethane and triethylamine (56.6 mg, 0.56 mmol) was added. The mixture was cooled to 0°C and cyclopropylformyl chloride (29.3 mg, 0.28 mmol) was added. This was left to react at room temperature for 2 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 60.0 mg of intermediate MDI-242-5 with yield 63.8%.

[00691] ¹ H NMR (400 MHz, CDCl3) δ 9.53 (d, J=7.4 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 5.86 (s , 2H), 4.97-4.67 (m, 4H), 3.68 -3.61 (m, 2H), 1.77-1.72 (m, 1H), 1.13-1.09 (m, 2H), 0.99-0.89 (m, 4H), -0.05 (s, 9H).

[00692] Synthesis of intermediate MDI-242-6: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[4, 3-c]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[00693] Intermediate MDI-242-5 (60 mg, 0.12 mmol) was dissolved in 5 ml dioxane and 1 ml water, and then added (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (56.7 mg, 0.14 mmol), Pd(PPh ₃ ) ₄ (13.8 mg , 0.01 mmol) and potassium carbonate (49.4 mg, 0.36 mmol). The atmosphere was replaced with nitrogen. The mixture was stirred at 100°C for 2 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 40 mg of intermediate MDI-242-6, yielding 48.4%.

[00694] ¹ H NMR (400 MHz, CDCl3) δ 9.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.26-7 .18 (m, 2H), 5.95-5.90 (m, 2H), 5.33 (s, 2H), 5.00-4.70 (m, 4H), 3.86-3.82 (m, 2H), 3.69-3.62 (m, 2H), 2.74-2.98 (m, 2H), 1.79-1.70 (m, 1H), 1.14-1 .08 (m, 5H), 1.02-0.96 (m, 4H), 0.92-0.88 (m, 2H), 0.03 (s, 9H), -0.02-0, 04 (m, 9H).

[00695] Synthesis of compound MDI-242: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6 -dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone (MDI-242)

[00696] Intermediate MDI-242-6 (40 mg, 0.06 mmol) was dissolved in 4 ml of methanol and 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated. The solid was dissolved in 1 ml of methanol and the pH was adjusted to 8-9 with aqueous ammonia. The resulting mixture was concentrated and purified on a preparation plate to obtain 8.0 mg of the final product with a yield of 32.0%.

[00697] ¹ H NMR (400 MHz, MeOD) δ 9.61 (d, J=1.0 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H), 7.16 (d , J=11.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.07-4.88 (m, 2H), 4.68-4.62 (m, 2H), 2.99-2.94 (m, 2H), 1.98-1.89 (m, 1H), 1.09-1.05 (m, 3H), 1.01-0.98 ( m, 2H), 0.96-0.94 (m, 2H).

[00698] Example 39: (Io-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)ketone (MDI-243)

[00699] Synthesis route for MDI-243:

[00700] Synthesis method:

[00701] Synthesis of intermediate MDI-243-1: (R)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3- hydroxylpyrrolidin-1-yl)ketone

[00702] Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml of dichloromethane and at 0° C., intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1 was added dropwise -((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol- 2-yl)-1H-indazole (130 mg, 0.18 mmol) in dichloromethane (5 ml). After addition, anhydrous triethylamine (55.2 mg, 0.55 mmol) was added dropwise. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. (R)-pyrrolidin-3-ol (31.8 mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 118 mg of intermediate MDI-243-1 in 78% yield. 4%.

[00703] ¹ H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.3 Hz, 1H), 7.75-7.73 (m, 2H), 7.47-7.35 ( m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.96 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H ), 5.23 (s, 2H), 4.95-4.56 (m, 4H), 4.50-4.45 (m, 1H), 3.79-3.72 (m, 2H), 3.66-3.58 (m, 5H), 3.46-3.42 (m, 1H), 2.54 (q, J=7.6 Hz, 2H), 2.06-2.01 ( m, 2H), 1.06 (t, J=7.5 Hz, 3H), 0.99-0.89 (m, 4H), 0.02 (s, 9H), -0.05 (d, J=3.4 Hz, 9H).

[00704] Synthesis of compound MDI-243: (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3, 4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

[00705] MDI-243-1 (118 mg, 0.14 mmol) was dissolved in 20 ml of methanol and 20 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 12 ml of methanol and 6 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 8 ml of methanol and 0.8 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 28 mg of the final product with a yield of 41.2%.

[00706] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 1H), 7.17 (d , J=8.4 Hz, 1H), 6.98-6.90 (m, 2H), 4.82-4.60 (m, 4H), 4.47-4.45 (m, 1H), 3.79-3.70 (m, 2H), 3.60-3.57 (m, 1H), 3.46-3.43 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.09-1.98 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

[00707] Example 40: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 (1H)-yl)(3-hydroxylasetidin-1-yl)ketone (MDI-244)

[00708] Synthesis route for MDI-244:

[00709] Synthesis method:

[00710] Synthesis of intermediate MDI-244-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylasetidin-1-yl )ketone

[00711] Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml of dichloromethane and the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1- was added dropwise at 0° C. ((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2 -yl)-1H-indazole (130 mg, 0.18 mmol) in dichloromethane (5 ml). After addition, anhydrous triethylamine (185 mg, 1.8 mmol) was added dropwise. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. Azetidin-3-ol (26.7 mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 110 mg of intermediate MDI-244-1 in 74% yield. 3%.

[00712] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H), 7.48-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.96 (m, 2H), 5.96 (s, 2H), 5.76 (s, 2H), 5.23 (s, 2H), 4.73-4.58 (m, 4H), 4.39-4.31 (m, 2H), 4.22-4.18 (m, 1H) , 4.03-4.00 (m, 1H), 3.88-3.85 (m, 1H), 3.65-3.57(m, 4H), 2.54 (q, J=7, 6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.99-0.89 (m, 4H), 0.02 (s, 9H), -0.05 (d , J=3.4 Hz, 9H).

[00713] Synthesis of MDI-244: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5-(1H)-yl)(3-hydroxylasetidin-1-yl)ketone

[00714] MDI-241-1 (110 mg, 0.14 mmol) was dissolved in 20 ml of methanol and 20 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 12 ml of methanol and 6 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 8 ml of methanol and 0.8 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 34 mg of the final product with a yield of 54.4%.

[00715] ¹ H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, 7=8, 4 Hz, 1H), 6.97-6.90 (m, 2H), 4.62-4.56 (m, 4H), 4.00-3.94 (m, 1H), 3.70 -3 .66 (m, 1H), 3.62-3.55 (m, 1H), 3.51 -3.46 (m, 1H), 3.41 -3.37 (m, 1H), 2.56 (q, 7=7.5 Hz, 2H), 1.08 (t, 7=7.5 Hz, 3H).

[00716] Example 41: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 (1H)-yl)(4-hydroxylpiperidin-1-yl)ketone (MDI-245)

[00717] Synthesis route for MDI-245:

[00718] Synthesis method:

[00719] Synthesis of intermediate MDI-245-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-hydroxylpiperidin-1- yl)ketone

[00720] Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml of dichloromethane to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl )-1H-indazole (130 mg, 0.18 mmol) in dichloromethane (5 ml) at 0°C, and then anhydrous triethylamine (185 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. Piperidin-4-ol (36.9 mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 116 mg of intermediate MDI-245-1 in 75% yield. 7%.

[00721] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35( m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97(m, 2H), 5.96 (s, 2H), 5.75 (s, 2H ), 5.37 (s, 2H), 4.79-4.66 (m, 4H), 3.95-3.92 (m, 1H), 3.75-3.72 (m, 2H), 3.66-3.52 (m, 4H), 3.12-3.07 (m, 2H), 2.54 (q, J=7.6 Hz, 2H), 2.02-1.91 ( m, 2H), 1.68-1.63 (m, 2H), 1.06 (t, J=7.5 Hz, 3H), 0.99-0.89 (m, 4H), 0.02 (s, 9H), -0.05 (d, J=3.4 Hz, 9H).

