Inhibitors of kinase networks and their uses

Abstract

Compounds are provided as dual kinase-demethylase inhibitors useful in the treatment of diseases mediated by kinases and / or histone demethylases, such as inflammation, cancer, viral and bacterial infections, neurological and immune disorders. The present invention relates to a compound of formula (IV). JPEG2022081529000373.jpg6381

Description

[Technical Field]

[0001] Cross-reference of related applications This U.S. Patent Application asserts the priority rights of U.S. Provisional Patent Application No. 62 / 478,069, filed on 29 March 2017, and U.S. Provisional Patent Application No. 62 / 616,643, filed on 12 January 2018, the latter of which are incorporated herein by reference in their entirety.

[0002] The present invention generally relates to compounds as kinase inhibitors, and to methods for treating kinase-mediated diseases such as inflammation, cancer, viral and bacterial infections, neurological disorders, and immune disorders. [Background technology]

[0003] This section describes aspects that may help facilitate a better understanding of the disclosure. Therefore, these descriptions should be read in this context and should not be understood as an acknowledgment of prior art.

[0004] Cells contain more than 500 types of kinases that control a variety of processes, including the cell cycle, growth, migration, and immune response. 1 Some deregulated kinases, i.e., kinases that have achieved gain-of-function mutations or are overexpressed, promote cancer growth. 1 Small molecule inhibitors of cancer driver kinases (e.g., BCR-ABL1 fusion protein, FLT3-ITD, mutated or overexpressed ALK, EGFR, PDGFR, Kit, VEGFR, B-Raf, BTK, PI3Kδ, ErbB2) have shown clinical success. 2 Recently, efforts have been made to inhibit cancer growth by targeting cell cycle kinases (CDKs), or other kinases such as histones, the cytoskeleton, or other processes important to cells. Most kinase inhibitors that reach clinical practice initially work, but over time, drug-resistant clones emerge that render the drug ineffective. 3。Various mechanisms account for cancer cell resistance to kinase inhibitors. For example, increased copy number, additional kinase mutations (such as secondary mutations occurring in the tyrosine kinase domain of the FLT3-ITD kinase), or activation of alternative kinase pathways and / or downstream targets can circumvent inhibition of specific kinase targets. 4 。Kinase inhibitors that inhibit cancer driver kinases and downstream targets (both kinase and non-kinase targets such as histone demethylases) and / or kinases that cooperate with driver kinases may have enhanced efficacy and a low probability of developing resistance to kinase inhibitors. 5 。However, the challenge with such polypharmacophores is to avoid promiscuous binding that can lead to toxicity.

[0005] Kinase inhibitors have also been shown to be effective in the treatment of immune disorders (such as JAK kinases 6 ), hypertension and erectile dysfunction (such as ROCK1 / 2 kinases 7 ), and glaucoma (such as ROCK and LIMK kinases 8 ). Other kinase targets such as LRRK2 have also been shown to be important for CNS-related diseases such as Alzheimer's disease or Parkinson's disease. 9 。Privileged chemical scaffolds that can be tuned to selectively inhibit disease-related kinases or inhibit a group of kinases present in a particular pathway or network can facilitate the treatment of diverse disease states.

Summary of the Invention

[0006] The present invention generally relates to compounds that inhibit kinase and / or histone demethylase networks as compounds useful for the treatment of kinase-mediated diseases such as inflammation, cancer, viral and bacterial infections, neuropathies, and immune disorders. Pharmaceutical compositions and methods for treating these diseases are within the scope of the present invention.

[0007] In some exemplary embodiments, the present invention provides a compound of the formula:

Chemical Formula

[0008] In some exemplary embodiments, the present invention is given by formula: [ka] [In the formula, n = 1 to 5; the bonds between A and B, and between B and D, may be double bonds or single bonds, but cannot be double bonds at the same time; A, B, and D independently represent C, O, N, and S, and at least one of A, B, and D is a heteroatom; R 1 These are amino, hydroxyl, and their derivatives, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, and each of these may be substituted; or R 2 and R 3 Together with the bonded carbon, it forms a cyclic or heterocyclic moiety that may be substituted; R4 This represents two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; Or two substituents, together with the bonded carbon, form a substituted or heterocyclic moiety; and Depending on elements A, B, and D, R 5 [This represents two or three substituents, each independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted.] This relates to compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0009] In some exemplary embodiments, the present invention relates to a compound having formula (II), wherein R 1 but, [ka] Regarding the compound in question.

[0010] In some exemplary embodiments, the present invention relates to formula (III): [ka] [In the formula, n = 1 to 5; the bonds between A and B, and between B and D may be double bonds or single bonds, but cannot be double bonds at the same time; A, B, and D independently represent C, O, N, and S, and at least one of A, B, and D is a heteroatom; R 1 These are amino, hydroxyl, and their derivatives, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; R 4 This represents two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; Alternatively, two substituents, together with the bonded carbon, may form a substituted or heterocyclic moiety; Depending on elements A, B, and D, R 5This represents two or three substituents, each independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; and Depending on nv, R 6 [This represents 2 to 6 substituents, each independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted.] This relates to compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0011] In some exemplary embodiments, the present invention relates to a compound having formula (III), wherein R 1 but, [ka] Regarding the compound in question.

[0012] In some exemplary embodiments, the present invention relates to formula (IV) [ka] [In the formula, n = 1 to 5; R 1 These are amino, hydroxyl, and their derivatives, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, and each of these may be substituted; or R 2 and R 3 Together with the bonded carbon, it forms a cyclic or heterocyclic moiety that may be substituted; R 4 This represents two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; Alternatively, two substituents, together with the bonded carbon, may form a substituted or heterocyclic moiety; Depending on the elements A and B specified below, R 5 This represents one or two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl options, each of which may be substituted; A and B independently underwent CR 8 , N, or NR 9 Represents R 8 and R 9 Each independently represents hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; Depending on nv, R 6 This represents 2 to 6 substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and derivatives thereof, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; and R 7[These are alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted.] This relates to compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0013] In some exemplary embodiments, the present invention relates to a compound having formula (IV), wherein R 1 but, [ka] Regarding the compound in question.

[0014] In some exemplary embodiments, the present invention relates to a compound having formula (IV), wherein R 1 teeth, [ka] A is carbon (C); B is nitrogen (N); R 5 , R 6 , and R 7 All of them represent hydrogen, and R 4 This represents two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; The present invention relates to compounds in which two substituents, together with the bonded carbon, form a cyclic or heterocyclic moiety that may be substituted.

[0015] In some exemplary embodiments, the present invention relates to a compound having formula (IV), wherein R 3 but, [ka] Regarding the compound in question.

[0016] In some exemplary embodiments, the present invention relates to a compound having formula (IV), wherein R 1 but, [ka] and R 3 but, [ka] Regarding the compound in question.

[0017] In some exemplary embodiments, the present invention relates to a compound having formula (I), [ka] Regarding the compound in question.

[0018] In some exemplary embodiments, the present invention relates to pharmaceutical compositions comprising one or more compounds disclosed herein or pharmaceutically acceptable salts thereof, together with one or more diluents, excipients, or carriers.

