Substituted 1H-pyrazolo[4,3-c]quinolines, methods for their preparation, and uses

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 TO RELATED APPLICATIONS) This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 256,260, filed October 15, 2021, and entitled "Substituted 1H-Pyrazolo[4,3-c]quinolines, Methods for Preparation Thereof, and Uses Thereof," the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] FIELD OF THEINVENTION The present invention is directed to novel anti-cancer agents and intermediates, and 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 progenitor kinase 1 (HPK1), pharmaceutical compositions containing 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 anti-cancer agents disclosed herein. The present invention also relates to methods for the preparation of novel anti-cancer agents and pharmaceutical compositions containing them. [Background technology]

[0003] BACKGROUND OF THEINVENTION The discovery of imatinib in 2001 was a breakthrough in targeted cancer therapy. It stimulated research on kinase inhibitors as a major drug class in oncology, which has proven to be the primary area of ​​use for kinase inhibitors. Currently, there are 71 small molecule kinase inhibitors (SMKIs) approved by the FDA, with an additional 16 SMKIs 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, hematopoietic progenitor kinase 1 (HPK1) and FMS-like tyrosine kinase 3 (FLT3) mutation inhibitors have attracted considerable interest.

[0005] HPK1 belongs to the protein kinase superfamily. STE Ser / Thr protein kinase family. STE20 subfamily. It is primarily expressed in hematopoietic organs, including bone marrow, spleen, and thymus. It is also expressed at very low levels in lung, kidney, mammary gland, 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 was initiated in patients receiving pembrolizumab in advanced solid malignancies. [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 Date12 / 01 / 2021. Last Updated:07 / 15 / 2021. https: / / www.yalemedicine.org / clinical-trials / 8756].

[0007] AML is a cancer of the myeloid blood lineage characterized by the rapid proliferation of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. As an acute leukemia, AML progresses rapidly and, if left untreated, is usually fatal 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 with multiple signaling pathways contributing to its pathogenesis. The major driver of AML is FLT3. Activating mutations in FLT3, primarily FLT3 internal tandem duplications (FLT3-ITD), are associated with reduced progression-free and overall survival. The identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of AML patients has stimulated efforts to develop therapeutic inhibitors of FLT3. These inhibitors show promising antileukemic activity but have so far only been effective as single agents and 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 affected by AML, resulting in 147,000 deaths. It most commonly occurs in older adults. Men are affected more frequently than women. Five-year survival rates are approximately 35% for those under 60 years of age and 10% for those over 60 years of age. Elderly people too healthy to undergo intensive chemotherapy usually have a survival time of 5-10 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 in cancer cells have been developed. Targeted drugs work differently from standard chemotherapy drugs and tend to cause various side effects.

[0011] Some patients with AML have a mutation in the FLT3 gene in their leukemia cells. This gene helps cells produce a protein (also called FLT3) that helps cells grow. 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) with FLT3 mutations detected by 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. The drug can treat adults who have a mutation in the FLT3 gene in their leukemia cells and whose AML has not improved with previous treatments or has relapsed. The structure of gilteritinib is shown below. [ka]

[0013] There is a need for therapeutic agents to treat adult patients with relapsed or refractory acute myeloid leukemia (AML) that have an FLT3 mutation. The present invention is intended to meet this unmet need associated with these FLT3 inhibitor therapies. (Summary of the invention)

[0014] A first aspect of the present invention relates to compounds of formula I, and pharma-ceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, or tautomers thereof: [ka] [In the formula, R a teeth, [ka] Selected from; Each R1 is 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, -WX-R1, or a group [ka] wherein 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 a group [ka] wherein R3 is optionally substituted with 1-6 groups R8; or R2 and R3, together with the atoms to which they are attached and any intervening atoms, form the group -KXM-; Each of R4, R5, R6, and R7 is H, halogen, -CN, 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 Alkenyl, C 2-6 Alkynyl, and C 3-8 cycloalkyl; Each R9 is H, halogen, or C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, and [ka] independently selected from the group consisting of: R 10 is H, halogen, -C 1-6 Alkyl, -OH, and -OC 1-6 alkyl; Or R9 and R 10 any one of these together with the atoms to which they are attached and any intervening atoms may form a group -XN(R 12 )-Y-form; R 11 is H, halogen, -C 1-6 Alkyl, -OH, and -OC 1-6 alkyl; R 12 is H or C1-6 is alkyl; X at each occurrence is independently selected from -CH2-, -(CH2)2-, and -(CH2)3-; Y at each occurrence is independently selected from -CH2-, -(CH2)2-, and -(CH2)3-; A, at each occurrence, is independently selected from CH and N; B, at each occurrence, is independently selected from CH, CH2, N, NH and O; L, at each occurrence, is a single bond, -(CH2) m -, -O(CH2) m - and -NH(CH2) m - independently selected; W is O, S, NH, or N(C 1-6 alkyl); K and M are independently selected from O, S, SO, SO2, CO, NH, and NR8; m is independently, for each occurrence, an integer selected from 1, 2, 3, 4, 5, and 6; n, for each occurrence, is selected from 0 and 1; o, for each occurrence, is independently selected from 1, 2, and 3; Where: Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings bonded together by fused or single bonds; 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, the remaining ring atoms being C; Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms independently selected from O, N, S, P, Se, or B; provided that the compound includes at least one selected from the group consisting of: R2 or R3 is (C 1-4 Alkyl)2N(CH2) m N(C 1-4Alkyl)-, (C 1-4 Alkyl)2N(CH2) m O-, Heterocyclyl, Heterocyclyl(CH2) m O-, heteroaryl, -WX-R1, or [ka] or R2 and R3 together with the atom to which they are attached and any intervening atoms form the group -KXM-; or R3 is [ka] or R9 and R 10 any one of these together with the atoms to which they are attached and any intervening atoms may form a group -XN(R 12 )-Y-; or any one of R9 is [ka] It is.]

[0015] In a more particular embodiment, the present invention relates to compounds of formula I (A, B, C, D and D', E and E', F and G) and pharma-ceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, or tautomers thereof: [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 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 [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; wherein each of R2 and R3 is optionally substituted with 1-6 groups R8; or R2 and R3, together with the atom to which they are attached and any intervening atoms, form the group -KXM-; Each of R4, R5, R6 and R7 is H, halogen, -CN, -C 1-4 independently selected from the group consisting of alkyl, -OR, -OCF, -COOR, -CONH, -CONHR, -CON(R), -SOOH, -SONHR, and -SON(R); R8 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 3-8 cycloalkyl; R 12 is H or C 1-6 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 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]; [ka] [In the formula, 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 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, -WX-R1, and [ka] 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, -WX-R1, and [ka] Selected from; wherein each of R2 and R3 is optionally substituted with 1-6 groups R8; or R2 and R3, together with the atoms to which they are attached and any intervening atoms, form the group -KXM-; -R4, R5, R6 and R7 are each H, halogen, -CN, -C 1-4 independently selected from the group consisting of alkyl, -OR, -OCF, -COOR, -CONH, -CONHR, -CON(R), -SOOH, -SONHR, and -SON(R); R8 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 3-8 cycloalkyl; R 11 H, halogen, -OH, -C 1-6 Alkyl, and -OC 1-6 alkyl; each K and M is independently selected from O, S, SO, SO2, CO, NH, and NR8; W is O, S, NH, and N(C 1-6 alkyl); L is a single bond or -OCH2CH2-; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is selected from 0 and 1]; [ka] [In the formula, 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 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, -WX-R1, and [ka] Selected from; 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; wherein each of R2 and R3 is optionally substituted with 1-6 groups R8; or R2 and R3, together with the atom to which they are attached and any intervening atoms, form the group -KXM-; Each of R4, R5, R6 and R7 is H, halogen, -CN, C 1-4independently selected from the group consisting of alkyl, -OR, -OCF, -COOR, -CONH, -CONHR, -CON(R), -SOOH, SONHR, and SON(R); R8 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 3-8 cycloalkyl; Each of K and M is independently selected from O, S, SO, SO2, CO, NH, and NR8; W is O, S, NH, and N(C 1-6 alkyl); L is a single bond or -OCH2CH2-; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is selected from 0 and 1; o is selected from 1, 2, and 3]; [ka] [In the formula, A is CH or N; B is CH, CH2, N, NH or O; L is a single bond or -OCH2CH2-; 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), or -N(C 1-6 alkyl)2; Each of R2 and R3 is a 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) mO-, Heterocyclyl, Heterocyclyl(CH2) m O-, heteroaryl, -WX-R1, and [ka] independently selected from the group consisting of: wherein each of R2 and R3 is optionally substituted with 1-6 groups R8; Each of R4, R5, R6 and R7 is H, halogen, -CN, C 1-4 independently selected from the group consisting of alkyl, -OR, -OCF, -COOR, -CONH, -CONHR, -CON(R), -SOOH, -SONHR, -SON(R); R8 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 3-8 cycloalkyl; Each R9 is H, halogen, or C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, and [ka] independently selected from the group consisting of: R 10 H, halogen, OH, -C 1-6 Alkyl, and -OC 1-6 alkyl; Or R9 and R 10 any one of these together with the atoms to which they are attached and any intervening atoms may form a group -XN(R 12 )-Y-form; R 11 H, halogen, OH, -C 1-6 Alkyl, and -OC 1-6 alkyl; R 12 is H or C 1-6 is alkyl; W is 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]; [ka] [In the formula, R1 is C 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl), or -N(C 1-6 alkyl)2; Each of R2 and R3 is H, halogen, or 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] independently selected from the group consisting of: wherein each of R2 and R3 is optionally substituted with 1-6 groups R8; X is selected from -CH2-, -(CH2)2-, and -(CH2)3-; Y is selected from -CH2-, -(CH2)2-, and -(CH2)3-; W is O, S, NH, and N(C 1-6 alkyl); Each of R4, R5, R6 and R7 is H, halogen, -CN, 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 Alkenyl, C2-6 Alkynyl, and C 3-8 cycloalkyl; 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, -OH, -C 1-6 Alkyl, and -OC 1-6 alkyl; Or R9 and R 10 any one of these together with the atoms to which they are attached and any intervening atoms may form a group -XN(R 12 )-Y-form; R 11 H, halogen, OH, -C 1-6 Alkyl, and -OC 1-6 alkyl; R 12 is H or C 1-6 is alkyl; L is a single bond or -OCH2CH2-; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is 0 or 1]; [ka] [In the formula, Each of K and M is independently selected from O, S, SO, SO2, CO, NH, or NR8; X is selected from -CH2-, -(CH2)2-, and -(CH2)3-; Y is selected from -CH2-, -(CH2)2-, and -(CH2)3-; Each of R4, R5, R6 and R7 is H, halogen, -CN, C 1-4independently selected from the group consisting of alkyl, -OR, -OCF, -COOR, -CONH, -CONHR, -CON(R), -SOOH, -SONHR, -SON(R); R8 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 3-8 cycloalkyl; 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, -OH, -C 1-6 Alkyl, and -OC 1-6 alkyl; Or R9 and R 10 any one of these together with the atoms to which they are attached and any intervening atoms may form a group -XN(R 12 )-Y-form; R 11 H, halogen, OH, -C 1-6 Alkyl, and -OC 1-6 alkyl; R 12 is H or C 1-6 is alkyl; A is CH or N; B is CH, CH2, N, NH or O; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is 0 or 1]; [ka] [In the formula, Het is heterocyclyl or heteroaryl; wherein Het is optionally substituted with 1-6 groups R8; Each of R4, R5, R6 and R7 is H, halogen, -CN, C 1-4 independently selected from alkyl, -OR8, -OCF3, -COOR8, -CONH2, -CONHR8, -CON(R8)2, -SO2OH, -SO2NHR8, -SO2N(R8)2; R8 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 3-8 cycloalkyl; 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, -OH, -C 1-6 Alkyl, or -OC 1-6 alkyl; Or R9 and R 10 any one of these together with the atoms to which they are attached and any intervening atoms may form a group -XN(R 12 )-Y-form; R 11 H, halogen, -OH, -C 1-6 Alkyl, and -OC 1-6 Selected from alkyl R 12 is H or C 1-6 is alkyl; A is CH or N; B is CH, CH2, N, NH or O; X is -CH2-, -(CH2)2- or (CH2)3-; Y is -CH2-, -(CH2)2-, or -(CH2)3-; n is 0 or 1.