[00722] Synthesis of MDI-245: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5-(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone

[00723] MDI-243-1 (116 mg, 0.14 mmol) was dissolved in 20 ml of methanol and 20 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 12 ml of methanol and 6 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 8 ml of methanol and 0.8 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 30 mg of the final product with a yield of 44.4%.

[00724] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.97-6.90 (m, 2H), 4.72-4.65 (m, 4H), 3.88-3.82 (m, 1H), 3.76-3.73 (m, 2H), 3.13-3.06 (m, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.97-1.95 (m, 2H), 1, 63-1.55 (m, 2H), 1.08 (t, 7=7.5 Hz, 3H).

[00725] Example 42: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-methyl-4,6-dihydropyrrolo[3,4-d] imidazole-5-(1H)-carboxamide (MDI-246)

[00726] MDI-246. Synthesis route:

[00727] Synthesis method:

[00728] Synthesis of intermediate MDI-246-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

[00729] Triphosgene (20.8 mg, 0.07 mmol) was dissolved in 5 ml of dry dichloromethane, to which was added dropwise the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-( (2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2- yl)-1H-indazole (50 mg, 0.07 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (70.9 mg, 0.70 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. Methylamine hydrochloride (9.5 mg, 0.14 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 42 mg of intermediate MDI-246-1 in 77.8 yield %.

[00730] ¹ H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.37 ( m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H ), 5.23 (s, 2H), 4.72-4.54 (m, 4H), 3.65-3.58 (m, 4H), 2.94 (s, 3H), 2.56 ( q, J=7.6 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), -0.04 - -0.05 (m, 9H).

[00731] Synthesis of MDI-246: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-methyl-4,6-dihydropyrrolo[3,4 -d]imidazole-5-(1H)-carboxamide

[00732] MDI-246-1 (42 mg, 0.055 mmol) was dissolved in 10 ml of methanol and 8 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of methanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 10.3 mg of the final product with a yield of 45.1%.

[00733] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.97-6.90 (m, 2H), 4.56 (s, 4H), 2.84 (s, 3H), 2.56 (q, J=7.5 Hz, 2H) , 1.08 (t, J=7.5 Hz, 3H).

[00734] Example 43: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d] imidazole-5-(1H)-carboxamide (MDI-247)

[00735] Synthesis route for MDI-247:

[00736] Synthesis method:

[00737] Synthesis of intermediate MDI-247-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

[00738] Triphosgene (22.9 mg, 0.08 mmol) was dissolved in 6 ml of dry dichloromethane, to which was added dropwise the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-( (2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2- yl)-1H-indazole (55 mg, 0.08 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (78.0 mg, 0.8 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. Ethylamine hydrochloride (12.9 mg, 0.16 mmol) was added. The resulting mixture was stirred at room temperature for 20 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 47 mg of intermediate MDI-247-1 in 77% yield. 7%.

[00739] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35 ( m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.97 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H ), 5.23 (s, 2H), 4.72-4.54 (m, 4H), 3.65-3.58 (m, 4H), 3.45-3.38 (m, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.18-1.14 (m, 3H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0 .89 (m, 4H), 0.02 (s, 9H), -0.05 (d, J=3.4 Hz, 9H).

[00740] Synthesis of MDI-247: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4 -d]imidazole-5-(1H)-carboxamide

[00741] MDI-247-1 (47 mg, 0.06 mmol) was dissolved in 10 ml of methanol and 8 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of methanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 11 mg of the final product with a yield of 42.4%.

[00742] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.98-6.90 (m, 2H), 4.57 (s, 4H), 3.38-3.28 (m, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H), 1.08 (t, 7=7.5 Hz, 3H).

[00743] Example 44: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-(2-hydroxyethyl)-4,6-dihydropyrrolo[3, 4-d]imidazole-5(1H)-carboxamide (MDI-248)

[00744] Synthesis route for MDI-248:

[00745] Synthesis method:

[00746] Synthesis of intermediate MDI-248-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-1H-(2-hydroxylstyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

[00747] Triphosgene (22.9 mg, 0.08 mmol) was dissolved in 6 ml of dichloromethane to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl )-1H-indazole (55 mg, 0.08 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (78 mg, 0.8 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. It was observed by TLC that the starting materials had disappeared. Ethanolamine (9.4 mg, 0.16 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 1 hour. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 44 mg of intermediate MDI-248-1 in 71.3 yield %.

[00748] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J=8.3 Hz, 1H), 7.73-7.51 (hl, 2H), 7.48-7.35 (m, 4H), 7.27-7.24 (m, 1H), 7.07-6.97 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.73-4.57 (m, 4H), 3.65-3.53 (m, 6H), 3.33-3.29 (m, 2H), 2, 54 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H ), -0.05 (s, 9H).

[00749] Synthesis of MDI-248: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo [3,4-d]imidazole-5(1H)-carboxamide

[00750] MDI-248-1 (44 mg, 0.06 mmol) was dissolved in 10 ml of methanol and 8 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of methanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 14 mg of the final product with a yield of 56.6%.

[00751] ¹ H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.97-6.90 (m, 2H), 4.59 (s, 4H), 3.68 (t, J=5.8 Hz, 2H), 3.40 (t, J= 5.8 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H)

[00752] Example 45: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4 -d]imidazole-5-carbonyl)azetidine-3-nitrile (MDI-249)

[00753] Synthesis route for MDI-249:

[00754] Synthesis method:

[00755] Synthesis of intermediate MDI-249-1: 1-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)azetidine-3-nitrile

[00756] Triphosgene (15.8 mg, 0.05 mmol) was dissolved in 5 ml of dry dichloromethane, to which was added dropwise the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-( (2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2- yl)-1H-indazole (38 mg, 0.05 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (53.9 mg, 0.50 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. Azetidine-3-nitrile hydrochloride (8.8 mg, 0.10 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 26 mg of intermediate MDI-249-1 in 59.4 yield %.

[00757] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.48-7.36 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97(m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.72-4.56 (m, 4H), 4.42-4.34 (m, 2H), 4.26-4.17 (m, 2H) , 3.65-3.58 (m, 4H), 3.46-3.39 (m, 1H), 2.53 (q, J=7.6 Hz, 2H), 1.05 (t, J =7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), -0.04 - -0.05 (m, 9H).

[00758] Synthesis of compound MDI-249: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[00758] 3,4-d]imidazole-5-carbonyl)azetidine-3-nitrile

[00759] MDI-249-1 (26 mg, 0.03 mmol) was dissolved in 10 ml of methanol and 6 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of methanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 5.3 mg of the final product with a yield of 33.5%.

[00760] ¹ H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.97-6.90 (m, 2H), 4.60 (s, 4H), 3.86-3.81 (m, 2H), 3.65-3.53 (m, 2H ), 3.19-3.13 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

[00761] Example 46: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4-5,6-tetrahydropyrrolo[3,4 -d]imidazole-5-carbonyl)pyrrolidine-3-nitrile (MDI-250)

[00762] Synthesis route for MDI-250:

[00763] Synthesis method:

[00764] Synthesis of intermediate MDI-250-1: 1-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidine-3-nitrile

[00765] Triphosgene (14.9 mg, 0.05 mmol) was dissolved in 6 ml of dichloromethane to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imvdazol-2-yl )-1H-Indazole (36 mg, 0.05 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (51.1 mg, 0.50 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. Pyrrolidine-3-nitrile hydrochloride (9.7 mg, 0.10 mmol) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 26 mg of intermediate MDI-250-1 in 61% yield. 6%.

[00766] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35( m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97(m, 2H), 5.96 (s, 2H), 5.77 (s, 2H ), 5.23 (s, 2H), 4.80-4.67 (m, 4H), 3.79-3.46 (m, 8H), 3.12-3.05 (m, 1H), 2.54 (q, J=7.6 Hz, 2H), 2.38-2.16 (m, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.96-0 .89 (m, 4H), 0.02 (s, 9H), -0.05 (d, J=3.4 Hz, 9H).