[0019] In some exemplary embodiments, the present invention relates to kinase inhibitors, wherein the kinases are FLT3, MNK1 / 2, JAK1 / 2 / 3, Limk1 / 2, various CDKs, Haspin, ROCK1 / 2, TOPK, LRRK2, GSK3a / 3b, RSK1-4, ERK, P70S6K, AKT, PI3K, p38, PKC, PKA, FGFR1-4, VEGFR1-3, ALK, AXL, LIMK1 / 2, Aurora The group selected consists of A / B, ABL1, AKT, CSF1R, CSNK1D, DCAMKL1, CSNK1G2, EPHA2, ERBB2, IKKα, IKKβ, JNK1 / 2 / 3, MARK3, MEK1 / 2, MET, MLK1, PAK1 / 2 / 4, PDGFRa / b, PIM1 / 2 / 3, PLK1 / 2 / 3 / 4, PRKCE, PRKX, RET, TAOK2, TRKA / B / C, ULK2, and receptor-interacting protein kinase 4 (RIPK4).

[0020] In some exemplary embodiments, the present invention relates to a method for treating a kinase and / or histone demethylase-mediated disease, including inflammation, cancer, viral and bacterial infections, gastrointestinal disorders, eye diseases, neurological disorders, cardiovascular disorders and immunodeficiencies, comprising the step of administering a therapeutically effective amount of one or more compounds disclosed herein, and one or more carriers, diluents, or excipients, to a patient in need of relief of said cancer.

[0021] In some exemplary embodiments, the present invention relates to a method for treating kinase and histone demethylase-mediated diseases, including inflammation, cancer, viral and bacterial infections, gastrointestinal disorders, eye diseases, neurological disorders, cardiovascular disorders and immunodeficiencies, comprising the step of administering a therapeutically effective amount of a compound disclosed herein, in combination with one or more other compounds having the same or different mechanisms of action, and one or more carriers, diluents, or excipients, to a patient in need of relief of said cancer.

[0022] These and other features, aspects and advantages of the present invention will be better understood by referring to the following detailed description and claims. [Modes for carrying out the invention]

[0023] While the concepts of this disclosure are illustrated and described in detail in this specification, the results of such descriptions should be considered illustrative and not limiting; only exemplary embodiments are shown and described, and it is understood that all changes and modifications within the spirit of this disclosure should be protected.

[0024] This invention relates to compounds as kinase inhibitors useful for treating kinase-mediated diseases such as inflammation, cancer, viral and bacterial infections, neurological disorders, and immune disorders. Pharmaceutical compositions and methods for treating these diseases are within the scope of this invention.

[0025] When used herein, the following terms and phrases shall have the meanings set forth below. Unless otherwise defined, all technical and scientific terms used herein shall have the same meanings as commonly understood by those skilled in the art.

[0026] In this disclosure, the term “about” may allow some variation in a value or range, for example, within 10%, 5%, or 1% of the limit of the specified value or range. In this disclosure, the term “substantially” may allow some variation in a value or range, for example, within 90%, 95%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% of the limit of the specified value or range.

[0027] In this document, the terms “one” or “it” are used to include one or more unless the context explicitly indicates otherwise. The term “or” is used to refer to a non-exclusive “or” unless otherwise specified. Furthermore, it should be understood that any usage or terminology used herein, unless specifically defined, is for illustrative purposes only and not for limitation. The use of section headings is intended to aid in the reading of the document and should not be interpreted as limiting. Furthermore, information relating to a section heading may occur within or outside that particular section. Furthermore, all publications, patents, and patent documents referenced in this document are incorporated herein by reference in whole, as if they were individually incorporated by reference. In the event of any conflicting usage between this document and any document thus incorporated by reference, the usage of the incorporated reference should be considered to complement the usage in this document; in the event of incompatible inconsistencies, the usage in this document shall prevail.

[0028] As used herein, the term “substituted” refers to a functional group in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. As used herein, the terms “functional group” or “substituent” refer to a group that may be present on a molecule or that may be substituted on a molecule. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms of groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxylic acid esters; sulfur atoms of groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms of groups such as amines, azides, hydroxylamines, cyanos, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms of various other groups.

[0029] As used herein, the term "alkyl" refers to a group of 1 to approximately 20 carbon atoms (C1-C1). 20), 1 to 12 carbon atoms (C1-C 12 This refers to substituted and unsubstituted linear and branched alkyl and cycloalkyl groups having 1 to 8 carbon atoms (C1-C8), or in some embodiments, 1 to 6 carbon atoms (C1-C6). Examples of linear alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Typical substituted alkyl groups can be substituted once or more with any of the groups described herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0030] As used herein, the term "alkenyl" refers to a group of 2 to 20 carbon atoms (C2-C2). 20 ), 2-12 carbon atoms (C2-C 12 This refers to substituted or unsubstituted linear and branched divalent alkenyl and cycloalkenyl groups having 2 to 8 carbon atoms (C2-C8), or in some embodiments, 2 to 4 carbon atoms (C2-C4) and at least one carbon-carbon double bond. Examples of linear alkenyl groups include those having 2 to 8 carbon atoms, such as -CH=CH- and -CH=CHCH2-. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)-.

[0031] An alkynyl group is a fragment containing an open bond site on a carbon atom, formed when a hydrogen atom bonded to a triple-bonded carbon is removed from an alkyne molecule. As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined herein, substituted with at least one hydroxyl (-OH) group.

[0032] As used herein, the term “cycloalkyl” refers to substituted or unsubstituted cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups may have 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. In some embodiments, cycloalkyl groups may have 3 to 6 carbon atoms (C3-C6). Cycloalkyl groups further include polycyclic cycloalkyl groups, including but not limited to norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and calenyl groups, as well as fused rings, including but not limited to dekalinyl.

[0033] As used herein, the term “acyl” refers to a group containing a carbonyl moiety, which is bonded via a carbonyl carbon atom. The carbonyl carbon atom may also be bonded to another carbon atom, which may be part of a substituted or unsubstituted alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, etc. In the special case where the carbonyl carbon atom is bonded to hydrogen, the group is a “formyl” group, which is the acyl group as defined herein. An acyl group may contain 0 to about 12-40, 6-10, 1-5, or 2-5 further carbon atoms bonded to the carbonyl group. The acryloyl group is an example of an acyl group. An acyl group may also contain heteroatoms within the scope of the meaning herein. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the scope of the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, that group is called a "haloacyl" group. One example is the trifluoroacetyl group.

[0034] As used herein, the term “aryl” refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, crisenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group has about 6 to about 14 carbon atoms (C6-C) in the ring portion of the group. 14 ) or 6-10 carbon atoms (C6-C 10 ) are included. The aryl group may be unsubstituted or substituted as defined herein. Typical substituted aryl groups may be monosubstituted or multiple substituted, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2- to 8-substituted naphthyl groups, which may be substituted with carbon or non-carbon groups as described herein.

[0035] As used herein, the terms “aralkyl” and “arylalkyl” refer to alkyl groups as defined herein, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined herein. Typical aralkyl groups include benzyl and phenylethyl groups, as well as condensed (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined herein.

[0036] As used herein, the term “heterocyclyl” refers to substituted or unsubstituted aromatic and unaromatic ring compounds comprising three or more ring members, one or more of which are heteroatoms such as, but not limited to, B, N, O, and S. Thus, heterocyclyls can be cycloheteroalkyl or heteroaryl, or, in the case of polycyclic, any combination thereof. In some embodiments, heterocyclyl groups contain 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups containing 3 to 8 carbon atoms (C3-C8), 3 to 6 carbon atoms (C3-C6), or 6 to 8 carbon atoms (C6-C8).

