Pyrazolo-pyrimidinone compounds for use in inhibiting Wee1A kinase

Abstract

A pyrazolopyrimidinone compound of formula I for use in methods of inhibiting Wee1A kinase or both Wee1A kinase and Myt1 kinase. In some embodiments, the disclosure provides a method for treating a disease or disorder related to Wee1A kinase, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need. In some embodiments, the disclosure provides a method for treating a disease or disorder related to both Wee1A kinase and Myt1 kinase, the method comprising administering a compound of formula I having dual activity or a pharmaceutically acceptable salt thereof to a patient in need. TIFF2026521468000228.tif58165

Description

[Background technology]

[0001] Cells are continuously exposed to endogenous and exogenous agents that affect DNA integrity. To maintain genomic stability and prevent the unwanted proliferation of damaged DNA, cells have established systematic signaling networks that recognize DNA damage, halt the cell cycle to allow DNA to be properly repaired, and then resume DNA replication or cell division. The DNA damage response and the cell cycle are closely linked through several cell cycle checkpoints, which are crucial regulatory steps for maintaining genomic integrity.

[0002] Cancer cells often have defects in the G1 / S checkpoint, which is frequently due to disruption of p53 activity resulting from mutations or deletions, or inactivation by viral oncoproteins. Therefore, cancer cells rely heavily on other cell cycle checkpoints, including the G2 / M checkpoint, to avoid the accumulation of harmful DNA damage and mitotic catastrophe. Thus, it is hypothesized that cancer cells are particularly vulnerable to the inhibition of proteins that protect against transition to mitosis. (Matheson, CJ et al. Trends Pharmacol Sci 37, 872-881 (2016)).

[0003] Wee1A kinase is a tyrosine kinase belonging to the Wee1 kinase family, which includes Wee1A kinase, Wee1B kinase, and Myt1 kinase. (Rora, AG Let al J Hematol Oncol 13, 126 (2020)). The main roles of this kinase family are to regulate cell cycle progression and the transition to mitosis (Wee1A kinase and Myt1 kinase) or meiosis (Wee1B kinase). The important complex that regulates the transition to mitosis is the Cdk1 / cyclin B1 complex (also known as mitotic factor). Wee1A kinase inhibits tyrosine at site 15 (Y 15By phosphorylating Cdk1, it restricts the activity of the Cdk1 / cyclin B1 complex. Therefore, inhibition of Wee1A kinase is inhibitory Y 15 By preventing phosphorylation, Cdk1 / cyclin B1 complex activity is effectively promoted. If the Cdk1 / cyclin B complex is activated too early, DNA damage is not resolved, and premature transition to mitosis is promoted, ultimately leading to mitotic catastrophe and cell death.

[0004] In addition to its well-established role in regulating mitotic transition at the G2 / M checkpoint, Wee1A kinase has also been suggested to be important at the intra-S phase checkpoint by limiting Cdk2 activity. (Elbaek, CR et al Cell Reports 38, 110261 (2022); Elbaek, CR et al Mutat Res Fundam Mol Mech Mutagen 819-820, 111694 (2020)). Cdk2 activity is regulated by Wee1A kinase in a similar manner to Cdk1 by tyrosine 15 phosphorylation. Cdk2 is the major Cdk driving DNA replication, and inhibition of Wee1A kinase leads to excessive DNA replication, resulting in nucleotide pool depletion and degradation of the ribonucleotide reductase subunit RRM2 (Pfister, SX et al Cancer Cell 28, 557-568 (2015)). Pfister et al. found that inhibiting Wee1A kinase leads to H3K through dNTP starvation resulting from RRM2 depletion. 36 It was shown that it selectively kills me3-deficient cancer cells. Histone methyltransferase SETD2 is H3K 36 It catalyzes me3 and promotes RRM2 expression and dNTP synthesis. Since SETD2 gene inactivation is frequently observed in renal clear cell carcinoma (ccRCC), it may be sensitive to Wee1A kinase inhibition. In a Phase II trial, AZD1775 is being tested in SETD2-deficient solid tumors (NCT03284385).

[0005] Furthermore, Wee1A kinase has been suggested to play a role in regulating histone stoichiometry by phosphorylating core histone H2B with tyrosine 37 during late S phase. (Koh, S.-B. Cell Signal 94, 110310 (2022)).

[0006] Increased sensitivity to Wee1A kinase inhibition was shown in high-risk human papillomavirus (HPV)-associated cancers (e.g., head and neck squamous cell carcinoma (HNSCC)). Diab, A. et al Proc National Acad Sci 117, 28287-28296 (2020). Several Wee1A kinase inhibitors are currently undergoing clinical trials (Bukhari, AB et al Frontiers Oncol 12, 828684 (2022)), and have shown activity in many indications. A Phase II trial of the Wee1A kinase inhibitor AZD1775 (adavosertib) showed promising results in women with serous uterine cancer. Liu, J Fe et al J Clin Oncol 39, 1531-1539 (2021). Adavosertib is used in RAS / TP 53 The treatment has also shown efficacy in mutated metastatic colorectal cancer compared to active monitoring. Seligmann, JFet al J Clin Oncol 39, 3705-3715 (2021). In a phase 1b clinical trial involving 18 patients with platinum-resistant ovarian cancer, the combination of ZN-c3 (azenocertib) and paclitaxel resulted in an ORR of 50% (J Clin Oncol 41, 2023 (suppl 16; abstr 5513)). Given the promising signs of clinical activity from Wee1A kinase inhibition, there is an urgent need for novel Wee1A kinase inhibitors with improved efficacy and selectivity, as well as compounds that inhibit both Wee1A kinase and Myt1 kinase, to maximize the efficacy potential of this target class. [Prior art documents] [Non-patent literature]

[0007]

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Summary of the Invention

Means for Solving the Problems

[0008] In some embodiments, the present disclosure provides a compound of formula I:

Chemical formula

[0009] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0010] In some embodiments, the present disclosure provides a method of inhibiting Wee1A kinase in a patient or a biological sample, the method comprising administering to the patient or contacting the biological sample with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides a method of inhibiting both Wee1A kinase and Myt1 kinase in a patient or a biological sample, the method comprising administering to the patient or contacting the biological sample with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with Wee1A kinase, the method comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with both Wee1A kinase and Myt1 kinase, the method comprising administering to a patient in need thereof a compound of formula I having dual activity or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the disease or disorder associated with Wee1A kinase is cancer. In some embodiments, the disease or disorder associated with Wee1A kinase and Myt1 kinase is cancer. In some embodiments, cancer is selected from brain tumors, cervical brain tumors, cardiac tumors, gastrointestinal cancers, esophageal cancers, thyroid cancers, small cell carcinomas, non-small cell carcinomas, breast cancers, lung cancers, gastric cancers, gallbladder / bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, endometrial cancers, cervical cancers, renal pelvis / ureteral cancers, bladder cancers, prostate cancers, penile cancers, testicular cancers, fetal cancers, Wilms' tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing's tumors, soft tissue sarcomas, acute leukemias, chronic lymphocytic leukemias, chronic myeloid leukemias, polycythemia vera, malignant lymphomas, multiple myelomas, Hodgkin lymphomas, and non-Hodgkin lymphomas. [Modes for carrying out the invention]

[0015] 1. General description of the compounds in this disclosure In some embodiments, the Disclosure provides inhibitors of Wee1A kinase. In some embodiments, such compounds include compounds of the formulas described herein or pharmaceutically acceptable salts thereof, where each variable is as defined and described herein.

[0016] In some embodiments, the present disclosure relates to compounds having structural formula AA: [ka] The formula provides a solvate, enantiomer, tautomer, or diastereomer thereof, or any pharmaceutically acceptable salt thereof, wherein, Each of X, Y, and Z is independently either CH or N. R 1 These are -O-, -NH-, or -N(C1-C3 alkyl)-, Each R 2These are independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluorosubstituted C1-C5 alkyl, or cyanosubstituted C1-C5 alkyl, with two R atoms bonded to the same carbon atom. 2 They optionally combine to form a spirocondensed C3-C7 cycloalkyl ring, or two R atoms bonded to different carbon atoms. 2 They optionally combine to form a crosslinked or condensed C3-C5 cycloalkyl ring, or one R 2 and R 8 They optionally combine to form cross-linked or condensed 3-5 membered rings. R 3 These are -C1-C3 alkyl or -CH2-CH=CH2, R 4 teeth, [ka] [ka] And, [ka] R 4 This represents the bonding point between the compound and the other compound. Each R 5 and each R 6 These are independently hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-(C1-C4 alkyl), C3-C6 cycloalkyl-substituted -O-(C1-C4 alkyl), N-bonded saturated 3-7 member heterocyclyl, 5-6 member heteroaryl, or phenyl, with two or fewer R 6 It is something other than hydrogen, and R on the adjacent ring atom 5 and R 6 R is an optional choice to join together. 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation, R 7 R is hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, or C3-C6 cycloalkyl, 7Any C1-C4 alkyl or C1-C4 alkylene moiety is optionally substituted with one or more substituents independently selected from halo and -CN. R 8 These are hydrogen, -C1-C4 alkyl, or 4-6 member saturated heterocycles. R 9 This is hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-C1-C4 alkyl, or optionally substituted phenyl. m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. m+n is 1, 2, 3, or 4. Any hydrogen atom is optionally replaced by deuterium.

[0017] In some embodiments, the present disclosure relates to compounds having structural formula A: [ka] The formula provides a solvate, enantiomer, tautomer, or diastereomer thereof, or any pharmaceutically acceptable salt thereof, wherein, Each of X, Y, and Z is independently either CH or N. R 1 These are -O-, -NH-, or -N(C1-C3 alkyl)-, Each R 2 These are independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluorosubstituted C1-C5 alkyl, or cyanosubstituted C1-C5 alkyl, with two R atoms bonded to the same carbon atom. 2 They optionally combine to form a spirocondensed C3-C7 cycloalkyl ring, or two R atoms bonded to different carbon atoms. 2 They optionally combine to form a crosslinked C3-C5 cycloalkyl ring, or one R 2 and R 8 They optionally come together to form a bridged 3-5 member ring. R 3These are -C1-C3 alkyl or -CH2-CH=CH2, R 4 teeth, [ka] [ka] And, [ka] R 4 This represents the bonding point between the compound and the other compound. Each R 5 and each R 6 These are independently hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-(C1-C4 alkyl), C3-C6 cycloalkyl-substituted -O-(C1-C4 alkyl), N-bonded saturated 3-7 member heterocyclyl, 5-6 member heteroaryl, or phenyl, with two or fewer R 6 It is something other than hydrogen, and R on the adjacent ring atom 5 and R 6 R is an optional choice to join together. 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation, R 7 R is hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, or C3-C6 cycloalkyl, 7 Any C1-C4 alkyl or C1-C4 alkylene moiety is optionally substituted with one or more substituents independently selected from halo and -CN. R 8 These are hydrogen, -C1-C4 alkyl, or 4-6 member saturated heterocycles. R 9 This is hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-C1-C4 alkyl, or optionally substituted phenyl. m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. m+n is 1, 2, 3, or 4. Any hydrogen atom is optionally replaced by deuterium.