[00767] Synthesis of MDI-250: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[00767] 3,4-d]imidazole-5-carbonyl)pyrrolidine-3-nitrile

[00768] MDI-250-1 (26 mg, 0.03 mmol) was dissolved in 10 ml of methanol and 6 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 4 ml of methanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 6 mg of the final product with a yield of 39.8%.

[00769] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.98-6.90 (m, 2H), 4.70 (s, 4H), 3.89-3.85 (m, 1H), 3.78-3.76 (m, 1H ), 3.70-3.59 (m, 2H), 3.23-3.18 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.42-2, 19 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

[00770] Example 47: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[00770] 3,4-d]imidazole-5(1H)-carboxamide(MDI-251)

[00771] Synthesis route for MDI-251:

[00772] Synthesis method:

[00773] Synthesis of intermediate MDI-251-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-N-(tetrahydrofuran-3-yl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)- carboxamide

[00774] Triphosgene (19.1 mg, 0.06 mmol) was dissolved in 6 ml of dry dichloromethane, to which was added dropwise the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-( (2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2- yl)-1H-indazole (46 mg, 0.06 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (65.3 mg, 0.6 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. Tetrahydrofuran-3-amine hydrochloride (16.4 mg, 0.13 mmol) was added. This was left to react at 38°C for 5 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 32 mg of intermediate MDI-251-1 in 60.3 yield %.

[00775] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H), 7.47-7.35 (m, 4H), 7.27-7.24 (m, 1H), 7.07-6.97(m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.70-4.53 (m, 4H), 4.51-4.41 (m, 1H), 4.06-3.58 (m, 8H), 2. 54 (q, J=7.6 Hz, 2H), 2.40-1.99 (m, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), -0.05 (s, 9H).

[00776] Synthesis of MDI-251: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6 -dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

[00777] MDI-251-1 (32 mg, 0.04 mmol) was dissolved in 10 ml of methanol and 6 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of methanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 3 mg of the final product with a yield of 16.3%.

[00778] ¹ H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.97-6.90 (m, 2H), 4.63 (s, 4H), 4.45-4.40 (m, 1H), 4.03-3.94 (m, 2H ), 3.87-3.81 (m, 1H), 3.71-3.68 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.32-1, 87 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

[00779] Example 48: Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-carboxylate (MDI-252)

[00780] Synthesis route for MDI-252:

[00781] Synthesis method:

[00782] Synthesis of intermediate MDI-252-1: Methyl-2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -indazol-3-yl)-1-((2-((trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

[00783] Triphosgene (16.6 mg, 0.06 mmol) was dissolved in 5 ml of dry dichloromethane, to which was added dropwise the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-( (2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2- yl)-1H-indazole (40 mg, 0.06 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (56.8 mg, 0.56 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. The reaction mixture was concentrated and dissolved in 10 ml of methanol. DMAP (6.9 mg, 0.06 mmol) was added. This was left to react at 70°C for 4 hours. The reaction mixture was concentrated to which water was added. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 30 mg of intermediate MDI-252-1 in 69.4% yield.

[00784] ¹ H NMR (400 MHz, CDCl3) δ 8.44-8.39 (m, 1H), 7.53-7.51 (m, 2H), 7.48-7.36 (m, 4H ), 7.23 (d, J=8.4 Hz, 1H), 7.05-6.96 (m, 2H), 5.95 (s, 2H), 5.78 (s, 2H), 5 .23 (s, 2H), 4.75-4.59 (m, 4H), 3.85 (s, 3H), 3.66-3.57 (m, 4H), 2.53 (q, J =7.6 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H), 0.95-0.88 (m, 4H), 0.02 (s, 9H), -0, 04 - -0.05 (m, 9H).

[00785] Synthesis of MDI-252: Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d ]imidazole-5(1H)-carboxylate

[00786] MDI-252-1 (30 mg, 0.04 mmol) was dissolved in 10 ml of methanol and 6 mg of carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of methanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of methanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 8 mg of the final product with a yield of 48.9%.

[00787] ¹ H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.97-6.90 (m, 2H), 4.61 (s, 4H), 3.83 (s, 3H), 2.56 (q, J=7.5 Hz, 2H) , 1.08 (t, J=7.5 Hz, 3H).

[00788] Example 49: Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-carboxylate (MDI-253)

[00789] Synthesis route for MDI-253:

[00790] Synthesis method:

[00791] Synthesis of intermediate MDI-253-1: Ethyl-2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

[00792] Triphosgene (20.1 mg, 0.07 mmol) was dissolved in 5 ml of dry dichloromethane, to which was added dropwise the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-( (2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2- yl)-1H-indazole (48 mg, 0.07 mmol) in dichloromethane (5 ml) at 0°C, then anhydrous triethylamine (68.1 mg, 0.67 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. Using TLC, it was observed that the starting materials disappeared. The reaction mixture was concentrated and dissolved in 10 ml of ethanol. DMAP (8.2 mg, 0.07 mmol) was added. This was left to react at 80°C for 4 hours. The reaction mixture was concentrated to which water was added. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 33 mg of intermediate MDI-253-1, 62.5% yield.

[00793] ¹ H NMR (400 MHz, CDCl3) δ 8.50-8.45 (m, 1H), 7.53-7.51 (m, 2H), 7.47-7.37 (m, 4H ), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5 .23 (s, 2H), 4.72-4.59 (m, 4H), 4.29-4.25 (m, 2H), 3.65-3.58 (m, 4H), 2.54 (q, J=7.6 Hz, 2H), 1.38-1.34 (m, 3H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 ( m, 4H), 0.02 (s, 9H), -0.05 (s, 9H).

[00794] Synthesis of MDI-253: Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d ]imidazole-5(1H)-carboxylate

[00795] MDI-253-1 (33 mg, 0.04 mmol) was dissolved in 10 ml ethanol and 6 mg carbon-supported palladium was added. The atmosphere was replaced with hydrogen. This was left to react at 40°C for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The concentrate was dissolved in 6 ml of ethanol and 3 ml of concentrated hydrochloric acid was added. This was allowed to react at 50°C for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in ethanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of ethanol and 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified to obtain 10 mg of the final product with a yield of 54.8%.

[00796] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.97-6.90 (m, 2H), 4.60 (s, 4H), 4.26 (q, J=7.1 Hz, 2H), 2.57 (q, J= 7.5 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).

[00797] Example 50: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6 -dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone (MDI-255)

[00798] Synthesis route for MDI-255:

[00799] Synthesis method:

[00800] Synthesis of intermediate MDI-551-1: 6-bromo-1H-pyrazolo[3,4-b]pyridine-3-formaldehyde

[00801] Sodium nitrite (2.80 g, 40.6 mmol) was dissolved in 15 ml DMF and 20 ml water and cooled to 0°C. 3N HCl (11.9 mL, 35.6 mmol) was added slowly dropwise and the reaction was carried out for 10 minutes after addition. At 0°C, 6-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol) in DMF (15 ml) was slowly added dropwise to the reaction solution. After addition, the mixture was heated to 50°C. The mixture was left to react for 5 hours. The resulting mixture was extracted with ethyl acetate 3 times and the organic phases were combined, washed 3 times with water, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 540 mg of intermediate MDI-255-1 in 47.0 yield %.

[00802] ¹ H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz , 1H).

[00803] Synthesis of intermediate MDI-255-2: Tert-butyl-2-(6-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-3a,4,6,6a-tetrahydropyrrolo[00803] 3,4-d]imidazole-5(1H)-carboxylate

[00804] Intermediate MDI-255-1 (540 mg, 2.39 mmol) and tert-butyl-3,4-diaminopyrroline-1-carboxylate (529 mg, 2.93 mmol) were dissolved in 30 ml of tert-butanol and stirred at room temperature for 30 minutes and then I ₂ (759 mg, 2.99 mmol) and K ₂ CO ₃ (989.1 mg, 7.17 mmol) were added. The mixture was heated to 70°C for 3 hours and cooled to room temperature. Saturated sodium thiosulfate was added and the mixture was stirred for 20 minutes until the iodine color disappeared. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 396 mg of intermediate MDI-255-2 in 40.7% yield.