[0037] A heteroaryl ring is one embodiment of a heterocyclyl group. The term "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, tetrazolyl, benzoxazolinyl, benzthiazolinyl, and benzimidazolinyl groups.

[0038] As used herein, the term “heterocyclylalkyl” refers to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group as defined herein is replaced by a bond to a heterocyclyl group as defined herein. Typical heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylmethyl, and indole-2-ylpropyl.

[0039] As used herein, the term “heteroarylalkyl” refers to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined herein.

[0040] As used herein, the term “alkoxy” refers to an oxygen atom bonded to an alkyl group, including cycloalkyl groups as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, and isohexyloxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may further contain double or triple bonds and may also contain heteroatoms. For example, the allyloxy group is an alkoxy group within the meaning of this specification. The methoxyethoxy group is also an alkoxy group within the meaning of this specification, such as the methylenedioxy group in which two adjacent atoms of the structure are substituted with methylenedioxy groups.

[0041] As used herein, the term “amine” refers to primary, secondary, and tertiary amines having the formula N(group)3, for example, where each group can independently be H or non-H such as alkyl or aryl. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, and alkylarylamines; R2NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, and heterocyclylamines; and R3N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, and triarylamines. The term “amine” also includes the ammonium ion as used herein.

[0042] As used herein, the term "amino group" refers to -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + Substituents in the form of -NR3, and non-protonable substituents. + This refers to each protonation form, excluding those specified above. Therefore, compounds substituted with an amino group can be considered amines. Within the scope of this specification, “amino group” can be a primary, secondary, tertiary, or quaternary amino group. The “alkylamino” group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0043] As used herein, the terms “halo,” “halogen,” or “halide” group mean, unless otherwise specified, a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent.

[0044] As used herein, the term “haloalkyl” group includes monohaloalkyl groups, polyhaloalkyl groups in which all halo atoms may be the same or different, and perhaloalkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as fluoroalkyl groups. Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and -CF(CH3)2.

[0045] As used herein, the terms “may be substituted” or “any substituent” mean that the group in question is either unsubstituted or substituted with one or more substituents specified. If the group in question is substituted with multiple substituents, the substituents may be the same or different. When the terms “independently,” “independently being,” or “independently selected from” are used, the group in question may be the same or different. Some terms defined herein may appear more than once in a structure, and in such occurrences, each term shall be defined independently of the others.

[0046] The compounds described herein may contain one or more chiral centers, or may exist as multiple stereoisomers. In one embodiment, the present invention as described herein is not limited to specific stereochemical requirements, and it should be understood that the compounds, as well as the compositions, methods, uses, and agents containing them, may be optically pure, or may be any mixture of various stereoisomers, including racemic mixtures and mixtures of other enantiomers, and mixtures of other diastereomers. It should also be understood that such a mixture of stereoisomers may contain a single stereochemical configuration at one or more chiral centers, or a mixture of stereochemical configurations at one or more other chiral centers.

[0047] Similarly, the compounds described herein may contain geometric centers such as cis, trans, E, and Z double bonds. In other embodiments, it should be understood that the inventions described herein are not limited to specific geometric isomer requirements, and the compounds, as well as the compositions, methods, uses, and agents containing them, may be pure or any mixture of various geometric isomers. It should also be understood that such a mixture of geometric isomers may contain single configurations with one or more double bonds, or a mixture of geometric configurations with one or more other double bonds.

[0048] As used herein, the terms “salt” and “pharmaceutically acceptable salt” refer to derivatives of disclosed compounds in which the parent compound is modified by forming an acid salt or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts also include conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0049] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. In some cases, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, whose disclosure is incorporated herein by reference.

[0050] The term "solvate" refers to a compound or salt thereof that further contains a stoichiometric or non-stoichiometric amount of solvent, bonded by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0051] The term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound, particularly the compounds of the present invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of the present invention that contain a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Certain prodrugs of compounds having a carboxyl functional group are lower alkyl esters of carboxylic acids. Carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0052] Furthermore, in each of the embodiments described above and below, it should be understood that the formula includes and represents not only all pharmaceutically acceptable salts of the compound, but also all hydrates and / or solvates of the formula of the compound or any salts thereof. It should be recognized that certain functional groups, such as hydroxyl groups and amino groups, form complexes and / or coordination compounds with water and / or various solvents in various physical forms of the compound. Therefore, the formula described above should be understood to include and represent their various hydrates and / or solvates. In each of the embodiments described above and below, it should also be understood that the formula includes and represents each possible isomer, such as stereoisomers and geometric isomers, both individually and in all possible mixtures. In each of the embodiments described above and below, it should also be understood that the formula includes and represents all crystalline, partially crystalline, amorphous and / or amorphous forms of the compound.

[0053] The term “pharmaceutically acceptable carrier” is recognized in the art and refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting any subject composition or its components. Each carrier must be compatible with the subject composition and its components and be “acceptable” in the sense that it is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) Distilled water from which pyrogenic substances have been removed; (17) Isotonic saline solution; (18) Ringer's solution; (19) Ethyl alcohol; (20) Phosphate buffer; and (21) Other non-toxic, suitable substances used in pharmaceutical formulations.

[0054] As used herein, the term “administer” includes, but is not limited to, all means of introducing the compounds and compositions described herein to a patient, including, orally (po), intravenously (iv), intramuscularly (im), subcutaneously (sc), percutaneously, by inhalation, orally, ocularly, sublingually, vaginally, rectally, and the like. The compounds and compositions described herein may be administered in unit dosage forms and / or formulations comprising conventional non-toxic, pharmaceutically acceptable carriers, adjuvants, and vehicles.

[0055] Exemplary forms of oral administration include tablets, capsules, elixirs, syrups, etc. Exemplary routes of parenteral administration include intravenous, intra-arterial, intraperitoneal, epidural, intraurethral, ​​intrasternal, intramuscular, and subcutaneous, as well as any other routes of parenteral administration recognized in the art.

[0056] Exemplary means of parenteral administration include needle (including microneedle) syringes, needleless syringes and injection techniques, as well as any other means of parenteral administration recognized in the art. Parenteral formulations are typically aqueous solutions (preferably in the pH range of about 3 to about 9) that may contain excipients such as salts, carbohydrates and buffers, but depending on the application, they may be more appropriately formulated as sterile non-aqueous solutions or as dry forms used in combination with a suitable vehicle such as sterile pyrogenically decontaminated distilled water. For example, the preparation of parenteral formulations under sterile conditions by lyophilization can be readily achieved using standard pharmaceutical techniques well known to those skilled in the art. Parenteral administration of compounds is exemplary in the form of saline or using compounds incorporated into liposomes. If the compound itself is not sufficiently soluble to dissolve, a solubilizing agent such as ethanol may be applied.

[0057] The dosage of each compound in the claimed combination depends on several factors, including the method of administration, the condition being treated, the severity of the condition, whether the condition is being treated or prevented, and the age, weight, and health status of the person being treated. Furthermore, pharmacological genomics (the influence of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic agent) information for a particular patient may influence the dosage used.

[0058] It should be understood that, in the methods described herein, the individual components of a co-administration or combination may be administered simultaneously, sequentially, separately, or in a single pharmaceutical formulation by any suitable means. When the compounds or compositions to be co-administered are administered in separate dosage forms, the number of daily doses for each compound may be the same or different. The compounds or compositions may be administered by the same or different routes of administration. The compounds or compositions may be administered simultaneously in divided or single forms at the same or different times during the course of treatment, according to a simultaneous or alternating regimen.

