Substituted 1H-pyrazolo[4,3-c]quinoline, method of preparation thereof, and use

Abstract

The present invention is generally directed to inhibitors of the hematopoietic progenitor kinase 1 (HPK1) and FMS-like tyrosine kinase 3 (FLT3) genes, which are useful in the treatment of diseases and disorders regulated by said HPK1 and FLT3, which have formula I: JPEG2024539633000180.jpg4979.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application was filed on 15 October 2021 and claims priority and interest to U.S. Provisional Patent Application No. 63 / 256,260, entitled “Substituting 1H-pyrazolo[4,3-c]quinoline, method of preparation thereof, and use thereof,” the disclosure thereof is incorporated herein by reference in its entirety for all purposes.

[0002] (Field of invention) The present invention relates to novel anticancer agents and intermediates, as well as their synthesis. More specifically, the present invention relates to compounds that are tyrosine kinase inhibitors, including inhibitors of FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML) and inhibitors of hematopoietic precursor kinase 1 (HPK1), pharmaceutical compositions comprising such compounds, methods for inhibiting FLT3 mutations, and methods for treating AML. The present invention also relates to novel substituted pyrazolo[4,3-c]quinolines as intermediates for the synthesis of novel anticancer agents disclosed herein. The present invention also relates to methods for producing novel anticancer agents and pharmaceutical compositions comprising them. [Background technology]

[0003] (Background of the invention) Imatinib, discovered in 2001, was a groundbreaking advance in cancer-targeted therapy. This stimulated research into kinase inhibitors as a major class of drugs in oncology, which has proven to be the primary area of ​​application for kinase inhibitors. Currently, there are 71 small molecule kinase inhibitors (SMKIs) approved by the FDA, with 16 more approved by other regulatory authorities. [MM Attwood et al.] Trends in kinase drug discovery: targets, indications and inhibitor design. Nat. Rev. Drug. Discov. 2021 Aug 5. doi: 10.1038 / s41573-021-00252-y.]

[0004] In recent years, inhibitors of hematopoietic precursor kinase 1 (HPK1) and FMS-like tyrosine kinase 3 (FLT3) mutations have attracted considerable attention.

[0005] HPK1 belongs to the protein kinase superfamily, the STE Ser / Thr protein kinase family, and the STE20 subfamily. It is primarily expressed in hematopoietic organs, including the bone marrow, spleen, and thymus. It is also expressed at very low levels in the lungs, kidneys, mammary glands, and small intestine. Two alternatively spliced ​​human isoforms have been reported. [https: / / www.phosphosite.org / proteinAction?id=1180&showAllSites=true. S. Sawasdikosol] at al. HPK1 as a novel target for cancer immunotherapy. Immunol. Res. 2012, 54(1-3), 262-265; doi: 10.1007 / s12026-012-8319-1. J. Liu at al. Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance. PLoS ONE 2019, 14(3), e0212670; https: / / doi.org / 10.1371 / journal.pone.0212670. Y. Wang et al. Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function. PLoS ONE 2020, 15(12), e0243145; https: / / doi.org / 10.1371 / journal.pone.0243145. D. You et al. Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor. J. Immunother. Cancer. 2021, 9(1); e001402. doi: 10.1136 / jitc-2020-001402. D. You et al. Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor.J. Immunother.Cancer 2021, 9, e001402. doi:10.1136 / jitc-2020-001402]。

[0006] In 2021, the first clinical trial (Phase 1.2) of the inhibitor in patients with advanced solid malignancies treated with pembrolizumab was initiated. [A First-In-Human, Phase 1 / 2 Study Of CFI-402411, a Hematopoietic Progenitor Kinase-1 (HPK1) Inhibitor, as a Single Agent and in Combination with Pembrolizumab in Subjects with Advanced Solid Malignancies. Study HIC#:2000029001. Start Date 04 / 13 / 2021. End Date 12 / 01 / 2021. Last Updated: 07 / 15 / 2021. https: / / www.yalemedicine.org / clinical-trials / 8756].

[0007] AML is a cancer of the myeloid hematopoietic system characterized by the rapid proliferation of abnormal cells that accumulate in the bone marrow and blood, interfering with normal blood cell production. A type of acute leukemia, AML progresses rapidly and, if left untreated, usually leads to death within weeks or months. [https: / / www.cancer.gov / types / leukemia / patient / adult-aml-treatment-pdq#section / all. Updated: March 6, 2020]

[0008] AML is a highly heterogeneous disease in which multiple signaling pathways contribute to its development. The primary factor in AML is FLT3. Activating mutations in FLT3, primarily FLT3 internal tandem duplication (FLT3-ITD), are associated with reduced progression-free survival and overall survival. The identified importance of FLT3-ITD and the FLT3 pathway in the prognosis of AML patients has stimulated efforts to develop therapeutic inhibitors of FLT3. While these inhibitors show promising anti-leukemic activity, their efficacy as monotherapy has been limited to date, and they may need to be used in combination with cytotoxic chemotherapy. [R. Swords, C. Freeman, F. Giles. Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. Leukemia 2012, 26 (10), 2176-2185; doi: 10.1038 / leu.2012.114. Epub 2012 Apr 27.]

[0009] In 2015, approximately 1 million people worldwide were diagnosed with AML, and 147,000 died. It most commonly occurs in older adults. Men are affected more frequently than women. The 5-year survival rate is about 35% for those under 60 and 10% for those 60 and older. Survival time for older adults whose health is too poor to receive intensive chemotherapy is typically 5 to 10 months. It accounts for approximately 1.1% of all cancer cases and 1.9% of cancer deaths in the United States. See https: / / en.wikipedia.org / wiki / Acute_myeloid_leukemia.

[0010] In recent years, drugs that target specific sites on cancer cells have been developed. Targeted drugs work differently from standard chemotherapy drugs and tend to cause a variety of side effects.

[0011] Some AML patients have mutations in the FLT3 gene of leukemia cells. This gene helps cells produce a protein (also known as FLT3) that aids in cell growth. Drugs that target the FLT3 protein can help treat some of these leukemias. The most advanced example of such a drug appears to be gilteritinib. [M. Levis, AE Perl. Gilteritinib: potent targeting of FLT3 mutations in AML. Blood advances 2020, 4 (6), 1178-1191]. Gilteritinib is a clinically active FLT3 inhibitor that shows broad activity against FLT3 kinase domain mutations [TC Tarver et al. Blood advances 2020, 4 (3), 514-524; LY Lee et al. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood 2017, 129 (2), 257-260].

[0012] In November 2018, the FDA approved gilteritinib for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) in whom an FLT3 mutation was detected in an FDA-approved test [https: / / en.wikipedia.org / wiki / Gilteritinib. S. Dhillon. Gilteritinib: First Global Approval. Drugs 2019; https: / / doi.org / 10.1007 / s40265-019-1062-3]. Gilteritinib (Xospata) works by blocking FLT3 and other proteins that help cancer cells grow. This drug can treat adults with leukemia cells that have a mutation in the FLT3 gene and whose AML has not improved with previous treatment or has relapsed. The structure of gilteritinib is shown below. [ka]

[0013] There is a need for a therapeutic agent for treating adult patients with relapsed or refractory acute myeloid leukemia (AML) having FLT3 mutations. The present invention intends to meet this unmet need related to these FLT3 inhibition therapies. (Summary of the Invention)

[0014] A first aspect of the present invention relates to a compound of formula I, and its pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, or tautomers: [Chemical formula] [Wherein, R a is [Chemical formula] selected from; Each R1 is independently selected from the group consisting of C 1-6 alkyl, -NH2, -NH(C 1-6 alkyl), and -N(C 1-6 alkyl)2; R2 is H, halogen, C 1-6 alkyl, -OC 1-6 alkyl, (C 1-4 alkyl)2N(CH2) m N(C 1-4 alkyl)-, (C 1-4 alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl(CH2) m O-, heteroaryl, -W-X-R1, or the group [Chemical formula] selected from, and R2 is optionally substituted with 1-6 groups R8; R3 is H, halogen, C 1-6 alkyl, -OC 1-6 alkyl, (C 1-4 alkyl)2N(CH2) m N(C 1-4 alkyl)-, (C 1-4Alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl (CH2) m O-, heteroaryl, -WX-R1, or base [ka] Selected from, R3 is optionally replaced with 1-6 bases R8; Alternatively, R2 and R3, together with the atom to which they are bonded and any intervening atom, form the group -KXM-; R4, R5, R6, or R7 each stand for H, halogen, -CN, and C. 1-4 Alkyl, -OH, -OR8, -OCF3, -COOR 8、 Independently selected from the group consisting of -CONH2, -CONHR8, -CON(R8)2, -SO2OH, -SO2NHR8, and -SO2N(R8)2; R8 is C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-8 Selected from cycloalkyl groups; Each R9 is H, halogen, C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, and [ka] Independently selected from the group consisting of; R 10 H, halogen, -C 1-6 Alkyl, -OH, and -OC 1-6 Selected from alkyl groups; Or R9 and R 10 Any one of them, along with the atom to which they are bonded and any intervening atom, forms the group-XN(R 12 )-Y- forms; R 11 H, halogen, -C 1-6 Alkyl, -OH, and -OC 1-6 Selected from alkyl groups; R 12 is H or C1-6 It is alkyl; X is independently selected from -CH2-, -(CH2)2-, and -(CH2)3- for each occurrence; Y is independently selected from -CH2-, -(CH2)2-, and -(CH2)3- for each occurrence; A is selected independently of CH and N for each occurrence; B is independently selected from CH, CH2, N, NH, and O for each occurrence; Each instance of L is a single bond, -(CH2) m -, -O(CH2) m -, and -NH(CH2) m -Selected independently of; W is O, S, NH, or N(C 1-6 Alkyl) is; K and M are independently selected from O, S, SO, SO2, CO, NH, and NR8; m is an integer independently selected from 1, 2, 3, 4, 5, and 6 for each occurrence; n is selected from 0 and 1 for each occurrence; o is selected independently from 1, 2, and 3 for each occurrence; Here, Aryls are cyclic aromatic hydrocarbon groups in which one to three aromatic rings are condensed or bonded to each other by single bonds; A heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C; A heterocyclyl is a saturated or partially unsaturated 3-10 membered monoring, 7-12 membered diring (fused, bridging, or spiroring), or 11-14 membered tricyclic system (fused, bridging, or spiroring) having one or more heteroatoms independently selected from O, N, S, P, Se, or B; However, the compound comprises at least one of the following groups: R2 or R3 is (C 1-4 Alkyl)2N(CH2) m N(C 1-4(Alkyl)-, (C 1-4 Alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl (CH2) m O-, heteroaryl, -WX-R1, or [ka] is; or R2 and R3, together with the atom to which they are bonded and any intervening atom, form the group -KXM-; or R3 is [ka] and; or R9 and R 10 Any one of them, along with the atom to which they are bonded and any intervening atom, forms the group-XN(R 12 )-Y- forms; or one of R9 is [ka] That is the case.

[0015] In more specific embodiments, the present invention relates to compounds of formula I (A, B, C, D and D', E and E', F and G), and their pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, or tautomers: [ka] [In the formula, X is selected from -CH2-, -(CH2)2-, and -(CH2)3-; Y is selected from -CH2-, -(CH2)2-, and -(CH2)3-; Each R1 is C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl), and -N(C 1-6 Independently selected from the group consisting of alkyl)2; R2 is H, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, (C 1-4Alkyl)2N(CH2) m N(C 1-4 (Alkyl)-, (C 1-4 Alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl (CH2) m O-, heteroaryl, -WX-R1, and from [ka] Selected; R3 is H, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, (C 1-4 Alkyl)2N(CH2) m N(C 1-4 (Alkyl)-, (C 1-4 Alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl (CH2) m O-, heteroaryl, -WX-R1, and [ka] Selected from; Here, each of R2 and R3 is optionally substituted with 1 to 6 bases R8; Alternatively, R2 and R3, together with the atom to which they are bonded and any intervening atom, form the group -KXM-; R4, R5, R6, and R7 are H, halogen, -CN, and -C respectively. 1-4 Independently selected from the group consisting of alkyl, -OR8, -OCF3, -COOR8, -CONH2, -CONHR8, -CON(R8)2, -SO2OH, -SO2NHR8, and -SO2N(R8)2; R8 is C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-8 Selected from cycloalkyl groups; R 12 is H or C 1-6 It is alkyl; K and M are independently selected from O, S, SO, SO2, CO, NH, and NR8; A is CH or N; B is selected from CH, CH2, N, NH, and O; L is a single bond or -OCH2CH2-; W is selected from O, S, NH, and N(C 1-6 alkyl); m is an integer selected from 1, 2, 3, 4, 5, and 6; n is 0 or 1; [Chemical formula] [wherein, A is CH or N; B is CH, CH2, N, NH, or O; X is selected from -CH2-, -(CH2)2-, and -(CH2)3-; Y is selected from -CH2-, -(CH2)2-, and -(CH2)3-; Each R1 is independently selected from C 1-6 alkyl, -NH2, -NH(C 1-6 alkyl), and -N(C 1-6 alkyl)2; R2 is H, halogen, C 1-6 alkyl, -OC 1-6 alkyl, (C 1-4 alkyl)2N(CH2) m N(C 1-4 alkyl)-, (C 1-4 alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl(CH2) m O-, heteroaryl, -W-X-R1, and [Chemical formula] selected from; R3 is H, halogen, C 1-6 alkyl, -OC 1-6 alkyl, (C 1-4 alkyl)2N(CH2) mN(C 1-4 alkyl)-, (C 1-4 alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl(CH2) m O-, heteroaryl, -W-X-R1, and

Chemical formula

Chemical formula

[0016] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I(AG), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include excipients, diluents, or surfactants.

[0017] Another aspect of the present invention relates to a method for treating a disease or disorder related to the regulation of hematopoietic precursor kinase 1 (HPK1). The method comprises administering to a patient in need of treatment for a disease or disorder related to the regulation of HPK1 an effective amount of a compound of formula I(AG), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0018] Another aspect of the present invention relates to a method for inhibiting hematopoietic precursor kinase 1 (HPK1). The method comprises administering an effective amount of a compound of formula I(AG), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0019] Another aspect of the present invention relates to a compound of formula I(AG), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting hematopoietic precursor kinase 1 (HPK1).

[0020] Another aspect of the present invention relates to the use of a compound of formula I(AG), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of hematopoietic precursor kinase 1 (HPK1).

[0021] Another aspect of the present invention relates to a method for treating a disease or disorder related to the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering to a patient in need of treatment for a disease or disorder related to the regulation of FLT3 an effective amount of a compound of formula I(AG), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition.

[0022] Another aspect of the present invention relates to a method for inhibiting tyrosine kinase 3 (FLT3). The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0023] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting tyrosine kinase 3 (FLT3).

[0024] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of tyrosine kinase 3 (FLT3).

[0025] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene.

[0026] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0027] Another aspect of the present invention relates to a compound of formula I(AG), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0028] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder disclosed herein in a subject that requires treatment or prevention of such disease or disorder. The method comprises administering an effective amount of a compound of formula I(AG), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient requiring treatment.

[0029] Another aspect of the present invention relates to the use of compounds of formula I(AG), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases or disorders disclosed herein.

[0030] The present invention further provides a method for treating a disease or disorder related to the regulation of hematopoietic precursor kinase 1 (HPK1), comprising administering to a patient suffering from at least one of the said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0031] The present invention provides inhibitors of hematopoietic precursor kinase 1 (HPK1), which are therapeutic agents used in the treatment of diseases and disorders.

[0032] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known hematopoietic precursor kinase 1 (HPK1) inhibitors. The disclosure also provides agents having novel mechanisms of action against protein tyrosine phosphatase enzymes in the treatment of various types of diseases.

[0033] The present invention further provides a method for treating a disease or disorder related to the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient suffering from at least one of the said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0034] This invention provides an inhibitor of the FMS-like tyrosine kinase 3 (FLT3) gene, which is a therapeutic agent for the treatment of diseases and disorders.

[0035] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known FMS-like tyrosine kinase 3 (FLT3) gene inhibitors. The disclosure also provides agents with novel mechanisms of action against FLT3 in the treatment of various types of diseases.

[0036] The present invention further provides a method for treating a disease, disorder, or condition selected from cancer, acute myeloid leukemia (AML), and cytogenetically normal acute myeloid leukemia (CN-AML), comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0037] Another aspect of the present invention relates to a method for synthesizing the compound of formula (I).

[0038] In some embodiments, the present disclosure provides compounds that can be obtained by or obtained by methods for preparing the compounds described herein.