[00805] ¹ H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.99-4 .94 (m, 1H), 4.54-4.50 (m, 1H), 3.76-3.68 (m, 3H), 3.60-3.58 (m, 1H), 1.45 (s, 9H).

[00806] Synthesis of intermediate MDI-255-3: Tert-butyl-2-(6-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazole-5(1H)-carboxylate

[00807] MDI-255-2 (396 mg, 0.97 mmol) was dissolved in 6 ml DMSO and IBX (543 mg, 1.94 mmol) was added. This was left to react at 50°C for 6 hours. The reaction was quenched by adding water. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 227 mg of intermediate MDI-255-3 in 57.6% yield.

[00808] ¹ H NMR (400 MHz, CDCl3) δ 10.59 (s, 1H), 8.64 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.64 (d , J=8.0 Hz, 1H), 4.67-4.53 (m, 4H), 1.56 (s, 9H).

[00809] Synthesis of intermediate MDI-255-4: Tert-butyl-2-(6-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy )methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[00810] Intermediate MDI-255-3 (227 mg, 0.56 mmol) was dissolved in 15 ml of dry tetrahydrofuran and cooled to 0° C., to which sodium hydride (60%) (67.2 mg, 1.68 mmol). The mixture was stirred for 10 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (280.3 mg, 1.68 mmol) was added slowly dropwise and after addition the reaction was carried out at room temperature for 1 hour. Water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 126 mg of intermediate MDI-255-4 in 42.0% yield.

[00811] ¹ H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.63 (dd, J=8.0 Hz, J =4.0 Hz, 1H), 5.90 (d, J=8.0 Hz, 2H), 4.67-4.52 (m, 4H), 3.69-3.64 (m, 2H) , 1.56 (s, 9H), 1.01-0.97 (m, 2H), 0.02 (s, 9H).

[00812] Synthesis of intermediate MDI-255-5: Tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[ 3,4-b]pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

[00813] Intermediate MDI-255-4 (126 mg, 0.24 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (143 mg, 0.36 mmol), Pd(PPh3)4 (27.2 mg, 0.02 mmol) and potassium carbonate (99.4 mg, 0.72 mmol) was dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100°C, reacted for 3 hours, and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 83 mg of intermediate MDI-255-5 in 47.7% yield.

[00814] ¹ H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H ), 7.25-7.21 (m, 2H), 5.95 (d, J=8.0 Hz, 2H), 5.36 (s, 2H), 4.69-4.54 (m, 4H), 3.89-3.84 (m, 2H), 3.72-3.65 (m, 2H), 2.82-2.76 (m, 2H)), 1.59 (s, 9H ), 1.18-1.12 (m, 3H), 1.04-0.99 (m, 4H), 0.05 (s, 9H), 0.02 (s, 9H).

[00815] Synthesis of intermediate MDI-255-6: 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-3-(1-((2-(trimethylsilanyl) )ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine

[00816] Intermediate MDI-255-5 (83 mg, 0.11 mmol) was dissolved in 15 ml dichloromethane and zinc bromide (103 mg, 0.46 mmol) was added. The mixture was stirred at 25°C for 4 hours and 10 ml of aqueous ammonia was added to the reaction solution. After liquid separation, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give 65 mg of intermediate MDI-255-6 in 95.6% yield. The crude product was used immediately in the next step.

[00817] Synthesis of intermediate MDI-255-7: (S)-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo [3,4-b]pyridin-3-yl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone

[00818] Intermediate MDI-241-6 (20 mg, 0.03 mmol) was dissolved in 5 ml of dry dichloromethane and cooled to 0°C, to which triphosgene (9.5 mg, 0.03 mmol) was added and added dropwise triethylamine (32.3 mg, 0.32 mmol). After addition, the mixture was stirred at room temperature for 10 minutes, to which (S)-3-hydroxypyrrolidine hydrochloride (7.7 mg, 0.06 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water was added and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 19 mg of intermediate MDI-255-7. The crude product was used immediately in the next step.

[00819] Synthesis of compound MDI-255: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- 4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

[00820] Intermediate MDI-255-1 (19 mg, 0.03 mmol) was dissolved in 4 ml of methanol, to which 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of aqueous ammonia was added for neutralization. The resulting mixture was concentrated and purified on a preparation plate to give 4.9 mg of the final product, 4.9 mg, with a total two-step yield of 32.0%.

[00821] ¹ H NMR (400 MHz, DMSO) δ 13.61 (s, 1H), 10.22 (s, 1H), 8.78 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.34 (d, J=12.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.93 (d , J=4.0 Hz, 1H), 4.75-4.42 (m, 4H), 4.30-4.27 (m, 1H), 3.58-3.53 (m, 2H), 3.41-3.40 (m, 1H), 3.26-3.23 (m, 1H), 2.73-2.71 (m, 2H), 2.01-1.79 (m, 2H ), 1.09 (t, J=8.0 Hz, 3H).

[00822] Example 51: 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5(1H)-yl)-3-hydroxypropionitrile (MDI-256)

[00823] Synthesis route for MDI-256:

[00824] Synthesis method:

[00825] Synthesis of intermediate MDI-256-1: 3-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)--1-((2-(trimethylsilyl)ethoxy)methyl) -1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-hydroxypropionitrile

[00826] 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl )-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indole (50 mg, 0.07 mmol) was dissolved in 5 ml of dichloromethane, to which Et3N (21, 2 mg, 0.21 mmol). The mixture was cooled to 0°C and 2-cyanoacetyl chloride (8.7 mg, 0.08 mmol) was added slowly. This was left to react at room temperature for 1 hour and water was added to quench the reaction. The resulting mixture was extracted twice with dichloromethane and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column to give 31 mg of intermediate MDI-256-1 in 56.7% yield.

[00827] Synthesis of compound MDI-256: 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4- d]imidazol-5(1H)-yl)-3-hydroxypropionitrile

[00828] Intermediate MDI-256-1 (31 mg, 0.04 mmol) was dissolved in methanol (6 ml) and 6 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40°C, reacted for 1 hour, filtered and concentrated, to which 4 ml of methanol and 1 ml of concentrated hydrochloric acid were added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of aqueous ammonia was added for neutralization. The resulting mixture was concentrated and purified on a preparation plate to obtain 3 mg of the final product with a yield of 17.4%.

[00829] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.0 Hz , 1H), 6.97 (dd, J=8.0 Hz, J=20.0 Hz, 2H), 4.77-4.70 (m, 4H), 3.62 (s, 2H), 2 .59-2.53 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

[00830] Example 52: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4- d]imidazole-5(1H)-carboxamide(MP1-257)

[00831] Synthesis route for MDI-257:

[00832] Synthesis method:

[00833] Synthesis of intermediate MDI-257-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

[00834] The synthesis process was similar to that for intermediate MDI-246-1 except that dimethylamine hydrochloride was used instead of methylamine hydrochloride.

[00835] Synthesis of MDI-257: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3 ,4-d]imidazole-5(1H)-carboxamide

[00836] Intermediate MDI-257-1 (41 mg, 0.05 mmol) was dissolved in methanol (6 ml) and 8 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40°C, reacted for 1 hour, filtered and concentrated, to which 4 ml of methanol and 1 ml of concentrated hydrochloric acid were added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of ammonia was added for neutralization. The resulting mixture was concentrated and purified on a preparation plate to obtain 8 mg of the final product with a yield of 35.2%.

[00837] ¹ H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 9.85 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.03 (d, J=12.0 Hz, 1H), 6.93 (d, J=12.0 Hz , 1H), 4.54-4.53 (m, 4H), 2.85 (s, 6H), 2.50-2.46 (m, 2H), 1.04 (t, J=8.0 Hz, 3H).