[0018] In some embodiments, the present disclosure relates to compounds having structural formula I: [ka] The formula provides a solvate, enantiomer, tautomer, or diastereomer thereof, or any pharmaceutically acceptable salt thereof, wherein, Each of X, Y, and Z is independently either CH or N. R 1 These are -O-, -NH-, or -N(C1-C3 alkyl)-, Each R 2 These are independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluorosubstituted C1-C5 alkyl, or cyanosubstituted C1-C5 alkyl, with two R atoms bonded to the same carbon atom. 2 They optionally combine to form a spirocondensed C3-C7 cycloalkyl ring, or two R atoms bonded to different carbon atoms. 2 They optionally combine to form a crosslinked C3-C5 cycloalkyl ring, or one R 2 and R 8 They optionally come together to form a bridged 3-5 member ring. R 3 These are -C1-C3 alkyl or -CH2-CH=CH2, R 4 teeth, [ka] [ka] And, [ka] R 4 This represents the bonding point between the compound and the other compound. Each R5 and each R 6 Each of the following is independently hydrogen, halo, -CN, optionally a halo-substituted -C1-C4 alkyl, or optionally a halo-substituted -O-(C1-C4 alkyl), and there are two or fewer R 6 It is something other than hydrogen, and R on the adjacent ring atom 5 and R 6 R is an optional choice to join together. 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation, R 7 R is hydrogen, -C1-C4 alkyl, or -C1-C4 alkylene-O-C1-C4 alkyl, 7 Any C1-C4 alkyl or C1-C4 alkylene moiety is optionally substituted with one or more substituents independently selected from halo and -CN. R 8 is hydrogen or a -C1-C4 alkyl group, R 9 This is hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-C1-C4 alkyl, or optionally substituted phenyl. m is either 0 or 1. n is 0, 1, 2, or 3, and m and n are not both 0 at the same time.

[0019] 2. Compounds and Definitions The compounds disclosed herein include, broadly speaking, those described above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise stated, the following definitions apply. For the purposes of this disclosure, chemical elements are defined as those in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. thIdentified according to Ed. Furthermore, the general principles of organic chemistry are found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5 th This is described in Ed.,Smith, MB and March, J., John Wiley & Sons, New York: 2001 (the entire contents of which are incorporated herein by reference).

[0020] As used herein, the terms “aliphatic” or “aliphatic group” mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as “carbocyclyl,” “alicyclic,” or “cycloalkyl”) and has a single attachment site on the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is either fully saturated or contains one or more unsaturated units but is not aromatic, and has a single attachment site on the rest of the molecule. Preferred aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups and their hybrids (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0021] As used herein, the term "alkyl" means a fully saturated linear or branched hydrocarbon chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.

[0022] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituteable nitrogen in a heterocyclic ring, e.g., N (like 3,4-dihydro-2H-pyrrolyl), NH (like pyrrolidinyl), or NR) + (Including N-substituted pyrrolidinyls))

[0023] As used herein, the term "unsaturated" means that a part has one or more unsaturated units.

[0024] As used herein, the term “partially unsaturated” refers to a moiety containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass moieties having multiple unsaturated sites, but when used to describe a ring, it is not intended to include aryl or heteroaryl moieties as defined herein.

[0025] The term "saturated" refers to a region that does not contain double or triple bonds.

[0026] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents for carbon atoms are those described later.

[0027] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents for carbon atoms are those described later.

[0028] "Halogen" and "halo" are used interchangeably and refer to F, Cl, Br, or I.

[0029] The term "aryl," used alone, or as part of a larger term such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic and bicyclic ring systems having 5 to 14 ring members in total, with each ring atom being carbon, at least one ring in the system being aromatic, and each ring in the system containing 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of this disclosure, "aryl" refers to an aromatic ring system (including, but not limited to, phenyl, biphenyl, naphthyl, anthratil, etc.) which may have one or more substituents. Groups in which an aromatic ring is fused with one or more non-aromatic carbocyclic rings are also included in the scope of the term "aryl" as used herein.

[0030] The term "cycloalkyl ring" refers to a fully saturated carbocyclic ring.

[0031] A first ring is "spiro-condensed" with a second ring when these two rings share a single ring carbon atom. An example of a spiro-condensed ring system is: [ka] There is.

[0032] The first ring is "condensed" with the second ring when these two rings share two ring carbon atoms and are directly connected to each other. An example of a condensed ring system is: [ka] There is.

[0033] The first ring is "bridged" to the second ring when the two rings share two ring carbon atoms separated by at least one ring carbon atom. Examples of bridged ring systems include

Chem.

[0034] Reference to the number of atoms in a bridged ring, for example, when one R 2 and R 8 come together to form a bridged 3- to 5-member ring, refers to the sum of the two bridgehead ring atoms and any additional ring atoms between these bridgehead atoms that form the existing ring and the bridged ring. For example, the structure

Chem.

Chem.

Chem.

[0035] The terms “heteroaryl” and “heteroara-” are used alone or as part of a larger phrase (e.g., “heteroaralkyl” or “heteroaralkoxy”) to refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, sharing 6, 10, or 14 π electrons within a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes oxidized forms of nitrogen or sulfur, and any quaternized forms of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroaryl-” include groups in which a heteroaromatic ring is fused with one or more aryl or heteroaryl rings, resulting in a bicyclic or polycyclic ring system that is entirely aromatic as a whole. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. Heteroaryl groups may be monocyclic or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently and optionally substituted.

[0036] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably 1 to 4, heteroatoms as defined above, in addition to the carbon atom. When used with respect to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (in the case of 3,4-dihydro-2H-pyrrolyl), NH (in the case of pyrrolidinyl), or +NR (in the case of N-substituted pyrrolidinyl).

[0037] Heterocyclic rings may bond to any heteroatom or carbon atom of their pendant group, resulting in a stable structure, or any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which a heterocyclic ring is fused with one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanslidinyl, or tetrahydroquinolinyl). Heterocyclyl groups may be monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl moiety and heterocyclyl moiety are independently and optionally substituted.

[0038] As used herein, the compounds of this disclosure may contain “optionally substituted” moieties. Generally, the term “substituted,” whether preceded by the term “optionally,” means that one or more hydrogens of the indicated moiety are replaced by preferred substituents. Unless otherwise indicated, an “optionally substituted” group may have preferred substituents at each of its substituted positions, and the substituents may be the same or different at all positions if two or more positions in any given structure can be replaced by two or more substituents selected from the specified group. The substituent combinations envisioned by this disclosure preferably result in the formation of stable or chemically feasible compounds. As used herein, “stability” means a compound that remains substantially unchanged when subjected to conditions that enable its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0039] "Cyano substitution C x -C y "Alkyl" and "Fluorosubstituted C" x -C y The term "alkyl" (where x and y are integers) refers to the corresponding alkyl group that has one or more of the substituents shown instead of hydrogen.

[0040] A suitable monovalent substituent on the replaceable carbon atom of the "optionally substituted" group is, independently, a halogen;-(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph(may be substituted with R°);-(CH2) 0-4 O(CH2) 0-1 P (may be substituted with R°); -CH=CHPh (may be substituted with R°); -(CH2)0-4 O(CH2) 0-1 -pyridyl (which may be substituted by R°); -NO2; -CN; -N3; (CH2) 0-4 N(R°)2; -(CH2) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2) 0-4 N(R°)C(O)NR°2; N(R°)C(S)NR°2; -(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; N(R°)N(R°)C(O)NR°2; N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°; -C(S)R°; -(CH2) 0-4 C(O)OR°; -(CH2) 0-4 C(O)SR°; (CH2) 0-4 C(O)OSiR°3; -(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR°、SC(S)SR°; -(CH2) 0-4 SC(O)R°; -(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°、(CH2) 0-4 OC(O)NR°2; C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; (CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°; -(CH2) 0-4 S(O)2OR°; -(CH2) 0-4 OS(O)2R°; -S(O)2NR°2; (CH2) 0-4 S(O)R°; N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; P(O)R°2; OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 linear or branched alkylene)O-N(R°)2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R°)2, where each R° may be substituted as defined below and is independently hydrogen, C 1-6Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 member heteroaryl), or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, the appearance of two independent R°s together with their intervening atom(s) to form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0041] Suitable monovalent substituents on R° (or rings formed by the appearance of two independent R° atoms together with their intervening atoms) are, independently, halogens, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2;O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● ,-(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. C(O)SR ● ,-(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● And each R ●If it is unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 The R° ring is selected from a 5-7 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on such a saturated carbon atom include =O and =S.

[0042] Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" groups include: =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-(where each independent R * The presence of hydrogen may be substituted as defined below. 1~6 (Selected from an aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur). Preferred divalent substituents bonded to a substituted carbon near the "optionally substituted" group include -O(CR * 2) 2-3 O- is mentioned, and in the formula, each independent R * The presence of hydrogen may be substituted as defined below. 1-6 Selected from aliphatic or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] R * Suitable substituents on the aliphatic group include halogens and -R ● , (HALO R), OH, -OR ● ,-O(HaroR● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and in the formula, each R ● If it is unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0044] A suitable substituent on the substituted nitrogen of the "optionally substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed, and in the formula, each R † C may be substituted independently with hydrogen, as defined below. 1~6 Aliphatic, unsubstituted-OPh, or substituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent R † The presence of these atoms, together with the intervening atom(s), forms a monocyclic or bicyclic aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which are either unsubstituted 3-12 member saturated, partially unsaturated, or nitrogen, oxygen, or sulfur.

[0045] R †The aliphatic group and the substituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur are, independently, halogens, -R ● , (HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or NO2, and each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0046] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within reasonable medical judgment, is suitable for use in contact with human or lower animal tissues without excessive toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (as incorporated herein by reference). pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed by using inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.