[0039] In some embodiments, the present disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein.

[0040] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0041] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure, comprising one or more steps described herein.

[0042] Another aspect of the present invention relates to an intermediate used in the synthesis of a compound of formula (I).

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Similar or equivalent methods and materials to those described herein may be used in the practice or testing of this disclosure, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References made herein are not considered prior art to the inventions described herein. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be limiting. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0044] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0045] Detailed description of the invention This disclosure relates to compounds and compositions that can inhibit the activity of the hematopoietic precursor kinase 1 (HPK1) and FMS-like tyrosine kinase 3 (FLT3) genes. This disclosure features a method for treating, preventing, or improving a disease or disorder in which FLT3 plays a role by administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient in need. The methods of the present invention can be used to treat a variety of diseases, disorders, and conditions, including cancer, acute myeloid leukemia (AML), and cytogenetically normal acute myeloid leukemia (CN-AML). In a first aspect of the present invention, a compound of formula I(AG): [ka] [ka] [ka] Or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, stereoisomers, and tautomers are described, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 A, B, X, Y, m, n, o, L, W, K, L, and Het are described in this specification.

[0046] Details of the present invention are described in the following appendix. Similar or equivalent methods and materials to those described herein may be used in the practice or testing of the present invention, but only exemplary methods and materials are described here. Other features, purposes and advantages of the present invention will become apparent from this specification and the claims. In this specification and the appendix claims, singular forms include plural forms unless the context makes it obvious otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0047] In this disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "element" means one or more elements.

[0048] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise specified.

[0049] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) bond to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group could be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group could have substituents other than hydrogen. For example, at any point along the chain, it could be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any further functional groups. Preferred substituents used for any substitution of the listed groups are, but are not limited to, halogens, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O This includes (OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents themselves may be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is set out below.

[0050] As used herein, the term “substituted” means that a particular group or site has one or more suitable substituents, and the substituents may be linked to the particular group or site at one or more positions. For example, an aryl substituted with a cycloalkyl group indicates that the cycloalkyl group is linked to one atom of the aryl group by bonding or by condensation with the aryl group, sharing two or more common atoms.

[0051] In this specification, the term "unsubstituted" means that a particular group does not have substituents.

[0052] Unless otherwise defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If it contains two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be bonded at one point (e.g., biphenyl) or condensed (e.g., naphthyl). The aryl group can be optionally substituted at any bonding point with one or more substituents, e.g., one to five substituents. Examples of substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. Substituents can be optionally substituted themselves. Furthermore, if the group contains two fused rings, the aryl group as defined herein may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Examples of these aryl ring systems include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenantrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannerenyl.

[0053] Unless otherwise defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, comprising one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being carbon. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl as defined herein also means a tricyclic heteroaromatic group comprising one or more ring heteroatoms selected from N, O, S, P, Se, or B. Aromatic radicals may optionally be independently substituted with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranil, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, tri Azinyl, imidazo[1,2-b]pyrazolyl, flo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl Indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, thieno[2,3-b]pyrazinyl, quinazolinyl Lu, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyridinyl, tetrahydropyrrolo[1,2-a]pyridinyl, 3,4-dihydro-2H-1λ 2-Pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyridinyl, flo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzisoxazolyl, flo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[ This includes, but is not limited to, [4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazole-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and their derivatives. Furthermore, if the heteroaryl ring system includes two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused with a fully unsaturated aromatic ring, for example, a five-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, S, P, Se, or B, or a six-membered heteroaromatic ring containing one to three nitrogen atoms, where the saturated or partially unsaturated ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se, or B and is optionally substituted with one or more oxos. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused with the saturated or partially unsaturated ring described herein.Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridine-7-onyl, 7,8-di This includes hydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrroridine, pyrazolo[1,5-a]pyrimidine-7(4H)-onlyl, 3,4-dihydropyrazino[1,2-a]indole-1(2H)-onyl, or benzo[c][1,2]oxabolol-1(3H)-olyl.

[0054] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0055] "Alkyl" refers to a linear or branched saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0056] "Alkoxy" refers to a linear or branched saturated hydrocarbon containing 1 to 12 carbon atoms, including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0057] An "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in its chain. The double bond of the alkenyl group may be unconjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. Alkenyl groups may be unsubstituted or substituted. Alkenyls as defined herein may be straight-chain or branched.

[0058] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0059] The terms "alkylene" or "alkylenyl" refer to a divalent alkyl radical. Any of the monovalent alkyl groups described above may be alkylenes obtained by the extraction of a second hydrogen atom from the alkyl. As defined herein, alkylenes may be C1-C6 alkylenes. Alkylenes may further be C1-C4 alkylenes. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0060] "Cycloalkyl" refers to a group of 3 to 30 carbon atoms (for example, C3-C3). 12 , C3-C 10This refers to monocyclic or polycyclic (e.g., fused ring, crosslinked ring, or spirocycle) saturated or partially unsaturated hydrocarbon systems having C3-C8. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl, octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl, 1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl, 3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl, bicyclo[3. This includes, but is not limited to, [1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, adamantyl, and their derivatives. In the case of polycyclic cycloalkyls, only one of the cycloalkyl rings must be non-aromatic.

[0061] Unless otherwise specified, "heterocyclyl," "heterocycle," or "heterocycloalkyl" refers to a saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridging, or spirocycle) or 11-14 member tricyclic ring system (fused, bridging, or spirocycle) having one or more heteroatoms (such as O, N, S, P, Se, or B) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4 -Oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]yl, 7 'H-Spiro[cyclohexane-1,5'-fl[3,4-b]pyridine]-yl, 3'H-Spiro[cyclohexane-1,1'-fl[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl This includes, but is not limited to, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octan-6-yl, and others.

[0062] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, which is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0063] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein, which is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0064] As used herein, the term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., C≡N.

[0065] As used herein, the term “amine” refers to primary (RNH2, where R is not H), secondary ((R)2NH, where both Rs are not H), and tertiary (R3N, where R is not H) amines. A substituted amine is intended to mean an amine in which at least one hydrogen atom is substituted with a substituent.

[0066] As used herein, the term “amino” means a substituent containing at least one nitrogen atom. Specifically, the terms “amino” include -NH2, -NH(alkyl) or alkylamino, -N(alkyl)2 or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents.

[0067] The term "solvate" refers to various stoichiometric complexes formed by a solute and a solvent. Such solvents for the purposes of this invention are not those that can impede the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are usually called hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0068] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. Structural differences can be in their composition (geometric isomers) or their ability to rotate the plane of polarization (stereoisomers). Regarding stereoisomers, the compound of formula (I) may have one or more chiral carbon atoms and can arise as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0069] The present invention also relates to isotope-labeled compounds of formula I (e.g., 2 H and 14 The intention is to deuterate (i.e., labeled with C). 2 H or D) isotopes and carbon-14 (i.e., 14 C) Isotopes are particularly preferred in terms of ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and may therefore be preferred in some situations. Isotope-labeled compounds of formula I can generally be prepared by replacing unisotopically labeled reagents with appropriate isotope-labeled reagents, following procedures similar to those disclosed in the following schemes and / or examples.

[0070] This disclosure also includes pharmaceutical compositions comprising effective amounts of the disclosed compounds and pharmaceutically acceptable carriers. Typical “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estrate, esylate, fuma Glutamate, fiunarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, N-methylglucamine ammonium salt, Contains 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate.

[0071] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0072] "Effective dose" is the amount effective to treat or prevent a disease or disorder in the subject described herein, when used in conjunction with the compound.

[0073] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and means materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in the transport or delivery of a pharmaceutical product from one organ or part of the body to another.

[0074] The term “to treat” in relation to an object refers to improving at least one symptom of the disorder in that object. Treating includes curing, improving, or at least partially improving the disorder.

[0075] In this disclosure, unless otherwise specified, the term “disability” is used to mean the term “disease, condition, or illness,” and is used interchangeably with the term “disease, condition, or illness.”

[0076] As used in this disclosure, the terms “administer,” “give administration,” or “give administration” refer to either directly administering the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to a subject, or administering a prodrug derivative or analogue of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject so that an equivalent amount of the active compound can be formed in the subject’s body.

[0077] As used in this disclosure, the term “prodrug” means a compound that can be converted in vivo into the disclosed compound by metabolic means (e.g., hydrolysis).

[0078] In some embodiments, R1 is methyl, ethyl, -N(CH3)2, or -N(C2H5)2.

[0079] In some embodiments, R2 is H, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, (C 1-4 Alkyl)2N(CH2) m N(C 1-4 (alkyl)-, or (C 1-4 Alkyl)2N(CH2) m It is O-.

[0080] In some embodiments, R2 is H, Cl, CH3-, -OCH3, -N(CH3)CH2CH2CH2N(CH3)2, or -OCH2CH2N(CH3)2.

[0081] In some embodiments, R3 is H, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, (C 1-4 alkyl)2N(CH2) m N(C 1-4 alkyl)-, (C 1-4 alkyl)2N(CH2) m O-, heterocyclyl, heterocyclyl(CH2) m O-, heteroaryl, and is selected from the group consisting of.

[0082] In a further embodiment, R3 is H, -CH3, -OCH3, morpholinyl, -N(CH3)CH2CH2CH2N(CH3)2, -OCH2CH2N(CH3)2, or -O(CH2)3 morpholinyl, pyridinyl.

[0083] In some embodiments, R4 is H, -OC 1-6 alkyl and is selected from the group consisting of. In a further embodiment, R4 is H, -OCH3.

[0084] In some embodiments, R5 is H.

[0085] In some embodiments, R6 is H, -CH3, -OCH3.

[0086] In some embodiments, R7 is H, -CH3, or -OCH3. In a further embodiment, R7 is H.

[0087] In some embodiments, R8 is -CH3.

[0088] ]> In some embodiments, R9 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, heterocyclyl.

[0089] In some embodiments, R9 is H, Cl, -CH3, 4-methylpiperazine, 4-N,N-dimethylpiperidine, morpholine.

[0090] In some embodiments, R 10 H, halogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy.

[0091] In some embodiments, R 11 This is H, a halogen, or a C1-C6 alkyl group.

[0092] In some embodiments, R 12 is H or C 1-6 It is alkyl.

[0093] In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

[0094] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0095] In some embodiments, o is 1, 2, or 3. In some embodiments, o is 1 or 2. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3.

[0096] Non-limiting exemplary compounds of this disclosure include: 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 4-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-4-methylpiperazine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 4-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; N-[3-(dimethylamino)propyl]-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-N-methylaniline; 4-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}pyridine; 4-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine; 4-(4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; (2-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(3-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}propyl)morpholine; 3-(2H-1,3-benzodioxol-5-yl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline; 3-(2H-1,3-benzodioxol-5-yl)-1-phenyl-1H-pyrazolo[4,3-c]quinoline; 3-(2H-1,3-benzodioxol-5-yl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline; 3-(2H-1,3-benzodioxol-5-yl)-8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline; 7-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-Dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-2,3-dihydro-1H-isoindole; 4-{2-[3-(3,4-Dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]ethyl}morpholine; 1-{3-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine; N-[3-(Dimethylamino)propyl]-3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-N-methylaniline; 4-(2-{5-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; (2-{5-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; (2-{4-[1-(3,4-Dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; 4-(2-{4-[1-(3,4-Dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{5-[1-(3,4-Dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; (2-{5-[1-(3,4-Dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; [2-(2-Methoxy-4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; 4-[2-(2-methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]dimethylamine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,3-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,5-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3-chloro-2-methylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-(trifluoromethoxy)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; 1-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)piperazine; 1-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)-4-methylpiperazine; 4-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; 1-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)piperazine; 1-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)-4-methylpiperazine; 4-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 4-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 4-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; 1-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)-4-methylpiperazine; 1-(4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)piperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-4-methylpiperazine; or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof.

[0097] It should be understood that all isomers, including mixtures thereof, are included in the present invention. If a compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration. All tautomers are also intended to be included.

[0098] The compounds of the present invention, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist as tautomers (e.g., as amides or iminoethers). All such tautomers are envisioned herein as part of the present invention.

[0099] The compounds of the present invention may contain chiral or asymmetric centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, and mixtures thereof, including racemic mixtures, are intended to form part of the present invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both cis and trans forms, as well as mixtures, are included in the scope of the present invention. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compounds may be in racemic or enantiomerically pure form, or in other stereochemical forms. Assay results may reflect data collected for racemic, enantiomerically pure, or other stereochemical forms.

[0100] Diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral alcohol or chiral auxiliary such as Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds of the present invention may also be atropisomers (e.g., substituted biaryls) and are considered part of the present invention. Enantiomers can also be separated using a chiral HPLC column.

[0101] The compounds of the present invention may also exist in different tautomers, and all such forms are included within the scope of the present invention. For example, both the keto-enol and imine-enamine forms of the compounds are included in the present invention.

[0102] All stereoisomers of the compound (including salts, solvates, esters, and prodrugs of the compound, as well as salts, solvates, and esters of prodrugs), including geometric isomers, optical isomers, enantiomeric isomers (which may exist even in the absence of a chiral carbon), rotameric forms, atropisomers, and diastereomers, which may exist due to chiral carbons on various substituents, are intended within the scope of the present invention, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, if the compound of formula (I) incorporates a double bond or a fused ring, both the cis and trans forms, as well as mixtures, are included in the scope of the present invention. Also, for example, the keto-enol and imine-enamine forms of the compound are all included in the present invention. Individual stereoisomers of the compounds of the present invention may, for example, substantially contain no other isomers, or may be, for example, as a racemate, or mixed with all or other selected stereoisomers. The chiral centers of the present invention may have an S or R configuration as defined by the IUPAC 1974 recommendation. The use of terms such as “salt,” “solvate,” “ester,” and “prodrug” is intended to also apply to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the present invention.)

[0103] The compounds of formula I may also form salts, which are also within the scope of this invention. Unless otherwise specified, references to compounds of formula I herein are understood to include references to their salts.

[0104] This invention relates to a compound that is a modulator of hematopoietic precursor kinase 1 (HPK1).

[0105] In one embodiment, the compound of the present invention is an inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0106] In some embodiments, the compound of formula I is a selective inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0107] This invention relates to a compound that is a modulator of hematopoietic precursor kinase 1 (HPK1).

[0108] In one embodiment, the compound of the present invention is an inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0109] In some embodiments, the compound of formula I is a selective inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0110] This invention relates to a compound that is a modulator of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0111] In one embodiment, the compound of the present invention is an inhibitor of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0112] In some embodiments, the compound of formula I is a selective inhibitor of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0113] The present invention relates to the compounds described herein, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, as well as pharmaceutical compositions comprising one or more of the compounds described herein, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers. Methods for synthesizing compounds

[0114] The compounds of the present invention can be prepared by various methods, including standard chemistry. A suitable synthesis route is shown in the scheme below.

[0115] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as partially defined by the following synthetic scheme. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed as needed, according to general principles or chemistry. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those skilled in the art. Whether a stereocenter is present in a compound of formula (I) can be recognized by those skilled in the art from the selection process, as well as the reaction conditions and sequence. Thus, the present invention includes both possible stereoisomers (unless specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. The separation of the final product, intermediate, or starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0116] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[0117] The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized by the methods described below, along with synthetic methods known in the art of organic synthesis, or by modifications thereof that will be understood by those skilled in the art. Suitable methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized by following the steps outlined in General Procedure A or General Procedure B, which include aggregate intermediates or compounds of different sequences. Starting materials are commercially available or can be prepared by any known procedure in the reported literature or as shown below.

[0118] General Procedure A [ka]

[0119] The synthesis method of compound I by general procedure A, including the following:

[0120] (a) Synthesis of substituted 2-benzoyl-3-(dimethylamino)propa-2-enoate from substituted ethyl 3-oxo-3-phenyl-propanoate and N,N-dimethylformamide dimethylacetal [ka]

[0121] (b) Synthesis of substituted ethyl 3-anilino-2-benzoylpropa-2-enoate [ka]

[0122] (c) Synthesis of substituted 3-benzoyl-1H-quinoline-4one [ka]

[0123] (d) Synthesis of substituted 1,3-diphenylpyrazolo[4,3-c]quinoline [ka] And then;

[0124] (e) Synthesis of substituted 1,3-diphenylpyrazolo[4,3-c]quinolines by further modification of functional groups, such as halogen substitution (with amines, arylation with boronic acids, etc.), or by etherification, hydrolysis, oxidation, or reduction of appropriate functional groups.