[0016] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I(AG) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

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

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

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

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

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

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

[0023] Another aspect of the invention relates to a compound of formula (I), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament 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 pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of diseases associated with the inhibition of tyrosine kinase 3 (FLT3).

[0025] Another aspect of the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament 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 pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease associated with the inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0027] Another aspect of the present invention pertains to a compound of formula I(AG), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0028] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need of treatment an effective amount of a compound of formula I(AG), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0029] Another aspect of the present invention relates to the use of a compound of formula I(AG), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

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

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

[0032] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known hematopoietic progenitor kinase 1 (HPK1) inhibitors. The present disclosure also provides agents with a novel mechanism 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 associated with the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0034] The present invention provides inhibitors of the FMS-like tyrosine kinase 3 (FLT3) gene that are therapeutic agents in the treatment of diseases and disorders.

[0035] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known FMS-like tyrosine kinase 3 (FLT3) gene inhibitors.The present 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 of treating a disease, disorder, or condition selected from cancer, acute myeloid leukemia (AML), cytogenetically normal acute myeloid leukemia (CN-AML), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

[0038] In some aspects, the disclosure provides compounds obtainable by or obtained by the methods of preparing the compounds described herein.

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

[0040] In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0041] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure, comprising one or more of the steps described herein.

[0042] Another aspect of the present invention relates to intermediates used in the synthesis of compounds of formula (I).

[0043] 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 this disclosure belongs. In this specification, the singular includes the plural unless the context clearly indicates otherwise. Methods and materials similar or equivalent 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 described herein are incorporated by reference. The documents cited herein are not admitted to be prior art to the invention described in the claims. In case of conflict, the present specification, including definitions, will prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. In case of conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure will prevail.

[0044] Other features and advantages of the disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Detailed Description of the Invention The present disclosure relates to compounds and compositions that can inhibit the activity of hematopoietic precursor kinase 1 (HPK1) and FMS-like tyrosine kinase 3 (FLT3) genes. The present disclosure features a method of treating, preventing, or ameliorating a disease or disorder in which FLT3 plays a role by administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient in need thereof. The method 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 pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof 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, Het are as described herein.

[0046] The details of the present invention are described in the attached description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described herein. Other features, objects and advantages of the present invention will become apparent from the present specification and claims. In this specification and the appended claims, the singular form includes the plural form unless the context clearly indicates 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 belongs. All patents and publications cited herein are incorporated herein in their entirety by reference. definition

[0047] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

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

[0049] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituents described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CHCN, -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 )(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). The substituents may themselves be optionally substituted. As used herein, "optionally substituted" means substituted or unsubstituted, the meaning of which is described below.

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

[0051] As used herein, the term "unsubstituted" means that the particular group bears no 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. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be attached at one point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary 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. The substituents may themselves be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein may have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Examples of ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0053] Unless otherwise defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 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. Heteroaryl, as defined herein, also means bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl, as defined herein, also means tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. Aromatic radicals may be optionally substituted independently 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, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triphenylphosphine ... Azinyl, imidazo[1,2-b]pyrazolyl, furo[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, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl , 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]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[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[ These include, but are 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]imidazol-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 derivatives thereof. Additionally, when containing two or more fused rings, heteroaryl groups as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, such as a 5-membered heteroaromatic ring containing 1-3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1-3 nitrogens, where the saturated or partially unsaturated ring contains 0-4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to a saturated or partially unsaturated ring as 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]pyridin-7-onyl, 7,8-dihydropyran-2-yl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-on ... 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]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl.

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

[0055] "Alkyl" refers to a straight or branched chain 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 straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms in the chain containing a terminal "O", i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

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

[0058] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "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 term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Exemplary 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" means a cycloalkyl group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10, or C3-C8) saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) systems. Examples of cycloalkyl groups are 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. Bicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, adamantyl, and derivatives thereof. In the case of polycyclic cycloalkyls, only one of the rings of the cycloalkyl need be non-aromatic.

[0061] "Heterocyclyl," "heterocycle," or "heterocycloalkyl," unless otherwise specified, refers to a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms (such as O, N, S, P, Se, or B), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur.Examples of heterocycloalkyl groups are piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-diaze ... -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-1,1'-isobenzofuran]-yl, 'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-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 , 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-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like.

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

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

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

[0065] The term "amine" as used herein refers to primary (RNH2, where R is not H), secondary ((R)2NH, where both R are not H), and tertiary (RN, where R is not H) amines. A substituted amine is intended to mean an amine in which at least one hydrogen atom is replaced with a substituent.

[0066] The term "amino" as used herein refers to a substituent containing at least one nitrogen atom. Specifically included within the term "amino" are -NH, -NH(alkyl) or alkylamino, -N(alkyl) or dialkylamino, amido, carbamido, urea, and sulfamido substituents.

[0067] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of the present invention, such solvents may not interfere with 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 that contain stoichiometric amounts of water, as well as compositions that contain variable amounts of water.

[0068] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural difference may be in the constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0069] The present invention also relates to isotopically labeled compounds of formula I, such as 2 H and 14 C) are intended to be deuterized (i.e., 2 H or D) isotopes and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to higher metabolic stability (e.g., increased half-life in vivo or reduced required dose), and therefore may be preferred in some circumstances. Isotopically labeled compounds of formula I can generally be prepared by replacing non-isotopically labeled reagents with suitable isotopically labeled reagents according to procedures similar to those disclosed in the following schemes and / or examples.

[0070] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharma- ceutically acceptable carrier. Representative "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, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, and the like. phosphate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, Includes 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, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate salts.

[0071] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0072] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease or disorder in a subject as described herein.

[0073] The term "carrier" as used in this disclosure encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0074] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

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

[0076] The terms "administer," "administering," or "administration" as used in this disclosure refer to either directly administering a disclosed compound, or a pharma- ceutically acceptable salt or composition of a disclosed compound, to a subject, or administering a prodrug derivative or analog of a compound, or a pharma- ceutically acceptable salt or composition of a compound, to a subject, allowing an equivalent amount of an active compound to form in the subject's body.

[0077] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (eg, hydrolysis) to a disclosed compound.

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

[0082] In further embodiments, 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 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 further embodiments, 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 and 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 is H, halogen, or C1-C6 alkyl.

[0092] In some embodiments, R 12 is H or C 1-6 It is an 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 the present disclosure include: 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 4-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-4-methylpiperazine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 4-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; N-[3-(dimethylamino)propyl]-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-N-methylaniline; 4-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}pyridine; 4-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine; 4-(4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; (2-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(3-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-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]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinolin-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]quinolin-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]morpholine; 4-[2-(2-methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]morpholine; [2-(2-methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]dimethylamine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,3-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,5-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3-chloro-2-methylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3,4-dimethylphenyl)-8-(trifluoromethoxy)-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; 1-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)piperazine; 1-(2-chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)-4-methylpiperazine; 4-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; 1-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)piperazine; 1-(2-chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)-4-methylpiperazine; 4-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 4-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine; 1-{2-chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 4-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; 1-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)-4-methylpiperazine; 1-(4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)piperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-4-methylpiperazine; or a pharma- ceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof.