[0047] Suitable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+ (C 1~4 Examples include alkyl)4 salts. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions (e.g., halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acid, and aryl sulfonic acid ions) where appropriate.

[0048] Unless otherwise specified, the structures shown herein are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or stereostructural)) in the structure, such as R and S configurations at each chiral center, Z and E double bond isomers, rotational isomers (atropisomers), and Z and E stereostructural isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomers, diastereomers, and geometric (or stereostructural) mixtures, are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of this disclosure are within the scope of this disclosure. In addition, unless otherwise specified, the structures shown herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, hydrogen substitution with deuterium or tritium, or 13 C or 14 Compounds having the structure of the present invention, including carbon substitution with 1C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to this disclosure.

[0049] The substituent-variable combinations envisioned in this disclosure are limited to those that result in the formation of stable compounds. As used herein, the term “stable” means a compound that possesses sufficient stability to enable manufacturing and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0050] The listing of a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. When embodiments for a variable are recited herein, the embodiments are also included as any single embodiment or in combination with any other embodiment or portion thereof.

[0051] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsy materials obtained from mammals or extracts thereof, and hair, skin, blood, saliva, urine, feces, sperm, tears, or other body fluids or extracts thereof. Inhibition of the activity of protein kinases (e.g., Wee1A kinase or variants thereof) in biological samples is useful for a variety of purposes known to those of skill in the art. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, preservation of biological specimens, and biological assays.

[0052] As used herein, "disease or disorder associated with Wee1A kinase" or "Wee1A kinase-mediated disease or disorder" means a disease or other adverse condition in which Wee1A kinase or a variant thereof is known or suspected to be involved.

[0053] As used herein, the term "subject" means a mammal, including human and animal subjects, e.g., domesticated animals (e.g., horses, dogs, cats, etc.). As used herein, the terms "subject" and "patient" are used interchangeably. In some embodiments, "patient" or "subject" means an animal, preferably a mammal, and most preferably a human.

[0054] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compounds formulated together. Examples of pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. The amount of the compounds of this disclosure that can be combined with a carrier material to prepare a composition in a single dosage form varies depending on the host being treated, the specific method of administration, and so on. The compositions provided are preferably formulated so that a dose of the inhibitor, of the target body weight / day, of 0.01 to about 100 mg / kg, or about 0.1 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, can be administered to a patient receiving these compositions to obtain the desired therapeutic effect. The amount of the compounds of this disclosure in the composition also depends on the specific compound in the composition.

[0055] As used herein, the terms “treatment,” “to treat,” and “to treat” mean, as described herein, partial or complete relief, suppression, delay of onset, prevention, improvement, and / or reduction of a disorder or condition, or one or more symptoms of a disorder or condition. In some embodiments, treatment may be administered after the onset of one or more symptoms. In some embodiments, the term “to treat” includes the prevention or cessation of the progression of a disease or disorder. In other embodiments, treatment may be performed even in the absence of symptoms. For example, treatment may be performed on a susceptible individual before the onset of symptoms (for example, taking into account a medical history of the symptoms and / or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay the recurrence of symptoms. Thus, in some embodiments, the term “to treat” includes preventing relapse or recurrence of a disease or disorder.

[0056] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits a target protein kinase with measurable affinity. In certain embodiments, the IC of the inhibitor 50 The and / or coupling constants are less than approximately 50 mM, less than approximately 1 mM, less than approximately 500 nM, less than approximately 100 nM, less than approximately 50 nM, less than approximately 20 nM, or less than approximately 10 nM.

[0057] As used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in Wee1A kinase or Myt1 kinase activity between a sample containing the compound or composition of the disclosed herein and an equivalent sample containing Wee1A kinase or Myt1 kinase in the absence of the compound or composition of the disclosed herein.

[0058] As used herein, the terms “dual inhibitor” and “dual Wee1A kinase / Myt1 kinase inhibitor” are interchangeable and are based on the following criteria: 1) Myt1 kinase binding activity IC2 50≤100nM (i.e., a rating of "A" or "B" in Table 3); or 2) Myt1 kinase target-binding EC 50 This refers to compounds disclosed herein that satisfy one or more of the following criteria: ≤500 nM (i.e., an evaluation of "A" or "B" in Table 4).

[0059] 3. Description of exemplary compounds In some embodiments, the present disclosure relates to compounds having structural formula AA: [ka] The formula provides a solvate, enantiomer, tautomer, or diastereomer thereof, or any pharmaceutically acceptable salt thereof, wherein, Each of X, Y, and Z is independently either CH or N. R 1 These are -O-, -NH-, or -N(C1-C3 alkyl)-, Each R 2 These are independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluorosubstituted C1-C5 alkyl, or cyanosubstituted C1-C5 alkyl, with two R atoms bonded to the same carbon atom. 2 They optionally combine to form a spirocondensed C3-C7 cycloalkyl ring, or two R atoms bonded to different carbon atoms. 2 They optionally combine to form a crosslinked or condensed C3-C5 cycloalkyl ring, or one R 2 and R 8 They optionally combine to form cross-linked or condensed 3-5 membered rings. R 3 These are -C1-C3 alkyl or -CH2-CH=CH2, R 4 teeth, [ka] [ka] And, [ka] R 4 This represents the bonding point between the compound and the other compound. Each R 5 and each R 6 These are independently hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-(C1-C4 alkyl), C3-C6 cycloalkyl-substituted -O-(C1-C4 alkyl), N-bonded saturated 3-7 member heterocyclyl, 5-6 member heteroaryl, or phenyl, with two or fewer R 6 It is something other than hydrogen, and R on the adjacent ring atom 5 and R 6 R is an optional choice to join together. 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation, R 7 R is hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, or C3-C6 cycloalkyl, 7 Any C1-C4 alkyl or C1-C4 alkylene moiety is optionally substituted with one or more substituents independently selected from halo and -CN. R 8 These are hydrogen, -C1-C4 alkyl, or 4-6 member saturated heterocycles. R 9 This is hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-C1-C4 alkyl, or optionally substituted phenyl. m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. m+n is 1, 2, 3, or 4. Any hydrogen atom is optionally replaced by deuterium.

[0060] In some embodiments, the present disclosure relates to compounds having structural formula A: [ka] The formula provides a solvate, enantiomer, tautomer, or diastereomer thereof, or any pharmaceutically acceptable salt thereof, wherein, Each of X, Y, and Z is independently either CH or N. R 1 These are -O-, -NH-, or -N(C1-C3 alkyl)-, Each R 2 These are independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluorosubstituted C1-C5 alkyl, or cyanosubstituted C1-C5 alkyl, with two R atoms bonded to the same carbon atom. 2 They optionally combine to form a spirocondensed C3-C7 cycloalkyl ring, or two R atoms bonded to different carbon atoms. 2 They optionally combine to form a crosslinked C3-C5 cycloalkyl ring, or one R 2 and R 8 They optionally come together to form a bridged 3-5 member ring. R 3 These are -C1-C3 alkyl or -CH2-CH=CH2, R 4 teeth, [ka] [ka] And, [ka] R 4 This represents the bonding point between the compound and the other compound. Each R 5 and each R 6 These are independently hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-(C1-C4 alkyl), C3-C6 cycloalkyl-substituted -O-(C1-C4 alkyl), N-bonded saturated 3-7 member heterocyclyl, 5-6 member heteroaryl, or phenyl, with two or fewer R 6 It is something other than hydrogen, and R on the adjacent ring atom 5 and R6 R is an optional choice to join together. 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation, R 7 R is hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, or C3-C6 cycloalkyl, 7 Any C1-C4 alkyl or C1-C4 alkylene moiety is optionally substituted with one or more substituents independently selected from halo and -CN. R 8 These are hydrogen, -C1-C4 alkyl, or 4-6 member saturated heterocycles. R 9 This is hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-C1-C4 alkyl, or optionally substituted phenyl. m is 0, 1, 2, or 3. n is 0, 1, 2, or 3. m+n=1, 2, 3, or 4, and any hydrogen atom in equation A is optionally substituted with deuterium.

[0061] In some embodiments, the present disclosure relates to compounds having structural formula I: [ka] The formula provides a solvate, enantiomer, tautomer, or diastereomer thereof, or any pharmaceutically acceptable salt thereof, wherein, Each of X, Y, and Z is independently either CH or N. R 1 These are -O-, -NH-, or -N(C1-C3 alkyl)-, Each R 2 These are independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluorosubstituted C1-C5 alkyl, or cyanosubstituted C1-C5 alkyl, with two R atoms bonded to the same carbon atom. 2They optionally combine to form a spirocondensed C3-C7 cycloalkyl ring, or two R atoms bonded to different carbon atoms. 2 They optionally combine to form a crosslinked C3-C5 cycloalkyl ring, or one R 2 and R 8 They optionally come together to form a bridged 3-5 member ring. R 3 These are -C1-C3 alkyl or -CH2-CH=CH2, R 4 teeth, [ka] [ka] And, [ka] R 4 This represents the bonding point between the compound and the other compound. Each R 5 and each R 6 Each of the following is independently hydrogen, halo, -CN, optionally a halo-substituted -C1-C4 alkyl, or optionally a halo-substituted -O-(C1-C4 alkyl), and there are two or fewer R 6 It is something other than hydrogen, and R on the adjacent ring atom 5 and R 6 R is an optional choice to join together. 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation, R 7 R is hydrogen, -C1-C4 alkyl, or -C1-C4 alkylene-O-C1-C4 alkyl, 7 Any C1-C4 alkyl or C1-C4 alkylene moiety is optionally substituted with one or more substituents independently selected from halo and -CN. R 8 is hydrogen or a -C1-C4 alkyl group, R 9This is hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-C1-C4 alkyl, or optionally substituted phenyl. m is either 0 or 1. n is 0, 1, 2, or 3. m and n are not both zero at the same time.

[0062] As generally defined above and discussed throughout, each of X, Y, and Z is independently CH or N.

[0063] In some embodiments, each of X, Y, and Z is CH (i.e., the ring containing X, Y, and Z is phen-2,6-diyl). In some embodiments, X is N and each of Y and Z is CH (i.e., the ring is pyridine-2,6-diyl). In some embodiments, X and Y are N and Z is CH (i.e., the ring is pyrimidine-2,6-diyl). In some embodiments, each of X and Z is N and Y is CH (i.e., the ring is pyrazine-2,6-diyl).