[0059] As used herein, the term “therapeutic dose” refers to the amount of an active compound or drug that elicits a biological or medical response in a tissue system, animal or human, as sought by researchers, veterinarians, physicians, or other clinicians, including relief of symptoms of the disease or disorder being treated. In one embodiment, a therapeutic dose is the amount that can treat or alleviate the symptoms of a disease or disorder with a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dose of the compounds and compositions described herein may be determined by the attending physician within the bounds of sound medical judgment. A specific therapeutically effective dose level for a particular patient depends on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient’s age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known to researchers, veterinarians, physicians, or other clinicians of the usual technique.

[0060] Depending on the route of administration, a wide range of acceptable doses is intended herein, including doses in the range of approximately 1 μg / kg to approximately 1 g / kg. Dosage may be a single dose or divided doses, and may be administered according to a variety of protocols, including qd (once daily), bid (twice daily), tid (three times daily), or every other day, once weekly, once monthly, once every three months, etc. In each of these cases, the therapeutically effective dose described herein is understood to correspond to the administration example or to the total daily, weekly, monthly, or three-monthly dose determined by the administration protocol.

[0061] In addition to the exemplary doses and administration protocols described herein, it should be understood that the effective dose of any one or a mixture of the compounds described herein may be determined by the attending diagnostician or physician by using known techniques and / or by observing the results obtained in similar circumstances. When determining the effective dose or dosage, the attending diagnostician or physician will consider many factors, including but not limited to the species of mammal, including human, its size, age, and general health status, the specific disease or disorder involved, the degree or severity of the involvement of the disease or disorder, the individual patient's response, the specific compound administered, the method of administration, the bioavailability characteristics of the formulation administered, the administration regimen chosen, the use of concomitant medications, and other relevant circumstances.

[0062] The term "patient" includes both humans and non-human animals, such as companion animals (dogs and cats, etc.) and domesticated animals. Domesticated animals are animals raised for food production. The patients being treated are preferably mammals, especially humans.

[0063] In some exemplary embodiments, the present invention is given by formula: [ka] [In the formula, R 1These are amino, hydroxyl, and their derivatives, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, and each of these may be substituted; Or, R 2 and R 3 Together with the bonded carbon, they form a substituted or heterocyclic moiety; and R 4 This represents four substituents, each independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; Alternatively, any two adjacent substituents of the four substituents may, together with the bonded carbon, form a substituted or heterocyclic moiety. This relates to compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0064] In some exemplary embodiments, the present invention is given by formula: [ka] [In the formula, n = 1 to 5; the bonds between A and B, and between B and D, may be double bonds or single bonds, but cannot be double bonds at the same time; A, B, and D independently represent C, O, N, and S, and at least one of A, B, and D is a heteroatom; R 1 These are amino, hydroxyl, and their derivatives, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, and each of these may be substituted; or R 2 and R 3 Together with the bonded carbon, it forms a cyclic or heterocyclic moiety that may be substituted; R 4This represents two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; Or two substituents, together with the bonded carbon, form a substituted or heterocyclic moiety; and Depending on elements A, B, and D, R 5 [This represents two or three substituents, each independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted.] This relates to compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0065] In some exemplary embodiments, the present invention relates to a compound having formula (II), wherein R 1 but, [ka] Regarding the compound in question.

[0066] In some exemplary embodiments, the present invention relates to formula (III): [ka] [In the formula, n = 1 to 5; the bonds between A and B, and between B and D may be double bonds or single bonds, but cannot be double bonds at the same time; A, B, and D independently represent C, O, N, and S, and at least one of A, B, and D is a heteroatom; R 1 These are amino, hydroxyl, and their derivatives, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; R 4 This represents two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; Alternatively, two substituents, together with the bonded carbon, may form a substituted or heterocyclic moiety; Depending on elements A, B, and D, R 5This represents two or three substituents, each independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; and Depending on nv, R 6 [This represents 2 to 6 substituents, each independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted.] This relates to compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0067] In some exemplary embodiments, the present invention relates to a compound having formula (III), wherein R 1 but, [ka] Regarding the compound in question.

[0068] In some exemplary embodiments, the present invention relates to formula (IV): [ka] [In the formula, n = 1 to 5; R 1 These are amino, hydroxyl, and their derivatives, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, and each of these may be substituted; or R 2 and R 3 Together with the bonded carbon, it forms a cyclic or heterocyclic moiety that may be substituted; R 4 This represents two substituents independently selected from the group consisting of hydrogen, deuterium, halo, azide, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted; Alternatively, two substituents, together with the bonded carbon, may form a substituted or heterocyclic moiety; Depending on the elements of A and B specified below, R 5 is independently selected from the group consisting of hydrogen, deuterium, halo, azido, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each representing one or two substituents which may be substituted; A and B independently represent CR 8 , N, or NR 9 , where R 8 and R 9 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted; Depending on the value of n, R 6 is independently selected from the group consisting of hydrogen, deuterium, halo, azido, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and their derivatives, as well as acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each representing 2 to 6 substituents which may be substituted; and R 7is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may be substituted] relates to a compound having the same or a pharmaceutically acceptable salt thereof.

[0069] In some exemplary embodiments, the invention is a compound having formula (IV), wherein R 1 is [Chemical formula] and relates to a compound that is

[0070] In some exemplary embodiments, the invention is a compound having formula (IV), wherein R 1 is [Chemical formula] ; A is carbon (C); B is nitrogen (N); R 5 , R 6 , and R 7 all represent hydrogen, and R 4 is independently selected from the group consisting of hydrogen, deuterium, halo, azido, cyano, nitro, hydroxy, amino, thio, carboxy, ester, amide, and derivatives thereof, and acyl, sulfoxyl, sulfonyl, phosphate, phosphoryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which may be substituted, and represents two substituents; The present invention relates to compounds in which two substituents, together with the bonded carbon, form a cyclic or heterocyclic moiety that may be substituted.

[0071] In some exemplary embodiments, the present invention relates to a compound having formula (IV), wherein R 3 but, [ka] Regarding the compound in question.

[0072] In some exemplary embodiments, the present invention relates to a compound having formula (IV), wherein R 1 but, [ka] is; and R 3 but, [ka] Regarding the compound in question.

[0073] In some exemplary embodiments, the present invention relates to a compound having formula (I), [ka] Regarding the compound in question.

[0074] In some exemplary embodiments, the present invention relates to a compound having formula (I), [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0075] In some exemplary embodiments, the present invention relates to pharmaceutical compositions comprising one or more compounds disclosed herein or pharmaceutically acceptable salts thereof, together with one or more diluents, excipients, or carriers.

[0076] In some exemplary embodiments, the present invention relates to kinase inhibitors, wherein the kinases are FLT3, MNK1 / 2, JAK1 / 2 / 3, Limk1 / 2, various CDKs, Haspin, ROCK1 / 2, TOPK, LRRK2, GSK3a / 3b, RSK1-4, ERK, P70S6K, AKT, PI3K, p38, PKC, PKA, FGFR1-4, VEGFR1-3, ALK, AXL, LIMK1 / 2, Aurora The group selected consists of A / B, ABL1, AKT, CSF1R, CSNK1D, DCAMKL1, CSNK1G2, EPHA2, ERBB2, IKKα, IKKβ, JNK1 / 2 / 3, MARK3, MEK1 / 2, MET, MLK1, PAK1 / 2 / 4, PDGFRa / b, PIM1 / 2 / 3, PLK1 / 2 / 3 / 4, PRKCE, PRKX, RET, TAOK2, TRKA / B / C, ULK2, and receptor-interacting protein kinase 4 (RIPK4).