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

[0098] The compounds of the present invention, and their pharma- ceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

[0099] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention and mixtures thereof, including racemic mixtures, form part of the present invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, if the compounds of the present invention incorporate double bonds or fused rings, both cis and trans forms, as well as mixtures, are within the scope of the present invention. Each compound disclosed herein includes all enantiomers that fit 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] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., hydrolysis). Some of the compounds of the present invention may also be atropisomers (e.g., substituted biaryls) and are considered as part of the present invention. Enantiomers can also be separated using a chiral HPLC column.

[0101] It is also possible that compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present invention.

[0102] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including salts, solvates, esters and prodrugs of the compounds, and salts, solvates and esters of the prodrugs), including, for example, enantiomers (which may exist even when no asymmetric carbon is present), rotameric forms, atropisomers, and diastereomeric forms, which may exist due to asymmetric carbons on the various substituents, are contemplated within the scope of the present invention, as are positional isomers (e.g., 4-pyridyl, 3-pyridyl, etc.). (For example, if a compound of formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are encompassed within the scope of the invention. Also, for example, keto-enol and imine-enamine forms of the compounds are all included in the invention. The individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be mixed, for example, as a racemate, or with all or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. Use of the terms "salts," "solvates," "esters," "prodrugs," and the like, are intended to apply equally to the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrug salts, solvates, esters and prodrugs of the compounds of the invention.

[0103] Compounds of formula I may form salts, which are also within the scope of the present invention. Reference herein to a compound of the formula is understood to include reference to its salts, unless otherwise indicated.

[0104] The present invention relates to compounds that are modulators of hematopoietic progenitor kinase 1 (HPK1).

[0105] In one embodiment, the compounds of the invention are inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0106] In some embodiments, compounds of formula I are selective inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0107] The present invention relates to compounds that are modulators of hematopoietic progenitor kinase 1 (HPK1).

[0108] In one embodiment, the compounds of the invention are inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0109] In some embodiments, compounds of formula I are selective inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0110] The present invention relates to compounds that are modulators of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0111] In one embodiment, the compounds of the invention are inhibitors of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0112] In some embodiments, the compounds of formula I are selective inhibitors of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0113] The present invention relates to the compounds described herein, and pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, as well as pharmaceutical compositions comprising one or more compounds described herein, or pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. Method for synthesizing compounds

[0114] The compounds of the invention may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes set out below.

[0115] Compounds of formula (I) may be prepared by methods known in the art of organic synthesis, as defined in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated 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 the compound synthesis using methods readily apparent to those skilled in the art. The presence or absence of stereocenters in compounds of formula (I) can be recognized by those skilled in the art by the selection process, as well as reaction conditions and sequences. Thus, the present invention includes both possible stereoisomers (unless specified in the synthesis), including not only racemates but also individual enantiomers and / or diastereomers. When 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. Separation of the final products, intermediates, or starting materials can be effected by any suitable method known in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-lnterscience, 1994).

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

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

[0118] General Procedure A [ka]

[0119] A method for the synthesis of compounds of formula I according to general procedure A comprising:

[0120] (a) Synthesis of Substituted 2-Benzoyl-3-(dimethylamino)prop-2-enoates from Substituted Ethyl 3-oxo-3-phenyl-propanoates and N,N-Dimethylformamide Dimethylacetal [ka]

[0121] (b) Synthesis of substituted ethyl 3-anilino-2-benzoyl-prop-2-enoates [ka]

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

[0123] (d) Synthesis of substituted 1,3-diphenylpyrazolo[4,3-c]quinolines [ka] And after that;

[0124] (e) Further modification of the functional groups such as substitution of halogens (e.g. with amines, arylation with boronic acids) or etherification, hydrolysis, oxidation or reduction of appropriate functional groups to synthesize substituted 1,3-diphenylpyrazolo[4,3-c]quinolines.

[0125] A non-limiting example of this type of modification can be halogen substitution on any of the aromatic rings of the system. [ka]

[0126] General Procedure B [ka]

[0127] A method for the synthesis of compounds of formula I according to general procedure B comprising:

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

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

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

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

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

[0133] (f) Further modification of the functional groups such as substitution of halogens (e.g. with amines, arylation with boronic acids) or etherification, hydrolysis, oxidation or reduction of appropriate functional groups to synthesize substituted 1,3-diphenylpyrazolo[4,3-c]quinolines. Methods of Use of the Disclosed Compounds

[0134] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation of hematopoietic progenitor kinase 1 (HPK1), comprising administering to a patient in need of treatment for a disease or disorder associated with the regulation of HPK1 an effective amount of a composition and compound of formula (I).

[0135] In another aspect, the present invention relates to a method of inhibiting hematopoietic progenitor kinase 1 (HPK1), the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

[0137] The present invention also relates to the use of an inhibitor of hematopoietic progenitor kinase 1 (HPK1) for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by HPK1, the medicament comprising a compound of formula (I).

[0138] In another aspect, the invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting or eliminating a disease or condition mediated by hematopoietic progenitor kinase 1 (HPK1), wherein the medicament 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 medicament for the treatment of a disease associated with the inhibition of hematopoietic progenitor kinase 1 (HPK1).

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

[0141] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient in need of treatment for a disease or disorder associated with the regulation of FLT3 an effective amount of the compositions and compounds of formula (I).

[0142] In another aspect, the present invention relates to a method for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

[0144] The present invention also relates to the use of an inhibitor of FMS-like tyrosine kinase 3 (FLT3) for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by the FLT3 gene, the medicament comprising a compound of formula (I).

[0145] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting or eliminating a disease or condition mediated by the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the medicament 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 medicament for the treatment of a disease associated with the inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

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

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

[0149] Another aspect of the present invention relates to a method for treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0150] Another aspect of the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0151] In one embodiment, the present invention relates to the use of an inhibitor of hematopoietic progenitor kinase 1 (HPK1) for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or disorder related to cancer.

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

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

[0154] In some embodiments, the cancer is selected from bladder cancer, bone cancer, brain cancer, 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 cancer, thymic cancer, thymic cancer, 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's 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 condition is an autoimmune disease selected from chronic obstructive pulmonary disease (COPD), asthma, bronchitis, lupus, dermatomyositis, Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis), contact dermatitis, as well as eczematous dermatitis, inflammatory bowel disease, interferonopathies, atherosclerosis, and amyotrophic lateral sclerosis.

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

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

[0160] In some embodiments, the viral infection is an 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.

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

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

[0163] In some embodiments, the disease, disorder, or condition is male fertility control.

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

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

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

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

[0168] In some embodiments, the vascular disorder is selected from erythemalgia, peripheral arterial 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, the 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, the neurodegenerative disease is a disease, disorder, or symptom selected from Alzheimer's disease, vascular dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies, collagen disease predominant senile dementia, Pick's disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam Parkinson's disease-dementia complex, FTDP-17, Ritiko-Bodidig disease, multiple sclerosis, traumatic brain injury (TBI), and Parkinson's disease.

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

[0174] The disclosed compounds of the invention can be administered in an effective amount to treat or prevent a disorder in a subject and / or to prevent its onset.

[0175] Administration of the disclosed compounds can be via any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0176] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid form, such as, for example, injections, tablets, suppositories, pills, time release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, and the like, optionally in unit dosage amounts, consistent with conventional pharmaceutical practice. Similarly, they can be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all of which forms well known to those of ordinary skill in the pharmaceutical arts can be used.

[0177] Exemplary pharmaceutical compositions include a compound of the invention and a pharma- ceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oil, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA or esters, triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; also for tablets; c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, charcoal. and / or; g) agents that enhance the absorption of the compound, such as cyclodextrin, cyclodextrin, cyclohexyl ether ...

[0178] Liquids, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved or mixed in a pharma- ceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable 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 can be prepared from fatty emulsions or suspensions; polyalkylene glycols, such as propylene glycol, are used as the carrier.

[0180] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from various phospholipids, including cholesterol, stearylamine, or phosphatidylcholine.In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to form a lipid layer that encapsulates the drug, as described in U.S. Patent No. 5,262,564, the entirety of which is incorporated herein by reference.

[0181] The disclosed compounds can also be delivered by using monoclonal antibodies as individual carriers to which the disclosed compounds are bound. The disclosed compounds can also be bound to soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the disclosed compounds can be bound to classes of biodegradable polymers useful for achieving controlled release of drugs, such as crosslinked or amphiphilic block copolymers of polylactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels. In embodiments, the disclosed compounds are not covalently bound to polymers, such as polycarboxylic acid polymers, or polyacrylates. Parenteral injectable administration is generally used for subcutaneous, intramuscular, or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0182] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier may further comprise an excipient, diluent or surfactant. In some embodiments, the pharmaceutical composition may further comprise an additional pharma- ceutical active agent. In some embodiments, the additional therapeutic agent is selected from an immune checkpoint inhibitor, a cell-based therapy, and a cytokine therapy.

[0183] In some embodiments, the immune checkpoint antibody is selected from a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody, a TIM3 antibody, a LAG3 antibody, and a 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, the cell-based therapy is a cancer vaccine.

[0187] In some embodiments, the cancer vaccine is selected from an anti-tumor vaccine or a neoantigen-based vaccine.

[0188] Cell-based therapies typically involve removing immune cells from the blood or tumor of a cancer-afflicted subject. Tumor-specific immune cells are activated, expanded, and then administered back into the cancer-afflicted 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, the cancer vaccine is based on natural killer cells.

[0191] In some embodiments, the cancer vaccine is based on lymphokine-activated killer cells.

[0192] In some embodiments, the cancer vaccine is based on cytotoxic T cells.