[0064] As generally defined above and discussed throughout, R 1 These are -O-, -NH-, or -N(C1-C3 alkyl)-.

[0065] In some embodiments, R 1 is -O-. In some embodiments, R 1 is -NH-. In some embodiments, R 1 is -N(CH3)-. In some embodiments, R 1 is -N(CH2CH3)-. In some embodiments, R 1 It is -N(CH2CH2CH3)-.

[0066] As generally defined above and discussed throughout, each R 2If present, these are independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluorosubstituted C1-C5 alkyl, or cyanosubstituted C1-C5 alkyl, with two R atoms bonded to the same carbon atom. 2 These may optionally combine to form a spirocondensed C3-C7 cycloalkyl ring, or two R atoms bonded to different carbon atoms. 2 They optionally combine to form a crosslinked or condensed C3-C5 cycloalkyl ring, or one R 2 and R 8 These elements optionally combine to form bridged or condensed 3-5 membered rings.

[0067] R 2 In the definition, a spiro-condensation, condensation, or crosslinking ring is a ring formed by two R 2 or R 2 and R 8 The ring formed by combining substituents, and how that ring is in formula I [ka] This indicates whether it is bonded to the ring shown as two R 2 or one R 2 and one R 8 Examples of such spiro-condensed, condensed, and cross-linked ring systems formed by combining them are, but are not limited to, [ka] These are some examples.

[0068] In some embodiments, R 2 It is absent. In some embodiments, one R 2 and R 8 They are together with the ring to which they are joined. [ka] Forms one R 2 and R 8 They are together with the ring to which they are joined. [ka] Forms one R 2 and R 8 They are together with the ring to which they are joined. [ka] It forms.

[0069] As generally defined above and discussed throughout, R 3 is -C1-C3 alkyl or -CH2-CH=CH2. In some embodiments, R 3 is -CH2-CH=CH2. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 It is n-propyl.

[0070] As generally defined above and discussed throughout, R 4 teeth, [ka] [ka] That is the case.

[0071] In some embodiments, R 4 teeth [ka] In some embodiments of this model, R 5 R is hydrogen. In some aspects of any of these embodiments, R 5 is a C1-C4 alkyl group. In some embodiments of this model, R 5 is methyl. In some embodiments of this embodiment, R 5is -CN. In some embodiments of any of these embodiments, R 5 is a halo. In some embodiments of this model, R 5 is chloro. In some embodiments of this model, R 5 is fluoro. In some embodiments of this embodiment, R 5 is bromo. In some embodiments of any of these embodiments, R 5 is optionally a halo-substituted -O-(C1-C4 alkyl). In some embodiments of any of these embodiments, R 5 is optionally substituted with fluoro-O-(C1-C4 alkyl). In some embodiments of this embodiment, R 5 is -OCF3. In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is a halo. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is chloro. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is fluoro. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is bromo. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is an optionally substituted -C1-C4 alkyl group with a halo. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is optionally a fluorosubstituted -C1-C4 alkyl. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is -CH3. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6is -CF3. In some aspects of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is optionally a halo-substituted -O(C1-C4 alkyl). In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is optionally substituted with fluoro-O(C1-C4 alkyl). In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is -OCH3. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is -OCH2CF3. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is -CN. In some embodiments of this model, R bonded to an adjacent ring atom 5 and R 6 These combine to form methylenedioxy. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is cyclopropylmethoxy. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is morpholinyl. In some embodiments of this embodiment, one R 6 R is methyl, and the other R is methyl 6 is morpholinyl. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is thiomorpholinyl. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is 2-methylpropan-1-yloxy. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is 1-methyl-1H-pyrazolyl. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6is a phenyl compound optionally substituted with a halo. In some embodiments of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 This is an ethyl oxy compound optionally substituted with a halo.

[0072] In some embodiments, R 4 is one of the following: phenyl, 3-methylphenyl, 3-chloro-5-bromophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-(1-methylpiperidine-4-yl)-5-methylphenyl, 4-trifluoromethoxyphenyl, 3-methyl-4-trifluoromethoxyphenyl, 4-(2,2,2-trifluoroethane-1-yl)oxyphenyl, 3-methyl-4-(2,2,2-trifluoroethane-1-yl)oxyphenyl, 4-trifluoromethylphenyl, 3-methyl-4-chlorophenyl, 3-methyl-4-fluorophenyl, 3-methyl-5-fluorophenyl, 3-methyl-4-cyanophenyl, 3-methyl-4-methoxyphenyl, 3-methyl-4-(2,2,2-trifluoroethane-1-yloxy)phenyl, or 3,4-methylenedioxyphenyl.

[0073] In some embodiments, R 44-(cyclopropylmethyloxy)phenyl, 4-(morpholine-4-yl)phenyl, 4-(thiomorpholine-4-yl)phenyl, 4-(2-methylpropane-1-yloxy)phenyl, 3-(1-methyl-1H-pyrazole-4-yl)phenyl, 4-(1-methyl-1H-pyrazole-4-yl)phenyl, 3-methyl-4-(morpholine-4-yl)phenyl, 4-(phenyl)phenyl, 3-bromophenyl, 3-cyanophenyl, 4-( It is one of the following: 2-fluoroethane-1-yloxy)phenyl, 4-cyanophenyl, 4-(1,1-dioxothiazinan-4-yl)phenyl, 3-(pyridine-3-yl)phenyl, 3-(pyrimidine-5-yl)phenyl, 3-(1H-imidazole-1-yl)phenyl, 3-(1H-pyrazole-1-yl)phenyl, 3-(d3-methyl)phenyl, 4-(3-fluoropropane-1-yloxy)phenyl, or 4-ethoxyphenyl.

[0074] In some embodiments, R 4 teeth [ka] In some embodiments, R 4 teeth [ka] In some embodiments of either of these two embodiments, R 5 R is hydrogen. In some aspects of any of these embodiments, R 5 is a halo. In some embodiments of any of these embodiments, R 5 is chloro. In some embodiments of any of these embodiments, R 5 is fluoro. In some embodiments of any of these embodiments, R 5 is cyano. In some embodiments of any of these embodiments, R 5 is a C1-C4 alkyl group optionally substituted with a halo. In some embodiments of any of these embodiments, R5 is optionally a fluorosubstituted C1-C4 alkyl. In some embodiments of any of these embodiments, R 5 is an -O-C1-C4 alkyl group. In some embodiments of any of these embodiments, R 5 R is methoxy. In some embodiments of any of these embodiments, R 5 is methyl. In some embodiments of any of these embodiments, R 5 is -CF3. In some aspects of any of these embodiments, R 6 R is hydrogen. In some aspects of any of these embodiments, R 6 is methyl. In some embodiments of any of these embodiments, R 6 is an -O-C1-C4 alkyl group. In some embodiments of any of these embodiments, R 6 R is methoxy. In some embodiments of any of these embodiments, R 6 R is a -O-C1-C4 haloalkyl. In some embodiments of any of these embodiments, R 6 It is 2-fluoroethoxy.

[0075] In some embodiments, R 4 This is one of the following: 2-methylpyridine-4-yl, 6-methylpyridine-3-yl, 2,6-dimethylpyridine-4-yl, 2-trifluoromethyl-6-methylpyridine-4-yl, or 2-trifluoromethylpyridine-4-yl.

[0076] In some embodiments, R 4 This is one of the following: pyridine-3-yl, 2-methylpyridine-5-yl, 2-methoxypyridine-4-yl, 2-methoxypyridine-5-yl, 3-chloropyridine-5-yl, 3-fluoropyridine-5-yl, 3-cyanopyridine-5-yl, 3-methylpyridine-5-yl, or 3-methoxypyridine-5-yl.

[0077] In some embodiments, R 4 It is 2-(2-fluoroethoxy)pyridine-5-yl.

[0078] In some embodiments, R 4 teeth [ka] In some embodiments of this model, R 7 is a C1-C4 alkyl group optionally substituted with a halo. In some embodiments of this embodiment, R 7 is a C1-C4 alkyl group optionally substituted with fluoropolymer. In some embodiments of this embodiment, R 7 is methyl. In some embodiments of this embodiment, R 7 is ethyl. In some embodiments of this embodiment, R 7 R is propyl. In some embodiments of this embodiment, R 7 is isopropyl. In some embodiments of this embodiment, R 7 is -CH2CH(CH3)2. In some aspects of this embodiment, R 7 is -CH2C(CH3)2F. In some embodiments of this embodiment, R 7 is -CH2CH2CF3. In some embodiments of this embodiment, R 4 This is one of the following: 1-methyl-1H-pyrazole-4-yl, 1-propyl-1H-pyrazole-4-yl, 1-isopropyl-1H-pyrazole-4-yl, 1-(2,2-dimethylethane-1-yl)pyrazole-4-yl, 1-(2-fluoro-2,2-dimethylethane-1-yl)-1H-pyrazole-4-yl, or 1-(3,3,3-trifluoropropane-1-yl)-1H-pyrazole-4-yl.

[0079] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 7 is hydrogen. In some embodiments of this embodiment, R 7 is a C1-C4 alkyl group optionally substituted with a halo. In some embodiments of this embodiment, R 7 is a C1-C4 alkyl group optionally substituted with fluoropolymer. In some embodiments of this embodiment, R 7 is methyl. In some embodiments of this embodiment, R 7 is ethyl. In some embodiments of this embodiment, R 7 R is propyl. In some embodiments of this embodiment, R 7 is isopropyl. In some embodiments of this embodiment, R 7 is -CH2CH(CH3)2. In some aspects of this embodiment, R 7 is -CH2C(CH3)2F. In some embodiments of this embodiment, R 7 is -CH2CH2CF3. In some embodiments of this embodiment, R 7 is cyclopropyl. In some embodiments of this embodiment, R 7 isobutyl. In some embodiments of this embodiment, R 7 R is 3-fluoropropyl. In some embodiments of this embodiment, 4 R is 1-methyl-1H-indazole-5-yl. In some embodiments, R 4 The following are selected from 1H-indazole-5-yl, 1-methyl-1H-indazole-5-yl, 1-ethyl-1H-indazole-5-yl, 1-isopropyl-1H-indazole-5-yl, 1-propyl-1H-indazole-5-yl, 1-(3-fluoropropan-1-yl)-1H-indazole-5-yl, 1-isobutyl-1H-indazole-5-yl, and 1-cyclopropyl-1H-indazole-5-yl.