[0077] In some exemplary embodiments, the present invention relates to a method for treating a kinase and / or histone demethylase-mediated disease, including inflammation, cancer, viral and bacterial infections, gastrointestinal disorders, eye diseases, neurological disorders, cardiovascular disorders and immunodeficiencies, comprising the step of administering a therapeutically effective amount of one or more compounds disclosed herein, and one or more carriers, diluents, or excipients, to a patient in need of relief of said cancer.

[0078] In some exemplary embodiments, the present invention relates to a method for treating kinase and histone demethylase-mediated diseases, including inflammation, cancer, viral and bacterial infections, gastrointestinal disorders, eye diseases, neurological disorders, cardiovascular disorders and immunodeficiencies, comprising the step of administering a therapeutically effective amount of a compound disclosed herein, in combination with one or more other compounds having the same or different mechanisms of action, and one or more carriers, diluents, or excipients, to a patient in need of relief of said cancer.

[0079] In some other exemplary embodiments, the present invention relates to a drug conjugate, which is either a small molecule or a biological conjugate, comprising one or more compounds disclosed herein, that confers cell-type or tissue-type targeting, or targets another pathway that synergistically acts with the action of the compounds.

[0080] In some exemplary embodiments, the present invention relates to drug conjugates, which are either small molecules or biological conjugates, comprising one or more compounds disclosed herein, that impart water solubility or low clearance.

[0081] In some exemplary embodiments, the present invention relates to a drug conjugate comprising one or more compounds disclosed herein and a moiety that assists in the degradation of a target protein via a system including, but not limited to, a ubiquitin ligase / proteosome degradation system.

[0082] In some exemplary embodiments, the present invention relates to a pharmaceutical composition comprising nanoparticles of one or more compounds disclosed herein, together with one or more diluents, excipients, or carriers.

[0083] In some exemplary embodiments, the present invention relates to a prodrug comprising one or more compounds disclosed herein, wherein the prodrug portion is removed at a specific location, such as in the gastrointestinal tract, blood, tissue, or cancer-specific location.

[0084] In some exemplary embodiments, the present invention relates to analogues of the compounds disclosed herein in which specific metabolic hotspots are modified with groups such as deuterium or fluorine.

[0085] Furthermore, it is recognized that the compounds described herein may be used in combination with other compounds administered to treat other symptoms of cancer, such as compounds administered to alleviate pain, nausea, vomiting, etc.

[0086] The following non-limiting exemplary embodiments are included herein for further illustration of the invention. These exemplary embodiments are not intended to limit the scope of the invention in any sense and should not be construed as limiting the scope of the invention. It should also be understood that numerous variations of these exemplary embodiments are contemplated herein.

[0087] Experimental items and characterization: General procedure for multi-component reactions: 10 Method A: A mixture of amine (1 mmol) and aldehyde (1 mmol) in 3 mL of anhydrous ethanol was refluxed for 2 hours, after which a cyclic ketone or acetaldehyde (2.1 mmol) was added to the reaction mixture. A catalytic amount of concentrated hydrochloric acid was added, and the reaction was continued to reflux for 6 to 12 hours. The reaction mixture was concentrated, dissolved in DCM (50 mL), and washed with brine (20 mL x 2). The organic layer was dried (Na2SO4), concentrated under reduced pressure, and purified by silica gel chromatography (dichloromethane:methanol (99:01 to 80:20)) to obtain the desired cyclized compound.

[0088] Method B: A mixture of amine (1 mmol) and aldehyde (1 mmol) in 3 mL of acetonitrile was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, alkene (2 mmol) and Y(OTf)3 (30 mol%) were added. The reaction mixture was refluxed overnight. The reaction mixture was concentrated and purified by silica gel chromatography (dichloromethane:methanol (99:01)) to obtain the desired cyclized compound.

[0089] Method C: A mixture of amine (1 mmol), aldehyde (1 mmol), and cyclic ketone (2 mmol) in 6 mL of tetrahydrofuran was refluxed for 6–12 hours in the presence of iodine (10 mol%). After the reaction was complete, the reaction mixture was concentrated and purified by silica gel chromatography (ethyl acetate:hexane (80:20) or dichloromethane:methanol (99:01)) to obtain the desired cyclized compound. (Note: Occasionally, the product may precipitate; this was filtered, washed with anhydrous ethanol, and further purified by column chromatography).

[0090] Kinase assay: Kinase / inhibitor interactions were measured using the HotSpot kinase screening assay (Reaction Biology). Kinases and substrates were mixed in a buffer containing 20 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO. A single dose (500 nM) of the compound was then added to each reaction mixture. After a 20-minute incubation, ATP (Sigma) and [γ- 33 P]ATP (Perkin Elmer) was added at room temperature for a further 2 hours to a final total concentration of 100 μM, followed by spotting onto P81 ion-exchange cellulose chromatography paper (Whatman, Inc.). The filter paper was washed with 0.75% phosphoric acid to remove unincorporated ATP. Using Prism 5 (GraphPad), the percentage of residual kinase activity in the vehicle containing the kinase reaction (DMSO) was calculated for each kinase / inhibitor pair.

[0091] LSD1 assay: The LSD1 activity of purified LSD1 enzyme was measured using an LSD1 assay kit. LSD1 buffer, 10 μM histone H3(1-21)K4me2 peptide, and the test compound or DMSO control were added to a 96-well plate. The reaction was initiated with the LSD1 enzyme. After incubation at room temperature for 30 minutes, peroxidase and Amplex Red reagent were added, and fluorescence (λex=530±13 nm, λem=590±18 nm) was measured after 5 minutes using a plate reader. The inhibition rate was calculated by dividing the fluorescence intensity in the presence of the inhibitor by the DMSO control and multiplying by 100%.

[0092] I C 50 Growth assay Cell lines and primary cells were seeded in 96-well plates in the afternoon prior to treatment. Approximately 18 hours later, the compound was semi-serially diluted with dimethyl sulfoxide (DMSO) and then with growth medium and added to the cells. After incubating the plates for 72 hours, Alamar Blue (Life Technologies, Carlsbad, CA) was added. After further incubation at 37°C for 4 hours, the plates were read using a Bio-Tek Synergy HT plate reader (Bio-Tek, Winooski, VT). The data were analyzed and graphed using GraphPad Prism Software (Graphpad, La Jolla, CA).