[0193] In some embodiments, the cancer vaccine is dendritic cell-based.

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

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

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

[0197] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0198] Dosage regimens utilizing the disclosed compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound being employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the agent required to prevent, counter, or arrest the progress of the condition.

[0199] Effective dosages of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compounds required to treat the condition. Compositions for in vivo or in vitro use can include about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compounds, or ranges from one amount to another in the dosage list. In one embodiment, the composition is in the form of a tablet that can be scored.

[0200] The use in the method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: inducible T-cell costimulator (ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibodies, PD1 and / or PD-L1 inhibitors, cluster of differentiation 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 mucin domain inhibitors. and / or a pharmacokinetic (TIM-3) inhibitor, a lymphocyte activation gene 3 (LAG-3) inhibitor, a CEACAM1 inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a V-domain immunoglobulin (Ig)-containing suppressor of T cell activation (VISTA) inhibitor, an anti-killer IgG-like receptor (KIR) inhibitor, a STING agonist, a CXC chemokine receptor type 4 (CXCR-4) inhibitor, a B7-H3 inhibitor, a CD73 inhibitor, an inhibitory RNA, an IL2 / 15 / 17 fusion protein, an MKNK1 / 2 inhibitor, a JAK inhibitor, a PI3K inhibitor, or a pharmacokinetically acceptable salt of any of the foregoing, or any combination thereof.

[0201] In some embodiments, the use in the method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: Rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016, ruxolitinib , N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide, XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, TGR1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI145, IPI-443, GSK2636771, BAY10824391, buparisib, BYL719, RG7604, MLN1117, WX037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)- (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or a pharma- ceutically acceptable salt of any of the foregoing, or any combination thereof. EXAMPLES

[0202] The present disclosure is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting the scope or spirit of the present 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 the present disclosure. In addition, it should be understood that various other embodiments, modifications, and equivalents that may be suggested to those skilled in the art can be relied upon without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0203] JPEG2024539633000045.jpg219133JPEG2024539633000046.jpg127160

[0204] The purity and identity of all synthesized compounds were confirmed by LC-MS analysis performed on a Shimadzu Analytical 10Avp 10Avp equipped with a PE SCIEX API 165 mass, Sedex 75 ELSD, and Shimadzu UV (254 and 215) detectors. 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 min.

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

[0206] Table 1 provides 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] JPEG2024539633000047.jpg208166JPEG2024539633000048.jpg233160JPEG202 4539633000049.jpg233160JPEG2024539633000050.jpg225160JPEG2024539633 000051.jpg225160JPEG2024539633000052.jpg225160JPEG2024539633000053. jpg225160JPEG2024539633000054.jpg225160JPEG2024539633000055.jpg93160 Intermediates

[0208] Table 2 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of their MS analysis, and the ID number of each compound for further reference.

[0209] JPEG2024539633000056.jpg59164

[0210] Table 3 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of their MS analysis, and the ID number of each compound for further reference.

[0211] JPEG2024539633000057.jpg42161

[0212] Table 4 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of their MS analysis, and the ID number of each compound for further reference.

[0213] JPEG2024539633000058.jpg68161

[0214] Table 5 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of their MS analysis, and the ID number of each compound for further reference.

[0215] JPEG2024539633000059.jpg76161

[0216] Table 6 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of their MS analysis, and the ID number of each compound for further reference.

[0217] JPEG2024539633000060.jpg100161

[0218] Table 7 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of MS analysis, and the ID number of each compound for further reference.

[0219] JPEG2024539633000061.jpg84161

[0220] Table 8 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of MS analysis, and the ID number of each compound for further reference.

[0221] JPEG2024539633000062.jpg134161

[0222] Table 9 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of MS analysis, and the ID number of each compound for further reference.

[0223] JPEG2024539633000063.jpg225164

[0224] Table 10 shows examples of intermediates that have been synthesized within the framework of the present invention and that are useful for the preparation of compounds according to the present invention, the results of MS analysis, and the ID number of each compound for further reference.

[0225] JPEG2024539633000064.jpg101161 General synthetic procedures and examples of 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 h and then concentrated under reduced pressure to give 7.25 g (100%) of ethyl 2-[(3-bromophenyl)carbonyl]-3-(dimethylamino)prop-2-enoate (P1-2), which was used in the next step without purification.

[0228] Ethyl 2-[(3-bromophenyl)carbonyl]-3-(dimethylamino)prop-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 under reflux overnight, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and EtOAc (10:1) to give 7.0 g (88%) of ethyl 2-[(3-bromophenyl)carbonyl]-3-[(4-methoxyphenyl)amino]prop-2-enoate (P1-3) as a mixture of Z- 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 stirred Ph2O (50 mL) at 200 °C. The resulting solution was stirred at 200-230 °C for 30 min, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 min. The formed precipitate was filtered and washed with hexane to give 0.50 g (19%) of 3-[(3-bromophenyl)carbonyl]-6-methoxyquinolin-4(1H)-one (P1-4) as a brown solid.

[0230] A mixture of 3-[(3-bromophenyl)carbonyl]-6-methoxyquinolin-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 h and cooled to ambient temperature. The precipitate formed was filtered and purified by recrystallization with AcOH (10 mL) followed by washing with Et2O to give 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 LCMS: [MH + ] 434, 435.

[0232] Preparation 3: 3-(4-bromo-3-chlorophenyl)-8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline (P41) [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, and phenylhydrazine hydrochloride instead of 3,4-dimethylphenylhydrazine hydrochloride. The product was analyzed by LCMS.

[0233] Preparation 4: 3-(4-bromo-3-chlorophenyl)-1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinoline (P42) [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 and aniline instead of p-anisidine. The product was analyzed by LCMS.

[0234] Preparation 5: 3-(4-bromo-3-chlorophenyl)-1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P43) [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, and phenylhydrazine hydrochloride instead of 3,4-dimethylphenylhydrazine hydrochloride. The product was analyzed by LCMS.

[0235] Preparation 6: 3-(4-bromophenyl)-8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinoline (P44) [ka] The compound was 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 product was analyzed by LCMS.

[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 h, then concentrated under reduced pressure to give 62.0 g (97%) of crude product ethyl 3-(dimethylamino)-2-[(3-methoxyphenyl)carbonyl]prop-2-enoate (P2-2), which was used in the next step without purification.

[0238] A mixture of ethyl 3-(dimethylamino)-2-[(3-methoxyphenyl)carbonyl]prop-2-enoate (P2-2) (15 g, 55 mmol), p-anisidine (8.1 g, 65 mmol), and anh.EtOH (100 mL) was stirred and heated under reflux overnight, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and EtOAc (10:1) to give 14.0 g (73%) of ethyl (2E)-3-[(4-methoxyphenyl)amino]-2-[(3-methoxyphenyl)carbonyl]prop-2-enoate (P2-3) as a mixture of Z- 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 stirred Ph2O (50 mL) at 200 °C. The resulting solution was stirred at 200-230 °C for 30 min, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 min. The formed precipitate was filtered and washed with hexane to give 5.70 g (44%) of 6-methoxy-3-[(3-methoxyphenyl)carbonyl]quinolin-4(1H)-one (P2-4) as a brown solid.

[0240] A mixture of 6-methoxy-3-[(3-methoxyphenyl)carbonyl]quinolin-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 h and cooled to ambient temperature. The precipitate formed was filtered and purified by recrystallization with AcOH (10 mL) followed by washing with Et2O to give 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]quinolin-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 h and cooled to ambient temperature. The precipitate that formed was filtered and purified by recrystallization from AcOH (10 mL) followed by washing with Et2O to give 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 h and then concentrated under reduced pressure to give 15.0 g (99%) of ethyl 3-(dimethylamino)-2-[(3,4-dimethylphenyl)carbonyl]prop-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]prop-2-enoate (P4-2) (15 g, 55 mmol), p-anisidine (8.1 g, 65 mmol), and anh.EtOH (100 mL) was stirred and heated under reflux overnight, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and EtOAc (10:1) to give 14.0 g (73%) of ethyl 2-[(3,4-dimethylphenyl)carbonyl]-3-[(4-methoxyphenyl)amino]prop-2-enoate (P4-3) as a mixture of Z- and E-isomers.

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

[0247] A mixture of 3-[(3,4-dimethylphenyl)carbonyl]-6-methoxyquinolin-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 h and cooled to ambient temperature. The precipitate formed was filtered and purified by recrystallization from AcOH (10 mL) followed by washing with Et2O to give 0.35 g (55%) of the title compound P4 as a light brown solid. The product was analyzed by LCMS.

[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-methoxyquinolin-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 h and cooled to ambient temperature. The precipitate that formed was filtered and purified by recrystallization from AcOH (10 mL) followed by washing with Et2O to give 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] To a mixture of compound 3-[(3-bromophenyl)carbonyl]-6-methoxyquinolin-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) was added AcOK (0.165 g, 1.76 mmol) and the mixture was stirred at 110° C. for 7 h. Then the mixture was 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 60% content of P6. The product was analyzed by LCMS.

[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 h and then concentrated under reduced pressure to give 6.20 g, (99%) of ethyl 2-[(4-bromophenyl)carbonyl]-3-(dimethylamino)prop-2-enoate (P7-2), which was used in the next step without purification.

[0252] A mixture of ethyl 2-[(4-bromophenyl)carbonyl]-3-(dimethylamino)prop-2-enoate (P7-2) (3 g, 9 mmol), p-anisidine (1.35 g, 11 mmol), and anh.EtOH (100 mL) was stirred and heated under reflux overnight, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and EtOAc (10:1) to give 3.1 g (83%) of ethyl 2-[(4-bromophenyl)carbonyl]-3-[(4-methoxyphenyl)amino]prop-2-enoate (P7-3) as a mixture of Z- 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 stirred Ph2O (50 mL) at 200 °C. The resulting solution was stirred at 200-230 °C for 30 min, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 min. The formed precipitate was filtered and washed with hexane to give 0.50 g (19%) of 3-[(4-bromophenyl)carbonyl]-6-methoxyquinolin-4(1H)-one (P7-4) as a brown solid.