[0125] A non-restrictive example of this type of modification could be halogen substitution at any aromatic ring in the system. [ka]

[0126] General Procedure B [ka]

[0127] The synthesis method of compound I by general procedure B, including the following:

[0128] (a) Synthesis of substituted 4-chloroquinoline-3-carbaldehyde [ka]

[0129] (b) Synthesis of substituted 1H-pyrazolo[4,3-c]quinoline [ka]

[0130] (c) Synthesis of substituted 3-iodo-1H-pyrazolo[4,3-c]quinoline [ka]

[0131] (d) Synthesis of substituted 3-phenyl-1H-pyrazolo[4,3-c]quinoline [ka] And then;

[0132] (e) Synthesis of substituted 1,3-diphenylpyrazolo[4,3-c]quinoline [ka]

[0133] (f) Synthesis of substituted 1,3-diphenylpyrazolo[4,3-c]quinolines by further modification of functional groups, such as halogen substitution (with amines, arylation with boronic acids, etc.), or by etherification, hydrolysis, oxidation, or reduction of appropriate functional groups. Method of use of the disclosed compound

[0134] Another aspect of the present invention relates to a method for treating diseases or disorders related to the regulation of hematopoietic precursor kinase 1 (HPK1). The method comprises administering an effective amount of a composition and compound of formula (I) to a patient who requires treatment for a disease or disorder related to the regulation of HPK1.

[0135] In another embodiment, the present invention relates to a method for inhibiting hematopoietic precursor kinase 1 (HPK1). The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0136] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient disease or disorder associated with the inhibition of hematopoietic precursor kinase 1 (HPK1), the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof. In one embodiment, the disease may be, but is not limited to, cancer.

[0137] The present invention also relates to the use of HPK1 inhibitors for the preparation of pharmaceuticals used in the treatment, prevention, inhibition or elimination of diseases or conditions mediated by hematopoietic precursor kinase 1 (HPK1), wherein the pharmaceutical comprises a compound of formula (I).

[0138] In another aspect, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by hematopoietic precursor kinase 1 (HPK1), wherein the pharmaceutical comprises a compound of formula (I).

[0139] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a pharmaceutical for treating diseases associated with the inhibition of hematopoietic precursor kinase 1 (HPK1).

[0140] In another aspect, the present invention relates to the use of a compound of formula (I) in the treatment of diseases associated with the inhibition of hematopoietic precursor kinase 1 (HPK1).

[0141] Another aspect of the present invention relates to a method for treating a disease or disorder related to the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering an effective amount of a composition and compound of formula (I) to a patient in need of treatment for a disease or disorder related to the regulation of FLT3.

[0142] In another embodiment, the present invention relates to a method for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0143] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient's disease or disorder associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene, the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0144] The present invention also relates to the use of FLT3 inhibitors for the preparation of pharmaceuticals used in the treatment, prevention, inhibition or elimination of diseases or conditions mediated by the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the pharmaceutical comprises a compound of formula (I).

[0145] In another aspect, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the pharmaceutical comprises a compound of formula (I).

[0146] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a pharmaceutical for treating diseases associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0147] In another aspect, the present invention relates to the use of a compound of formula (I) in the treatment of diseases associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0148] In some embodiments, the FMS-like tyrosine kinase 3 (FLT3) gene is a mutant FLT3 gene.

[0149] Another aspect of the present invention relates to a method for treating cancer. The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0150] Another aspect of the present invention relates to a method for treating or preventing cancer. The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0151] In one embodiment, the present invention relates to the use of hematopoietic precursor kinase 1 (HPK1) inhibitors for the preparation of pharmaceuticals used for the treatment, prevention, inhibition, or elimination of cancer-related diseases or disorders.

[0152] In some embodiments, the disease, disorder, or symptom is selected from cancer, autoimmune diseases, HBV, HIV, cancer, and / or hyperproliferative diseases.

[0153] In some embodiments, the disease, disorder, or symptom is cancer.

[0154] In some embodiments, cancer is selected from bladder cancer, bone cancer, brain tumor, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), acute myeloid leukemia (AML), and acute promyelocytic leukemia (APL).

[0155] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, transitional cell carcinoma, and urothelial carcinoma. In some embodiments, the cancer is a solid tumor.

[0156] In some embodiments, the disease, disorder, or condition is an autoimmune disease.

[0157] In some embodiments, the disease, disorder, or symptom is an autoimmune disease selected from chronic obstructive pulmonary disease (COPD), asthma, bronchitis, lupus, dermatomyositis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type 1 diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's disease and autoimmune thyroiditis), contact dermatitis, as well as eczematous dermatitis, inflammatory bowel disease, interferonopathy, atherosclerosis, and amyotrophic lateral sclerosis.

[0158] In some embodiments, inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

[0159] In some embodiments, the disease, disorder, or symptom is a viral infection.

[0160] In some embodiments, viral infections are infections caused by viruses selected from human adenovirus, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus, human immunodeficiency virus (HIV), HPS-associated hantavirus, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and coronaviruses.

[0161] In some embodiments, the viral infection is an infection caused by the hepatitis B virus (HBV).

[0162] In some embodiments, the viral infection is infection by human immunodeficiency virus (HIV).

[0163] In some embodiments, the disease, disorder, or symptom is a control of male reproductive capacity.

[0164] In some embodiments, the disease, disorder, or symptom is a benign hyperplasia.

[0165] In some embodiments, the benign hyperplasia is selected from benign hyperplasia of the prostate and benign hyperplasia of the mammary gland.

[0166] In some embodiments, the disease, disorder, or symptom is sepsis.

[0167] In some embodiments, the disease, disorder, or symptom is a vascular disorder.

[0168] In some embodiments, the vascular disorder is selected from erythematous pain, peripheral artery disease, renal artery stenosis, Buerger's disease, Raynaud's disease, disseminated intravascular coagulation, and cerebrovascular disease.

[0169] In some embodiments, the disease, disorder, or condition is atherosclerosis.

[0170] In some embodiments, atherosclerosis is selected from myocardial infarction and stroke.

[0171] In some embodiments, the disease, disorder, or condition is a neurodegenerative disorder.

[0172] In some embodiments, neurodegenerative diseases are selected from Alzheimer's disease, vascular dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, collagen disease-dominant senile dementia, Pick's disease (PiD), argyrophilic cereal disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam Parkinson's disease-dementia complex, FTDP-17, Ritico-Bodidig disease, multiple sclerosis, traumatic brain injury (TBI), and Parkinson's disease, where the disease, disorder, or symptom is selected from Alzheimer's disease, vascular dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP

[0173] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0174] The disclosed compounds of the present invention may be administered in effective amounts to treat or prevent a disorder in a subject, and / or prevent its onset.

[0175] The disclosed compounds may be administered in any mode of administration of the therapeutic agent. These modes include systemic or topical administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration.

[0176] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, or suspensions, and may be in unit doses to conform to conventional pharmaceutical practices. Similarly, they may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and all forms well known to those skilled in the pharmaceutical art may be used.

[0177] Exemplary pharmaceutical compositions include the compounds of the present invention and pharmaceutically acceptable carriers, for example: a) diluents, for example, purified water, triglyceride oils, for example, hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example, EPA or DHA, or esters thereof, triglycerides or mixtures, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; also for tablets; c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, charcoal Tablets and gelatin capsules containing magnesium sulfate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) disintegrants such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants such as Tween80, Labrasol, HPMC, DOSS, caproyl909, labrafac, labrafil, peceol, transcutol, capmulMCM, capmulPG-12, captex355, gelucire, vitamin ETGPS or other acceptable emulsifiers; and / or; g) agents that enhance the absorption of compounds such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200, etc.

[0178] Liquids, particularly injection compositions, can be prepared by means of dissolution, dispersion, etc. For example, the disclosed compounds can be dissolved or mixed in a pharmaceutically acceptable solvent such as water, physiological saline, aqueous dextrose, glycerol, or ethanol to form an injectionable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0179] The disclosed compounds can also be formulated as suppositories, which may be prepared from lipid emulsions or suspensions; using polyalkylene glycols such as propylene glycol as a carrier.

[0180] The disclosed compounds may also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer lamellar vesicles, and multilayer vesicles. The liposomes may be formed from a variety of phospholipids, including cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, a film of lipid components is hydrated with an aqueous solution of the drug to form a lipid layer encapsulating the drug, as described in U.S. Patent No. 5,262,564, which is incorporated entirely herein by reference.

[0181] The disclosed compounds may also be delivered by using monoclonal antibodies as individual carriers to which the disclosed compounds are conjugated. The disclosed compounds may also be conjugated to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspanamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds may be conjugated to a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In embodiments, the disclosed compounds are not covalently bonded to polymers, such as polycarboxylic acid polymers or polyacrylates. Parenteral injection administration is generally used by subcutaneous injection, intramuscular injection or intravenous injection and infusion. Injectable preparations can be prepared in conventional forms, such as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid before injection.

[0182] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include excipients, diluents, or surfactants. In some embodiments, the pharmaceutical composition may further include additional pharmaceutically active agents. In some embodiments, the additional therapeutic agent is selected from immune checkpoint inhibitors, cell-based therapies, and cytokine therapies.

[0183] In some embodiments, the immune checkpoint antibody is selected from PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, TIM3 antibody, LAG3 antibody, and TIGIT antibody.

[0184] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0185] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[0186] In some embodiments, cell-based therapies are cancer vaccines.

[0187] In some embodiments, the cancer vaccine is selected from antitumor vaccines or neoantigen-based vaccines.

[0188] Cell-based therapies typically involve removing immune cells from the blood or tumor of a cancer-affected subject. Tumor-specific immune cells are activated, proliferate, and then returned to the cancer-affected subject, where they provide an immune response against the cancer.

[0189] In some embodiments, the immune cells are selected from natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, and dendritic cells.

[0190] In some embodiments, cancer vaccines are based on natural killer cells.

[0191] In some embodiments, cancer vaccines are based on lymphokine-activated killer cells.

[0192] In some embodiments, cancer vaccines are based on cytotoxic T cells.

[0193] In some embodiments, cancer vaccines are based on dendritic cells.

[0194] In some embodiments, cell-based therapies are selected from CAR-T therapy (e.g., chimeric antigen receptor T cells, which are T cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), and TCR gene therapy.

[0195] In some embodiments, cytokine therapy is interleukin-2 therapy.

[0196] In some embodiments, the cytokine therapy is interferon-alpha therapy.

[0197] Each composition may be prepared according to a conventional mixing, granulation, or coating method, and the pharmaceutical compositions of the present invention may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds.

[0198] Dosage regimens utilizing the disclosed compounds are selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed compound to be employed. A physician or veterinarian skilled in the art can easily determine and prescribe the effective dose of the drug necessary for the prevention, treatment, or cessation of the progression of the condition.

[0199] The effective dose of the disclosed compound, when used for the indicated effect, ranges from about 0.5 mg to about 5000 mg of the disclosed compound necessary to treat the symptoms. Compositions for in vivo or in vitro use may contain the disclosed compound in amounts ranging from about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg, or from one amount to another on the dose list. In one embodiment, the composition is in the form of a scoreable tablet.

[0200] Use in methods for inhibiting the growth or proliferation of cancer cells in subjects where it is necessary to inhibit the growth or proliferation of cancer cells further comprises administering one or more additional therapeutic agents selected from the group consisting of: inducible T cell costimulatory factor (ICOS) agonists, cytotoxic T lymphocyte antigen 4 (CTLA-4) blocking antibodies, PD1 and / or PD-L1 inhibitors, differentiation cluster 47 (CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28 agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8) agonists, T cell immunoglobulins and mucindomyne TIM-3 (TIM-3) inhibitors, LAG-3 (LAG-3) inhibitors, CEACAM1 inhibitors, T-cell immune receptor (TIGIT) inhibitors with Ig and ITIM domains, V-domain immunoglobulin (Ig)-containing T-cell activation suppressor (VISTA) inhibitors, anti-killer IgG-like receptor (KIR) inhibitors, STING agonists, CXC chemokine receptor 4 (CXCR-4) inhibitors, B7-H3 inhibitors, CD73 inhibitors, inhibitory RNAs, IL2 / 15 / 17 fusion proteins, MKNK1 / 2 inhibitors, JAK inhibitors, PI3K inhibitors, or any pharmaceutically acceptable salts of any of the above, or any combination thereof.

[0201] In some embodiments, use in methods for inhibiting the growth or proliferation of cancer cells in subjects where it is necessary to inhibit the growth or proliferation of cancer cells further comprises administering one or more additional therapeutic agents selected from the group consisting of: rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016, ruxolitinib N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidine-4-yl]benzamide, XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, Wartmannin, LY294002, TGR1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI145, IPI-443, GSK2636771, BAY10824391, Buparicib, BYL719, RG7604, MLN1117, WX037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purine-6-yl)amino)propyl)-5-fluoro-3-phenylquinazoline-4(3H)-one, (S)-2-(1-((9H-purine-6-yl)amino)eth (L)-6-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purine-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or any pharmaceutically acceptable salt thereof, or any combination thereof. [Examples]

[0202] This disclosure is further illustrated by the following examples and synthesis schemes, which are not intended to limit the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to limit the scope of this disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents may be suggested to those skilled in the art without departing from the spirit of this disclosure and / or the appended claims.

[0203] JPEG0007900840000044.jpg219133JPEG0007900840000045.jpg127160

[0204] The purity and identification of all synthesized compounds were confirmed by LC-MS analysis performed on a Shimadzu Analytical 10Avp with a PE SCIEX API 165 mass, Sedex 75 ELSD, and Shimadzu UV (254 and 215) detector. Separation was performed on a C18 column, 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1 TFA, gradient 5–87, 10 minutes.

[0205] Preparative HPLC purification was performed using a Shimadz instrument equipped with an SPD-10Avp detector and an FRC-10A fraction collector. Separation was performed using a YMC-Pack ODS-AQ column, 250×20 mmol, S-10 μm, 12 nm, with a gradient solution A-solution B (A: 1000 mL H2O - 226 μL TFA; B: 1000 mL CH3CN - 226 μL TFA).

[0206] Table 1 shows examples of compounds synthesized within the framework of the present invention, the results of MS analysis, and the ID number of each compound for further reference.

[0207] JPEG0007900840000046.jpg208166JPEG0007900840000047.jpg233160JPEG000 7900840000048.jpg233160JPEG0007900840000049.jpg225160JPEG0007900840 000050.jpg225160JPEG0007900840000051.jpg225160JPEG0007900840000052. jpg225160JPEG0007900840000053.jpg225160JPEG0007900840000054.jpg93160 intermediate

[0208] Table 2 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0209] JPEG0007900840000055.jpg59164

[0210] Table 3 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0211] JPEG0007900840000056.jpg42161

[0212] Table 4 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0213] JPEG0007900840000057.jpg68161

[0214] Table 5 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0215] JPEG0007900840000058.jpg76161

[0216] Table 6 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0217] JPEG0007900840000059.jpg100161

[0218] Table 7 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0219] JPEG0007900840000060.jpg84161

[0220] Table 8 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0221] JPEG0007900840000061.jpg134161

[0222] Table 9 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0223] JPEG0007900840000062.jpg225164

[0224] Table 10 shows examples of intermediates synthesized within the framework of the present invention and useful for preparing the compounds described in the present invention, the results of MS analysis, and, for further reference, the ID numbers of each compound.

[0225] JPEG0007900840000063.jpg101161 Examples of general synthesis procedures and compound preparation. Preparation of intermediates

[0226] Preparation 1: 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-pyrazolo[4,3-c]quinoline [ka]

[0227] A mixture of ethyl 3-(3-bromophenyl)-3-oxopropanoate (P1-1) (6.0 g, 22 mmol) and DMF-DMA (13.2 g, 110 mmol) was stirred and heated under reflux for 8 hours. The mixture was then concentrated under reduced pressure to obtain 7.25 g (100%) of ethyl 2-[(3-bromophenyl)carbonyl]-3-(dimethylamino)propa-2-enoate (P1-2), which was used in the next step without purification.

[0228] Ethyl 2-[(3-bromophenyl)carbonyl]-3-(dimethylamino)propa-2-enoate (P1-2) (6.4 g, 119 mmol), p-anisidine (2.9 g, 23 mmol), and anh.EtOH (100 mL) were stirred and heated overnight under reflux, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and ELISA (10:1) to obtain 7.0 g (88%) of ethyl 2-[(3-bromophenyl)carbonyl]-3-[(4-methoxyphenyl)amino]propa-2-enoate (P1-3) as a mixture of Z-isomers and E-isomers.