[00838] Example 53: N-(2-cyanoethyl)-2-(6-(2-ztyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3, 4-d]imidazole-5(1H)-carboxamide (MDI-258)

[00839] Synthesis route for MDI-258:

[00840] Synthesis method:

[00841] Synthesis of intermediate MDI-258-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-N-(2-cyanoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

[00842] The synthesis process was similar to that for intermediate MDI-246-1 except that 3-aminopropionitrile was used instead of methylamine hydrochloride.

[00843] Synthesis of MDI-258: N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo [3,4-d]imidazole-5(1H)-carboxamide

[00844] Intermediate MD1-258-1 (36 mg, 0.04 mmol) was dissolved in methanol (4 ml) and 3.6 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40°C, reacted for 1 hour, filtered and concentrated. The concentrated product was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added to it. The mixture was heated to 60°C, reacted for 6 hours and concentrated. The solid was dissolved in methanol, and the pH was adjusted to 8-9 using aqueous ammonia. The resulting mixture was concentrated and purified on a preparation plate to obtain 7.0 mg of the final product with a yield of 34.2%.

[00845] ¹ H NMR (400 MHz, MeOD) δ 8.25 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.16 (d, J=8.4 Hz , 1H), 6.91 (dd, J=20.8, 10.3 Hz, 2H), 4.61-4.54 (m, 4H), 3.55-3.50 (m, 2H), 2.96-2.51 (m, 4H), 1.06 (t, J=7.5 Hz, 3H).

[00846] Example 54: N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazole-5(1H)-carboxamide (MDI-259)

[00847] Synthesis route for MDI-259:

[00848] Synthesis method:

[00849] Synthesis of intermediate MDI-259-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-N-cyclopropyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

[00850] The synthesis process was similar to that for intermediate MDI-246-1 except that cyclopropylamine was used instead of methylamine hydrochloride.

[00851] Synthesis of compound MDI-259: N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4 -d]imidazole-5(1H)-carboxamide

[00852] Intermediate MDI-259-1 (36 mg, 0.04 mmol) was dissolved in methanol (4 ml) and 3.6 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40°C, reacted for 1 hour, filtered and concentrated. The concentrated product was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added to it. The mixture was heated to 60°C, reacted for 6 hours and concentrated. The solid was dissolved in methanol, and the pH was adjusted to 8-9 using aqueous ammonia. The resulting mixture was concentrated and purified on a preparation plate to obtain 8.0 mg of the final product with a yield of 39.6%.

[00853] ¹ H NMR (400 MHz, MeOD) δ 8.25 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.16 (dd, J=8.4, 1.4 Hz, 1H), 6.91 (dd, J=20.6, 10.4 Hz, 2H), 4.66-4.48 (m, 4H), 2.98-2.92 (m , 1H), 2.59-2.53 (m, 2H), 1.08 (t, J=7.5 Hz, 3H), 0.76-0.71 (m, 2H), 0.60- 0.56 (m, 2H).

[00854] Example 55: N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazole-5(1H)-carboxamide (MDI-260)

[00855] Synthesis path for MDI-260:

[00856] Synthesis method:

[00857] Synthesis of intermediate MDI-260-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -3-yl)-N-cyclobutyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

[00858] The synthesis process was similar to that for intermediate MDI-246-1 except that cyclobutylamine was used instead of methylamine hydrochloride.

[00859] Synthesis of MDI-260: N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4 -d]imidazole-5(1H)-carboxamide

[00860] Intermediate MDI-260-1 (37 mg, 0.04 mmol) was dissolved in methanol (4 ml) and 3.7 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40°C, reacted for 1 hour, filtered and concentrated. The concentrated product was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added to it. The mixture was heated to 60°C, reacted for 6 hours and concentrated. The solid was dissolved in methanol, and the pH was adjusted to 8-9 using aqueous ammonia. The resulting mixture was concentrated and purified on a preparation plate to obtain 4.0 mg of the final product with a yield of 19.0%.

[00861] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 7.01-6.85 (m, 2H), 4.57 (s, 4H), 4.35-4.31 (m, 1H), 2.59-2.53 (m, 2H ), 2.36-2.30 (m, 2H), 2.11-2.04 (m, 2H), 1.76-1.69 (m, 2H), 1.08 (t, J=7 .5 Hz, 3H).

[00862] Example 56: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 (1H)-yl)(2,6-diazaspiro[3,3]heptan-2-yl)ketone (MDI-261)

[00863] Synthesis route for MDI-261:

[00864] Synthesis method:

[00865] Synthesis of intermediate MDI-261-1: Tert-butyl-6-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)- 2,6-diazaspiro[3,3]heptane-2-carboxylate

[00866] The synthesis process was similar to that for intermediate MDI-246-1 except that tert-butyl-2,6-diazaspiro[3,3]heptane-2-carboxylate oxalate was used instead of methylamine hydrochloride.

[00867] Synthesis of MDI-261: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)(2,6-diazaspiro[3,3]heptan-2-yl)ketone

[00868] Intermediate MDI-261-1 (52 mg, 0.06 mmol) was dissolved in methanol (6 ml) and 10.1 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated 3 times. The mixture was heated to 40°C, reacted for 1 hour, filtered and concentrated, and then 4 ml of methanol and 1 ml of concentrated hydrochloric acid were added. The mixture was heated to 50°C, reacted for 6 hours and concentrated to obtain a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of ammonia was added for neutralization. The resulting mixture was concentrated and purified on a preparation plate to obtain 6 mg of the final product with a yield of 22.2%.

[00869] ¹ H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.19 (d, J=8.0 Hz , 1H), 6.95 (dd, J=12.0 Hz, J=12.0 Hz, 2H), 4.90 (s, 2H), 4.66 (s, 2H), 4.22 (d , J=12.0 Hz, 2H), 4.02-3.94 (m, 4H), 3.60 (d, J=4.0 Hz, 2H), 2.59-2.54 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

[00870] Example 57: (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole -2-yl)-1H-indazole (MDI-262)

[00871] Synthesis route for MDI-262:

[00872] Synthesis method:

[00873] Synthesis of intermediate MDI-262-1: Tert-butyl(S)-2-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3 ,4-d]imidazole-5-carbonyl)pyrrolidine-1-carboxylate

[00874] Tert-butyl-2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (65.0 mg, 0 .08 mmol) was dissolved in 10 ml of DCM, to which zinc bromide (68.6 mg, 0.31 mmol) was added. The mixture was stirred for 5 hours and water was added to quench the reaction. The resulting mixture was extracted with DCM twice and the organic phases were combined, washed with aqueous ammonia, then washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was dissolved in 10 ml DMF to which Boc-L-proline (19.7 mg, 0.09 mmol), HATU (34.71 mg, 0.09 mmol) and DIPEA (11.8 mg, 0.09 mmol) were added. 09 mmol). After addition it was left to react at room temperature. Water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 43.0 mg of intermediate MDI-262-1 in 59.4% yield.

[00875] ¹ H NMR (400 MHz, CDCl3) δ 8.50-8.41 (m, 1H), 7.47-7.45 (m, 1H), 7.25-7.22 (m, 1H ), 7.16 (d, J=8.0 Hz, 1H), 7.01 (d, J=10.3 Hz, 1H), 6.05-5.87 (m, 2H), 5.76 -5.75 (m, 2H), 5.31 (s, 2H), 5.02-4.23 (m, 5H), 3.89-3.83 (m, 2H), 3.70-3 .42 (m, 6H), 2.57-2.51 (m, 2H), 2.37-1.88 (m, 3H), 1.73-1.70 (m, 1H), 1.47 (s, 9H), 1.07-0.98 (m, 5H), 0.94-0.88 (m, 4H), 0.03(s, 9H), -0.06 - -0.08 (m, 18H).