[0080] In some embodiments, R4 but [ka] If so, one of R 6 R is hydrogen, and the other R is hydrogen. 6 is methyl or halo. In some embodiments of this model, R 4 These are 3-chloro-1H-indazole-5-yl, 3-methyl-1H-indazole-5-yl, or 1,3-dimethyl-1H-indazole-5-yl.

[0081] In some embodiments, R 4 teeth [ka] In some embodiments of this model, R 7 is hydrogen. In some embodiments of this embodiment, R 7 is methyl. In some embodiments of this embodiment, R 7 is ethyl. In some embodiments of this embodiment, R 7 is t-butyl. In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 4 is 2-methyl-2H-indazole-5-yl or 2-ethyl-2H-indazole-5-yl. In some embodiments of this embodiment, R 4 It is 2-(t-butyl)-2H-indazole-5-yl.

[0082] In some embodiments, R 4 teeth [ka] In some embodiments of this model, R 9 R is a optionally substituted phenyl. In some embodiments of this embodiment, R 9 R is an unsubstituted phenyl. In some embodiments of this embodiment, R4 It is 3-phenylisothiazole-5-yl.

[0083] In some embodiments, R 4 teeth [ka] In some embodiments, R 4 teeth [ka] In some aspects of each of these embodiments, each R 6 is hydrogen. In some embodiments of each of these embodiments, two R 6 It is hydrogen, and the other R 6 is something other than hydrogen. In some aspects of each of these embodiments, one R 6 is hydrogen, and the other two R 6 is something other than hydrogen. In some aspects of this embodiment, R 4 is benzofuran-6-yl. In some embodiments of this embodiment, R 4 It is benzofuran-5-yl.

[0084] In some embodiments, R 4 teeth [ka] In some embodiments of this model, R 7 is a C1-C4 alkyl group. In some embodiments of this model, R 7 is methyl. In some embodiments of this embodiment, R 7 is -C(O)CH3. In some embodiments of this model, each R 6 is hydrogen. In some aspects of this embodiment, two R 6 It is hydrogen, and the other R 6 is something other than hydrogen. In some aspects of this embodiment, one R 6 is hydrogen, and the other two R6 is something other than hydrogen. In some aspects of this embodiment, R 4 R is 1-methyl-1H-indole-5-yl. In some embodiments of this model, R 4 It is 1-acetyl-1H-indole-5-yl.

[0085] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 4 It is 1,2,4-triazolo[1,5-a]pyridine-6-yl.

[0086] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 4 It is quinoxaline-6-yl.

[0087] In some embodiments, R 4 teeth, [ka] Selected from one of the following. In some embodiments of this model, each R 6 is hydrogen. In some embodiments of this embodiment, R 4 These are quinoline-6-yl, quinoline-7-yl, isoquinoline-6-yl, or isoquinoline-7-yl.

[0088] In some embodiments, R 4 teeth, [ka] In some embodiments of these embodiments, each R 6 is hydrogen. In some embodiments of these embodiments, one R 6 R is hydrogen, and the other R is hydrogen. 6 R is methyl. In some embodiments of these embodiments, R 4 These are 2-methylbenzo[d]oxazole-5-yl or 2-methylbenzo[d]oxazole-6-yl.

[0089] In some embodiments, R 4 teeth [ka] In some embodiments of these embodiments, each R 6 is hydrogen. In some embodiments of these embodiments, R 4 It is benzo[d]isoxazole-6-yl.

[0090] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this model, one R 6 R is hydrogen, and the other R is hydrogen. 6 is methyl. In some embodiments of this embodiment, R 4 These are benzo[d]thiazole-6-yl or 2-methylbenzo[d]thiazole-6-yl.

[0091] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R7 is methyl. In some embodiments of this embodiment, R 4 R is 1-methyl-1H-benzo[d]imidazole-5-yl. In some embodiments of this model, R 7 is isopropyl. In some embodiments of this embodiment, R 4 It is 1-isopropyl-1H-benzo[d]imidazole-5-yl.

[0092] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 4 It is benzo[d]thiazole-5-yl.

[0093] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 7 is methyl. In some embodiments of this embodiment, R 4 It is 1-methyl-1H-indazole-6-yl.

[0094] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 7 is methyl. In some embodiments of this embodiment, R 4 It is 2-methyl-2H-indazole-6-yl.

[0095] In some embodiments, R 4 teeth [ka] In some aspects of this embodiment, each R 6 is hydrogen. In some embodiments of this embodiment, R 4 It is imidazo[1,2-a]pyridine-6-yl.

[0096] In some embodiments, R 4 teeth [ka] In some embodiments of this model, R 6 is hydrogen. In some embodiments of this embodiment, R 7 is a C1-C4 alkyl group. In some embodiments of this model, R 7 is isopropyl. In some embodiments of this embodiment, R 4 It is 1-isopropyl-1H-pyrazolo[3,4-b]pyridine-5-yl.

[0097] In some embodiments, R 4 teeth [ka] In some embodiments of this model, R 6 is hydrogen. In some embodiments of this embodiment, R 7 is a C1-C4 alkyl group. In some embodiments of this model, R 7 is isopropyl. In some embodiments of this embodiment, R 4 It is 1-isopropyl-1H-benzo[d][1,2,3]triazole-5-yl.

[0098] As generally defined above and discussed throughout, R 5(is hydrogen, halo, -CN, optionally a halo-substituted -C1-C4 alkyl, or optionally a halo-substituted -O-(C1-C4 alkyl), or R on an adjacent ring atom) 5 and R 6 They came together, R 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halo. In some embodiments, R 5 is chloro. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is a C1-C4 alkyl group optionally substituted with a halo. In some embodiments, R 5 is a C1-C4 alkyl group optionally substituted with fluoropolymer. In some embodiments, R 5 is methyl. In some embodiments, R 5 is -CF3. In some embodiments, R on adjacent ring atoms 5 and R 6 Together, R 4 It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation. In some embodiments, R on adjacent ring atoms 5 and R 6 Together, R 4 It condenses with it to form methylenedioxy.

[0099] As generally defined above and discussed throughout, each R 6 Each of the following is independently hydrogen, halo, -CN, optionally a halo-substituted -C1-C4 alkyl, or optionally a halo-substituted -O-(C1-C4 alkyl), and there are two or fewer R 6 is something other than hydrogen. In some embodiments, one or less R 6 is something other than hydrogen. In some embodiments, each R 6 is hydrogen. In some embodiments, one R 6is a halo. In some embodiments, one R 6 is chloro. In some embodiments, one R 6 is fluoro. In some embodiments, one R 6 is bromo. In some embodiments, one R 6 is an optionally substituted -C1-C4 alkyl group with a halo. In some embodiments, one R 6 is an optionally fluorosubstituted -C1-C4 alkyl. In some embodiments, one R 6 is -CH3. In some embodiments, one R 6 is -CF3. In some aspects of this embodiment, one R 6 R is hydrogen, and the other R is hydrogen. 6 is a halo. In some embodiments, one R 6 is optionally a halo-substituted -O(C1-C4 alkyl). In some embodiments, one R 6 is optionally substituted with fluoro-O(C1-C4 alkyl). In some embodiments, one R 6 is -OCH3. In some embodiments, one R 6 is -OCH2CF3. In some embodiments, R 6 is -CN.

[0100] As generally defined above and discussed throughout, R 7 R is hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, or C3-C6 cycloalkyl, 7 Any C1-C4 alkyl or C1-C4 alkylene moiety is optionally substituted with one or more substituents independently selected from halo and -CN. In some embodiments, R 7 is a C1-C4 alkyl group optionally substituted with a halo. In some embodiments, R 7is a C1-C4 alkyl group optionally substituted with fluoropolymer. In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is propyl. In some embodiments, R 7 is isopropyl. In some embodiments, R 7 is -CH2CH(CH3)2. In some embodiments, R 7 is -CH2C(CH3)2F. In some embodiments, R 7 is -CH2CH2CF3. In some embodiments, R 7 is -CH2CH2CH2F3. In some embodiments, R 7 is cyclopropyl. In some embodiments, R 7 It is -C(O)CH3.

[0101] As generally defined above and discussed throughout, R 8 is hydrogen, a -C1-C4 alkyl group, or a 4- to 6-membered saturated heterocycle. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is propyl. In some embodiments, R 8 It is oxetane-3-yl.

[0102] As generally defined above and discussed throughout, R 9 R is hydrogen, halo, -CN, optionally halo-substituted -C1-C4 alkyl, optionally halo-substituted -O-C1-C4 alkyl, or optionally substituted phenyl. In some embodiments, R 9 It is an unsubstituted phenyl compound.

[0103] Structure, as generally defined above and discussed throughout: [ka] A monocyclic or heterocyclic ring represented by can contain 4 (when the sum of m+n is 1) to 7 (when the sum of m+n is 4) ring atoms. In some embodiments, two R atoms bonded to the same carbon atom 2 When these combine to form a C3-C7 cycloalkyl ring, the ring may be a spiro-condensed bicyclic ring. In some embodiments, two R atoms bonded to different carbon atoms 2 When they come together to form a C3-C5 cycloalkyl ring, that ring may be a bridging bicyclic ring. In some embodiments, one R 2 and R 8 When these combine to form a 3- to 5-membered ring, the ring may be a bridging bicyclic ring. In some embodiments, two R atoms bonded to different carbon atoms 2 When they come together to form a C3-C5 cycloalkyl ring, that ring may be a fused bicyclic ring. In some embodiments, one R 2 and R 8 When these elements combine to form a 3- to 5-membered ring, that ring can be a fused bicyclic ring.