[0254] A mixture of 3-[(4-bromophenyl)carbonyl]-6-methoxyquinolin-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 h and cooled to ambient temperature. The precipitate formed was filtered and purified by recrystallization from AcOH (10 mL) followed by washing with Et2O to give 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 under reflux overnight, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and EtOAc (10:1) to give 2.0 g (58%) of ethyl 2-[(4-bromophenyl)carbonyl]-3-(phenylamino)prop-2-enoate (P8-1) as a mixture of Z- 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 stirred Ph2O (50 mL) at 200 °C. The resulting solution was stirred at 200-230 °C for 30 min, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 min. The formed precipitate was filtered and washed with hexane to give 0.50 g (19%) of 3-[(4-bromophenyl)carbonyl]quinolin-4(1H)-one (P8-2) as a brown solid.

[0258] A mixture of 3-[(4-bromophenyl)carbonyl]quinolin-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 h and cooled to ambient temperature. The precipitate that formed was filtered and purified by recrystallization from AcOH (10 mL) followed by washing with Et2O to give 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]quinolin-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 h and cooled to ambient temperature. The precipitate that formed was filtered and purified by recrystallization from AcOH (10 mL) followed by washing with Et2O to give 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]quinolin-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 h, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was treated with water (200 mL), and the precipitate formed was filtered and dried by lyophilization to give 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 and heated under reflux for 2 h, concentrated under reduced pressure to ⅔ of the original volume, and acidified to pH = 1-2. The formed precipitate was filtered, washed with water, and dried by lyophilization to give 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 h 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 h, and then the solution of imidazolide was added. The resulting mixture was stirred and heated under reflux overnight, cooled, and treated with 10% aqueous HCl to dissolve the precipitate that formed. 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 EtOAc (10:1) to give 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 h and then concentrated under reduced pressure to give 17.25 g (99%) of ethyl (2Z)-2-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-3-(dimethylamino)prop-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)prop-2-enoate (P10-4) (16.13 g, 58 mmol), and p-anisidine (8.61 g, 70 mmol), and anh. EtOH (100 mL) was stirred and heated under reflux overnight, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and EtOAc (10:1) to give 14.8 g (72%) of ethyl (2Z)-2-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-3-[(4-methoxyphenyl)amino]prop-2-enoate (P10-5) as a mixture of Z- 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 stirred Ph2O (50 mL) at 200 °C. The resulting solution was stirred at 200-230 °C for 30 min, cooled to ambient temperature, and poured into hexane (200 mL). The resulting mixture was stirred for 30 min. The formed precipitate was filtered and washed with hexane to give 2.50 g (40%) of 3-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-6-methoxyquinolin-4(1H)-one (P10-6).

[0267] A mixture of 3-{[4-(benzyloxy)-3-methoxyphenyl]carbonyl}-6-methoxyquinolin-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 h and cooled to ambient temperature. The precipitate formed was filtered and purified by recrystallization from AcOH followed by washing with Et2O to give 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), EtOAc (20 mL), DMF (4 mL), and Ni / Re (300 mg) was hydrogenated at ambient temperature and 20 atm for 16 h, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from acetone to give 0.51 g (62%) of 4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-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]quinolin-3-yl]-2-methoxyphenol (P27) [ka] The compound was synthesized according to the procedure described in Preparation 15, substituting 3-hydroxy-4-methoxybenzoic acid for 4-hydroxy-3-methoxybenzoic acid. The product was analyzed by LCMS.

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

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

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

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

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

[0275] The compound was 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 product was analyzed by LCMS.

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

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

[0278] Preparation 24: 4-[1-(2,4-dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenol (P35) [ka] The compound was synthesized according to the procedure described in Preparation 15, substituting p-toluidine for p-anisidine and 2,4-dimethylphenylhydrazine for 3,4-dimethylphenylhydrazine. The product was analyzed by LCMS.

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

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

[0281] Preparation 27: 4-[1-(3-chloro-2-methylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenol (P38) [ka] The compound was synthesized according to the procedure described in Preparation 15, substituting p-toluidine for p-anisidine and 3-chloro-2-methylphenylhydrazine for 3,4-dimethylphenylhydrazine. The product was analyzed by LCMS.

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

[0283] Preparation 29: 3-(1,3-benzodioxol-5-ylcarbonyl)quinolin-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 to reflux for 8 h and concentrated under reduced pressure to give 12.32 g, (97%) of ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(dimethylamino)prop-2-enoate (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)prop-2-enoate (P11-2) (10.0 g, 34.3 mmol), aniline (3.50 g, 37.8 mmol), and anh.EtOH (100 mL) was stirred and heated under reflux overnight, then concentrated under reduced pressure. The residue was subjected to silica CC and eluted with a mixture of hexane and EtOAc (10:1) to give 8.15 g (70%) of ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(phenylamino)prop-2-enoate (P11-3) as a mixture of Z- 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 stirred Ph2O (50 mL) at 200 °C. The resulting solution was stirred at 200-230 °C for 30 min, cooled to ambient temperature, and poured into hexane (100 mL). The resulting mixture was stirred for 30 min. The formed precipitate was filtered and washed with hexane to give 1.64 g (38%) of 3-(1,3-benzodioxol-5-ylcarbonyl)quinolin-4(1H)-one (P11).

[0287] Preparation 30: 3-(1,3-benzodioxol-5-ylcarbonyl)-6-methoxyquinolin-4(1H)-one (P12) [ka] The compound was synthesized according to the procedure described in Preparation 29, substituting 4-methoxyaniline for aniline. The product was analyzed by LCMS.

[0288] Preparation 31: 4-Chloroquinoline-3-carbaldehyde (P13) [ka] The Vilsmeier reagent was prepared by first adding POCl3 (23 mL, 246 mmol) dropwise to stirred DMF (50 mL) in an inert atmosphere, maintaining the temperature at -5 to 0 °C, followed by stirring the mixture at ambient temperature for 30 min. 1-(2-aminophenyl)ethanone (5.0 mL, 41 mmol) was then added dropwise to the stirred mixture within 30 min. The reaction mixture was stirred and heated at 60 °C for 16 h, 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 portionwise addition of NaHCO3. The precipitate was filtered, dissolved in CHCl, washed with water, dried over NaSO, filtered, concentrated under reduced pressure, and the residue was purified by recrystallization with a mixture of EtOAc and heptane (1:2) to give 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 according to the procedure described in Preparation 31, using 1-(2-amino-5-methoxyphenyl)ethanone instead of 1-(2-aminophenyl)ethanone. 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 according to the procedure described in Preparation 31, using 1-(2-amino-3-methoxyphenyl)ethanone instead of 1-(2-aminophenyl)ethanone. 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 and heated at 120 °C for 15 h, cooled to ambient temperature, and poured into stirred cold water (250 mL). The precipitate that formed was filtered, washed with water, ethanol, and dried at 60 °C to give 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) was added I2 (10.15 g, 40 mmol). The mixture was stirred at 55 °C for 18 h and poured into ice-cold water (300 mL). The formed precipitate was filtered, washed with water and dried at 60 °C to give 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 according to the procedure described in Preparation 38, using 8-methoxy-1H-pyrazolo[4,3-c]quinoline (P18) instead of 1H-pyrazolo[4,3-c]quinoline. 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 according to the procedure described in Preparation 38, using 6-methoxy-1H-pyrazolo[4,3-c]quinoline (P19) instead of 1H-pyrazolo[4,3-c]quinoline. 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) and Na2CO3 (5.72 g, 54 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), dioxane (150 mL), and water (30 mL) was degassed and stirred at 100 °C under Ar for 15 h, cooled, diluted with water (450 mL), and extracted with i-PrOAc (3 x 150 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was treated with MTBE, filtered and dried at 60° C. to give 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 according to the procedure described in Preparation 41, using 3-iodo-8-methoxy-1H-pyrazolo[4,3-c]quinoline (P21) instead of 3-iodo-1H-pyrazolo[4,3-c]quinoline. 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 according to the procedure described in Preparation 41, using 3-iodo-6-methoxy-1H-pyrazolo[4,3-c]quinoline (P22) instead of 3-iodo-1H-pyrazolo[4,3-c]quinoline. 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-morpholin-4-ylethyl)-2H-pyrazolo[4,3-c]quinoline (1.40) and 3-(3,4-dimethoxyphenyl)-8-methoxy-2-(2-morpholin-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), CsCO (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 h, diluted with EtOAc, washed with water, brine, and concentrated under reduced pressure. The residue was subjected to HPLC purification to give 17 mg (6%) of 3-(3,4-dimethoxyphenyl)-8-methoxy-2-(2-morpholin-4-ylethyl)-2H-pyrazolo[4,3-c]quinoline (P26, 1.40) and 50 mg (19%) of 3-(3,4-dimethoxyphenyl)-8-methoxy-2-(2-morpholin-4-ylethyl)-2H-pyrazolo[4,3-c]quinoline (P26A). Structure 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-morpholin-4-ylphenyl)-1H-pyrazolo[4,3-c]quinoline (1.2). [ka] The compound was synthesized following the procedure described in Example 2, using morpholine instead of 4-dimethylamino-piperidine. 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-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.3). [ka] The compound was synthesized according to the procedure described in Example 2, using N-methylpiperazine instead of 4-dimethylamino-piperidine. 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]quinolin-1-yl]phenyl}-N,N-dimethylpiperidin-4-amine (1.4). [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. 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-methylpiperazin-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]quinolin-1-yl]-4-methylphenyl}-N,N-dimethylpiperidin-4-amine (1.7) [ka] The compound was synthesized following the procedure described in Example 2, substituting P3 for 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-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.8) [ka] The compound was synthesized following 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]quinolin-1-yl]-4-methylphenyl}-N,N-dimethylpiperidin-4-amine (1.10). [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 in 53% yield. 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-methylpiperazin-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]quinolin-1-yl]phenyl}-N,N-dimethylpiperidin-4-amine (1.13) [ka] The compound was synthesized according to the procedure described in Example 2, 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.