[00876] Synthesis of compound MDI-262: (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4- d]imidazol-2-yl)-1H-indazole

[00877] Intermediate MDI-262-1 (33.0 mg, 0.04 mmol) was dissolved in 4 ml MeOH to which 2 ml concentrated hydrochloric acid was added. After addition, the temperature was raised to 50°C for reaction. After 6 hours of reaction, the temperature was lowered to room temperature and the reaction solvent was evaporated by concentration under reduced pressure, and then 4 ml of methanol and 0.5 ml of aqueous ammonia were added. After concentration, the residue was subjected to thin layer chromatography to obtain 1.8 mg of white solid MDI-262 with a yield of 11.3%.

[00878] ¹ H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J=8.5 Hz , 1H), 6.96 (d, J=11.7 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H), 4.80-4.64 (m, 4H), 4 .09-4.05 (m, 1H), 3.26-3.22 (m, 2H), 2.59-2.53 (m, 2H), 2.06-1.86 (m, 4H) , 1.08 (t, J=8.0 Hz, 3H). LC-MS m/z (ESI) [M+H] ⁺ calculated value for C ₂ 5H ₂ 6FN ₆ O ₂ : 461.2; measured value: 461.2.

[00879] Example 58: (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole -2-yl)-1H-indazole (MDI-263)

[00880] The synthesis process was similar to that for MDI-262, except that Boc-D-proline was used instead of Boc-L-proline.

[00881] ¹ H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J=8.4 Hz , 1H), 6.96 (d, J=12.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.82-4.60 (m, 4H), 4 .21-4.15 (m, 1H), 3.33-3.23 (m, 1H), 3.08-2.99 (m, 1H), 2.59-2.53 (m, 2H) , 2.08-1.86 (m, 4H), 1.08 (t, J=8.0 Hz, 3H).

[00882] Example 59: Evaluation of Pharmacological Activity I

[00883] 1. Experimental principle

[00884] A drug screening system based on the kinases JAK1, JAK2, JAK3 and TYK2 was used to identify the ability of small molecule compounds to inhibit kinase activity. The kinase undergoes an enzymatic reaction with its substrates IRS1, IGF1Rtide and Poly (4:1 Glu, Tyr), consuming ATP and producing ADP, and the ADP-Glo reagent and luminescence-based method can be used to detect the amount of product , reflecting the activity of the kinase.

[00885] 2. Experimental design

[00886] 2.1 Materials and instruments used in the experiment

[00887] 2.2 Experimental Methods

[00888] 2.2.1 Composition of reagents for the kinase reaction

[00889] 2.2.1.1 1× kinase reaction buffer (400 ml)

2 mM DTT, ready to use

[00890] 2.2.1.2 2× kinase formulation

[00891] 2.2.1.3 2× substrate mixture composition

[00892] 2.2.1.4 Compounds to be tested

[00893] 2.2.2 Kinase Reaction Experiment Procedure

[00894] 2.2.2.1 Experimental Procedure for JAK1 and JAK2 Kinase Reaction

a) Dilute filgotinib (10 mM stock solution) 10-fold and dilute the test compound solution 10-fold using 100% DMSO, then perform a 1:3 dilution series in a 384-well dilution plate (Labcyte, PP-0200). Filgotinib concentrations: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, 0.02, and 0 μM; and concentrations of the compound to be tested: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 and 0 µM.

b) Use an Echo dispenser to transfer 0.1 µl of the test compound solution (prepared in step a) into a 384-well reaction plate (PE, 6007290) and centrifuge it at 1000 rpm. within 1 minute.

c) Transfer 5 µl of kinase (prepared according to 2.2.1.2) into a 384-well reaction plate (prepared in step b), centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 15 minutes.

d) Transfer 5 µl of the substrate mixture (prepared in accordance with 2.2.1.3) into a 384-well reaction plate and centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 60 minutes. In the reaction system, the final concentrations of filgotinib were 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentrations of the compound to be tested are: 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005 and 0 µM. The final concentration of DMSO is 1%.

e) Transfer 10 µl of ADP-Glo into a 384-well reaction plate and centrifuge at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

f) Transfer 20 µl of detection solution to a 384-well reaction plate and centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

g) Use an Envision multifunction tablet reader to read the signal in RLU (Relative Luminescence Units). Signal intensity is used to characterize the amount of kinase activity.

[00895] 2.2.2.2 JAK3 Kinase Reaction Experiment Procedure

a) Dilute filgotinib (10 mM stock solution) and test compound solution 10-fold using 100% DMSO and then perform a 1:3 dilution series in a 384-well dilution plate (Labcyte, PP-0200) . Filgotinib concentrations are: 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.51, 0.17, and 0 μM; and the concentrations of the compound to be tested are: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 and 0 µM.

b) Use an Echo dispenser to transfer 0.1 µl of the test compound solution (prepared in step a) into a 384-well reaction plate (PE, 6007290) and centrifuge it at 1000 rpm. within 1 minute.

c) Transfer 5 µl of kinase (prepared according to 2.2.1.2) into a 384-well reaction plate (prepared in step b), centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 15 minutes.

d) Transfer 5 µl of the substrate mixture (prepared in accordance with 2.2.1.3) into a 384-well reaction plate and centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 60 minutes. In the reaction system, the final concentrations of filgotinib were 100, 33.33, 11.11, 3.70, 1.23, 0.412, 0.137, 0.046, 0.015, 0.005, 0.002, and 0 μM. The final concentrations of the compound to be tested are: 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005 and 0 µM. The final concentration of DMSO is 1%.

e) Transfer 10 µl of ADP-Glo into a 384-well reaction plate and centrifuge at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

f) Transfer 20 µl of detection solution to a 384-well reaction plate and centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

g) Use an Envision multifunction tablet reader to read the signal in RLU (Relative Luminescence Units). Signal intensity is used to characterize the amount of kinase activity.

[00896] 2.2.2.3 Experimental Procedure for TYK2 Kinase Reaction

[00897] a) Dilute filgotinib (10 mM stock solution) 3.3-fold and the test compound solution 10-fold using 100% DMSO, and then perform a 1:3 dilution series in a 384-well plate to dilution (Labcyte, PP-0200). Filgotinib concentrations are: 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM; and the concentrations of the compound to be tested are: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 and 0 µM.

[00898] b) Use an Echo dispenser to transfer 0.1 μl of the test compound solution (prepared in step a) into a 384-well reaction plate (PE, 6007290) and centrifuge it at 1000 rpm. within 1 minute.

[00899] c) Transfer 5 µl of kinase (prepared in accordance with 2.2.1.2) into a 384-well reaction plate (prepared in step b), centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 15 minutes.

[00900] d) Transfer 5 µl of substrate mixture (prepared in accordance with 2.2.1.3) into a 384-well reaction plate, centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 60 minutes. In the reaction system, the final concentrations of filgotinib are 30, 10, 3.3333, 1.1111, 0.3704, 0.1235, 0.0412, 0.0137, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentrations of the compound to be tested are: 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005 and 0 µM. The final concentration of DMSO is 1%.

[00901] f) Transfer 10 μl of ADP-Glo into a 384-well reaction plate, centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

[00902] f) Transfer 20 μl of detection solution to a 384-well reaction plate, centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

[00903] g) Use an Envision multifunction tablet reader to read the signal in RLU (Relative Luminescence Units). Signal intensity is used to characterize the amount of kinase activity.

[00904] 2.2.3 Method for processing experimental data

[00905] Compound inhibition rate (% inhibition) = (negative control - compound) / (negative control - positive control) * 100%

[00906] Negative control: DMSO

[00907] Positive control: 10 µM/100 µM/30 µM filgotinib

[00908] The IC50 (half-maximal inhibition concentration) for a compound can be obtained using the following formula to approximate the nonlinear relationship:

[00909] Y=Lower point+(Upper point-Lower point)/(1+10 ^∧ ((LogIC50-X)*Slope))

[00910] X: logarithmic value of the compound concentration

[00911] Y: compound inhibition rate (% inhibition)

[00912] The equation for calculating the Z' factor is:

[00913] Z'=1-3(SDmin+SDmax)/(AVEmax-AVEmin),

in which:

Min is the RLU value of the positive control of 10 μM/100 μM/30 μM filgotinib, and Max is the RLU value of the negative control; And

SD represents the mean squared error and AVE represents the average value in RLU.