[0104] In some embodiments, the structure: [ka] The ring represented by is a piperidinyl ring. In some embodiments of these embodiments, the piperidinyl ring is a piperidin-3-yl ring (i.e., n is 1 and m is 2; or n is 3 and m is 0). In some embodiments of these embodiments, the piperidinyl ring is a piperidin-4-yl ring (i.e., n is 2 and m is 1). In some embodiments of these embodiments, R on such a piperidinyl ring 8 The substituent is hydrogen. In some embodiments of these embodiments, such as R on the piperidinyl ring 8The substituent is methyl. In some embodiments of these embodiments, such as R on the piperidinyl ring 8 The substituent is triduteromethyl(methyl-d3). In some embodiments of these embodiments, such R on the piperidinyl ring 8 The substituent is ethyl. In some embodiments of these embodiments, such as R on the piperidinyl ring 8 The substituent is isopropyl. In some embodiments of these embodiments, such as R on the piperidinyl ring 8 The substituent is propyl. In some embodiments of these embodiments, R 2 is absent. In some embodiments of these embodiments, one or more R 2 is methyl. In some aspects of these embodiments, the piperidinyl ring is piperidinyl-4-yl, piperidinyl-3-yl, 1-methylpiperidine-4-yl, 1-d3-methylpiperidine-4-yl, 1-methylpiperidine-3-yl, 1-ethylpiperidine-4-yl, 1-propylpiperidine-4-yl, 1,2-dimethylpiperidine-4-yl, 2,2-dimethylpiperidine-4-yl, 2-methylpiperidine-4-yl, 1,2,2-trimethylpiperidine-4-yl, or 1-(oxetan-3-yl)piperidine-4-yl.

[0105] In some embodiments, the structure: [ka] The ring represented by is a pyrrolidinyl ring. In some embodiments of these embodiments, the pyrrolidinyl ring is a pyrrolidine-3-yl ring (i.e., n is 1 and m is 1, or n is 2 and m is 0). In some embodiments of these embodiments, R on such a pyrrolidinyl ring 8 The substituent is hydrogen. In some embodiments of these embodiments, such as R on the pyrrolidinyl ring 8 The substituent is methyl. In some embodiments of these embodiments, such as R on the pyrrolidinyl ring 8The substituent is ethyl. In some embodiments of these embodiments, such as R on the pyrrolidinyl ring 8 The substituent is isopropyl. In some embodiments of these embodiments, R 2 He is absent.

[0106] In some embodiments, the structure: [ka] The ring represented by is a quinuclidinyl ring. In some embodiments of these embodiments, the quinuclidinyl ring is a quinuclidin-3-yl ring (i.e., n is 1 and m is 2, or n is 3 and m is 0, with 1 R 2 and R 8 (together they form a crosslinked four-membered ring). In some embodiments of these embodiments, R on such a quinuclidinyl ring 8 The substituent is hydrogen. In some embodiments of these embodiments, such as R on the quinuclidinyl ring 8 The substituent is methyl. In some embodiments of these embodiments, such as R on the quinuclidinyl ring 8 The substituent is ethyl. In some embodiments of these embodiments, such as R on the quinuclidinyl ring 8 The substituent is isopropyl. In some embodiments of these embodiments, R 2 He is absent.

[0107] In some embodiments, the structure: [ka] The ring represented by is an azabicyclo[3.2.1]octanyl ring. In some embodiments of these embodiments, the azabicyclo[3.2.1]octanyl ring is an 8-azabicyclo[3.2.1]octan-3-yl ring (i.e., n is 1 and m is 2, or n is 3 and m is 0, with two R bonded to different carbon atoms). 2(together they form a crosslinked C4 cycloalkyl ring). In some embodiments of these embodiments, R on such azabicyclo[3.2.1]octanyl ring 8 The substituent is hydrogen. In some embodiments of these embodiments, such as R on the azabicyclo[3.2.1]octanyl ring 8 The substituent is methyl. In some embodiments of these embodiments, such as R on the azabicyclo[3.2.1]octanyl ring 8 The substituent is ethyl. In some embodiments of these embodiments, such as R on the azabicyclo[3.2.1]octanyl ring 8 The substituent is isopropyl. In some embodiments of these embodiments, R 2 He is absent.

[0108] In some embodiments, the structure: [ka] The ring represented by is an azabicyclo[3.3.1]nonanyl ring. In some aspects of these embodiments, the azabicyclo[3.3.1]nonanyl ring is a 9-azabicyclo[3.3.1]nonane-3-yl ring (i.e., n is 1 and m is 2, or n is 3 and m is 0, with two R atoms bonded to different carbon atoms). 2 (together they form a crosslinked C5 cycloalkyl ring). In some embodiments of these embodiments, R on such azabicyclo[3.3.1]nonanyl ring 8 The substituent is hydrogen. In some embodiments of these embodiments, such as R on the azabicyclo[3.3.1]nonanyl ring 8 The substituent is methyl. In some embodiments of these embodiments, such as R on the azabicyclo[3.3.1]nonanyl ring 8 The substituent is ethyl. In some embodiments of these embodiments, such as R on the azabicyclo[3.3.1]nonanyl ring 8 The substituent is isopropyl. In some embodiments of these embodiments, R 2 He is absent.

[0109] In some embodiments, the structure: [ka] The ring represented by is an azabicyclo[2.2.2]octanyl ring. In some embodiments of these embodiments, the azabicyclo[2.2.2]octanyl ring is a 2-azabicyclo[2.2.2]octan-5-yl ring (i.e., n is 1 and m is 2, or n is 3 and m is 0, with two R bonded to different carbon atoms). 2 (together they form a crosslinked C4 cycloalkyl ring). In some embodiments of these embodiments, R on such azabicyclo[2.2.2]octanyl ring 8 The substituent is methyl.

[0110] In some embodiments, the structure: [ka] The ring represented by is an azepanyl ring. In some embodiments of these embodiments, the azepanyl ring is azepan-4-yl (i.e., n is 2 and m is 2). In some embodiments of these embodiments, R on such an azepanyl ring 8 The substituent is hydrogen. In some embodiments of these embodiments, such as R on the azepanyl ring 8 The substituent is methyl.

[0111] In some embodiments, the compound of formula I may be a compound selected from Table 1, or a pharmaceutically acceptable salt thereof, the table of which includes the chemical structure of each compound and the LCMS and LCMS analysis of the compound. 11H NMR is included. Chemical shifts are reported in ppm(δ) using the residual solvent as an internal standard. Peak magnifications, expressed in Hz, are as follows: s: singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doublets, t: triplet, dt: triplet of doublets, q: quartet, dq: quartet of doublets, p: pentet, h: heptet, m: multiplet, br s: broad singlet. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83 Table 1-84 Table 1-85 Table 1-86 Table 1-87 Table 1-88 Table 1-89

Table 1-90

[0112] 4. Use, formulation, and administration Medicinally acceptable compositions In another embodiment, the Disclosure provides compositions comprising a compound of the Disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the Disclosure is such that it is effective in measurably inhibiting Wee1A kinase or its variants in a biological sample or patient. In certain embodiments, the compositions of the Disclosure are formulated for administration to a patient requiring such a composition. In some embodiments, the compositions of the Disclosure are formulated for oral administration to a patient.

[0113] As used herein, the term “patient” means an animal, preferably a mammal, most preferably a human.

[0114] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compounds formulated together. Examples of pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0115] "Medically acceptable derivative" means any non-toxic salt, ester, ester salt, or other derivative of the compound herein that, when administered to a recipient, can directly or indirectly provide the compound herein or a metabolite or residue of its activity.

[0116] The compositions of this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implantable reservoir. As used herein, the term “parenterally” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injection forms of the compositions of this disclosure may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. Alternatively, the sterile injection preparations may be sterile injection solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent (e.g., as a solution in 1,3-butanediol). Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixatives have traditionally been used as solvents or suspension media.

[0117] For this purpose, any non-irritating fixative oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, particularly their polyoxyethylene versions, are useful in the preparation of injectable solutions, as are naturally pharmaceutically acceptable oils (e.g., olive oil or castor oil). Solutions or suspensions of these oils may also contain diluents or dispersants of long-chain alcohols (e.g., carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions). Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, can also be used for formulation purposes.

[0118] In some embodiments, the compounds or compositions disclosed herein are administered orally. The pharmaceutically acceptable compositions of this disclosure may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavorings, or colorings may be added as desired.

[0119] Alternatively, the pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. Such suppositories may be prepared by mixing with a suitable non-irritating excipient that is solid at room temperature but becomes liquid at rectal temperature, and therefore melts in the rectum to release the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0120] The pharmaceutically acceptable compositions of this disclosure may also be administered topically, particularly when the therapeutic target includes a site or organ that is easily accessible by topical application (including diseases of the eyes, skin, or lower intestine). Suitable topical formulations are readily prepared for each of these areas or organs.

[0121] Local application to the lower intestinal tract can be performed using rectal suppositories (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0122] For topical application, the pharmaceutically acceptable compositions provided can be formulated into suitable ointments containing the active components suspended or dissolved in one or more carriers. Suitable carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated into suitable lotions or creams containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0123] For ophthalmic use, the pharmaceutically acceptable compositions provided can be formulated as a finely powdered suspension in isotonic pH-adjusted sterile saline, or, preferably, as a solution in isotonic pH-adjusted sterile saline with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as an ointment (e.g., petrolatum).

[0124] The pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers for enhancing bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0125] Most preferably, the pharmaceutically acceptable compositions of this disclosure are formulated for oral administration.

[0126] The amount of the compound of this disclosure that can be combined with a carrier material to produce a composition in a single dosage form varies depending on the host being treated and the specific mode of administration. Preferably, the composition provided should be formulated so that a dose of 0.001 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving such a composition.

[0127] Furthermore, it should be understood that a specific dosage and treatment regimen for any particular patient depends on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, elimination rate, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of this disclosure in a composition also depends on the specific compound in the composition.

[0128] Use of compounds and pharmaceutically acceptable compositions The compounds and compositions described herein are widely useful for inhibiting the protein kinase activity of one or more enzymes.

[0129] Examples of kinases inhibited by the compounds and compositions described herein and for which the methods described herein are useful include Wee1A kinase, or both Wee1A kinase and Myt1 kinase.

[0130] The activity of compounds used in this disclosure as inhibitors of Wee1A kinase or Myt1 kinase, or any of the aforementioned variants, can be assayed in vitro, in vivo, or in cell lines. In vitro assays include those that quantify the phosphorylation activity and / or subsequent functional consequences, or inhibition of ATPase activity, of activated Wee1A kinase, activated Myt1 kinase, or any of the aforementioned variants. Alternative in vitro assays quantify the ability of inhibitors to bind to Wee1A kinase.

[0131] Inhibition of the DNA damage response (DDR) pathway in cancer treatment has recently attracted attention, and various DDR inhibitors are being developed. Among these, the most promising inhibitors target the Wee1 kinase family, which plays a crucial role in cell cycle regulation and the identification and repair of DNA damage in both non-malignant and cancer cells.