[0093] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0094] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0095] 4-(8,9-dihydro-3H-cyclobuta[c]pyrrolo[3,2-f]quinoline-7-yl)phenol

number

[0096] 4-(3,8,9,10-tetrahydrocyclopenta[c]pyrrolo[3,2-f]quinoline-7-yl)phenol

number

[0097] 4-(9-methyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0098] 2,6-Dibromo-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0099] 7-(4-bromophenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0100] 4-(9-methyl-3H-pyrrolo[3,2-f]quinoline-7-yl)phenol

number

[0101] 7-(3,4,5-trimethoxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0102] 4-(9,9-dimethyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0103] 5-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzene-1,2,3-triol

number

[0104] 4-(6,7,8,9-tetrahydro-1H-pyrrolo[2,3-c]phenanthridine-5-yl)phenol

number

[0105] 7-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0106] 7-(1-methyl-1H-imidazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0107] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzene-1,3-diol

number

[0108] 4-(3,8,9,10,11,12-hexahydrocyclohepta[c]pyrrolo[3,2-f]quinoline-7-yl)phenol

number

[0109] 4-(8,9,10,11-tetrahydro-3H-[1,2,3]triazolo[4,5-a]phenanthridine-7-yl)phenol

number

[0110] 4-(2,3,4,8-tetrahydro-1H-pyrrolo[3,2-b]phenanthridine-5-yl)phenol

number

[0111] 4-(2,3,4,8-tetrahydro-1H-pyrrolo[3,2-b]phenanthridine-5-yl)phenol

number

[0112] 2,2'-((4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenyl)azandiyl)diethanol

number

[0113] 2-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)phenol

Number

[0114] 7-(Pyridin-4-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

Number

[0115] 4-(2,3,4,9-Tetrahydro-1H-indolo[3,2-a]phenanthridin-5-yl)phenol

Number

[0116] 4-(3-Methyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)phenol

Number

[0117] 5-(8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)pyridin-2-ol

Number

[0118] 4-(8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)aniline ​​​​​​​​5-(8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)pyridin-2-ol

Number

[0120] 4-(8,9,10,11-Tetrahydrofuro[3,2-a]phenanthridin-7-yl)phenol

Number

[0121] 4-(8,9,10,11-Tetrahydrothieno[3,2-a]phenanthridin-7-yl)phenol

Number

[0122] 2,6-Difluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridin-7-yl)phenol

Number

[0123] 4-(8,9,10,11-Tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7- -yl)aniline

Number

[0124] 2,6-Difluoro-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridin-7-yl)phenol Method A:

Number

[0125] 2-Methyl-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0126] 2-Chloro-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0127] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-9-carbonitrile

number

[0128] 4-(1,2,4,9-tetrahydropyrano[3,4-c]pyrrolo[3,2-f]quinoline-5-yl)phenol

number

[0129] 6-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)pyridine-3-ol

number

[0130] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzoic acid

number

[0131] 5-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzene-1,3-diol

number

[0132] 5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)pyridine-2-amine

number

[0133] 7-(pyrimidine-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0134] 5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)thiazole-2-amine

number

[0135] 2-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0136] 5-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)thiazole-2-amine

number

[0137] 2-Hydroxy-5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzoic acid

number

[0138] Methyl 2-hydroxy-5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)methyl benzoate

number

[0139] 3-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)pyridine-2(1H)-one

number

[0140] 2-Hydroxy-5-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)methyl benzoate

number

[0141] 2-(7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-9-yl)isoindoline-1,3-dione 12.11

number

[0142] Benzyl(7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo [3,2-a] Phenanthridine-9-yl) Calbamate

number

[0143] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-9-ol

number

[0144] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)-2-(trifluoromethoxy)phenol

number

[0145] 3-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0146] 5-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)pyrimidine-2-amine

number

[0147] 2-((dimethylamino)methyl)-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0148] 2,6-Diiodo-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0149] 3-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0150] 3-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)pyridine-2(1H)-one

number

[0151] Benzyl(7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-yl)carbamate

number

[0152] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-ol

number

[0153] 2-(7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-yl)isoindorin-1,3-dione

number

[0154] 2-Chloro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenant Lysine-7-yl)phenol

number

[0155] 4-(1-bromo-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol Method A:

number

[0156] 7-(6-chloropyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0157] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-2-(trifluoromethyl)phenol

number

[0158] 2-Methoxy-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0159] 3-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0160] 4-(9-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0161] 4-(3,8,9,10-tetrahydrocyclopenta[c]pyrazolo[4,3-f]quinoline-7-yl)phenol

number

[0162] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-carbonitrile

number

[0163] 2-((dimethylamino)methyl)-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0164] 7-(6-fluoropyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0165] 2-Iodo-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0166] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzoic acid

number

[0167] 4-(8,9-dihydro-3H-cyclobuta[c]pyrazolo[4,3-f]quinoline-7-yl)phenol

number

[0168] 4-(3,8-dihydro-2H-fl[3,2-c]pyrazolo[4,3-f]quinoline-4-yl)phenol

number

[0169] 7-(1H-indazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0170] 7-(1H-indazole-6-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0171] 5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-1H-benzo[d]imidazole-2(3H)-one

number

[0172] 4-(8,9,10,11-tetrahydro-1H-pyrazolo[3,4-a]phenanthridine-7-yl)phenol

number

[0173] 5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)pyrimidine-2,4(1H,3H)-dione

number

[0174] 2-methyl-6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[d]thiazole

number

[0175] 3,5-Difluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0176] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-carboxylic acid

number

[0177] 5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[d]thiazole-2-amine

number

[0178] 4-(3,8,10,11-tetrahydropyrano[3,4-c]pyrazolo[4,3-f]quinoline-7-yl)phenol

number

[0179] N-(7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-yl)acetamide [Number]

[0180] 4-(6,7,8,9-tetrahydro-1H-pyrazolo[3,4-c]phenanthridine-5-yl)phenol

number

[0181] 4-(6,7,8,9-tetrahydro-3H-pyrazolo[4,3-c]phenanthridine-5-yl)phenol

number

[0182] 7-(1H-pyrrolo[2,3-b]pyridine-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0183] 4-(8,9,10,11-tetrahydro-1H-pyrazolo[3,4-a]phenanthridine-7-yl)phenol

number

[0184] 3,5-dimethyl-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)isoxazole

number

[0185] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-1-carbonitrile

number

[0186] tert-butyl(6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)pyridine-2-yl)carbamate

number

[0187] 4-(5-methoxy-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0188] 4-(3-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0189] 7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4, 3-a] Phenanthridine

number

[0190] 7-(1H-indazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0191] 7-(1H-indole-2-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0192] 7-(1H-indole-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0193] 7-Cyclopropyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0194] 2-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-4H-chromene-4-one

number

[0195] 7-(bicyclo[2.2.1]hept-5-en-2-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0196] 7-(1H-indazole-5-yl)-1-iodo-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0197] 1-Bromo-7-(1H-indazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0198] N-(7-(1H-indazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-yl)acetamide

number

[0199] 7-(1H-indazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-amine

number

[0200] (4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)boronic acid

number

[0201] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzonitrile

number

[0202] 4-(9-amino-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0203] (2-fluoro-3-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)boronic acid

number

[0204] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0205] 7-(1H-benzo[d]imidazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0206] 4-(1-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0207] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-2-carboxylate methyl

number

[0208] 7-(4-fluorophenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0209] 7-(4-fluorophenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0210] 7-phenyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0211] 7-phenyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0212] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-2-carboxylic acid

number

[0213] 7-(2-bromo-4-fluorophenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0214] 7-(4-ethynylphenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0215] 7-(4-chlorophenyl)-8,9,10,11-tetrahydro-3H-naphtho[1,2-e]indazole

number

[0216] 7-(4-chlorophenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0217] 7-(3-fluorophenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0218] 7-(3-fluorophenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0219] 4-(8,9,10,11-tetrahydro-3H-8,11-methanopyrazolo[4,3-a]phenanthridine-7-yl)phenol 1193

number

[0220] 4-(2-methyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0221] 6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)pyridine-3-ol

number

[0222] 7-(6-fluoropyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0223] 7-(pyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0224] 7-(2-bromophenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0225] 3-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0226] 2-Fluoro-4-(2-methyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0227] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzimidoamide hydrochloride

number

[0228] N-hydroxy-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzimidoamide [ka]