[0229] Ethyl 2-[(3-bromophenyl)carbonyl]-3-[(4-methoxyphenyl)amino]prop-2-enoate (P1-3) (3.00 g, 7.42 mmol) was added to 50 mL of Ph2O stirred at 200 °C. The resulting solution was stirred at 200-230 °C for 30 minutes, cooled to ambient temperature, and poured into 200 mL of hexane. The resulting mixture was stirred for 30 minutes. The precipitate formed was filtered and washed with hexane to obtain 0.50 g (19%) of 3-[(3-bromophenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P1-4) as a brown solid.

[0230] A mixture of 3-[(3-bromophenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P1-4) (0.50 g, 1.40 mmol), 3,4-dimethylphenylhydrazine hydrochloride (0.29 g, 1.68 mmol), AcOK (0.165 g, 1.68 mmol), and AcOH (10 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized with AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.35 g (55%) of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P1) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): 9.55 (s, 1H), 8.23-8.15 (m, 3H), 7.75-7.73 (m, 1H), 7.58-7.51 (m, 5H), 6.87 (s, 1H), 3.66 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H).

[0231] Preparation 2: 3-(4-bromo-3-chlorophenyl)-1-phenyl-1H-pyrazolo[4,3-c]quinoline (P40) [ka] The compound was synthesized according to the procedure described in Preparation 1, using ethyl 3-(4-bromo-3-chlorophenyl)-3-oxopropanoate instead of ethyl 3-(3-bromophenyl)-3-oxopropanoate, aniline instead of p-anisidine, and phenylhydrazine hydrochloride instead of 3,4-dimethylphenylhydrazine hydrochloride. The product was analyzed by LC-MS: [MH] + 434, 435.

[0232] Preparation 3: 3-(4-bromo-3-chlorophenyl)-8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline (P41) [ka] The compounds were synthesized according to the procedure described in Preparation 1, using ethyl 3-(4-bromo-3-chlorophenyl)-3-oxopropanoate instead of ethyl 3-(3-bromophenyl)-3-oxopropanoate, and phenylhydrazine hydrochloride instead of 3,4-dimethylphenylhydrazine hydrochloride. The products were analyzed by LC-MS.

[0233] Preparation 4: 3-(4-bromo-3-chlorophenyl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (P42) [ka] The compounds were synthesized according to the procedure described in Preparation 1, using ethyl 3-(4-bromo-3-chlorophenyl)-3-oxopropanoate instead of ethyl 3-(3-bromophenyl)-3-oxopropanoate, and aniline instead of p-anisidine. The products were analyzed by LC-MS.

[0234] Preparation 5: 3-(4-bromo-3-chlorophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P43) [ka] The compounds were synthesized according to the procedure described in Preparation 1, using ethyl 3-(4-bromo-3-chlorophenyl)-3-oxopropanoate instead of ethyl 3-(3-bromophenyl)-3-oxopropanoate, and phenylhydrazine hydrochloride instead of 3,4-dimethylphenylhydrazine hydrochloride. The products were analyzed by LC-MS.

[0235] Preparation 6: 3-(4-bromophenyl)-8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline (P44) [ka] The compounds were synthesized according to the procedure described in Preparation 1, using ethyl 3-(bromophenyl)-3-oxopropanoate instead of ethyl 3-(3-bromophenyl)-3-oxopropanoate, and phenylhydrazine hydrochloride instead of 3,4-dimethylphenylhydrazine hydrochloride. The products were analyzed by LC-MS.

[0236] Preparation 7: 1-(3-bromophenyl)-8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P2, 1.79) [ka]

[0237] A mixture of ethyl 3-(3-methoxyphenyl)-3-oxopropanoate (P2-1) (51 g, 230 mmol) and DMF-DMA (136 g, 1.14 mmol) was stirred and heated under reflux for 8 hours. The mixture was then concentrated under reduced pressure to obtain 62.0 g (97%) of crude ethyl 3-(dimethylamino)-2-[(3-methoxyphenyl)carbonyl]propa-2-enoate (P2-2), which was used in the next step without purification.

[0238] A mixture of ethyl 3-(dimethylamino)-2-[(3-methoxyphenyl)carbonyl]propa-2-enoate (P2-2) (15 g, 55 mmol), p-anisidine (8.1 g, 65 mmol), and anh. EtOH (100 mL) was stirred and heated overnight under reflux, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and ELISA (10:1) to obtain 14.0 g (73%) of ethyl (2E)-3-[(4-methoxyphenyl)amino]-2-[(3-methoxyphenyl)carbonyl]propa-2-enoate (P2-3) as a mixture of Z-isomers and E-isomers.

[0239] Ethyl (2E)-3-[(4-methoxyphenyl)amino]-2-[(3-methoxyphenyl)carbonyl]prop-2-enoate (P2-3) (14.0 g, 40 mmol) was added to Ph2O (50 mL) stirred at 200°C. The resulting solution was stirred at 200-230°C for 30 minutes, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 minutes. The formed precipitate was filtered and washed with hexane to obtain 5.70 g (44%) of 6-methoxy-3-[(3-methoxyphenyl)carbonyl]quinoline-4(1H)-one (P2-4) as a brown solid.

[0240] A mixture of 6-methoxy-3-[(3-methoxyphenyl)carbonyl]quinoline-4(1H)-one (P2-4) (0.435 g, 1.43 mmol), 3-bromophenylhydrazine hydrochloride (0.479 g, 2.15 mmol), AcOK (0.210 g, 2.15 mmol), and AcOH (10 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized with AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.20 g (31%) of the title compound P2 (1.79) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): 9.42 (s, 1H), 8.14-8.12 (m, 2H), 7.93 (d, J=8.1 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.72-7.67 (m, 2H), 7.57 (s, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.43 (d, J=6.6 Hz, 1H), 7.10 (d, J=6.2 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 3.88 (s, 3H), 3.60 (s, 3H).

[0241] Preparation 8: 1-(5-chloro-2-methylphenyl)-8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P3, 1.6) [ka]

[0242] A mixture of 6-methoxy-3-[(3-methoxyphenyl)carbonyl]quinoline-4(1H)-one (P2-4) (0.30 g, 0.97 mmol), 3-chloro-6-methylphenylhydrazine hydrochloride (0.243 g, 1.26 mmol), AcOK (0.165 g, 1.68 mmol), and AcOH (7 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized from AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.18 g (43%) of the title compound P3(1.6) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): 9.45 (s, 1H), 8.13(d, J=9.2 Hz, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.76 (d, J=6.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.59-7.58 (m, 1H), 7.52 (t, J=8.2 Hz, 1H), 7.43 (d, J=6.4 Hz, 1H), 7.10 (d, J=5.3 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 3.88 (s, 3H), 3.53 (s, 3H), 1.96 (s, 3H).

[0243] Preparation 9: 1-(5-chloro-2-methylphenyl)-3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P4, 1.9) [ka]

[0244] A mixture of ethyl 3-(3,4-dimethylphenyl)-3-oxopropanoate (P4-1) (12.1 g, 55 mmol) and DMF-DMA (33.0 g, 275 mmol) was stirred and heated under reflux for 8 hours, then concentrated under reduced pressure to obtain 15.0 g (99%) of ethyl 3-(dimethylamino)-2-[(3,4-dimethylphenyl)carbonyl]propa-2-enoate (P4-2), which was used in the next step without purification.

[0245] A mixture of ethyl 3-(dimethylamino)-2-[(3,4-dimethylphenyl)carbonyl]propa-2-enoate (P4-2) (15 g, 55 mmol), p-anisidine (8.1 g, 65 mmol), and anh. EtOH (100 mL) was stirred and heated overnight under reflux, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and ELISA (10:1) to obtain 14.0 g (73%) of ethyl 2-[(3,4-dimethylphenyl)carbonyl]-3-[(4-methoxyphenyl)amino]propa-2-enoate (P4-3) as a mixture of Z-isomers and E-isomers.

[0246] 14.0 g, 40 mmol of 2-[(3,4-dimethylphenyl)carbonyl]-3-[(4-methoxyphenyl)amino]propa-2-enoate (P4-3) was added to 50 mL of Ph2O stirred at 200°C. The resulting solution was stirred at 200-230°C for 30 minutes, cooled to ambient temperature, and poured into 200 mL of hexane. The resulting mixture was stirred for 30 minutes. The formed precipitate was filtered and washed with hexane to obtain 5.70 g (44%) of 3-[(3,4-dimethylphenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P4-4) as a brown solid.

[0247] A mixture of 3-[(3,4-dimethylphenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P4-4) (0.500 g, 1.63 mmol), 3-chloro-6-methylphenylhydrazine hydrochloride (0.470 g, 2.44 mmol), AcOK (0.24 g, 2.44 mmol), and AcOH (7 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized from AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.35 g (55%) of the title compound P4 as a light brown solid. The product was analyzed by LC-MS.

[0248] Preparation 10: 1-(3-bromophenyl)-3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P5, 1.12) [ka] A mixture of 3-[(3,4-dimethylphenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P4-4) (0.50 g, 1.63 mmol), 3-bromophenylhydrazine hydrochloride (0.546 g, 2.44 mmol), AcOK (0.24 g, 2.44 mmol), and AcOH (7 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized from AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.36 g (48%) of the title compound P5 as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): 9.45 (s, 1H), 8.14-8.12 (m, 2H), 7.93-7.81 (m, 4H), 7.71-7.68 (m, 1H), 7.45-7.43 (m, 1H), 7.35-7.34 (m, 1H), 6.88-6.87 (m, 1H), 3.59 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H).

[0249] Preparation 11: 3-(3-bromophenyl)-1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P6) [ka] AcOK (0.165 g, 1.76 mmol) was added to a mixture of the compounds 3-[(3-bromophenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P1-4) (0.420 g, 1.18 mmol) and 2,3-dimethylphenylhydrazine hydrochloride (0.303 g, 1.76 mmol) in AcOH (10 ml), and the mixture was stirred at 110 °C for 7 hours. The mixture was then cooled to room temperature, and the precipitate was filtered. The solid was recrystallized from AcOH (10 ml), filtered, and washed with Et2O to obtain 0.200 g of crude product with a 60% P6 content. The product was analyzed by LC-MS.

[0250] Preparation 12: 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P7) [ka]

[0251] A mixture of ethyl 3-(4-bromophenyl)-3-oxopropanoate (P7-1) (5.2 g, 19 mmol) and DMF-DMA (13.2 g, 110 mmol) was stirred and heated under reflux for 8 hours, then concentrated under reduced pressure to obtain 6.20 g, (99%) ethyl 2-[(4-bromophenyl)carbonyl]-3-(dimethylamino)propa-2-enoate (P7-2), which was used in the next step without purification.

[0252] A mixture of ethyl 2-[(4-bromophenyl)carbonyl]-3-(dimethylamino)propa-2-enoate (P7-2) (3 g, 9 mmol), p-anisidine (1.35 g, 11 mmol), and anh. EtOH (100 mL) was stirred and heated overnight under reflux, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and ELISA (10:1) to obtain 3.1 g (83%) of ethyl 2-[(4-bromophenyl)carbonyl]-3-[(4-methoxyphenyl)amino]propa-2-enoate (P7-3) as a mixture of Z-isomers and E-isomers.

[0253] Ethyl 2-[(4-bromophenyl)carbonyl]-3-[(4-methoxyphenyl)amino]prop-2-enoate (P7-3) (3.00 g, 7.42 mmol) was added to Ph2O (50 mL) stirred at 200°C. The resulting solution was stirred at 200-230°C for 30 minutes, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 minutes. The formed precipitate was filtered and washed with hexane to obtain 0.50 g (19%) of 3-[(4-bromophenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P7-4) as a brown solid.

[0254] A mixture of 3-[(4-bromophenyl)carbonyl]-6-methoxyquinoline-4(1H)-one (P7-4) (0.50 g, 1.40 mmol), 3,4-dimethylphenylhydrazine hydrochloride (0.29 g, 1.68 mmol), AcOK (0.165 g, 1.68 mmol), and AcOH (10 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The formed precipitate was filtered, recrystallized from AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.35 g (55%) of the title compound P7 as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): 9.79 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.64-7.61 (m, 2H), 7.54 (s, 2H), 6.87 (s, 1H), 3.57 (s, 3H), 2.41 (s, 3H), 2.38 (s, 3H).

[0255] Preparation 13: 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (P8) [ka]

[0256] A mixture of ethyl 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (P7-2, see Preparation 12) (3 g, 9 mmol), aniline (1.04 g, 11 mmol), and anh. EtOH (100 mL) was stirred and heated overnight under reflux, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and SiO (10:1) to obtain 2.0 g (58%) of ethyl 2-[(4-bromophenyl)carbonyl]-3-(phenylamino)propa-2-enoate (P8-1) as a mixture of Z-isomers and E-isomers.

[0257] Ethyl 2-[(4-bromophenyl)carbonyl]-3-(phenylamino)prop-2-enoate (P8-1) (5.0 g, 13.3 mmol) was added to Ph2O (50 mL) stirred at 200°C. The resulting solution was stirred at 200-230°C for 30 minutes, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 minutes. The formed precipitate was filtered and washed with hexane to obtain 0.50 g (19%) of 3-[(4-bromophenyl)carbonyl]quinoline-4(1H)-one (P8-2) as a brown solid.

[0258] A mixture of 3-[(4-bromophenyl)carbonyl]quinoline-4(1H)-one (P8-2) (1.6 g, 4.8 mmol), 3,4-dimethylphenylhydrazine hydrochloride (0.73 g, 5.3 mmol), AcOK (0.165 g, 1.68 mmol), and AcOH (10 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized from AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.4 g (19%) of the title compound P8 as a light brown solid. 1H NMR (400 MHz, DMSO-d6): 9.63 (s, 1H), 8.20 (d, J=8Hz, 1H), 8.09-8.07 (d, J=8Hz, 2H), 7.80-7.75 (m, 3H), 7.56-7.49 (m, 3H), 7.47 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H).

[0259] Preparation 14: 3-(4-bromophenyl)-1-phenyl-1H-pyrazolo[4,3-c]quinoline (P9) [ka] A mixture of 3-[(4-bromophenyl)carbonyl]quinoline-4(1H)-one (P8-2, see Preparation 13) (0.55 g, 1.17 mmol), phenylhydrazine hydrochloride (0.36 g, 2.5 mmol), AcOK (0.165 g, 1.68 mmol), and AcOH (10 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized from AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.30 g (45%) of the title compound P9 as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): 9.59 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.1 (d, J=8.0 Hz, 2H), 7.82-7.75 (m, 8H), 7.50-7.49 (m, 2H).

[0260] Preparation 15: 4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P10) [ka]

[0261] A mixture of 4-hydroxy-3-methoxybenzoic acid (13.25 g, 78 mmol), benzyl bromide (33.7 g, 197 mmol), K2CO3 (38.1 g, 276 mmol), and DMF (75 mL) was stirred at ambient temperature for 12 hours, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was treated with water (200 mL), the resulting precipitate was filtered, and dried by freeze-drying to obtain 27.2 g (99%) of benzyl 4-(benzyloxy)-3-methoxybenzoate (P10-1), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): 7.60 (d, J=9.2 Hz, 1H), 7.49 (s, 2H), 7.46-7.44 (m, 4H), 7.42-7.38 (m, 4H), 7.36-7.32 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 5.33(s, 2H), 5.18 (s, 2H), 3.82 (s, 3H).

[0262] A mixture of benzyl 4-(benzyloxy)-3-methoxybenzoate (P10-1) (27.2 g, 78 mmol), KOH (6.5 g, 117 mmol), MeOH (200 mL), and water (15 mL) was stirred, heated under reflux for 2 hours, concentrated under reduced pressure to 2 / 3 of the original volume, and acidified to pH = 1-2. The formed precipitate was filtered, washed with water, and dried by freeze-drying to obtain 4-(benzyloxy)-3-methoxybenzoic acid (P10-2, 17.5 g, 88% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 12.60 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.47-7.45 (m, 3H), 7.42-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 5.16 (s, 2H), 3.81 (s, 3H).