[0132] Wee1 kinase family The Wee1 kinase family consists of three serine / threonine kinases that share a conserved molecular structure and are encoded by the following genes: WEE1 (alternatively WEE1 G2 checkpoint kinase or Wee1A kinase), PKMYT1 (alternatively MYT1 kinase or membrane-associated tyrosine and threonine-specific cdc2 inhibitor kinase), and WEE2 (alternatively WEE2 oocyte meiosis inhibitor kinase or Wee1B kinase). In eukaryotic cells, Wee1A kinase and PKMYT1 kinase are involved in the cell cycle, particularly the transition to mitosis (Schmidt M, Rohe A, Platzer C, et al. Regulation of G2 / M transition by inhibition of Wee1 and PMyt1 Kinases. Molecules. 2017;22:2045). Their roles as regulators are crucial during normal cell cycle progression and in responding to DNA damage as part of the DNA damage response (DDR) pathway. Similarly, Wee1B kinase regulates cell cycle progression, particularly meiosis (Solc P, Schultz RM, Motlik J. Prophase I arrest and progression to metaphase I in mouse oocytes: Comparison of resumption of meiosis and recovery from G2-arrest in somatic cells. Mol Hum Reprod. 2010;16:654-64).

[0133] Wee1B kinase Wee1B kinase expression is embryonic cell-specific and inhibits meiosis by phosphorylating Tyr15 of the CDK1-cyclin B complex (JY Zhu et al. 2017;60(18),7863-7875). Due to its distinctive role in meiosis, Wee1B kinase has not been targeted by drug discovery efforts in the past or present. Wee1B kinase plays a dual regulatory role in oocyte meiosis by preventing early restart before ovulation and enabling the completion of metaphase II at fertilization (Nakanishi M,Ando H,Watanabe N, et al. Identification and characterization of human Wee1B, a new member of the Wee1 family of Cdk-inhibitory kinases. Genes Cells. 2000;5(10):839-47). Despite the identification of WEE2 somatic mutations (1.9% of cases) and copy number (CN) alterations (22.5% of patients with CN loss and 22.5% of patients with CN increase) across several cancer types (https: / / portal.gdc.cancer.gov), these have not yet been functionally linked to tumorigenesis.

[0134] Myt1 kinase Myt1 kinase is a multifunctional protein kinase localized to the ER-Golgi complex and is known to play a regulatory role in the cell cycle by inhibiting Cdk1 / cyclin B1-mediated mitosis (JY Zhu et al., J Med Chem. 2017;60(18), 7863-7875). As mentioned above and throughout this text, Myt1 kinase inhibits Cdk1 / cyclin B1 activity by phosphorylating Tyr15 and Thr14 of Cdk1 and by sequestering Cdk1 from the nucleus. Furthermore, Myt1 kinase has been associated with the organization of the ER-Golgi complex at the end of mitosis.

[0135] Wee1A kinase Wee1A kinase regulates the transition to mitosis during the G2 / M transition in S phase by phosphorylating Tyr15 of Cdk1 and inactivating the Cdk1 / cyclin B complex. Cells with disrupted G1 checkpoint activity (e.g., cancer cells) rely on Wee1A kinase to inhibit Cdk1, which allows them to stop G2 / M for DNA repair. When Wee1A kinase activity is altered, disrupted cells may prematurely proceed to mitosis without having the opportunity to fully replicate the entire DNA content or repair any DNA damage that may have occurred during S phase. This characterization of Wee1A kinase's role in the cell cycle has made it an attractive target for anticancer drugs, particularly in combination with DNA damaging agents (JY Zhu et al. 2017;60(18),7863-7875).

[0136] As used herein, the terms “treatment,” “to treat,” and “to treat” mean reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more of its symptoms described herein. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be performed even in the absence of symptoms. For example, treatment may be performed on a susceptible individual before the onset of symptoms (for example, taking into account the history of the symptoms and / or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay the recurrence of symptoms.

[0137] Since the compounds provided are inhibitors of Wee1A kinase, they are useful for treating one or more disorders related to Wee1A kinase activity. Accordingly, in certain embodiments, the Disclosure provides a method for treating a Wee1A kinase-mediated disorder, comprising the step of administering the compounds of the Disclosure or a pharmaceutically acceptable composition thereof to a subject in need thereof.

[0138] Some of the compounds provided exhibit potent inhibitory activity against Myt1 kinase as well, and are therefore useful dual inhibitors for treating one or more disorders related to the activity of both Wee1A kinase and Myt1 kinase. Accordingly, in certain embodiments, the present disclosure provides a method for treating a Wee1A kinase / Myt1 kinase-mediated disorder, comprising the step of administering a dual inhibitor compound of the present disclosure or a pharmaceutically acceptable composition thereof to a subject in need thereof.

[0139] As used herein, “Wee1A kinase-mediated” disorder or condition means a disease or other adverse condition in which Wee1A kinase or its variants are known to be involved. Accordingly, another embodiment of the present disclosure relates to the treatment or reduction of the severity of one or more diseases in which Wee1A kinase or its variants are known to be involved. Specifically, the present disclosure relates to a method for treating or reducing the severity of a disease or condition selected from proliferative disorders, the method comprising administering a compound or composition according to the present disclosure to a patient in need thereof.

[0140] As used herein, the term “Wee1A kinase / Myt1 kinase-mediated” disorder or condition means a disease or other adverse condition in which both Wee1A kinase and Myt1 kinase, or any or both of the aforementioned variants, are known to be involved. Accordingly, another embodiment of the present disclosure relates to the treatment or reduction of the severity of one or more diseases in which both Wee1A kinase and Myt1 kinase, or any or both of the aforementioned variants, are known to be involved. Specifically, the present disclosure relates to a method for treating or reducing the severity of a disease or condition selected from proliferative disorders, the method comprising administering a compound or composition according to the present disclosure to a patient in need thereof.

[0141] In some embodiments, the Disclosure provides a method for inhibiting Wee1A kinase activity in a subject, comprising the step of administering an effective amount of a compound of the Disclosure or a pharmaceutically acceptable composition to the subject.

[0142] In some embodiments, the Disclosure provides a method for inhibiting both Wee1A kinase activity and Myt1 kinase activity in a subject, comprising the step of administering an effective amount of a compound of the Disclosure or a pharmaceutically acceptable composition that is a dual inhibitor to the subject.

[0143] In some embodiments, the Disclosure provides a method for treating or reducing the severity of one or more disorders selected from cancer, comprising the step of administering an effective amount of a compound of the Disclosure or a pharmaceutically acceptable composition thereof to a target. In some embodiments, cancer is associated with solid tumors.

[0144] In some embodiments, the Disclosure provides a method for treating a subject suffering from cancer or other disordered cell growth characterized by abnormal Wee1A kinase activity, the method comprising the step of administering an effective amount of the compound of the Disclosure or a pharmaceutically acceptable composition thereof to the subject. In some embodiments, the abnormal Wee1A kinase activity includes elevated activity, overexpression, or undesirable activity compared to a non-disease state. In some such embodiments, the abnormal Wee1A kinase activity may include disrupted p53 activity, Cdk1 activity, Cdk2 activity, replication stress, mitotic modification, and DNA damage. In some embodiments, the subject suffers from cancer associated with p53 inactivation.

[0145] In some embodiments, the Disclosure provides a method for treating a subject suffering from cancer or other disordered cell growth characterized by both abnormal Wee1A kinase activity and abnormal Myt1 kinase activity, the method comprising the step of administering an effective amount of the compound of the Disclosure or a pharmaceutically acceptable composition thereof to the subject. In some embodiments, the abnormal Wee1A kinase activity and abnormal Myt1 kinase activity include elevated activity, overexpression, or undesirable activity compared to a non-disease state. In some such embodiments, the abnormal Wee1A kinase activity and abnormal Myt1 kinase activity may include disrupted Cdk1 activity, replication stress, mitotic modification, and DNA damage. In some embodiments, the subject to be treated has previously been treated with either a monospecific Wee1A kinase inhibitor or a Myt1 kinase inhibitor (neither of which is a dual inhibitor) and has become resistant to or refractory to such treatment. For example, such subjects may be resistant to or unresponsive to the Myt1 kinase inhibitor RP-6306, or the Wee1A kinase inhibitors AZD1775, Debio0123, or ZnC3.

[0146] In some embodiments, the cancers treated with the compounds disclosed herein are selected from brain tumors, cervical brain tumors, cardiac tumors, gastrointestinal cancers, esophageal cancers, thyroid cancers, small cell carcinomas, non-small cell carcinomas, breast cancers, lung cancers, gastric cancers, gallbladder / bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, endometrial cancers, cervical cancers, renal pelvis / ureteral cancers, bladder cancers, prostate cancers, penile cancers, testicular cancers, fetal cancers, Wilms' tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing's tumors, soft tissue sarcomas, acute leukemias, chronic lymphocytic leukemias, chronic myeloid leukemias, polycythemia vera, malignant lymphomas, multiple myelomas, Hodgkin lymphomas, and non-Hodgkin lymphomas. In some embodiments, the subjects have cancers selected from serous uterine cancers and renal cancers.

[0147] In some embodiments, breast cancer is selected from ductal carcinoma in situ (DCIS), invasive ductal carcinoma in situ (IDC), lobular carcinoma in situ (LCIS), lobular carcinoma in situ (ILC), triple-negative breast cancer (TNBC), inflammatory breast cancer (IBC), metastatic breast cancer (MBC), medullary carcinoma, tubular carcinoma, mucinous carcinoma (colloidal), and Paget's disease of the breast or nipple (commonly known as Paget's disease).

[0148] In some embodiments, uterine cancer is selected from endometrial cancer and uterine sarcoma. In some embodiments, uterine cancer is endometrial cancer. In some embodiments, uterine cancer is uterine sarcoma.

[0149] In some embodiments, ovarian cancer is selected from epithelial ovarian cancer, germ cell tumors, and stromal cell tumors.

[0150] In some embodiments, gastric cancer is selected from adenocarcinoma, lymphoma, gastrointestinal stromal tumor (GIST), carcinoid tumor, and hereditary (familial) diffuse gastric cancer.

[0151] In some embodiments, esophageal cancer is selected from squamous cell carcinoma, small cell carcinoma, and adenocarcinoma. In some embodiments, esophageal cancer is selected from squamous cell carcinoma and adenocarcinoma. In some embodiments, esophageal cancer is squamous cell carcinoma. In some embodiments, esophageal cancer is adenocarcinoma.

[0152] In some embodiments, lung cancer is selected from non-small cell lung cancer, lung nodules, small cell lung cancer, and mesothelioma. In some embodiments, lung cancer is non-small cell lung cancer.