[0312] Example 12: 1-{3-[1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine (1.14). [ka] The compound was synthesized according to the procedure described in Example 2, 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. 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-morpholin-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-methylpiperazin-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]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine (1.17) [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. 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]quinolin-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-morpholin-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-methylpiperazin-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-morpholin-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 following the procedure described in Example 2, using piperazine instead of 4-dimethylamino-piperidine.

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

[0322] Example 22: 1-(3,4-dimethylphenyl)-8-methoxy-3-(4-pyridin-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), pyridin-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 and heated at 100 °C in a sealed tube for 12 h, cooled, diluted with EtOAc, and filtered through a Celite pad. The filtrate was washed with a saturated aqueous solution of NaHCO3, water, brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was subjected to silica CC eluting with a mixture of DCM and EtOAc (9:1) to give 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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxylic acid instead of 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylic acid and methylamine hydrochloride instead of ethylamine hydrochloride.

[0324] Example 24: 1-(3,4-dimethylphenyl)-3-(4-piperazin-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. 40% yield of tert-butyl 4-{4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine-1-carboxylate (1.22.1).

[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 h, diluted with DCM (5 mL), washed with 10% aqueous NaHCO3, water, dried under Na2SO4, and concentrated under reduced pressure. The residue was subjected to HPLC purification, and the resulting TFA salt was converted to the HCl salt by treating its solution in DCM with an excess of 3 M HCl in dioxane, followed by dilution with Et2O. The formed precipitate was separated by centrifugation, washed twice with Et2O, and dried to give 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]quinolin-3-yl]-2-methoxyphenoxy}-N,N-dimethylethanamine (1.24) [ka] A mixture of 4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-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 h, cooled to ambient temperature, and diluted with water (10 mL). The precipitate formed was filtered, washed with water, Et2O, and dried in air at 50 °C to give 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-morpholin-4-ylethoxy)phenyl]-1H-pyrazolo[4,3-c]quinoline (1.25) [ka] The compound was synthesized according to the procedure described in Example 25, using 4-(2-chloroethyl)morpholine hydrochloride instead of (2-chloroethyl)dimethylamine. 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-morpholin-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-(morpholin-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]quinolin-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-(morpholin-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]quinolin-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)quinolin-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 h and cooled to ambient temperature. The precipitate that formed was filtered and purified by recrystallization from AcOH (10 mL) followed by washing with Et2O to give 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 according to the procedure described in Example 30, substituting phenylhydrazine hydrochloride for 1.27.1. 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 according to the procedure described in Example 30, using 3-(1,3-benzodioxol-5-ylcarbonyl)-6-methoxyquinolin-4(1H)-one (P12) instead of P11. 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-methoxyquinolin-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-tetrahydroisoquinolin-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), KCO (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 at 145 °C under Ar for 72 h, cooled to ambient temperature, diluted with CHCl, washed with 1% aqueous NaEDTA, and concentrated under reduced pressure. The whole grain was subjected to HPLC to give 87 mg (33%) of tert-butyl 7-(3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-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 dioxane (2 mL) was added a solution of 3N HCl in dioxane (2 mL) and the mixture was stirred at ambient temperature for 4 h. The precipitate formed was filtered, washed with ether and dried under reduced pressure at 50° C. to give 40 mg (78%) of the title compound 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-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-tetrahydroisoquinolin-6-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.32) [ka] The compound was synthesized according to the procedure described in Example 34, using tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate instead of 1.31.1. 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-isoindol-5-yl)-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.33) [ka] The compound was synthesized according to the procedure described in Example 34, using tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate instead of 1.31.1. 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-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.34) [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. 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-tetrahydroisoquinolin-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-isoindol-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-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline dihydrochloride (1.37) [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. 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-tetrahydroisoquinolin-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-isoindol-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 potency of HPK1 enzyme activity inhibition. Compound activity was measured using recombinant HPK1 protein and MBP substrate (both Promega, catalog number V6398) in an in vitro enzyme reaction. The enzyme assay used to measure activity was a luminescence assay using Microplate Reader ClarioStar Plus. Enzyme reaction was carried out in assay buffer (40mM TRIS-HCl pH 7.4-7.6, 20mM MgCl2, 0.05mM DTT, 0.1mg / ml BSA). Compounds were dispensed onto 384-well diamond well plates (Axigen, catalog number P-384-120SQ-CS) in 100x solution of compound in DMSO using Biomek FX liquid handling system. A 2x HPK1-MBP mixture (final concentration 0.64ng / μl HPK1 and 45ng / μl MBP) was prepared in 1x assay buffer and 5.5μl of the mixture per well was added to a 384w white reaction plate with NBS (Corning, Cat. No. 4513). 5.5μl of MBP substrate without HPK1 in 1x buffer was used as a negative control. The plate was centrifuged at 100g for 1 min. In the next step, compounds were added to the reaction plate using a Biomek station according to the following steps: 1μl of 100x compound (in DMSO) was thoroughly mixed with 49μl of 2x 10uM ATP in assay buffer, then 5.5μl of this mixture was added to the reaction plate along with 5.5μl of the HPK1-MBP mixture. The plate was centrifuged at 100g for 1 min and incubated at room temperature for 1 h. Next, 3 μL of ADP-Glo ​​Reagent (Promega, ADP-Glo™ Kinase Assay, Catalog No. V9102) was added per well. The plate was incubated at room temperature for 30 minutes. Next, 6 μL of Kinase Detection Reagent (Promega, ADP-Glo™ Kinase Assay, Catalog No. V9102) was added per well and luminescence was measured using a microplate reader. The % inhibition was then used to calculate IC 50 The IC values ​​were calculated. 50The values ​​are shown in Table A, where "A" corresponds to Ki<10.0 nM, "B" corresponds to 10.0 nM≦Ki<20.0 nM, "C" corresponds to 20.0 nM≦Ki<50.0 nM, and "D" corresponds to 50.0 nM≦Ki.

[0346] JPEG2024539633000149.jpg89108

[0347] Example B. MV4-11 Cytotoxicity Assay. CC50 was measured using the MV4-11 cell line in RPMI-1640 medium (PanEco Catalog No. C363). Compounds were prepared as 200x stocks with serial dilutions in 100% DMSO and a final concentration of 1x. 40μL was distributed in 384-well plates at a concentration of 4000 cells per well using the robot station Biomek (Beckman). Before adding the compounds, the cells were incubated at 37°C. Dilution plates were prepared by pouring 78μL of the appropriate medium using the robot station Biomek (Beckman). Then, 2μL of the substance was taken using the robot station and added to 78μL of medium (40x dilution of the compound). 10μl was removed from it and added to the cells of the plate (5x dilution of the compound). The plates were incubated at a temperature of 37°C for 3 days. After 3 days, 10 μL of CellTiter-Glo (Promega) was added to the cells and luminescence was measured. 50 The values ​​are given in Table B, where "A" is CC 50 <50.0nM, and "B" corresponds to 50.0nM ≤ CC 50 <100.0nM, and "C" corresponds to 100.0nM ≤ CC 50 <500.0nM, and "D" corresponds to 500.0nM ≤ CC 50 Corresponds to.

[0348] JPEG2024539633000150.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 given in Table C, where "A" is CC 50 <500.0nM, and "B" corresponds to 500.0nM ≤ CC 50 <1000.0nM, and "C" corresponds to 1000.0nM≦CC 50 <5000.0nM, and "D" corresponds to 5000.0nM≦CC 50 Corresponds to.

[0350] JPEG2024539633000151.jpg66112

[0351] Example D. FLT3 Inhibitory Activity and Cytotoxicity. This assay was used to determine the potency of FLT3 enzymatic activity inhibition. The corresponding biochemical inhibition of FLT3(wt), FLT3(D835Y), and FLT3(ITD) enzymatic activity was measured using recombinant protein constructs of the kinase domain via an activity-based FLT3 kinase assay for compound screening and profiling by radiometric HotSpot™ kinase assay (Reaction Biology). Peptide substrate [EAIYAAPFAKKK]. Compounds were dissolved in DMSO to 10 mM. Compounds were tested in IC50 mode at 10 doses with 3-fold serial dilutions starting from 0.3 μM. The control compound staurosporine was tested in IC50 mode at 10 doses with 4-fold serial dilutions starting from 20 μM. Alternative control compounds were tested in IC50 mode at 10 doses with 3-fold serial dilutions starting from 20 μM. Reactions were run with 1 μM ATP. Estimated Ki values ​​were calculated using the following formula applicable to ATP-competitive inhibitors: Ki = IC50 / (1 + [S] / Km). IC 50The values ​​are shown in Table D, where "A" corresponds to Ki<0.5nM, "B" corresponds to 0.5nM≦Ki<2.0nM, "C" corresponds to 2.0nM≦Ki<5.0nM, and "D" corresponds to 5.0nM≦Ki. Table E shows the cytotoxicity in HEK293.

[0352] JPEG2024539633000152.jpg65160

[0353] JPEG2024539633000153.jpg69158 equivalent

[0354] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the claims.