[0263] A mixture of 4-(benzyloxy)-3-methoxybenzoic acid (P10-2, 17.5 g, 68 mmol), CDI (12.1 g, 75 mmol), and ethyl acetate (200 mL) was stirred at 50°C for 3 hours to form a solution of imidazolide. A mixture of MgCl2 (25.8 g, 271 mmol), potassium salt of ethyl malonate (23.0 g, 136 mmol), and THF (200 mL) was stirred at 60°C for 3 hours, and then the imidazolide solution was added. The resulting mixture was stirred, heated overnight under reflux, cooled, and treated with a 10% aqueous HCl solution to dissolve the formed precipitate. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and ELISA (10:1) to obtain 14.7 g (66%) of ethyl 3-[4-(benzyloxy)-3-methoxyphenyl]-3-oxopropanoate (P10-3). 1 H NMR (400 MHz, DMSO-d6): 7.59 (d, J=8.0 Hz, 1H), 7.47-7.45 (m, 3H), 7.42-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.17 (d, J=8.4 Hz, 1H), 5.2 (s, 2H), 4.14-4.08 (m, 4H), 3.83 (s, 3H). 1.2-1.6 (t, 3H).

[0264] A mixture of ethyl 3-[4-(benzyloxy)-3-methoxyphenyl]-3-oxopropanoate (P10-3) (14.7 g, 45 mmol) and DMF-DMA (58.0 g, 675 mmol) was stirred and heated under reflux for 8 hours, then concentrated under reduced pressure to obtain 17.25 g (99%) of ethyl (2Z)-2-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-3-(dimethylamino)propa-2-enoate (P10-4), which was used in the next step without purification.

[0265] A mixture of ethyl 2-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-3-(dimethylamino)propa-2-enoate (P10-4) (16.13 g, 58 mmol), p-anisidine (8.61 g, 70 mmol), and anh. EtOH (100 mL) was stirred and heated overnight under reflux, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and ELISA (10:1) to obtain 14.8 g (72%) of ethyl (2Z)-2-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-3-[(4-methoxyphenyl)amino]propa-2-enoate (P10-5) as a mixture of Z-isomers and E-isomers.

[0266] Ethyl 2-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-3-[(4-methoxyphenyl)amino]prop-2-enoate (P10-5) (7.00 g, 15.16 mmol) was added to 50 mL of Ph2O stirred at 200 °C. The resulting solution was stirred at 200-230 °C for 30 minutes, cooled to ambient temperature, and poured into 200 mL of hexane. The resulting mixture was stirred for 30 minutes. The formed precipitate was filtered and washed with hexane to obtain 2.50 g (40%) of 3-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-6-methoxyquinoline-4(1H)-one (P10-6).

[0267] A mixture of 3-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-6-methoxyquinoline-4(1H)-one (P10-6, 1.65 g, 3.98 mmol), 3,4-dimethylphenylhydrazine hydrochloride (0.82 g, 4.77 mmol), AcOK (0.48 g, 4.77 mmol), and AcOH (30 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized from AcOH, and subsequently purified by washing with Et2O to obtain 1.10 g (53%) of 3-[4-(benzyloxy)-3-methoxyphenyl]-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P10-7). 1H NMR (400 MHz, DMSO-d6): 9.41 (s, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.64 (dd, J1=8.3 Hz, J2=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7,55 (s, 1H), 7.51-7.38 (m, 8H), 7.24 (d, J=8.2 Hz, 1H), 6.86-6.85 (m, 1H), 5.19 (s, 2H), 3.90 (s, 3H), 3.53 (s, 3H), 2.40 (s, 3H), 2.36 (s, 3H).

[0268] A mixture of 3-[4-(benzyloxy)-3-methoxyphenyl]-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P10-7, 1.00 g, 1.93 mmol), siRNA (20 mL), DMF (4 mL), and Ni / Re (300 mg) was hydrogenated at ambient temperature and 20 atm for 16 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from acetone to obtain 0.51 g (62%) of 4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P10) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): 9.73 (br., 1H), 9.41 (s, 1H), 8.00 (br., 1H), 7.51-7.36 (m, 6H), 6.99-6.90(m, 2H), 3.87(s, 3H), 3.50 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H).

[0269] Preparation 16: 5-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P27) [ka] The compound was synthesized using 3-hydroxy-4-methoxybenzoic acid instead of 4-hydroxy-3-methoxybenzoic acid, following the procedure described in Preparation 15. The product was analyzed by LC-MS.

[0270] Preparation 17: 4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P28) [ka] The compound was synthesized using aniline instead of p-anisidine according to the procedure described in Preparation 15. The product was analyzed by LC-MS.

[0271] Preparation 18: 5-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P29) [ka] The compound was synthesized according to the procedure described in Preparation 15, using 3-hydroxy-4-methoxybenzoic acid instead of 4-hydroxy-3-methoxybenzoic acid and aniline instead of p-anisidine. The product was analyzed by LC-MS.

[0272] Preparation 19: 2-Methoxy-4-(1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl)phenol (P30) [ka] The compound was synthesized according to the procedure described in Preparation 15, using phenylhydrazine instead of 3,4-dimethylphenylhydrazine and aniline instead of p-anisidine. The product was analyzed by LC-MS.

[0273] Preparation 20: 2-Methoxy-4-(8-Methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl)phenol (P31) [ka] The compound was synthesized using phenylhydrazine instead of 3,4-dimethylphenylhydrazine, following the procedure described in Preparation 15. The product was analyzed by LC-MS.

[0274] Preparation 21: 2-Methoxy-5-(1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl)phenol (P32) [ka]

[0275] The compounds were synthesized according to the procedure described in Preparation 15, using phenylhydrazine instead of 3,4-dimethylphenylhydrazine, aniline instead of p-anisidine, and 3-hydroxy-4-methoxybenzoic acid instead of 4-hydroxy-3-methoxybenzoic acid. The products were analyzed by LC-MS.

[0276] Preparation 22: 2-Methoxy-5-(8-Methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl)phenol (P33) [ka] The compound was synthesized according to the procedure described in Preparation 15, using phenylhydrazine instead of 3,4-dimethylphenylhydrazine and 3-hydroxy-4-methoxybenzoic acid instead of 4-hydroxy-3-methoxybenzoic acid. The product was analyzed by LC-MS.

[0277] Preparation 23: 4-[1-(3,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P34) [ka] The compound was synthesized using p-toluidine instead of p-anisidine, following the procedure described in Preparation 15. The product was analyzed by LC-MS.

[0278] Preparation 24: 4-[1-(2,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P35) [ka] The compounds were synthesized according to the procedure described in Preparation 15, using p-toluidine instead of p-anisidine and 2,4-dimethylphenylhydrazine instead of 3,4-dimethylphenylhydrazine. The products were analyzed by LC-MS.

[0279] Preparation 25: 4-[1-(2,3-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P36) [ka] The compound was synthesized according to the procedure described in Preparation 15, using p-toluidine instead of p-anisidine and 2,3-dimethylphenylhydrazine instead of 3,4-dimethylphenylhydrazine. The product was analyzed by LC-MS.

[0280] Preparation 26: 4-[1-(2,5-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P37) [ka] The compound was synthesized according to the procedure described in Preparation 15, using p-toluidine instead of p-anisidine and 2,5-dimethylphenylhydrazine instead of 3,4-dimethylphenylhydrazine. The product was analyzed by LC-MS.

[0281] Preparation 27: 4-[1-(3-chloro-2-methylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P38) [ka] The compounds were synthesized according to the procedure described in Preparation 15, using p-toluidine instead of p-anisidine and 3-chloro-2-methylphenylhydrazine instead of 3,4-dimethylphenylhydrazine. The products were analyzed by LC-MS.

[0282] Preparation 28: 4-[1-(3,4-dimethylphenyl)-8-(trifluoromethoxy)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P39) [ka] The compound was synthesized using p-trifluoromethoxyaniline instead of p-anisidine according to the procedure described in Preparation 15. The product was analyzed by LC-MS.

[0283] Preparation 29: 3-(1,3-benzodioxol-5-ylcarbonyl)quinoline-4(1H)-one (P11) [ka]

[0284] A mixture of ethyl 3-(1,3-benzodioxol-5-yl)-3-oxopropanoate (P11-1) (10 g, 42.3 mmol) and DMF-DMA (27.2 g, 228 mmol) was heated under reflux for 8 hours and concentrated under reduced pressure to obtain 12.32 g, (97%) ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(dimethylamino)propanoate (P11-2), which was used in the next step without further purification.

[0285] A mixture of ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(dimethylamino)propa-2-enoate (P11-2) (10.0 g, 34.3 mmol), aniline (3.50 g, 37.8 mmol), and anh was prepared. EtOH (100 mL) was stirred and heated overnight under reflux, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and ELISA (10:1) to obtain 8.15 g (70%) of ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(phenylamino)propa-2-enoate (P11-3) as a mixture of Z-isomers and E-isomers.

[0286] Ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(phenylamino)prop-2-enoate (5.0 g, 14.8 mmol) was added to Ph2O (50 mL) stirred at 200°C. The resulting solution was stirred at 200-230°C for 30 minutes, cooled to ambient temperature, and poured into hexane (100 mL). The resulting mixture was stirred for 30 minutes. The formed precipitate was filtered and washed with hexane to obtain 1.64 g (38%) of 3-(1,3-benzodioxol-5-ylcarbonyl)quinoline-4(1H)-one (P11).

[0287] Preparation 30: 3-(1,3-benzodioxol-5-ylcarbonyl)-6-methoxyquinoline-4(1H)-one (P12) [ka] The compound was synthesized using 4-methoxyaniline instead of aniline, following the procedure described in Preparation 29. The product was analyzed by LC-MS.

[0288] Preparation 31: 4-Chloroquinoline-3-carbaldehyde (P13) [ka] The Vilsmeyer reagent was first prepared by adding POCl3 (23 mL, 246 mmol) dropwise to DMF (50 mL) stirred in an inert atmosphere, maintaining the temperature at -5 to 0°C, and then stirring the mixture at ambient temperature for 30 minutes. Next, 1-(2-aminophenyl)ethanone (5.0 mL, 41 mmol) was added dropwise to the stirred mixture within 30 minutes. The reaction mixture was stirred, heated at 60°C for 16 hours, cooled to ambient temperature, poured into a vigorously stirred mixture of crushed ice (400 g) and water (200 mL), and neutralized to pH 6-7 by gradually adding NaHCO3. The precipitate was filtered, dissolved in CHCl3, washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by recrystallization of the residue with a mixture of RINKAN and heptane (1:2) to obtain 4.45 g (57%) of 4-chloroquinoline-3-carbaldehyde (P13). 1 H NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 9.14 (s, 1H), 8.41 (m, 1H), 8.16 (m, 1H), 8.04 (m, 1H), 7.88 (m, 1H).

[0289] Preparation 32: 4-Chloro-6-methoxyquinoline-3-carbaldehyde (P14) [ka] The compound was synthesized using 1-(2-amino-5-methoxyphenyl)ethanone instead of 1-(2-aminophenyl)ethanone, following the procedure described in Preparation 31. 1 H NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 8.99 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 4.00 (s, 3H).

[0290] Preparation 33: 4-Chloro-8-methoxyquinoline-3-carbaldehyde (P15) [ka] The compound was synthesized using 1-(2-amino-3-methoxyphenyl)ethanone instead of 1-(2-aminophenyl)ethanone, following the procedure described in Preparation 31. 1 H NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 9.06 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 4.01 (s, 3H).

[0291] Preparation 34: 4-Chloro-6-(trifluoromethoxy)quinoline-3-carbaldehyde (P16) [ka] The compound was synthesized according to the procedure described in Preparation 31, using 1-[2-amino-5-(trifluoromethoxy)phenyl]ethanone instead of 1-(2-aminophenyl)ethanone.

[0292] Preparation 35: 1H-pyrazolo[4,3-c]quinoline (P17) [ka] A mixture of 4-chloroquinoline-3-carbaldehyde (P13, 4.0 g, 21 mmol) and hydrazine hydrate (40 mL) was stirred, heated at 120°C for 15 hours, cooled to ambient temperature, and poured into stirred cold water (250 mL). The resulting precipitate was filtered, washed with water and ethanol, and dried at 60°C to obtain 3.41 g (96%) of 1H-pyrazolo[4,3-c]quinoline (P17). 1 H NMR (400 MHz, DMSO-d6): δ 14.33 (s, 1H), 9.24 (s, 1H), 8.42 (m, 2H), 8.12 (d, J = 7.6 Hz, 1H), 7.74 (m, 2H).

[0293] Preparation 36: 8-Methoxy-1H-pyrazolo[4,3-c]quinoline (P18) [ka] The compound was synthesized according to the procedure described in Preparation 35, using 4-chloro-6-methoxyquinoline-3-carbaldehyde instead of 4-chloroquinoline-3-carbaldehyde. 1 H NMR (400 MHz, DMSO-d6): δ 14.11 (s, 1H), 9.08 (s, 1H), 8.36 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.38 (dd, J1= 9.2 Hz, J2= 2.8 Hz, 1H), 3.95 (s, 3H).

[0294] Preparation 37: 6-Methoxy-1H-pyrazolo[4,3-c]quinoline (P19) [ka] The compound was synthesized according to the procedure described in Preparation 35, using 4-chloro-8-methoxyquinoline-3-carbaldehyde instead of 4-chloroquinoline-3-carbaldehyde. 1 H NMR (400 MHz, DMSO-d6): δ 14.25 (brs, 1H), 9.17 (s, 1H), 8.39 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H).

[0295] Preparation 38: 3-iodo-1H-pyrazolo[4,3-c]quinoline (P20) [ka] To a stirred mixture of 1H-pyrazolo[4,3-c]quinoline (P17, see Preparation 35) (3.40 g, 20 mmol) and K2CO3 (6.90 g, 50 mmol) in DMF (200 mL), I2 (10.15 g, 40 mmol) was added. The mixture was stirred at 55 °C for 18 hours and then poured into ice-cold water (300 mL). The resulting precipitate was filtered, washed with water, and dried at 60 °C to obtain 5.81 g (98%) of 3-iodo-1H-pyrazolo[4,3-c]quinoline (P20). 1 H NMR (400 MHz, DMSO-d6): δ 14.75 (s, 1H), 8.89 (s, 1H), 8.41 (m, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.81 (m, 1H), 7.74 (m, 1H).

[0296] Preparation 39: 3-iodo-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P21) [ka] The compound was synthesized using 8-methoxy-1H-pyrazolo[4,3-c]quinoline (P18) instead of 1H-pyrazolo[4,3-c]quinoline, following the procedure described in Preparation 38. 1 H NMR (400 MHz, DMSO-d6): δ 14.57 (s, 1H), 8.73 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.42 (dd, J1= 9.2 Hz, J2= 2.0 Hz, 1H), 3.95 (s, 3H).

[0297] Preparation 40: 3-iodo-6-methoxy-1H-pyrazolo[4,3-c]quinoline (P22) [ka] The compound was synthesized using 6-methoxy-1H-pyrazolo[4,3-c]quinoline (P19) instead of 1H-pyrazolo[4,3-c]quinoline, following the procedure described in Preparation 38. 1H NMR (400 MHz, DMSO-d6): δ 14.69 (s, 1H), 8.82 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H).

[0298] Preparation 41: 3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P23) [ka] A mixture of 3-iodo-1H-pyrazolo[4,3-c]quinoline (P20, see Preparation 38) (5.31 g, 18 mmol), 3,4-dimethoxyboronic acid (3.93 g, 21.6 mmol), Na2CO3 (5.72 g, 54 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), dioxane (150 mL), and water (30 mL) was degassed, stirred at 100°C for 15 hours under an Ar atmosphere, cooled, diluted with water (450 mL), and extracted with i-PrOAc (3 × 150 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was treated with MTBE, filtered, and dried at 60°C to obtain 3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P23). 1 H NMR (400 MHz, DMSO-d6): δ 14.33 (s, 1H), 9.49 (s, 1H), 8.47 (m, 1H), 8.15 (m, 1H), 7.77 (m, 2H), 7.66 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H).

[0299] Preparation 42: 3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P24) [ka] The compound was synthesized using 3-iodo-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P21) instead of 3-iodo-1H-pyrazolo[4,3-c]quinoline, following the procedure described in Preparation 41. 1 H NMR (400 MHz, DMSO-d6): δ 14.18 (s, 1H), 9.34 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.65 (dd, J1= 8.0 Hz, J2= 1.6 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.41 (dd, J1= 9.2 Hz, J2= 2.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H).