[0229] To a solution of NH2OH.H2O (1.5 equivalents) in DMSO (3 mL), KOtBut (3 equivalents) was slowly added at 0°C, and the suspension was stirred for 30 minutes. Then, 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzonitrile (0.5 mmol) was added to the mixture, and the reaction was continued at room temperature for 4 hours. After the reaction was complete, cold water was added to the reaction mixture, the resulting precipitate was filtered, washed with water, and dried. The solid was recrystallized with ethanol to obtain the desired product.

number

[0230] N-(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)acetamide

number

[0231] 4-(3,8-dihydro-2H-fl[3,2-c]pyrrolo[3,2-f]quinoline-4-yl)phenol

number

[0232] 4-(3,8-dihydro-2H-fl[3,2-c]pyrrolo[3,2-f]quinoline-4-yl)phenol

number

[0233] 2-Fluoro-4-(1-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0234] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzonitrile

number

[0235] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)methyl benzoate

number

[0236] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzamide

number

[0237] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)methyl benzoate

number

[0238] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)methyl benzoate

number

[0239] N-hydroxy-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzimidoamide [ka] The following general procedure for 1207 is followed for synthesis.

number

[0240] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzamide

number

[0241] 2,3-difluoro-4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0242] 2,3-Difluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0243] 2-Fluoro-5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzonitrile

number

[0244] 2-Fluoro-5-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzonitrile

number

[0245] 3-Methoxy-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0246] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)-2-(trifluoromethyl)phenol

number

[0247] 2,5-Difluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0248] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthidine

number

[0249] 7-(3-methyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0250] 1-Methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0251] 1-Methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0252] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)-3-(trifluoromethyl)phenol

number

[0253] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-3-(trifluoromethyl)phenol

number

[0254] 7-(5-(trifluoromethyl)-1H-pyrazole-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0255] 4-(9-(trifluoromethyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0256] 4-(9-(trifluoromethyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0257] 4-(9,9-difluoro-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0258] 4-(9,9-difluoro-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenol

number

[0259] 8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-carboxylate ethyl

number

[0260] 7-(4-hydroxyphenyl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-1-carbonitrile

number

[0261] 4-(7,8,9,10-tetrahydrophenanthridine-6-yl)phenol

number

[0262] 4-(6,7,8,9-tetrahydro-3H-pyrrolo[3,2-c]phenanthridine-5-yl)phenol

number

[0263] 4-(3-(2-hydroxyethyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0264] 6-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzo[d]thiazole-2-amine

number

[0265] 6-(3,8,9,10-tetrahydrocyclopenta[c]pyrazolo[4,3-f]quinoline-7-yl)benzo[d]thiazole-2-amine

number

[0266] N-(4-(2-methyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)phenyl)methanesulfonamide

number

[0267] N-(4-(3,8,9,10-tetrahydrocyclopenta[c]pyrrolo[3,2-f]quinoline-7-yl)phenyl)methanesulfonamide

number

[0268] 7-(2-aminobenzo[d]thiazole-6-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-1-carbonitrile

number

[0269] 6-(1-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[d]thiazole-2-amine

number

[0270] 7-(3,5-dimethyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0271] 7-(1H-indazole-5-yl)-1-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0272] 7-(1H-indazole-5-yl)-1,2-dimethyl-8,9,10,11-tetrahydro-2H-pyrazolo[4,3-a]phenanthridine

number

[0273] 7-(1H-indazole-5-yl)-2-methyl-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0274] 7-(1H-indazole-5-yl)-1-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0275] 7-(1H-pyrrolo[3,2-c]pyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0276] 7-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0277] 7-(1H-pyrrolo[2,3-b]pyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine

number

[0278] 7-(5H-pyrrolo[3,2-d]pyrimidine-7-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0279] 7-(6-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0280] 7-(1H-pyrrolo[3,2-b]pyridine-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0281] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzenesulfonamide

number

[0282] 4-(8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine-7-yl)benzenesulfonamide

number

[0283] 7-(1H-pyrrolo[2,3-b]pyridine-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0284] 7-(1-methyl-1H-indazole-5-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0285] 9-methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0286] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3,8,9,10-tetrahydrocyclopenta[c]pyrazolo[4,3-f]quinoline

number

[0287] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3,8,9,10,11,12-hexahydrocyclohepta[c]pyrazolo[4,3-f]quinoline

number

[0288] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9-dihydro-3H-cyclobuta[c]pyrazolo[4,3-f]quinolone

number

[0289] 9-Methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3H-pyrazolo[4,3-f]quinoline

number

[0290] 7-(1H-1,2,3-triazol-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0291] 3-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-1H-pyrrole-2-carboxylate methyl

number

[0292] 2-(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-1H-pyrazole-1-yl)ethane-1-ol

number

[0293] 7-(1,3-dimethyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0294] 7-(1H-imidazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0295] 1-Iodo-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0296] 7-(3-phenyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0297] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-9-amine

number

[0298] 3-Methyl-3-(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-1H-pyrazole-1-yl)tetrahydrothiophene 1,1-dioxide

number

[0299] 7-(3-(pyridine-3-yl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0300] 7-(1-phenyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0301] 7-(3-(thiophen-3-yl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0302] 7-(3-(tert-butyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0303] 4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)-1H-pyrazole-3-carboxylic acid

number

[0304] 7-(1-(2-chloroethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0305] 2,3-dimethyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3,6,8,9,10,11-hexahydro-2H-pyrazolo[3,4-a]phenanthidine

number

[0306] 5-Fluoro-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0307] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-5-ol

number

[0308] 5-Bromo-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0309] 5-Chloro-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0310] 4-methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0311] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-[1,2,3]triazolo[4,5-a]phenanthidine

number

[0312] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydroisoxazolo[4,5-a]phenanthidine

number

[0313] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydroisothiazolo[4,5-a]phenanthidine

number

[0314] 3-methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0315] 6-(5-fluoro-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[d]thiazole-2-amine

number

[0316] 6-(8,9,10,11-tetrahydro-3H-[1,2,3]triazolo[4,5-a]phenanthridine-7-yl)benzo[d]thiazole-2-amine

number

[0317] 7-(3-isopropyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0318] 4-(7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-9-yl)morpholine

number

[0319] 6-(3-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[d]thiazole-2-amine

number

[0320] 7-(2-aminobenzo[d]thiazole-6-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-1-carboxylate methyl

number

[0321] N-(6-(8,9,10,11-Ttetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[d]thiazole-2-yl)acetamide Compound HSD992 (93 mg, 0.25 mmol) was dissolved in a mixture of DMF (2 mL) and triethylamine (2 equivalents), followed by the addition of acetyl chloride (30 mg, 1.5 mmol). The reaction was then allowed to continue overnight at room temperature. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (2 x 20 mL), washed with brine, and the crude product was purified by flash column chromatography with dichloromethane:methanol (90:10) to obtain the desired product as a yellow solid (73 mg, 70%).

number

[0322] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-imidazo[4,5-a]phenanthidine

number

[0323] 2-(trifluoromethyl)-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-imidazo[4,5-a]phenanthidine

number

[0324] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-1-carboxylate methyl

number

[0325] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-carbonitrile

number

[0326] 1-Methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-9-carbonitrile

number

[0327] 8,9,10,11-Tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-carboxylic acid (HSD1251) [ka] Off-white solid (40%).