Claims

1. A compound of formula (I): 【Chemical Formula 1】 or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [Wherein, R ａ is 【Chemical Formula 2】 selected from; each R １ is independently selected from the group consisting of C １－６ alkyl, -NH ２ , -NH(C １－６ alkyl), and -N(C １－６ alkyl) ２ ; R ２ is 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 【Chemical Formula 3】 selected from, R ２ is optionally substituted with 1-6 groups R ８ ; R ３ is 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 ) ｍO−, heterocyclyl, heterocyclyl(CH ２ ), ｍ O−, heteroaryl, -W-X-R １ and 【Chemical Formula 4】 selected from, and R ３ is optionally substituted with 1-6 groups R ８ ; or R ２ and R ３ together with the atoms to which they are attached and any intervening atoms form the group -K-X-M-; Each R ４ , R ５ , R ６ or R ７ is independently selected from the group consisting of H, halogen, -CN, C １－４ alkyl, -OH, -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 ; R ８ is selected from C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; Each R ９ is independently selected from the group consisting of H, halogen, C １－６ alkyl, -OH, -OC １－６ alkyl, or the group 【Chemical Formula 5】 ; R １０ is H, halogen, -C １－６ alkyl, -OH, or -OC １－６ alkyl; Or R ９ and R １０ Any one of them, together with the atoms to which they are attached and any intervening atoms, forms the group -X-N(R １２ ). R １１ is selected from H, halogen, -C １－６ alkyl, -OH, and -OC １－６ alkyl; R １２ is H or C １－６ alkyl; X, each occurrence, is independently selected from -CH ２ -, -(CH ２ ) ２ -, and -(CH ２ ) ３ -; Y, each occurrence, is independently selected from -CH ２ -, -(CH ２ ) ２ -, and -(CH ２ ) ３ -; A is independently, each occurrence, CH or N; B is, each occurrence, independently selected from CH, CH ２ , N, NH and O; L is, each occurrence, independently selected from a single bond, -(CH ２ ) ｍ -, -O(CH ２ ) ｍ -, and -NH(CH ２ ) ｍ -; W is selected from O, S, NH, and N(C １－６ alkyl); Each of K and M is independently selected from O, S, SO, SO ２ , CO, NH, and NR ８ ; m is independently, each occurrence, an integer selected from 1, 2, 3, 4, 5, and 6; n is, each occurrence, selected from 0 and 1; o is, each occurrence, independently selected from 1, 2, and 3; Here, aryl is a cyclic aromatic hydrocarbon group in which 1 to 3 aromatic rings are fused or singly bonded to each other; 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, and the remaining ring atoms being C; heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms independently selected from O, N, S, P, Se, or B; provided that the compound contains at least one of the group selected from: R ２ or R ３ is (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 [Chemical Formula 6] is; or R ２ and R ３ together with the atoms to which they are attached and any intervening atoms form the group -K-X-M-; or R ３ is [Chemical Formula 7] is; or R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form the group -X-N(R １２ )-Y-; or R ９ is [Chemical Formula 8] is. ] Claim 2 wherein the compound is of formula I-A: 【Chemical Formula 9】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [wherein, X is selected from -CH ２ -, -(CH ２ ) ２ -, and -(CH ２ ) ３ -; Y is selected from -CH ２ -, -(CH ２ ) ２ -, and -(CH ２ ) ３ -; R ２ is 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 【Chemical Formula 10】 selected from, and R ２ is optionally substituted with 1 to 6 groups R ８ ; R ３ is 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 a group 【Chemical Formula 11】 selected from, each R ３ is optionally substituted with 1-6 groups R ８ ; or R ２ and R ３ together with the atoms to which they are attached and any intervening atoms form the group -K-X-M-; R ４ , R ５ , R ６ and R ７ each independently is selected from the group consisting of 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 ; R ８ is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; R １２ is H or C １－６ alkyl; K and M each independently are selected from O, S, SO, SO ２ , CO, NH, and NR ８ ; A is CH or N; B is CH, CH ２ , N, NH or O; W is O, S, NH, or N(C １－６ alkyl); L is a single bond or -OCH ２ CH ２ -; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is 0 or 1. ]

3. The compound is of formula I-B: 【Chemical Formula 12】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [Wherein, A is CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ -, -(CH ２ ) ２ - or (CH ２ ) ３ -; Y is -CH ２ -, -(CH ２ ) ２ - or -(CH ２ ) ３ -; R １ is C １－６ alkyl, -NH ２ , -NH(C １－６ alkyl), and -N(C １－６ alkyl) ２ selected from; R ２ is 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 ) ｍO−, heterocyclyl, heterocyclyl(CH ２ ), ｍ O−, heteroaryl, -W-X-R １ and 【Chemical Formula 13】 selected from, each R ２ is optionally substituted with 1-6 groups R ８ ; R ３ is 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 【Chemical Formula 14】 selected from, each R ３ is optionally substituted with 1-6 groups R ８ ; or R ２ and R ３ together with the atoms to which they are attached and any intervening atoms form the group -K-X-M-; R ４ R ５ R ６ and R ７ each 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 ２N(R ８ ) ２ independently selected from the group consisting of; R ８ is selected from C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; R １１ is selected from H, halogen, OH, -C １－６ alkyl, and -OC １－６ alkyl; K and M are each independently selected from O, S, SO, SO ２ , CO, NH, and NR ８ ; W is O, S, NH, or N(C １－６ alkyl); L is a single bond or -OCH ２ CH ２ -; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is selected from 0 and 1. ]

4. The compound is of formula I-C: 【Chemical 15】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [Wherein, A is CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ -, -(CH ２ ) ２ - or (CH ２ ) ３ -; 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 ; R ２ is 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 [Chemical Formula 16 selected from, R ２ is optionally substituted with 1-6 groups R ８ ; R ３ is 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 [Chemical Formula 17 selected from, R ３ is optionally substituted with 1-6 groups R ８ ; Or R ２ and R ３together with the atoms to which they are attached and any intervening atoms, form the group -K-X-M-; R ４ , R ５ , R ６ and R ７ each independently is selected from the group consisting of 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 ; R ８ is selected from C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; K and M each independently are selected from O, S, SO, SO ２ , CO, NH, and NR ８ ; W is O, S, NH, or N(C １－６ alkyl); L is a single bond or -OCH ２ CH ２ -; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is selected from 0 and 1; o is selected from 1, 2, and 3. ]

5. The compound is of formula I-D or I-D': 【Chemical 18】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [wherein, A is CH or N; B is CH, CH ２ , N, NH or O; L is a single bond or -OCH ２ CH ２ -; 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 is independently selected from the group consisting of C １－６ alkyl, -NH(C １－６ alkyl), and -N(C １－６ alkyl) ２ ; R ２ and R ３ each are independently selected from 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 [Chemical Formula 19] selected independently from; where R ２ and R ３ are each optionally substituted with 1-6 groups R ８ ; R ４ , R ５ and R ６ and R ７ each is independently selected from the group consisting of 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 ; R ８ is selected from C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; R ９ is selected from H, halogen, -C １－６ alkyl, -OH, and -OC １－６ alkyl; R １０ is selected from H, halogen, OH, -C １－６ alkyl, and -OC １－６ alkyl; Alternatively, either R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form the group -X-N(R １２ ); R １１ is selected from H, halogen, OH, -C １－６ alkyl, and -OC １－６ alkyl; R １２ is H or C １－６ alkyl; W is O, S, NH, or N(C １－６ alkyl); m is an integer selected from 1, 2, 3, 4, 5, and 6; n is 0 or 1.

6. The compound is of formula I-E or I-E': 【Chemical Formula 20】 【Chemical Formula 21】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [Wherein, R １ is selected from C １－６ alkyl, -NH ２ , -NH(C １－６ alkyl), and -N(C １－６ alkyl) ２ ; R ２ and R ３ each independently is selected from the group consisting of H, halogen, -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-, and heteroaryl; Here, R ２ and R ３ are each optionally substituted with 1-6 groups R ８ ; W is O, S, NH, or N(C １－６ alkyl); R ４ , R ５ , R ６ and R ７ each independently is H, halogen, -CN, C １－４ alkyl, -OH, -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 is C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; Each R ９ is H, halogen, C １－６ alkyl, -OH, -OC １－６ alkyl, and [Chemical formula 22] independently selected from the group consisting of; R １０ is H, halogen, -OH, -C １－６ alkyl, and -OC １－６ alkyl; Or R ９ and R １０ Any one of forms, together with the atoms to which they are attached and any intervening atoms, the group -X-N(R １２ )-Y-; R １１ is H, halogen, OH, -C １－６ alkyl, or -OC １－６ alkyl; R １２ is H or C １－６ alkyl; A is CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ - or -(CH ２ ) ２ - or (CH ２ ) ３ -; Y is -CH ２ - or -(CH ２ ) ２ - or -(CH ２ ) ３ - is; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is 0 or 1. ]

7. The compound is of formula I-F: 【Chemical formula 23】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [Wherein, Each of K and M is independently selected from O, S, SO, SO ２ , CO, NH, and NR ８ ; R ４ , R ５ , R ６ and R ７ are each independently selected from the group consisting of 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 ; R ８ is selected from C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; Each R ９ is H, halogen, C １－６ alkyl, -OH, -OC １－６ alkyl, and 【Chemical formula 24】 independently selected from the group consisting of; R １０ is selected from H, halogen, -OH, -C １－６ alkyl, and -OC １－６ alkyl independently; or R ９ and R １０ any one of which, together with the atoms to which they are attached and any intervening atoms, forms the group -X-N(R １２ ); R １１ is selected from H, halogen, OH, -C １－６ alkyl, and -OC １－６ alkyl; R １２ is H or C １－６ alkyl; A is CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ - or -(CH ２ ) ２ - or (CH ２ ) ３ -; Y is -CH ２ - or -(CH ２ ) ２ - or -(CH ２ ) ３ -; m is an integer selected from 1, 2, 3, 4, 5, and 6; n is 0 or 1. ]