[0300] Preparation 43: 3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline (P25) [ka] The compound was synthesized using 3-iodo-6-methoxy-1H-pyrazolo[4,3-c]quinoline (P22) instead of 3-iodo-1H-pyrazolo[4,3-c]quinoline, following the procedure described in Preparation 41. 1 H NMR (400 MHz, DMSO-d6): δ 14.28 (s, 1H), 9.43 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.65 (m, 2H), 7.59 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H). Representative Examples of Compounds

[0301] Example 1: 3-(3,4-dimethoxyphenyl)-8-methoxy-2-(2-morpholine-4-ylethyl)-2H-pyrazolo[4,3-c]quinoline (1.40) and 3-(3,4-dimethoxyphenyl)-8-methoxy-2-(2-morpholine-4-ylethyl)-2H-pyrazolo[4,3-c]quinoline (1.40a) [ka] A mixture of 3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P24) (198 mg, 0.59 mmol), Cs2CO3 (385 mg, 1.18 mmol), 4-(2-chloroethyl)morpholine hydrochloride (110 mg, 0.59 mmol), and DMF (2 mL) was stirred at ambient temperature for 48 hours, diluted with ELISA, washed with water and brine, and concentrated under reduced pressure. The residue was purified by HPLC to obtain 17 mg (6%) of 3-(3,4-dimethoxyphenyl)-8-methoxy-2-(2-morpholine-4-ylethyl)-2H-pyrazolo[4,3-c]quinoline (P26, 1.40) and 50 mg (19%) of 3-(3,4-dimethoxyphenyl)-8-methoxy-2-(2-morpholine-4-ylethyl)-2H-pyrazolo[4,3-c]quinoline (P26A). Structural assignment was performed using 2D-NOESY NMR spectroscopy. P26(1.40): 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.58 (dd, J1= 8.0 Hz, J2= 1.6 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.46 (dd, J1= 8.8 Hz, J2= 2.4 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.03 (t, J = 7.0 Hz, 2H), 4.02 (s, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 3.53 (m, 4H), 2.91 (t, J = 7.0 Hz, 2H), 2.51 (m, 4H); LCMS (ESI) m / z 449.5 [M + H] + P26A: 1 H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.31 (m, 3H), 7.23 (m, 1H), 4.58 (t, J = 6.0 Hz, 2H), 3.96 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.43 (m, 4H), 2.89 (t, J = 6.0 Hz, 2H), 2.25 (m, 4H); LCMS (ESI) m / z 449.5 [M + H] + .

[0302] Example 2: 1-{3-[1-(3,4-ジメチルフェニル)-8-メトキシ-1H-ピラゾロ[4,3- c]キノリン-3-イル]フェニル}-N,N-ジメチルピペリジン-4-アミン(1.1).

change

[0303] Example 3: 1-(3,4-dimethylphenyl)-8-methoxy-3-(3-morpholine-4-ylphenyl)-1H-pyrazolo[4,3-c]quinoline (1,2). [ka] The compound was synthesized using morpholine instead of 4-dimethylamino-piperidine, following the procedure described in Example 2. 1H NMR (400 MHz, CDCl3): 9.39 (s, 1H), 8.19 (d, J=9.4 Hz, 1H), 7.59-7.39 (m, 6H), 7.35-7.32 (m, 1H), 7.06-7.03 (m, 1H), 6.99-6.98 (m, 1H), 3.91-3.89 (m, 4H), 3.57 (s, 3H), 3.30-3.28 (m, 4H), 2.43 (s, 3H), 2.40 (s, 3H).

[0304] Example 4: 1-(3,4-dimethylphenyl)-8-methoxy-3-[3-(4-methylpiperazine-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1,3). [ka] The compound was synthesized using N-methylpiperazine instead of 4-dimethylamino-piperidine, following the procedure described in Example 2. 1 H NMR (400 MHz, DMSO-d6): 9.37 (s, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.55-7.38 (m, 7H), 7.11-7.09 (m, 1H), 6.87 (d, J=2.7 Hz, 1H), 3.54 (s, 3H), 3.26-3.23 (m, 4H), 2.51-2.48 (m, 4H), 2.40 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H).

[0305] Example 5: 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-N,N-dimethylpiperidine-4-amine (1,4). [ka] The compound was synthesized using 1-(3-bromophenyl)-8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P2) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, following the procedure described in Example 2. Yield: 21%. 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.53-7.51 (m, 3H), 7.40-7.38 (m, 1H), 7.27-7.25 (m, 2H), 7.10 (t, J = 7.4 Hz, 2H), 6.92 (s, 1H), 3.95-3.87 (m, 4H), 3.55 (s, 3H), 3.35-3.28 (m, 2H), 2.80-2.74 (m, 2H), 2.51-2.48 (m, 6H), 2.00-1.94 (m, 2H), 1.66-1.60 (m, 2H).

[0306] Example 6: 8-Methoxy-3-(3-methoxyphenyl)-1-[3-(4-methylpiperazine-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.5). [ka] The compound was synthesized according to the procedure described in Example 2, using 1-(3-bromophenyl)-8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P2) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and 1-methylpiperazine instead of 4-dimethylamino-piperidine. Yield: 44%. 1H NMR (400 MHz, DMSO-d6): 9.42 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.56-7.59 (m, 3H), 7.42-7.38 (m, 1H), 7.28-7.26 (m, 2H), 7.12-7.08 (m, 2H), 6.92-6.91 (m, 1H), 3.87 (s, 3H), 3.55 (s, 3H), 3.31-3.22 (m, 7H), 2.27-2.20 (m, 4H).

[0307] Example 7: 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-N,N-dimethylpiperidine-4-amine(1.7) [ka] The compounds were synthesized according to the procedure described in Example 2, using P3 instead of P1 and 4-dimethylamino-piperidine. 1 H NMR (400 MHz, DMSO-d6): 9.45 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.43-7.41 (m, 2H), 7.25-7.23 (m, 1H), 7.19-7.18 (m, 1H), 7.09-7.08 (m, 1H), 6.64-6.62 (m, 1H), 3.88 (s, 3H), 3.82-3.79 (m, 2H), 3.50 (s, 3H), 3.31 (br., 1H), 2.74-2.67 (m, 2H), 2.31-2.29 (br, 6H), 1.86-1.81 (m, 5H), 1.56-1.57 (m, 2H).

[0308] Example 8: 8-Methoxy-3-(3-methoxyphenyl)-1-[2-methyl-5-(4-methylpiperazine-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.8) [ka] The compound was synthesized according to the procedure described in Example 2, using 1-(5-chloro-2-methylphenyl)-8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P3) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and 1-methyl-piperazine instead of 4-dimethylamino-piperidine. Yield: 18%. 1 H NMR (400 MHz, DMSO-d6): 9.45 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.43-7.38 (m, 2H), 7.24-7.18 (m, 2H), 7.10-7.07 (m, 1H), 6.64-6.63 (m, 1H), 3.88 (s, 3H), 3.50 (s, 3H), 3.19-3.15 (m, 2H), 2.44-2.41 (m, 2H), 2.19 (s, 3H), 1.82 (s, 3H).

[0309] Example 9: 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-N,N-dimethylpiperidine-4-amine (1.10). [ka] The compound was synthesized using 1-(5-chloro-2-methylphenyl)-3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P4) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, following the procedure described in Example 2, yielding 53%. 1 H NMR (400 MHz, DMSO-d6): 9.45 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J=8.8 1H), 742-7.34 (m, 3H), 7.27-7.21 (m, 1H), 7.19-7.18 (m, 1H), 6.64-6.62 (m, 1H), 3.84-3.79 (m, 2H), 3.50 (s, 3H), 2.75-2.68 (m, 2H), 2.36-2.32 (m, 9H), 1.91-1.80 (m, 5H), 1.59-1.50 (m, 2H).

[0310] Example 10: 3-(3,4-dimethylphenyl)-8-methoxy-1-[2-methyl-5-(4-methylpiperazine-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.11). [ka] The compound was synthesized according to the procedure described in Example 2, using 1-(5-chloro-2-methylphenyl)-3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P4) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and 1-methyl-piperazine instead of 4-dimethylamino-piperidine. Yield: 41%. 1H NMR (400 MHz, DMSO-d6): 9.45 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.88-7.83 (m, 2H), 7.42-7.34 (m, 4H), 7.24 (d, J=9.0 Hz, 1H), 7.17-7.18 (m, 1H), 6.64-6.63 (m, 1H), 3.50 (s, 3H), 3.19-3.16 (m, 4H), 2.44-2.41 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.20-2.18 (m, 3H), 1.82 (s, 3H).

[0311] Example 11: 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-N,N-dimethylpiperidine-4-amine (1.13) [ka] The compound was synthesized using 1-(3-bromophenyl)-3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P5) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, following the procedure described in Example 2.

[0312] Example 12: 1-{3-[1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine (1.14). [ka] The compound was synthesized using 3-(3-bromophenyl)-1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P6) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, following the procedure described in Example 2. Yield: 12%. 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.69 - 7.31 (m, 7H), 7.13 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 3.91 (m, 2H), 3.42 (s, 3H), 2.77 (t, J = 12.1, 2H), 2.53 (s, 3H), 2.42 (s, 3H), 2.00 (m, 2H), 1.81 (s, 3H), 1.64 (m, 2H).

[0313] Example 13: 1-(3,4-dimethylphenyl)-8-methoxy-3-(4-morpholine-4-ylphenyl)-1H-pyrazolo[4,3-c]quinoline (1.15) [ka] The compound was synthesized according to the procedure described in Example 2, using 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P7) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline and morpholine instead of 4-dimethylamino-piperidine. Yield: 22%. 1 H-NMR (400 MHz, CDCl3) δ: 9.39 (s, 1H), 8.18 (d, J = 9.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.48 (s, 1H), 7.45-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.09 (d, J = 8.3 Hz, 2H), 7.01-6.96 (m, 1H), 3.96-3.89 (m, 4H), 3.58 (s, 3H), 3.34-3.26 (m, 4H), 2.43 (s, 3H), 2.40 (s, 3H).

[0314] Example 14: 1-(3,4-dimethylphenyl)-8-methoxy-3-[4-(4-methylpiperazine-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.16) [ka] The compound was synthesized according to the procedure described in Example 2, using 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P7) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and 1-methyl-piperazine instead of 4-dimethylamino-piperidine. Yield: 29%. 1 H-NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.54 (s, 1H), 7.47 (s, 2H), 7.38 (dd, J1= 9.0 Hz, J2= 2.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 2.8 Hz, 1H), 3.54 (s, 3H), 3.29-3.20 (m, 4H), 2.53-2.44 (m, 4H), 2.40 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H).

[0315] Example 15: 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine (1.17) [ka] The compound was synthesized using 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P7) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, following the procedure described in Example 2. Yield: 5%. 1 H NMR (400 MHz, DMSO-d6): 9.37 (s, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.53-7.46 (m, 3H), 7.39 (d, J=6.5 Hz, 1H), 7.14 (d, J=8.6 Hz, 2H), 6.87 (d, J=2.4 Hz, 1H), 3.94-3.91 (m, 2H), 3.53 (s, 3H), 3.45-3.40 (m, 1H), 2.82-2.78 (m, 2H), 2.51-2.47 (m, 6H), 2.40 (s, 3H), 2.36 (s, 3H), 2.00-1.95 (m, 2H), 1.64-1.56 (m, 2H).

[0316] Example 16: N-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N',N'-trimethylpropane-1,3-diamine(1.18) [ka] The compound was synthesized according to the procedure described in Example 2, using 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P7) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and N,N,N'-trimethylpropane-1,3-diamine instead of 4-dimethylamino-piperidine. Yield: 17%. 1H NMR (400 MHz, DMSO-d6): 9.37 (s, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.53-7.46 (m, 3H), 7.38 (d, J=6.8 Hz, 1H), 6.89-6.87 (m, 3H), 3.53 (s, 3H), 3.45-3.42 (m, 2H), 2.98 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H), 2.23-2.21 (m, 5H), 1.74-1.68 (m, 2H).

[0317] Example 17: 1-(3,4-dimethylphenyl)-3-(4-morpholine-4-ylphenyl)-1H-pyrazolo[4,3-c]quinoline (1.20) [ka] The compound was synthesized according to the procedure described in Example 2, using 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (P8) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and morpholine instead of 4-dimethylamino-piperidine. Yield: 39%. 1 H-NMR (400 MHz, CDCl3) δ: 9.51 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.71 (t, J = 7.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.46 (s, 1H), 7.43-7.36 (m, 3H), 7.09 (d, J = 8.7 Hz, 2H), 3.97-3.87 (m, 4H), 3.35-3.25 (m, 4H), 2.45 (s, 3H), 2.40 (s, 3H).

[0318] Example 18: 1-(3,4-dimethylphenyl)-3-[4-(4-methylpiperazine-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.21) [ka] The compound was synthesized according to the procedure described in Example 2, using 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (P8) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and 1-methyl-piperazine instead of 4-dimethylamino-piperidine. Yield: 13%. 1 H-NMR (400 MHz, CDCl3) δ: 9.50 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.71-7.64 (m, 2H), 7.45-7.36 (m, 4H), 7.11 (d, J=8.7 Hz, 2H), 3.39-3.36 (m, 4H), 2.67-2.65 (m, 4H), 2.44 (s, 3H), 2.41 (s, 3H), 2.38(s, 3H).

[0319] Example 19: 3-(4-morpholine-4-ylphenyl)-1-phenyl-1H-pyrazolo[4,3-c]quinoline (1.23) [ka] The compound was synthesized according to the procedure described in Example 2, using 3-(4-bromophenyl)-1-phenyl-1H-pyrazolo[4,3-c]quinoline (see Preparation 14) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline, and morpholine instead of 4-dimethylamino-piperidine. 1H-NMR (400 MHz, CDCl3) δ: 9.52 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.72-7.60 (m, 7H), 7.40-7.36 (m, 1H), 7.10 (d, J=8.4 Hz, 2H), 3.93-3.91 (m, 4H), 3.30-3.25 (m, 4H).

[0320] Example 20: 1-(3,4-dimethylphenyl)-8-methoxy-3-[3-(piperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.41) [ka] The compound was synthesized using piperazine instead of 4-dimethylamino-piperidine, following the procedure described in Example 2.

[0321] Example 21: N-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N',N'-trimethylpropane-1,3-diamine(1.42) [ka] The compound was synthesized using N,N,N'-trimethylpropane-1,3-diamine instead of 4-dimethylaminopiperidine, following the procedure described in Example 2.

[0322] Example 22: 1-(3,4-dimethylphenyl)-8-methoxy-3-(4-pyridine-4-ylphenyl)-1H-pyrazolo[4,3-c]quinoline (1.19) [ka] A degassed mixture of 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P7, 140 mg, 0.305 mmol), pyridine-4-ylboronic acid (45 mg, 0.366 mmol), cesium carbonate (199 mg, 0.611 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol), and dioxane (5 mL) was stirred, heated in a sealed tube at 100°C for 12 hours, cooled, diluted with ethyl acetate, and filtered through a Celite pad. The filtrate was washed with saturated aqueous solution of NaHCO3, water, and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was subjected to silica CC elution with a mixture of DCM and ethyl acetate (9:1) to obtain 100 mg (71%) of the title compound 1.19 as a white solid. 1 H NMR (400 MHz, DMSO-d6): 9.72 (s, 1H), 8.97 (d, J = 6.0 Hz, 2H), 8.36 (d, J=8.4 Hz, 2H), 8.24-8.18 (m, 5H), 7.62 (s, 1H), 7.51-7.48 (m, 1H), 7.55-7.53(m, 3H), 6.89 (d, J=2.8 Hz, 1H), 2.42 (s, 3H), 2.39 (s, 3H).

[0323] Example 23: 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-N-methyl-2-[(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)amino]pyrimidine-5-carboxamide-compound 44. The compound was synthesized according to the procedure described in Example 19, using 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)amino]pyrimidine-5-carboxylic acid instead of 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)amino]pyrimidine-5-carboxylic acid and methylamine hydrochloride instead of ethylamine hydrochloride.

[0324] Example 24: 1-(3,4-dimethylphenyl)-3-(4-piperazine-1-ylphenyl)-1H-pyrazolo[4,3-c]quinoline (1.22) [ka] The compound was synthesized according to the procedure described in Example 2, using 3-(4-bromophenyl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (P8) instead of 3-(3-bromophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline and tert-butyl piperazine-1-carboxylate instead of 4-dimethylamino-piperidine. The result was tert-butyl 4-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine-1-carboxylate (1.22.1) in 40% yield.