number

[0328] N-Cyclopropyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-carboxamide To a solution of HSD1251 (50 mg, 0.18 mmol) in DMF (2.5 mL), cyclopropylamine (0.19 mmol), HOBt (0.18 mmol), EDCl.HCl (0.18 mmol), and DIPEA (0.39 mmol) were added. The reaction was allowed to continue at room temperature for 12 hours and monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate, washed with brine solution, and dried over Na2SO4. The crude product was purified by flash chromatography to obtain the desired product as a white solid (yield 70%, 39 mg).

number

[0329] 9-methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-indazolo[5,4-c][2,7]naphthyridine

number

[0330] 6-(9-methyl-8,9,10,11-tetrahydro-3H-indazolo[5,4-c][2,7]naphthyridine-7-yl)benzo[d]thiazole-2-amine

number

[0331] N-(7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-yl)acetamide

number

[0332] 7-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)-5-fluoro-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0333] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-indazolo[5,4-c][2,7]naphthyridine In this case, tert-butyl 4-oxopiperidine-1-carboxylate was used as a cyclic ketone using Method A, the Boc group was deprotected in situ due to the presence of HCl in the reactant, the desired compound was precipitated in the reaction mixture, filtered, and washed with ethanol.

number

[0334] 5-Fluoro-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-indazolo[5,4-c][2,7]naphthyridine

number

[0335] N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-7-carboxamide To a solution of HSD1251 (50 mg, 0.18 mmol) in DMF (2.5 mL), 4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)aniline (0.19 mmol), HATU (0.18 mmol), and DIPEA (0.39 mmol) were added. The reaction was allowed to continue at room temperature for 12 hours and monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate, washed with brine solution, and dried over Na2SO4. The crude product was purified by flash chromatography to obtain the desired product as an off-white solid (yield 50%, 47 mg).

number

[0336] 7-(2-aminobenzo[d]thiazole-6-yl)-3H-pyrazolo[4,3-f]quinoline-9-carboxylic acid

number

[0337] 7-(isoquinoline-6-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0338] 7-(isoquinoline-8-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0339] 7-(isoquinoline-7-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0340] 7-(quinoline-2-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0341] 7-(isoquinoline-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0342] 9-(pyridine-2-yl)-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3H-pyrazolo[4,3-f]quinoline

number

[0343] 7-(quinoline-6-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0344] 7-(quinoline-3-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0345] 3-Chloro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0346] 3-Fluoro-5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0347] 7-(isoquinoline-1-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0348] 1-Methoxy-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0349] 1-Methyl-7-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-9-carbonitrile

number

[0350] 7-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0351] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3,8,10,11-tetrahydropyrazolo[4,3-f]thiopyrano[3,4-c]quinolone

number

[0352] 1-(7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3,8,10,11-tetrahydro-9H-indazolo[5,4-c][2,7]naphthyridine-9-yl)ethane-1-one

number

[0353] 9-Cyclopropyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3H-pyrazolo[4,3-f]quinolone

number

[0354] 4-(3,8,9,10,11,12-hexahydrocyclohepta[c]pyrazolo[4,3-f]quinoline-7-yl)-2,6-diiodophenol

number

[0355] 7-(4-hydroxy-3,5-diiodophenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-ol

number

[0356] 2,6-Dibromo-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0357] 7-(4-hydroxy-3,5-diiodophenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-1-carbonitrile

number

[0358] 2,6-Diiodo-4-(1-methyl-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenol

number

[0359] (5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)thiophen-3-yl)boronic acid

number

[0360] N-(2-(4-methylpiperazine-1-yl)ethyl)-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-1-carboxamide

number

[0361] 1-Methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-9-amine

number

[0362] (2-Methoxy-5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)boronic acid

number

[0363] (5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)furan-2-yl)boronic acid

number

[0364] 5-Fluoro-7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0365] (7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-1-yl)methanol Compound HSD1329 (100 mg) was dissolved in anhydrous THF and cooled under argon using dry ice acetone. Then, LAH (1 molar solution in THF, 1 equivalent) was added dropwise, and the reaction mixture was stirred overnight at room temperature. The reaction was terminated by slowly adding a mixture of water and THF under cooling conditions. The reaction mixture was filtered and purified by flash column chromatography.

number

[0366] 1-Methyl-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine-8,8,9,9,10,10,-d6 Using the same method A, deuterated (D8) cyclohexanone was used as the ketone.

number

[0367] 5-Fluoro-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-8,8,9,9,10,10,-d6 Using the same method A, deuterated (D8) cyclohexanone was used as the ketone.

number

[0368] 7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-3H-pyrazolo[4,3-f]quinoline-9-carboxylic acid Pyruvate as a ketone substrate.

number

[0369] 3,3-dimethyl-5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[c][1,2]oxabolol-1(3H)-ol

number

[0370] 3,3-dimethyl-6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzo[c][1,2]oxabolol-1(3H)-ol

number

[0371] (2-Methoxy-3-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)boronic acid

number

[0372] (7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-5-yl)ethane-1,2-diamine N 1 ,N 1 ,N 2 Trimethylethane-1,2-diamine (0.5 mL) was added to a mixture of compound HSH-1-156 (50 mg, 0.13 mmol) dissolved in DMSO (1 mL) and powdered K2CO3 (2 equivalents). The reaction mixture was heated in a pressure tube at 200°C for 24 hours. After the reaction was complete, the reaction product was purified by silica gel flash chromatography using dichloromethane:methanol (80:20) as the solvent system.

number

[0373] 5-(piperidine-1-yl)-7-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthidine

number

[0374] 7-(4-fluoro-3-nitrophenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0375] 2-Fluoro-5-(8,9,10,11-tetrahydro-3H-naphtho[1,2-e]indazole-7-yl)aniline Compound HSD1404 (100 mg) was dissolved in 5 mL of THF and purged with argon for 15 minutes. Then, palladium (10% on carbon, 20 mol%) was added, and a hydrogen balloon was used for 6 hours for hydrogenation. After completion, the reaction mixture was filtered through a sintered funnel, concentrated, and purified by flash column chromatography.

number

[0376] 7-(3-fluoro-4-nitrophenyl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine

number

[0377] Those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above. Implementations should not be limited to the specific limitations described; other implementations may also be possible.

[0378] While the present invention has been illustrated and described in detail in the drawings and the foregoing description, it should be understood that these are illustrative and not limiting in nature, illustrating and describing only specific embodiments, and that it is desirable that all changes and modifications within the spirit of the invention be protected.

[0379] The scope of the methods and compositions of the present invention is intended to be defined by the following claims. However, it should be understood that this disclosure may be carried out in ways other than those specifically described and illustrated without departing from its spirit or scope. It should be understood by those skilled in the art that various substitutes for the embodiments described herein may be used when carrying out the claims without departing from the spirit and scope defined in the following claims.

[0380] References: TIFF0007837179000335.tif163163

Claims

【Request Item 1】 【Chemistry 1-1】 【Chemistry 1-2】 [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] [Chemistry 1-7] [Chemistry 1-8] [Chemistry 1-9] 【Chemistry 1-10】 【Chemistry 1-11】 【Chemistry 1-12】 【Chemistry 1-13】 [Chemistry 1-14] 【Chemistry 1-15】 【Chemistry 1-16】 【Chemistry 1-17】 【Chemistry 1-18】 【Chemistry 1-19】 【Chemistry 1-20】 【Chemistry 1-21】 A compound selected from the group consisting of the following.

Images