8. The compound is of formula I-G: 【Chemical Formula 25】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [Wherein, Het is heterocyclyl or heteroaryl; Here, Het is optionally substituted with 1 - 6 groups R ８ ; R ４ R ５ R ６ and R ７ each independently is selected from the group consisting of 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 ; R ８ is selected from C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C ３－８ cycloalkyl; Each R ９ is independently selected from the group consisting of H, halogen, C １－６ alkyl, -OH, -OC １－６ alkyl, and [Chemical Formula 26] ; R １ is selected from C １－６ alkyl, -NH ２ -NH(C １－６ alkyl), and -N(C １－６ alkyl) ２ ; R １０ is selected from H, halogen, OH, -C １－６ alkyl, and -OC １－６ alkyl; Alternatively, either one of R ９ and R １０ together with the atoms to which they are attached and any intervening atoms forms a group -X-N(R １２Form -Y-; R １１ is selected from H, halogen, OH, -C １－６ alkyl, and -OC １－６ alkyl; R １２ is H or C １－６ alkyl; A is CH or N; B is CH, CH ２ , N, NH or O; X is -CH ２ - or -(CH ２ ) ２ - or (CH ２ ) ３ -; Y is -CH ２ - or -(CH ２ ) ２ - or -(CH ２ ) ３ -; n is 0 or 1. ]

9. A compound selected from the following: 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 4-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-4-methylpiperazine; 1-{3-[8-Methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[8-Methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[3-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-4-methylphenyl}-4-methylpiperazine; 1-{3-[3-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[1-(2,3-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 4-{4-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; N-[3-(Dimethylamino)propyl]-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-N-methylaniline; 4-{4-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}pyridine; 4-{4-[1-(3,4-Dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{4-[1-(3,4-Dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-Dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine; 4-(4-{1-Phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; (2-{4-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)dimethylamine; 4-(2-{4-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(3-{4-[1-(3,4-Dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-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]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-Dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-Dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-Dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-Dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-Dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-Dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-Dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinolin-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]quinolin-3-yl}phenoxy)ethyl]morpholine; [2-(2-Methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-Methoxy-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]morpholine; 4-[2-(2-Methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]morpholine; [2-(2-Methoxy-5-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]dimethylamine; 4-[2-(2-Methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]morpholine; [2-(2-Methoxy-5-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenoxy)ethyl]dimethylamine; 4-(2-{4-[1-(3,4-Dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,4-Dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,3-Dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(2,5-Dimethylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3-Chloro-2-methylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-{4-[1-(3,4-Dimethylphenyl)-8-(trifluoromethoxy)-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenoxy}ethyl)morpholine; 4-(2-Chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; 1-(2-Chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)piperazine; 1-(2-Chloro-4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)-4-methylpiperazine; 4-(2-Chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; 1-(2-Chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)piperazine; 1-(2-Chloro-4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)-4-methylpiperazine; 4-{2-Chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{2-Chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine; 1-{2-Chloro-4-[1-(3,4-dimethylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 4-{2-Chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}morpholine; 1-{2-Chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}piperazine; 1-{2-Chloro-4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 4-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)morpholine; 1-(4-{8-methoxy-1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)-4-methylpiperazine; 1-(4-{1-phenyl-1H-pyrazolo[4,3-c]quinolin-3-yl}phenyl)piperazine; 1-{3-[3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]phenyl}-4-methylpiperazine; or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

10. The compound according to claim 1, selected from the group consisting of: 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 1-{3-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{3-[1-(2,3-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-4-methylpiperazine; 1-{4-[1-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-3-yl]phenyl}-N,N-dimethylpiperidin-4-amine; 7-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl]-2,3-dihydro-1H-isoindole; 7-[3-(3,4-dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 6-[3-(3,4-Dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-1,2,3,4-tetrahydroisoquinoline; 5-[3-(3,4-Dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinolin-1-yl]-2,3-dihydro-1H-isoindole or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

11. A compound selected from the group consisting of the following, which is useful for the preparation of Compound I: 3-(1,3-Benzodioxole-5-carbonyl)-6-methoxy-1H-quinolin-4-one; 4-Chloro-6-(trifluoromethoxy)quinoline-3-carbaldehyde; 8-Methoxy-1H-pyrazolo[4,3-c]quinoline; 6-Methoxy-1H-pyrazolo[4,3-c]quinoline; 3-Iodo-1H-pyrazolo[4,3-c]quinoline; 3-Iodo-8-methoxy-1H-pyrazolo[4,3-c]quinoline; 3-Iodo-6-methoxy-1H-pyrazolo[4,3-c]quinoline; 3-(3,4-Dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinoline; 3-(3,4-Dimethoxyphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline; 3-(3,4-Dimethoxyphenyl)-6-methoxy-1H-pyrazolo[4,3-c]quinoline; 1-(5-Chloro-2-methylphenyl)-8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline; 1-(5-Chloro-2-methylphenyl)-3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline; 4-[1-(3-Chloro-2-methylphenyl)-8-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxyphenol; 1-(3-Bromophenyl)-3-(3,4-dimethylphenyl)-8-methoxy-1H-pyrazolo[4,3-c]quinoline; 1-(3-Bromophenyl)-8-methoxy-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-c]quinoline; 3-(3-Bromophenyl)-1-(2,3-dimethylphenyl)-8-methoxy-pyrazolo[4,3-c]quinoline; 3-(4-Bromo-3-chloro-phenyl)-1-phenyl-pyrazolo[4,3-c]quinoline; 3-(4-Bromo-3-chloro-phenyl)-8-methoxy-1-phenyl-pyrazolo[4,3-c]quinoline; 3-(4-Bromo-3-chloro-phenyl)-1-(3,4-dimethylphenyl)pyrazolo[4,3-c]quinoline; 3-(4-Bromo-3-chloro-phenyl)-1-(3,4-dimethylphenyl)-8-methoxy-pyrazolo[4,3-c]quinoline; 4-[1-(3,4-Dimethylphenyl)-8-methoxy-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 4-[1-(3,4-Dimethylphenyl)pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 2-Methoxy-4-(1-phenylpyrazolo[4,3-c]quinolin-3-yl)phenol; 2-Methoxy-4-(8-methoxy-1-phenyl-pyrazolo[4,3-c]quinolin-3-yl)phenol; 4-[1-(3,4-Dimethylphenyl)-8-methyl-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 4-[1-(2,4-Dimethylphenyl)-8-methyl-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 4-[1-(2,3-Dimethylphenyl)-8-methyl-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 4-[1-(2,5-Dimethylphenyl)-8-methyl-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 4-[1-(3,4-Dimethylphenyl)-8-(trifluoromethoxy)pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 5-[1-(3,4-Dimethylphenyl)-8-methoxy-pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 5-[1-(3,4-Dimethylphenyl)pyrazolo[4,3-c]quinolin-3-yl]-2-methoxy-phenol; 2-Methoxy-5-(1-phenylpyrazolo[4,3-c]quinolin-3-yl)phenol; 2-Methoxy-5-(8-methoxy-1-phenyl-pyrazolo[4,3-c]quinolin-3-yl)phenol. Claim 12 A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier. Claim 13 The pharmaceutical composition according to claim 12, further comprising an additional pharmaceutically active agent. Claim 14 Use of the compound according to any one of claims 1 to 10 in the preparation of a medicament for treating a disease, disorder or condition associated with the inhibition of hematopoietic progenitor kinase 1 (HPK1). Claim 15 Use of the compound according to any one of claims 1 to 10 in the preparation of a medicament for treating a disease, disorder or condition associated with the inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene. Claim 16 Use of the compound according to any one of claims 1 to 10 in the preparation of a medicament for treating a disease, disorder or condition associated with the inhibition of hematopoietic progenitor kinase 1 (HPK1) and a disorder or condition associated with the inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene. Claim 17 Use of the compound according to any one of claims 1 to 10 in the preparation of a medicament for inhibiting hematopoietic progenitor kinase 1 (HPK1), wherein the compound is administered to a subject in need of treatment for cancer. Use of a compound according to any one of claims 1 to 10 in the preparation of a medicament for treating a disease, disorder or symptom associated with inhibition of hematopoietic progenitor kinase 1 (HPK1), wherein said compound is administered to a subject in need of treatment. Use of a compound according to any one of claims 1 to 10 in the preparation of a medicament for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene, wherein said compound is administered to a subject in need of cancer treatment. Use of a compound according to any one of claims 1 to 10 in the preparation of a medicament for treating a disease, disorder or symptom associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene, wherein said compound is administered to a subject in need of treatment.

21. The use according to claim 18, wherein the disease, disorder or symptom is selected from cancer, proliferative diseases or viral infections.

22. The use according to claim 21, wherein the disease, disorder or symptom is 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, spinal and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymic carcinoma, thymoma, 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).

23. The use according to claim 21, wherein the disease, disorder, or symptom is a viral infectious disease 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-related hantavirus, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and coronavirus.

24. The use according to claim 23, wherein the viral infectious disease is an infectious disease caused by hepatitis B virus (HBV).

25. The use according to claim 23, wherein the viral infectious disease is an infectious disease caused by human immunodeficiency virus (HIV).

26. The use according to claim 20, wherein the disease, disorder, or symptom is selected from cancer and hyperproliferative diseases.

27. The use according to claim 26, wherein the disease, disorder, or symptom is cancer selected from leukemia.

28. The use according to claim 27, wherein the disease, disorder, or symptom is cancer selected from chronic myelogenous leukemia (CML) or refractory acute myelogenous leukemia (AML).

29. The use according to claim 17, wherein the subject is a mammal.

30. The use according to claim 29, wherein the subject is a human.

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