[0325] A mixture of 1.22.1 (50.0 mg, 0.094 mmol), DCM (1 mL), and TFA (0.3 mL) was stirred at ambient temperature for 2 hours, diluted with DCM (5 mL), washed with 10% NaHCO3 aqueous solution and water, dried under Na2SO4, and concentrated under reduced pressure. The residue was subjected to HPLC purification, and the resulting TFA salt was converted to an HCl salt by treating its solution in DCM with an excess of 3 M HCl dioxane solution, followed by dilution with Et2O. The formed precipitate was separated by centrifugation, washed twice with Et2O, and dried to obtain 12.0 mg (28%) of the title compound 1.22. 1H-NMR (400 MHz, DMSO-d6) δ: 9.91 (s, 1H), 9.51 (br s, 2H), 8.50 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.99 (t, J = 8.3 Hz, 1H), 7.73 (t, J = 8.3 Hz, 1H), 7.63-7.56 (m, 2H), 7.43-7.37.526 (s, 2H), 7.20 (d, J = 8.3 Hz, 2H), 3.61-3.50 (m, 4H), 3.29-3.17 (m, 4H), 2.43 (s, 3H), 2.37 (s, 3H).

[0326] Example 25: 2-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}-N,N-dimethylethaneamine (1.24) [ka] A mixture of 4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P10, 100 mg, 0.235 mmol), K2CO3 (83 mg, 0.600 mmol), (2-chloroethyl)dimethylamine hydrochloride (1.24.1) (44 mg, 0.305 mmol), and DMF (1 mL) was stirred at 50°C for 16 hours, cooled to ambient temperature, and diluted with water (10 mL). The resulting precipitate was filtered, washed with water and Et2O, and dried in air at 50°C to obtain 48 mg (41%) of the title compound. 1 H-NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.17-8.02 (m, 1H), 7.69-7.34 (m, 6H), 7.25-7.13 (m, 1H), 6.86 (s, 1H), 4.22-4.05 (m, 2H), 3.88 (s, 3H), 3.53 (s, 3H), 2.78-2.60 (m, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.24 (s, 6H).

[0327] Example 26: 1-(3,4-dimethylphenyl)-8-methoxy-3-[3-methoxy-4-(2-morpholine-4-ylethoxy)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.25) [ka] The compound was synthesized using 4-(2-chloroethyl)morpholine hydrochloride instead of (2-chloroethyl)dimethylamine, following the procedure described in Example 25. Yield: 31%. 1 H-NMR (400 MHz, DMSO-d6) δ: 9.41 (br, 1H), 8.11-8.08 (m, 1H), 7.66-7.38 (m, 6H), 7.21-7.19 (m, 1H), 6.87-6.86 (m, 1H), 4.19-4.15 (m, 2H), 3.88 (s, 3H), 3.61-3.58 (m, 4H), 3.53 (s, 3H), 2.77-2.72 (m, 2H), 2.54-2.36 (m, 10H).

[0328] Example 27: 1-(3,4-dimethylphenyl)-8-methoxy-3-[3-methoxy-4-(3-morpholine-4-ylpropoxy)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.26) [ka] The compound was synthesized according to the procedure described in Example 25, using 4-(3-chloropropyl)morpholine hydrochloride instead of (2-chloroethyl)dimethylamine. Yield: 21%. 1H-NMR (400 MHz, DMSO-d6) δ: 9.41 (br, 1H), 8.11-8.08 (m, 1H), 7.67-7.39 (m, 6H), 7.17-7.14 (m, 1H), 6.87-6.86 (m, 1H), 4.13-4.07 (m, 2H), 3.90-3.87 (m, 2H), 3.51-3.30 (m, 6H), 3.33-3.29 (m, 2H), 2.55-2.35 (m, 12H), 1.97-1.90 (m, 2H).

[0329] Example 28: 1-(3,4-dimethylphenyl)-8-methoxy-3-{4-methoxy-3-[2-(morpholine-4-yl)ethoxy]phenyl}-1H-pyrazolo[4,3-c]quinoline (1.43) [ka] The compound was synthesized according to the procedure described in Example 25, using 5-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenol (P27) instead of P10 and 4-(2-chloroethyl)morpholine hydrochloride instead of 1.24.1.

[0330] Example 29: 3-{4-methoxy-3-[2-(morpholine-4-yl)ethoxy]phenyl}-1-phenyl-1H-pyrazolo[4,3-c]quinoline (1.53) [ka] The compound was synthesized according to the procedure described in Example 25, using 2-methoxy-5-(1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl)phenol (P32) instead of P10 and 4-(2-chloroethyl)morpholine hydrochloride instead of 1.24.1.

[0331] Example 30: 3-(1,3-benzodioxol-5-yl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (1.27) [ka] A mixture of 3-(1,3-benzodioxol-5-ylcarbonyl)quinoline-4(1H)-one (P11) (0.50 g, 1.40 mmol), 3,4-dimethylphenylhydrazine hydrochloride (0.295 g, 1.70 mmol), AcOK (0.170 g, 1.70 mmol), and AcOH (10 mL) was stirred and heated under reflux for 7 hours, then cooled to ambient temperature. The resulting precipitate was filtered, recrystallized from AcOH (10 mL), and subsequently purified by washing with Et2O to obtain 0.330 g (51%) of the title compound (1.27). 1 H-NMR (400 MHz, DMSO-d6) δ: 9.52 (s, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.75 (t, J = 8.4 Hz, 1H), 7.63 (dd, J1= 8.1 Hz, J2= 1.7 Hz, 1H), 7.59-7.52 (m, 3H), 7.51-7.48 (m, 1H), 7.46 (s, 2H), 7.13 (d, J = 7.9 Hz, 1H), 6.14 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H).

[0332] Example 31: 3-(1,3-benzodioxol-5-yl)-1-phenyl-1H-pyrazolo[4,3-c]quinoline (1.28). [ka] The compound was synthesized using phenylhydrazine hydrochloride instead of 1.27.1, following the procedure described in Example 30. 1 H-NMR (400 MHz, DMSO-d6) δ: 9.37 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.78-7.71 (m, 6H), 7.64 (d, J=6.5 Hz, 1H), 7.59 (s, 1H), 7.49-7.48 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.13 (s, 2H).

[0333] Example 32: 3-(1,3-benzodioxol-5-yl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (1.29) [ka] The compound was synthesized using 3-(1,3-benzodioxol-5-ylcarbonyl)-6-methoxyquinoline-4(1H)-one (P12) instead of P11, following the procedure described in Example 30. 1 H-NMR (400 MHz, DMSO-d6) δ: 9.37 (s, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 9.2 Hz, 2H), 7.47 (s, 2H), 7.39 (dd, J1=8.8 Hz, J2=1.5 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.89-6.85 (m, 1H), 6.13 (s, 2H), 3.54 (s, 3H), 2.40 (s, 3H), 2.36 (s, 3H).

[0334] Example 33: 3-(1,3-benzodioxol-5-yl)-8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline (1.30) [ka] The compound was synthesized according to the procedure described in Example 30, using 3-(1,3-benzodioxol-5-ylcarbonyl)-6-methoxyquinoline-4(1H)-one (P12) instead of P11 and phenylhydrazine hydrochloride instead of 1.27.1. 1H-NMR (400 MHz, DMSO-d6) δ: 9.37 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.78-7.71 (m, 5H), 7.63 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.40 (d, J=6.6 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 6.81-6.80 (m, 1H), 6.13 (s, 2H), 3.52 (s, 3H).

[0335] Example 34: 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.31) [ka] A mixture of 3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline (P23) (153 mg, 0.5 mmol), tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.31.1) (172 mg, 0.55 mmol), K2CO3 (83 mg, 0.6 mmol), CuI (10 mg, 0.05 mmol), N,N-dimethylglycine (11 mg, 0.1 mmol), and DMAA (2 mL) was stirred under Ar at 145°C for 72 hours, cooled to ambient temperature, diluted with CHCl3, washed with 1% Na2EDTA aqueous solution, and concentrated under reduced pressure. The whole grains were subjected to HPLC to obtain 87 mg (33%) of Tert-butyl 7-(3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.31.2). 1H NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.77 (m, 1H), 7.69 (dd, J1= 8.0 Hz, J2= 1.6 Hz, 1H), 7.63 (s, 1H), 7.57 (m, 3H), 7.51 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 4.63 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.68 (m, 2H), 2.98 (m, 2H), 1.45 (s, 9H). LCMS (ESI) m / z 538 [MH] + .

[0336] To a solution of 1.31.2 (45 mg, 0.084 mmol) in 2 mL of dioxane, a solution of dioxane in 3 N HCl (2 mL) was added, and the mixture was stirred at ambient temperature for 4 hours. The resulting precipitate was filtered, washed with ether, and dried under reduced pressure at 50°C to obtain 40 mg (78%) of the title compound 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.31). 1 H NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.80 (brs, 2H), 8.50 (d, J = 8.4 Hz, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.74 (m, 4H), 7.59-7.66 (m, 3H), 7.20 (d, J = 7.6 Hz, 1H), 4.40 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.49 (m, 2H), 3.23 (t, J = 6.0 Hz, 2H).

[0337] Example 35: 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.32) [ka] The compound was synthesized using tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate instead of 1.31.1, following the procedure described in Example 34. 1 H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.85 (brs, 2H), 8.53 (d, J = 8.4 Hz, 1H), 8.02 (m, 1H), 7.70-7.78 (m, 4H), 7.60-7.65 (m, 3H), 7.20 (d, J = 8.4 Hz, 1H), 4.47 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.46 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H).

[0338] Example 36: 1-(2,3-dihydro-1H-isoindole-5-yl)-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.33) [ka] The compound was synthesized using tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate instead of 1.31.1, following the procedure described in Example 34. 1 H NMR (400 MHz, DMSO-d6): δ 10.27 (brs, 2H), 9.93 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (m, 2H), 7.71 (t, J = 7.6 Hz, 1H), 7.61 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 4.69 (m, 4H), 3.90 (s, 3H), 3.88 (s, 3H).

[0339] Example 37: 3-(3,4-dimethoxyphenyl)-8-methoxy-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.34) [ka] The compound was synthesized using 3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P24) instead of P23, following the procedure described in Example 34. 1 H NMR (400 MHz, DMSO-d6): δ 9.82 (brs, 2H), 9.80 (s, 1H), 8.43 (d, J = 9.2 Hz, 1H), 7.75 (m, 3H), 7.59-7.67 (m, 3H), 7.19 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 2.8 Hz, 1H), 4.41 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.62 (s, 3H), 3.47 (m, 2H), 3.22 (m, 2H).

[0340] Example 38: 3-(3,4-dimethoxyphenyl)-8-methoxy-1-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.35) [ka] The compound was synthesized according to the procedure described in Example 34, using 3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P24) instead of P23 and tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate instead of 1.31.1. 1H NMR (400 MHz, DMSO-d6): δ 9.90 (brs, 2H), 9.80 (s, 1H), 8.45 (d, J = 9.2 Hz, 1H), 7.74 (m, 3H), 7.66 (dd, J1= 9.2 Hz, J2= 2.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 4.46 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.61 (s, 3H), 3.45 (m, 2H), 3.18 (m, 2H).

[0341] Example 39: 1-(2,3-dihydro-1H-isoindole-5-yl)-3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.36) [ka] The compound was synthesized according to the procedure described in Example 34, using 3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P24) instead of P23 and tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate instead of 1.31.1. 1H NMR (400 MHz, DMSO-d6): δ 10.25 (brs, 2H), 9.79 (s, 1H), 8.41 (d, J = 9.2 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.75 (dd, J1= 8.4 Hz, J2= 1.6 Hz, 1H), 7.65 (m, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 4.68 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H), 3.60 (s, 3H).

[0342] Example 40: 3-(3,4-dimethoxyphenyl)-6-methoxy-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.37) [ka] The compound was synthesized using 3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline (P25) instead of P23, following the procedure described in Example 34. 1 H NMR (400 MHz, DMSO-d6): δ 9.67 (brs, 2H), 9.60 (s, 1H), 7.70 (m, 3H), 7.57-7.66 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.40 (m, 2H), 4.12 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.49 (m, 2H), 3.22 (m, 2H).

[0343] Example 41: 3-(3,4-dimethoxyphenyl)-6-methoxy-1-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.38) [ka] The compound was synthesized according to the procedure described in Example 34, using 3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline (P25) instead of P23 and tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate instead of 1.31.1. 1 H NMR (400 MHz, DMSO-d6): δ 9.90 (brs, 2H), 9.61 (s, 1H), 7.55-7.73 (m, 7H), 7.22 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.46 (m, 2H), 4.13 (s, 3H), 3.88 (s, 3H), 3.88 (s, 3H), 3.45 (m, 2H), 3.17 (t, J = 6.0 Hz, 2H).

[0344] Example 42: 1-(2,3-dihydro-1H-isoindole-5-yl)-3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.39) [ka] The compound was synthesized according to the procedure described in Example 34, using 3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline (P25) instead of P23 and tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate instead of 1.31.1. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (m, 2H), 9.61 (s, 1H), 7.88 (s, 1H), 7.75-7.81 (m, 2H), 7.73 (dd, J1= 8.4 Hz, J2= 2.0 Hz, 1H), 7.65 (t, J = 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.14 (dd, J1= 8.4 Hz, J2= 0.8 Hz, 1H), 4.68 (m, 4H), 4.13 (s, 3H), 3.88 (s, 3H), 3.88 (s, 3H). Biotechnology

[0345] Example A. Primary assay used to determine the efficacy of HPK1 enzyme activity inhibition. The activity of the compound was measured in an in vitro enzymatic reaction using recombinant HPK1 protein and MBP substrate (both Promega, catalog no. V6398). The enzymatic assay used to measure activity was a luminescence assay using a Microplate Reader ClarioStar Plus. The enzymatic reaction was carried out in assay buffer (40 mM TRIS-HCl pH 7.4-7.6, 20 mM MgCl2, 0.05 mM DTT, 0.1 mg / ml BSA). The compound was dispensed into a 384-well diamond well plate (Axigen, catalog no. P-384-120SQ-CS) in 100× solution of the compound in DMSO using a Biomek FX liquid processing system. A 2x HPK1-MBP mixture (final concentrations of 0.64 ng / μl HPK1 and 45 ng / μl MBP) was prepared in 1x assay buffer, and 5.5 μl of the mixture per well was added to a 384w white reaction plate containing NBS (Corning, catalog no. 4513). 5.5 μl of MBP substrate without HPK1 in 1x buffer was used as a negative control. The plate was centrifuged at 100 g for 1 minute. In the next step, compounds were added to the reaction plate using a Biomek station according to the following steps: 1 μl of 100x compound (in DMSO) was thoroughly mixed with 49 μl of 2x 10 μM ATP in assay buffer, and then 5.5 μl of this mixture was added to the reaction plate along with 5.5 μl of the HPK1-MBP mixture. The plate was centrifuged at 100 g for 1 minute and incubated at room temperature for 1 hour. Next, 3 μL of ADP-Glo ​​reagent (Promega, ADP-Glo® Kinase Assay, catalog number V9102) was added per well. The plate was incubated at room temperature for 30 minutes. Then, 6 μL of kinase detection reagent (Promega, ADP-Glo® Kinase Assay, catalog number V9102) was added per well, and luminescence was measured using a microplate reader. Subsequently, IC was measured using inhibition %. 50 The value was calculated. IC 50The values ​​are shown in Table A, where "A" corresponds to Ki < 10.0nM, "B" corresponds to 10.0nM ≤ Ki < 20.0nM, "C" corresponds to 20.0nM ≤ Ki < 50.0nM, and "D" corresponds to 50.0nM ≤ Ki.

[0346] JPEG0007900840000148.jpg89108

[0347] Example B. MV4-11 Cytotoxicity Assay. CC50 was measured using the MV4-11 cell line in RPMI-1640 medium (PanEco catalog number C363). The compound was serially diluted with 100% DMSO to prepare a 200-fold stock at a final concentration of 1x. Using a Biomek (Beckman) robotic station, 40 μL was dispersed into a 384-well plate at a concentration of 4000 cells per well. Cells were incubated at 37°C before adding the compound. A diluted plate was prepared by pouring 78 μL of appropriate medium using a Biomek (Beckman) robotic station. Subsequently, 2 μL of the substance was taken using the robotic station and added to 78 μL of medium (40-fold dilution of the compound). 10 μL was taken from there and added to the cells in the plate (5-fold dilution of the compound). The plate was incubated at 37°C for 3 days. Three days later, 10 μL of CellTiter-Glo (Promega) was added to the cells and luminescence was measured. 50 The values ​​are shown in Table B, where "A" is CC. 50 Supports <50.0nM, and "B" is 50.0nM≦CC 50 Supports <100.0nM, and "C" represents 100.0nM ≤ CC 50 Supports <500.0nM, and "D" represents 500.0nM ≤ CC 50 It corresponds to.