[00914] 3. Experimental results

[00915] 3.1 Quality Control Results for Binding Experiments

[00916] 3.1.1 Quality control result of JAK1 binding experiment

Z'=0.77CV%(min)=0%CV%(max)=6.2%

[00917] 3.1.2 Quality control result of JAK2 binding experiment

Z'=0.78CV%(min)=2.9%CV%(max)=5.7%

[00918] 3.1.3 Quality Control Result of JAK3 Binding Experiment

Z'=0.71CV%(min)=7.0%CV%(max)=11.3%

[00919] 3.1.4 Quality control result of TYK2 binding experiment

Z'=0.77CV%(min)=3.9%CV%(max)=6.8%

[00920] 3.2 Summary of research findings

[00921] For brevity, only IC50 values are presented for the compounds studied below.

[00922] The experimental results presented above demonstrate that:

MDI-2, MDI-201, MDI-202, MDI-206, MDI-203, MDI-204, MDI-207, MDI-209, MDI-211, MDI-213 and MDI-217 can inhibit JAK1, JAK2, JAK3 and TYK2 at extremely low concentrations, and the inhibitory activities of the compounds in these examples are much higher than those of filgotinib.

[00923] Example 60: Pharmacological Activity Evaluation II

[00924] 1. Experimental principle

[00925] The principle of the experiment to evaluate pharmacological activity in this example is the same as described in example 59, but the materials or instruments used in the experiment and/or some parameters of the specific conditions of the study (such as kinase composition, substrate composition, experimental procedures with the reaction of kinases, etc.) were changed and corrected.

[00926] 2. Experimental design

[00927] 2.1 Materials and instruments used in the experiment

[00928] 2.2 Experimental Methods

[00929] 2.2.1 Composition of reagents for the kinase reaction

[00930] 2.2.1.1 1× kinase reaction buffer (400 ml)

[00931] It was the same as the composition of the 1× kinase reaction buffer in Example 59.

[00932] 2.2.1.2 2× kinase formulation

[00933] 2.2.1.3 4× substrate mixture composition

[00934] 2.2.1.4 Compounds to be tested

[00935] 2.2.2 Kinase Reaction Experiment Procedure

[00936] 2.2.2.1 Experimental Procedure for JAK1 and JAK2 Kinase Reaction

a) Dilute the solution of the compound to be tested 5 times using 100% DMSO. Then, using 100% DMSO as a diluent, perform a 1:3 dilution series of filgotinib (10 mM stock solution) and the test compound solution in a 96-well dilution plate. Take 1 µl of the compound solution and add it to 49 µl of kinase reaction buffer and shake the resulting mixture on a microplate shaker for 20 minutes.

b) Transfer 2 µl of kinase (prepared according to 2.2.1.2) to a 384-well reaction plate, add 1 µl of the test compound solution (prepared in step a) to a 384-well reaction plate (Greiner, 784075), centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 10 minutes.

c) Transfer 1 µl of substrate mixture (prepared in accordance with 2.2.1.3) into a 384-well reaction plate and centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 60 minutes. In the reaction system, the final concentrations of filgotinib were 50, 12.5, 3.125, 0.7812, 0.1953, 0.0488, 0.0122, 0.003, 0.00076, 0.00019, and 0.000047 μM. The final concentrations of the compound to be tested are: 10, 2.5, 0.625, 0.15625, 0.039, 0.0097, 0.0024, 0.0006, 0.0015, 0.000038 and 0.0000095 µM. The final concentration of DMSO is 0.5%.

d) Transfer 4 µl of ADP-Glo into a 384-well reaction plate and centrifuge at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

e) Transfer 8 µl of detection solution to a 384-well reaction plate and centrifuge at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

f) Use a Biotek multifunctional plate reader to read the signal in RLU (relative luminescence units). Signal intensity is used to characterize the amount of kinase activity.

[00937] 2.2.2.2 Experimental Procedure for JAK3 and TYK2 Kinase Reaction

a) Dilute the solution of the compound to be tested 5 times using 100% DMSO. Then, using 100% DMSO as a diluent, perform a 1:3 dilution series of filgotinib (10 mM stock solution) and the test compound solution in a 96-well dilution plate. Take 1 µl of the compound solution and add it to 49 µl of kinase reaction buffer and shake the resulting mixture on a microplate shaker for 20 minutes.

b) Transfer 2 µl of kinase (prepared according to 2.2.1.2) to a 384-well reaction plate and add 1 µl of the test compound solution (prepared in step a) to a 384-well reaction plate (Greiner, 784075), centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 10 minutes.

c) Transfer 1 µl of substrate mixture (prepared in accordance with 2.2.1.3) into a 384-well reaction plate and centrifuge it at 1000 rpm. for 1 minute and incubate at 25°C for 60 minutes. In the reaction system, the final concentrations of filgotinib are 50, 16.67, 5.555, 1.851, 0.617, 0.205, 0.0686, 0.0228, 0.00762 and 0 .0025 µM. The final concentrations of the compound to be tested are 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015 and 0.0005 µM. The final concentration of DMSO is 0.5%.

d) Transfer 4 µl of ADP-Glo into a 384-well reaction plate and centrifuge at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

e) Transfer 8 µl of detection solution to a 384-well reaction plate and centrifuge at 1000 rpm. for 1 minute and incubate at 25°C for 40 minutes.

f) Use a Biotek multifunctional plate reader to read the signal in RLU (relative luminescence units). Signal intensity is used to characterize the amount of kinase activity.

[00938] 2.2.3 Experimental data processing method Same as the experimental data processing method used in Example 59.

[00939] 3. Experimental results

[00940] The experimental results presented above demonstrate that among the compounds of the present disclosure tested in Example 60, with the exception of those few illustrative compounds that have activity comparable to filgotinib, most of the tested compounds can inhibit JAK1, JAK2, JAK3 and TYK3 in very low concentrations, and the inhibitory activities of these compounds are much higher than those of filgotinib.

[00941] Although specific embodiments of the present disclosure have been illustrated and described, these embodiments are not meant to illustrate and describe all possible forms of implementation of the present disclosure. More precisely, the language used in this specification are descriptive terms only and not restrictive. It will be apparent to those skilled in the art that various types of changes and modifications can be made without departing from the general scope of the present disclosure. Thus, the appended claims are intended to include all of these changes and modifications within the scope of the present invention.