[0348] JPEG0007900840000149.jpg77108

[0349] Example C. MOLM-13 cytotoxicity assay. The assay was performed according to the procedure described in OA Elgamal et al. J. Hematol. Oncol. 2020, 13, 8 (https: / / doi.org / 10.1186 / s13045-019-0821-7). CC 50 The values ​​are shown in Table C, where "A" is CC 50 Supports <500.0nM, and "B" represents 500.0nM ≤ CC 50 It supports <1000.0nM, and "C" represents 1000.0nM≦CC 50 It supports <5000.0nM, and "D" is 5000.0nM≦CC 50 It corresponds to.

[0350] JPEG0007900840000150.jpg66112

[0351] Example D. FLT3 Inhibitory Activity and Cytotoxicity. This assay was used to determine the potency of FLT3 enzyme activity inhibition. The corresponding biochemical inhibition of the enzyme activity of FLT3(wt), FLT3(D835Y), and FLT3(ITD) was measured using recombinant protein constructs of the kinase domain via an activity-based FLT3 kinase assay for compound screening and profiling by radioanalytic analysis HotSpot® kinase assay (reaction biology). Peptide substrate [EAIYAAPFAKKK]. The compound was dissolved in DMSO to 10 mM. The compound was tested in IC50 mode at 10 doses, starting from 0.3 μM and undergoing 3-fold serial dilutions. The control compound, staurosporine, was tested in IC50 mode at 10 doses, starting from 20 μM and undergoing 4-fold serial dilutions. An alternative control compound was tested in IC50 mode at 10 doses, starting from 20 μM and undergoing 3-fold serial dilutions. The reaction was carried out with 1 μM ATP. The estimated Ki value was calculated using the following formula applicable to ATP competitive inhibitors: Ki = IC50 / (1+[S] / Km). 50The values ​​are shown in Table D, where "A" corresponds to Ki < 0.5 nM, "B" corresponds to 0.5 nM ≤ Ki < 2.0 nM, "C" corresponds to 2.0 nM ≤ Ki < 5.0 nM, and "D" corresponds to 5.0 nM ≤ Ki. Table E shows the cytotoxicity of HEK293.

[0352] JPEG0007900840000151.jpg65160

[0353] JPEG0007900840000152.jpg69158 Equal parts

[0354] Those skilled in the art can identify or confirm, by routine experimentation alone, numerous equivalents to the specific embodiments described herein. Such equivalents shall be included in the claims.

Claims

1. Compounds of formula I-A: 【Chemistry 1】 A compound, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [In the formula, X is -CH ２ -, - (CH ２ ) ２ -, and - (CH ２ ) ３ - Selected from; Y is -CH ２ -, -(CH ２ ) ２ -, and -(CH ２ ) ３ is selected from; R ２ H, halogen, -C １－６ Alkyl, -OC １－６ Alkyl, (C １－４ Alkyl) ２ N(CH ２ ) ｍ N(C) １－４ (Alkyl)-, (C １－４ Alkyl) ２ N(CH ２ ) ｍ O-, heterocyclyl, heterocyclyl (CH ２ ) ｍ O-, heteroaryl, -W-X-R １ , and 【Chemistry 2】 Selected from, R ２ This consists of 1 to 6 bases R ８ It is optionally replaced by; R ３ H, halogen, -C １－６ Alkyl, -OC １－６ Alkyl, (C １－４ Alkyl) ２ N(CH ２ ) ｍ N(C) １－４ (Alkyl)-, (C １－４ Alkyl) ２ N(CH ２ ) ｍ O-, heterocyclyl, heterocyclyl (CH ２ ) ｍ O-, heteroaryl, -W-X-R １ , or base 【Transformation 3】 Selected from, each R ３ This consists of 1 to 6 bases R ８ It is optionally replaced by; Or R ２ and R ３ Together with the atoms to which they are bonded and any intervening atoms, they form the group -K-X-M-; Each R １ C １－６ Alkyl, -NH ２ ,-NH(C １－６ Alkyl), and -N(C １－６ Alkyl) ２ Independently selected from the group consisting of, R ４ , R ５ , R ６ and R ７ Each of these is H, halogen, -CN, C １－４ Alkyl, -OR ８ , -OCF ３ , -COOR ８ , -CONH ２ , -CONHR ８ , -CON(R ８ ) ２ , -SO ２ OH, -SO ２ NHR ８ , -SO ２ N(R) ８ ) ２ Independently selected from the group consisting of; R ８ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－８ Selected from cycloalkyl; R １２ is H or C １－６ It is alkyl; K and M are O, S, SO, SO, respectively. ２ CO, NH, and NR ８ Selected independently of; A is either CH or N; B is CH, CH ２ , N, NH or O; W is O, S, NH, or N(C) １－６ It is alkyl; L is a single bond or -OCH ２ CH ２ - and; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is either 0 or 1.

2. Compounds of formula I-B: 【Chemistry 4】 A compound, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [In the formula, A is either CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ -, - (CH ２ ) ２ - or - (CH ２ ) ３ - and; Y is -CH ２ -, -(CH ２ ) ２ - or -(CH ２ ) ３ -; R １ is selected from C １－６ alkyl, -NH ２ , -NH(C １－６ alkyl), and -N(C １－６ alkyl) ２ ; and is selected from R ２ H, halogen, -C １－６ Alkyl, -OC １－６ Alkyl, (C １－４ Alkyl) ２ N(CH ２ ) ｍ N(C) １－４ (Alkyl)-, (C １－４ Alkyl) ２ N(CH ２ ) ｍ O-, heterocyclyl, heterocyclyl (CH ２ ) ｍ O-, heteroaryl, -W-X-R １ , and 【Transformation 5】 Selected from, each R ２ This consists of 1 to 6 bases R ８ It is optionally replaced by; R ３ H, halogen, -C １－６ Alkyl, -OC １－６ Alkyl, (C １－４ Alkyl) ２ N(CH ２ ) ｍ N(C) １－４ (Alkyl)-, (C １－４ Alkyl) ２ N(CH ２ ) ｍ O-, heterocyclyl, heterocyclyl (CH ２ ) ｍ O-, heteroaryl, -W-X-R １ , and 【Transformation 6】 Selected from, each R ３ This consists of 1 to 6 bases R ８ It is optionally replaced by; Or R ２ and R ３ Together with the atoms to which they are bonded and any intervening atoms, they form the group -K-X-M-; R ４ , R ５ , R ６ and R ７ Each of these is H, halogen, -CN, C １－４ Alkyl, -OR ８ , -OCF ３ , -COOR ８ , -CONH ２ , -CONHR ８ , -CON(R ８ ) ２ , -SO ２ OH, -SO ２ NHR ８ , and -SO ２ N(R) ８ ) ２ Independently selected from the group consisting of; R ８ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－８ Selected from cycloalkyl; R １１ H, halogen, OH, -C １－６ Alkyl and -OC １－６ Selected from alkyl groups; K and M are O, S, SO, SO, respectively. ２ CO, NH, and NR ８ Selected independently of; W is O, S, NH, or N(C) １－６ It is alkyl; L is a single bond or -OCH ２ CH ２ - and; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is selected from 0 and 1.

3. Compounds of formula I-D or I-D': 【Transformation 7】 A compound, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [In the formula, A is either CH or N; B is CH, CH ２ , N, NH or O; L is a single bond or -OCH ２ CH ２ - and; X is -CH ２ -, - (CH ２ ) ２ -, and - (CH ２ ) ３ - Selected from; Y is -CH ２ -, - (CH ２ ) ２ -, and - (CH ２ ) ３ - Selected from; Each R １ C １－６ Alkyl, -NH(C) １－６ Alkyl), and -N(C １－６ Alkyl) ２ Independently selected from the group consisting of; R ２ and R ３ Each of these is H, halogen, and C. １－６ Alkyl, -OC １－６ Alkyl, (C １－４ Alkyl) ２ N(CH ２ ) ｍ N(C) １－４ (Alkyl)-, (C １－４ Alkyl) ２ N(CH ２ ) ｍ O-, heterocyclyl, heterocyclyl (CH ２ ) ｍ O-, heteroaryl, -W-X-R １ , and 【Transformation 8】 Selected independently of; Here, R ２ and R ３ Each of these consists of 1 to 6 bases R ８ It is optionally replaced by; R ４ , R ５ , R ６ and R ７ Each of these is H, halogen, -CN, C １－４ Alkyl, -OR ８ , -OCF ３ , -COOR ８ , -CONH ２ , -CONHR ８ , -CON(R ８ ) ２ , -SO ２ OH, -SO ２ NHR ８ , -SO ２ N(R) ８ ) ２ Selected independently from the group; R ８ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－８ Selected from cycloalkyl; R ９ H, halogen, -C １－６ Alkyl, -OH, and -OC １－６ Selected from alkyl groups; R １０ H, halogen, OH, -C １－６ Alkyl and -OC １－６ Selected from alkyl groups; Or R ９ and R １０ Either of them, along with the atom to which they are bonded and any intervening atom, forms the group -X-N(R １２ ) -Y- forms; R １１ H, halogen, OH, -C １－６ Alkyl and -OC １－６ Selected from alkyl groups; R １２ is H or C １－６ It is alkyl; W is O, S, NH, or N(C) １－６ It is alkyl; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is either 0 or 1.

4. Compounds of formula I-F: 【Chemistry 9】 A compound, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [In the formula, K and M are each O, S, SO, SO ２ CO, NH, and NR ８ Selected independently of; R ４ , R ５ , R ６ and R ７ Each of these is H, halogen, -CN, C １－４ Alkyl, -OR ８ , -OCF ３ , -COOR ８ , -CONH ２ , -CONHR ８ , -CON(R ８ ) ２ , -SO ２ OH, -SO ２ NHR ８ , -SO ２ N(R) ８ ) ２ Independently selected from the group consisting of; R ８ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－８ Selected from cycloalkyl; Each R ９ H, halogen, C １－６ Alkyl, -OH, -OC １－６ Alkyl, and 【Chemistry 10】 Independently selected from the group consisting of; Each R １ C １－６ Alkyl, -NH ２ ,-NH(C １－６ Alkyl), and -N(C １－６ Alkyl) ２ Independently selected from the group consisting of, R １０ H, halogen, -OH, -C １－６ Alkyl and -OC １－６ Selected independently of alkyl; Or R ９ and R １０ Any one of them, along with the atom to which they are bonded and any intervening atom, forms the group-X-N(R １２ ) -Y- forms; R １１ H, halogen, OH, -C １－６ Alkyl and -OC １－６ Selected from alkyl groups; R １２ is H or C １－６ It is alkyl; A is either CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ - or - (CH ２ ) ２ - or - (CH ２ ) ３ - and; Y is -CH ２ - or - (CH ２ ) ２ - or - (CH ２ ) ３ - and; n is either 0 or 1.

5. Compounds of formula I-G: 【Chemistry 11】 A compound, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [In the formula, Het is a heterocyclyl or heteroaryl; Here, Het is composed of 1-6 bases R ８ It is optionally replaced by; R ４ , R ５ , R ６ and R ７ Each of these is H, halogen, -CN, C １－４ Alkyl, -OR ８ , -OCF ３ , -COOR ８ , -CONH ２ , -CONHR ８ , -CON(R ８ ) ２ , -SO ２ OH, -SO ２ NHR ８ , -SO ２ N(R) ８ ) ２ Independently selected from the group consisting of; R ８ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－８ Selected from cycloalkyl; Each R ９ H, halogen, C １－６ Alkyl, -OH, -OC １－６ Alkyl, and 【Chemistry 12】 Independently selected from the group consisting of; R １ C １－６ Alkyl, -NH ２ ,-NH(C １－６ Alkyl), and -N(C １－６ Alkyl) ２ Selected from; R １０ H, halogen, OH, -C １－６ Alkyl and -OC １－６ Selected from alkyl groups; Or R ９ and R １０ Any one of them, along with the atom to which they are bonded and any intervening atom, forms the group-X-N(R １２ ) -Y- forms; R １１ H, halogen, OH, -C １－６ Alkyl and -OC １－６ Selected from alkyl groups; R １２ is H or C １－６ It is alkyl; A is either CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ - or - (CH ２ ) ２ - or - (CH ２ ) ３ - and; Y is -CH ２ - or - (CH ２ ) ２ - or - (CH ２ ) ３ - and; n is either 0 or 1.

6. The following compounds can be selected: 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 4-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-4-methylpiperazine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 4-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; N-[3-(dimethylamino)propyl]-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-N-methylaniline; 4-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}pyridine; 4-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine; 4-(4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; (2-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(3-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}propyl)morpholine; 3-(2H-1,3-benzodioxol-5-yl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline; 3-(2H-1,3-benzodioxol-5-yl)-1-phenyl-1H-pyrazolo[4,3-c]quinoline; 3-(2H-1,3-benzodioxol-5-yl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline; 3-(2H-1,3-benzodioxol-5-yl)-8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline; 7-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-2,3-dihydro-1H-isoindole; 4-{2-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]ethyl}morpholine; 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine; N-[3-(dimethylamino)propyl]-3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-N-methylaniline; 4-(2-{5-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; (2-{5-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; (2-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; 4-(2-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{5-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; (2-{5-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; [2-(2-methoxy-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; 4-[2-(2-methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenoxy)ethyl]dimethylamine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,3-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,5-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3-chloro-2-methylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-(trifluoromethoxy)-1H-pyrazolo[4,3-c]quinoline-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; 1-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)piperazine; 1-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)-4-methylpiperazine; 4-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; 1-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)piperazine; 1-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)-4-methylpiperazine; 4-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 4-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}morpholine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}piperazine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 4-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)morpholine; 1-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)-4-methylpiperazine; 1-(4-{1-phenyl-1H-pyrazolo[4,3-c]quinoline-3-yl}phenyl)piperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]phenyl}-4-methylpiperazine; or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

7. Compounds selected from the following group: 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{3-[1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-3-yl]phenyl}-N,N-dimethylpiperidine-4-amine; 7-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline-1-yl]-2,3-dihydro-1H-isoindole or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, further comprising an additional pharmaceutically active agent.

10. Use of the compound according to any one of claims 1 to 7 in the preparation of a pharmaceutical product for treating a disease, disorder, or symptom related to the inhibition of hematopoietic precursor kinase 1 (HPK1).

11. Use of a compound according to any one of claims 1 to 7 in the preparation of a pharmaceutical product for treating a disease, disorder, or symptom associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

12. Use of a compound according to any one of claims 1 to 7 in the preparation of a pharmaceutical product for treating diseases, disorders or symptoms associated with inhibition of hematopoietic precursor kinase 1 (HPK1) and disorders or symptoms associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

13. Use of a compound according to any one of claims 1 to 7 in the preparation of a pharmaceutical for inhibiting hematopoietic precursor kinase 1 (HPK1), wherein the compound is administered to a subject requiring treatment for cancer.

14. Use of a compound according to any one of claims 1 to 7 in the preparation of a pharmaceutical for treating a disease, disorder, or symptom related to the inhibition of hematopoietic precursor kinase 1 (HPK1), wherein the compound is administered to a subject in need of treatment.

15. Use of a compound according to any one of claims 1 to 7 in the preparation of a pharmaceutical for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the compound is administered to a subject requiring treatment for cancer.

16. Use of a compound according to any one of claims 1 to 7 in the preparation of a pharmaceutical for treating a disease, disorder, or symptom associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the compound is administered to a subject in need of treatment.

17. The use according to claim 14, wherein the disease, disorder, or symptom is selected from cancer, hyperproliferative disease, or viral infection.

18. The use according to claim 17, wherein the disease, disorder, or symptom is a cancer selected from bladder cancer, bone cancer, brain tumor, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell carcinoma, thymic cancer, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

19. The use of claim 17, wherein the disease, disorder, or symptom is a viral infection caused by a virus selected from human adenovirus, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus, human immunodeficiency virus (HIV), HPS-associated hantavirus, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and coronavirus.

20. The use according to claim 19, wherein the viral infection is an infection caused by hepatitis B virus (HBV).

21. The use according to claim 19, wherein the viral infection is an infection caused by human immunodeficiency virus (HIV).

22. The use according to claim 16, wherein the disease, disorder, or symptom is selected from cancer, hyperproliferative disease, etc.

23. The use according to claim 22, wherein the disease, disorder, or symptom is a cancer selected from leukemia.

24. The use according to claim 23, wherein the disease, disorder, or symptom is a cancer selected from chronic myeloid leukemia (CML) or refractory acute myeloid leukemia (AML).

25. The use according to claim 13, wherein the subject is a mammal.

26. The use according to claim 25, wherein the subject is a human.

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