Claims (125)

1. Compound of formula (G) or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein L represents C=O, O=S=O, CH ₂ or a bond; And X ₁ represents N or CR ₁₄ ; And X ₂ represents N or CR ₁₅ ; And X ₃ represents N or CR ₁₆ ; And R ₁₄ , R ₁₅ , R ₁₆ are each independently selected from H, C _1-6 alkyl, and R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl or C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7- membered heteroaryl or 5-11 membered bicyclic heteroalkyl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ , where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and they are optionally substituted with one or more substituents, each independently selected from -OH, -CN, or R ₁₇ , R ₁₈ and the N atom connected thereto form a 3-14 membered ring; And 0, 1, 2, 3 or 4 R ₂ are present in formula (G) and R ₂ is selected from halogen, C _1-6 alkyl; And R ₁ is selected from -OH, -CN, C _1-8 alkyl, C _3-7 cycloalkyl, 3-10 membered heterocycloalkyl, wherein 3-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ₄ ; And R ₄ is each independently selected C _1-6 alkyl. 2. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ represents N. 3. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₂ represents N. 4. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₃ represents N. 5. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is CR ₁₄ , X ₂ is N or CR ₁₅ , and X ₃ is CR ₁₆ . 6. The compound, or its optical isomer, or its pharmaceutically acceptable salt according to claim 1, where X ₁ , X ₂ and X ₃ are the same. 7. The compound, or its optical isomer, or its pharmaceutically acceptable salt according to claim 6, where X ₁ , X ₂ and X ₃ represent CH. 8. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where L represents C=O, O=S=O or CH ₂ . 9. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof, according to any one of paragraphs. 1-7, where R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, -C _1-6 alkyl or C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 membered heteroaryl, or 5-11 membered bicyclic heteroalkyl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ where R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl , C _3-7 cycloalkyl, C _3-7 heterocycloalkyl, and optionally substituted with one or more of -OH, -CN. 10. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl , 5-7 membered heteroaryl and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ . 11. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, C _1-6 alkyl, C _3-7 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 -membered heteroaryl and R ₁₃ is substituted with 0, 1, 2 or 3 R ₁ . 12. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, wherein R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl and C _3-7 heterocycloalkyl and are optionally substituted by one or more of -OH, -CN. 13. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₇ , R ₁₈ and the N atom connected to them form a 4-10-membered ring. 14. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where L represents C=O, and R ₁₃ represents -N(R ₁₇ )(R ₁₈ ), C _1-6 alkoxy, and R ₁₃ is substituted with 0, 1, 2, 3 or 4 R ₁ , wherein R ₁₇ and R ₁₈ are each independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 heterocycloalkyl and are optionally substituted by one or more of -OH, -CN, or R ₁₇ , R ₁₈ and atom N connected to them form a 3-14 membered ring. 15. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, wherein 1, 2 or 3 R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl. 16. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 11, wherein 1 or 2 R ₂ are present and R ₂ is selected from halogen and C _1-6 alkyl. 17. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, where R ₁₃ is substituted with 0 or 1 R ₁ and R ₁ is selected from -OH, C _1-6 alkyl, 5-7 membered heterocycloalkyl and C _3-7 cycloalkyl, wherein 5-7 membered heterocycloalkyl is optionally substituted with 1 , 2, 3 or 4 C _1-3 alkyls. 18. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7, wherein the compound is selected from the group consisting of: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-(piperidin-1-yl)pyrazin-2-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-morpholinylpyrazin-2-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 1-methylpiperidin-4-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone; (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4 -methylpiperazin-1-yl)pyrazin-2-yl)ketone; 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )phenol; 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole -6-yl)phenol; 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol; cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone; 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol; cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl) ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)( 3-hydroxylcyclobutyl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-4-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl )(pyridazin-3-yl)ketone; (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-( 1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone; 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6 -yl)phenol; 4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol; 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol; 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2- fluorophenol; 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole -2-yl)-1H-indazol-6-yl)phenol; 4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol ; 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl) -1H-indazol-6-yl)phenol; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)ethan-1-one; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)propan-1-one; (1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-yl)-2-methylpropan-1-one); 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)ethan-1-one; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H) -yl)-3-methylbutan-1-one; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(pyrrolidin-1-yl)ketone; azetidin-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5 -(1H)-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(piperidin-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(morpholino)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(4-methylpiperazin-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl )(4-ethylpiperazin-1-yl)ketone; cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone; cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5( 1H)-yl)ketone; (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole -5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone; cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone; (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H )-yl)(3-hydroxylpyrrolidin-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxylasetidin-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (4-hydroxylpiperidin-1-yl)ketone; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-carboxamide; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H )-carboxamide; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-carboxamide; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5 -carbonyl)azetidine-3-nitrile; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5 -carbonyl)pyrrolidine-3-nitrile; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazole-5(1H)-carboxamide; methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate ; ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate ; (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4 -d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone; 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)- yl)-3-hydroxypropionitrile; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5( 1H)-carboxamide; N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol- 5(1H)-carboxamide; N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H) -carboxamide; N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H) -carboxamide; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (2,6-diazaspiro[3,3]heptan-2-yl)ketone; (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-indazole and (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)- 1H-indazole. 19. A pharmaceutical composition for the treatment and/or prevention of a JAK-mediated disease or disorder, containing a compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims. 1-18 in a therapeutically effective amount and one or more pharmaceutically acceptable carriers, adjuvants or excipients. 20. Use of a compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-18 or the pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment and/or prevention of a JAK-mediated disease or disorder. 21. The use of claim 20, wherein the JAK-mediated disease or disorder is selected from the group consisting of arthritis, autoimmune diseases or disorders, cancer or tumor, diabetes, eye diseases, disorders or conditions, inflammation, allergies or bowel conditions, neurodegenerative diseases , skin diseases, conditions or disorders, allergies, asthma and other obstructive airway diseases and transplant rejection. 22. Compound of formula (I) or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein L represents C=O, O=S=O, CH ₂ or a bond; And X represents CH or N; ring A is C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _5-7 aryl, 5-7 member heteroaryl; 0, 1, 2, 3 or 4 R ₁ are present in formula (I), and R ₁ is selected from C _1-8 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, wherein 3-7 membered heterocycloalkyl is optional substituted with 1, 2, 3 or 4 R ₄ , 0, 1, 2, 3 or 4 R ₂ are present in formula (I), and R ₂ is selected from C _1-6 alkyl halogen; R ₄ is selected from C _1-3 alkyl. 23. The compound, or its optical isomer, or its pharmaceutically acceptable salt according to claim 22, where L represents C=O, O=S=O or CH ₂ . 24. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 22, wherein X represents CH. 25. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, where ring A is a 5-6 membered heteroaryl or phenyl. 26. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, wherein 0 or 1 R ₁ is present, and R ₁ is selected from C _1-6 alkyl and 5-7 membered heterocycloalkyl, wherein the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 C _1-3 alkyls. 27. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, wherein 1 or 2 R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl. 28. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, where L represents C=O and O=S=O; X represents CH; ring A is 5-7 membered heteroaryl or C _5-7 aryl; 0, 1, 2, 3 or 4 R ₁ are present, and R ₁ is selected from C _1-8 alkyl and 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ₄ . 1, 2 or 3 R ₂ are present and R ₂ is selected from halogen; R ₄ is selected from C _1-3 alkyl. 29. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 28, wherein ring A is a 5-6 membered heteroaryl or phenyl. 30. A compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 28, wherein 0 or 1 R ₁ is present and R ₁ is selected from C _1-6 alkyl and 5-7 membered heterocycloalkyl, wherein 5-7- the member heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 C _1-3 alkyls. 31. The compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 28, wherein 1 or 2 R ₂ are present and R ₂ is selected from halogen, C _1-6 alkyl. 32. A compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-24, wherein the compound is selected from the group consisting of: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-(piperidin-1-yl)pyrazin-2-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (5-morpholinepyrazin-2-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (1-methyl-1H-pyrazol-4-yl)ketone; 5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H -indazol-6-yl}phenol; 5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H -indazol-6-yl}phenol; 3-ethyl-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6 -yl}phenol; 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl )phenol and 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole -6-yl)phenol. 33. A pharmaceutical composition for the treatment and/or prevention of a JAK-mediated disease or disorder, containing a compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims. 22-32 in a therapeutically effective amount and one or more pharmaceutically acceptable carriers, adjuvants or excipients. 34. Use of a compound, or its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 22-32 or the pharmaceutical composition according to claim 33 in the manufacture of a medicament for the treatment and/or prevention of a JAK-mediated disease or disorder. 35. The use of claim 34, wherein the JAK-mediated disease or disorder is selected from the group consisting of arthritis, autoimmune diseases or disorders, cancer or tumor, diabetes, eye diseases, disorders or conditions, inflammation, allergies or bowel conditions, neurodegenerative diseases , skin diseases, conditions or disorders, allergies, asthma and other obstructive airway diseases and transplant rejection.