[0153] In some embodiments, colorectal cancer is selected from adenocarcinoma, gastrointestinal stromal tumor (GIST), lymphoma, carcinoid, Turcott syndrome, Peutz-Jeghers syndrome (PJS), familial colorectal cancer (FCC), and juvenile adenomatous polyposis.

[0154] In some embodiments, cancer is associated with the deregulation of cyclin E1. In some embodiments, the cancer associated with the deregulation of cyclin E1 is ovarian cancer.

[0155] In some embodiments, cancers are associated with p53 deregulation. In some embodiments, cancers associated with p53 deregulation are selected from brain tumors, cervical brain tumors, cardiac tumors, gastrointestinal cancers, esophageal cancers, thyroid cancers, small cell carcinomas, non-small cell carcinomas, breast cancers, lung cancers, gastric cancers, gallbladder / bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, endometrial cancers, cervical cancers, renal pelvis / ureteral cancers, bladder cancers, prostate cancers, penile cancers, testicular cancers, fetal cancers, Wilms' tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing's tumors, soft tissue sarcomas, acute leukemias, chronic lymphocytic leukemias, chronic myeloid leukemias, polycythemia vera, malignant lymphomas, multiple myelomas, Hodgkin lymphomas, and non-Hodgkin lymphomas. In some such embodiments, cancers associated with p53 deregulation are selected from serous uterine cancers and kidney cancers.

[0156] In some embodiments, cancers are associated with Cdk1 deregulation. In some embodiments, cancers associated with Cdk1 deregulation are selected from brain tumors, cervical brain tumors, cardiac tumors, gastrointestinal cancers, esophageal cancers, thyroid cancers, small cell carcinomas, non-small cell carcinomas, breast cancers, lung cancers, gastric cancers, gallbladder / bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, endometrial cancers, cervical cancers, renal pelvis / ureteral cancers, bladder cancers, prostate cancers, penile cancers, testicular cancers, fetal cancers, Wilms' tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing's tumors, soft tissue sarcomas, acute leukemias, chronic lymphocytic leukemias, chronic myeloid leukemias, polycythemia vera, malignant lymphomas, multiple myelomas, Hodgkin lymphomas, and non-Hodgkin lymphomas. In some such embodiments, cancers associated with Cdk1 deregulation are selected from serous uterine cancers and kidney cancers.

[0157] In some embodiments, cancers are associated with Cdk2 deregulation. In some embodiments, cancers associated with Cdk2 deregulation are selected from brain tumors, cervical brain tumors, cardiac tumors, gastrointestinal cancers, esophageal cancers, thyroid cancers, small cell carcinomas, non-small cell carcinomas, breast cancers, lung cancers, gastric cancers, gallbladder / bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, endometrial cancers, cervical cancers, renal pelvis / ureteral cancers, bladder cancers, prostate cancers, penile cancers, testicular cancers, fetal cancers, Wilms' tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing's tumors, soft tissue sarcomas, acute leukemias, chronic lymphocytic leukemias, chronic myeloid leukemias, polycythemia vera, malignant lymphomas, multiple myelomas, Hodgkin lymphomas, and non-Hodgkin lymphomas. In some such embodiments, cancers associated with Cdk1 deregulation are selected from serous uterine cancers and kidney cancers.

[0158] Depending on the specific condition or disease to be treated, additional therapeutic agents that are typically administered to treat that condition may be present in the compositions of this disclosure. When used herein, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as “appropriate for the disease or condition to be treated.”

[0159] For example, the compounds of this disclosure or pharmaceutically acceptable compositions thereof are administered in combination with chemotherapeutic agents to treat proliferative disorders and cancer. Known chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon, platinum derivatives, taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophilotoxin (e.g., etoposide), cisplatin, mTOR inhibitors (e.g., rapamycin), methotrexate, actinomycin D, dorastatin 10, colchicine, emetine, trimethrexate, methoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin, cisplatin, metronidazole, and Gleevec®. In other embodiments, the compounds of the present disclosure are administered in combination with biological agents such as Avastin or VECTIBIX.

[0160] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable compositions thereof include fasudil, sirolimus, imatinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, lapatinib, nilotinib, temsirolimus, everolimus, pazopanib, ruxolitinib, vandetanib, vemurafenib, crizotinib, icotinib, axitinib, tofacitinib, and bosutinib. Cabozantinib, ponatinib, regorafenib, afatinib, dabrafenib, trametinib, ibrutinib, nintedanib, idelalisib, ceritinib, apatinib, riboceranib, ripasudil, alectinib, cobimetinib, lenvatinib, palbociclib, radotinib, osimertinib, olmutinib, neratinib, ribociclib, copanlisib, abemaciclib, acalabrutinib, mid Staurin, brigatinib, baricitinib, netalusdil, tivozanib, cimotinib, fostamatinib, encorafenib, binimetinib, catekentinib, dubellisib, dacomitinib, lorlatinib, lalotrectinib, gilteritinib, pirotinib, fluquintinib, erdafitinib, alpelisib, umbralisib, reniolisib, pexidartinib, entrectinib, upadacitinib It is administered in combination with a drug selected from the following: fedratinib, zanubrutinib, flumatinib, peficitinib, delgocitinib, avapritinib, selumetinib, tucatinib, pemigatinib, capmatinib butabreta, serpercatinib, lipretinib, tirabrutinib, almonertinib, pralcetinib, filgotinib, tilvanibrin, olerabrutinib, tepotinib, and trilasiclib. See the list of clinically approved kinase inhibitors | MRC Protein Phosphorylation Ubiquitylation Unit (available at www.ppu.mrc.ac.uk / list-clinically-approved-kinase-inhibitors) (the entire list is incorporated herein by reference).

[0161] In certain embodiments, the compounds of the Disclosure or pharmaceutically acceptable compositions thereof include avalerix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amiphostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, live BCG, bevacizumab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, carsterone, capecitabine, camptothecin, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine, and clofalabi. , cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, decitabine, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, drostanolone propionate, epirubicin, epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydro Xyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alpha-2a, interferon alpha-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisol, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelbequin, oxaliplatin, paclitaxel, parif Shelmin, Pamidronate, Pegademase, Pegaspargase, Pegfilgrastim, Pemetrexed disodium, Pentostatin, Pipobroman, Plicamycin, Porfimer sodium, Procarbazine, Quinacrine, Rasburicase, Rituximab, Salglamostim, Sorafenib, Streptozocin, Sunitinib maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testolactone, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tositumomab, Trastuzumab, Tretinoin, ATRA,It is administered in combination with one or more antiproliferative agents or chemotherapeutic agents selected from uracil mustard, barbicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid.

[0162] In certain embodiments, the compounds of the present disclosure or pharmaceutically acceptable compositions thereof are administered co-administered with a pharmaceutically acceptable Myt1 kinase inhibitor. In some such embodiments, the Myt1 kinase inhibitor is RP-6306.

[0163] In certain embodiments, the compounds of the present disclosure or pharmaceutically acceptable compositions thereof are administered co-administered with a pharmaceutically acceptable DNA damaging agent.

[0164] In certain embodiments, the compounds of the present disclosure or pharmaceutically acceptable compositions thereof are co-administered with radiation.

[0165] In certain embodiments, the compounds of the present disclosure or pharmaceutically acceptable compositions thereof are administered in combination with monoclonal antibodies or siRNA therapeutic agents.

[0166] In certain embodiments, the compounds of the Disclosure or pharmaceutically acceptable compositions thereof include: (i) inhibitors of kinases selected from MET, MEK, mTOR, FLT3, BRAF, KIT, PDGFR, FDFR, PI3K, EGFR, AKT, and KRAS; (ii) inhibitors of fusion kinases such as BCR-ABL, ALK, RET, and ROS, JAK, CDK4 / 6, and KRAS; (iii) epigenetic modulators such as HDAC inhibitors; (iv) cancer immunotherapy agents (e.g., those targeting PD1, PDL1, and CTLA4); and (v) antibody-drug conjugates (e.g., Her2, CD38, BCMA, CD19, NECTI). It is administered in combination with targeted therapies selected from (i)

[0167] In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable compositions thereof are administered in combination with inhibitors of DNA repair proteins other than Wee1A kinase or Myt1 kinase. Such inhibitors include those that inhibit one or more of the following: CHK1, CHK2, ATM, ATR, Pol theta, CDC7, DNAPK, PLK1, WRN, PARP, and Aurora A / B.

[0168] These additional agents may be administered separately from the composition containing the compounds of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form, which is a mixture of the compounds of the present disclosure into a single composition. When administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain period of time from each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours from each other.

[0169] In some such embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof, in particular compounds that do not exhibit significant Myt1 kinase activity (e.g., compounds that do not evaluate to A or B in the Myt1 kinase binding assay disclosed in Example 6 herein), are administered as part of a multi-dose regimen with a pharmaceutically acceptable Myt1 kinase inhibitor. In certain embodiments, the compounds of the Disclosure or pharmaceutically acceptable compositions thereof are administered as part of a multi-dose regimen with a Myt1 kinase inhibitor selected from RP-6306.

[0170] In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof, in particular compounds that do not exhibit significant Myt1 kinase activity, are administered to subjects in whom Myt1 kinase inhibitors are used as first-line or second-line treatment. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in whom Myt1 kinase inhibitors are used as first-line treatment. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in whom Myt1 kinase inhibitors selected from RP-6306 are used as first-line treatment.

[0171] In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof, particularly compounds lacking significant Myt1 kinase activity, are administered to subjects in whom Myt1 kinase inhibitors are used as a second-line treatment. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to subjects in whom Myt1 kinase inhibitors selected from RP-6306 are used as a second-line treatment.

[0172] As used herein, the terms “combined administration,” “combined administration,” and “simultaneous administration” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to this disclosure. For example, the compounds of this disclosure may be administered simultaneously or sequentially with another therapeutic agent, in separate unit dosage forms or together in a single unit dosage form. Accordingly, this disclosure provides a single unit dosage form comprising the compound provided, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0173] The amounts of the compound of the present invention and additional therapeutic agents (in the case of a composition containing additional therapeutic agents as described above), which can be combined with a carrier material to produce a single dosage form, vary depending on the host being treated and the specific mode of administration. Preferably, the compositions of the present disclosure should be formulated so that the compound of the present invention can be administered at a dose of 0.001 to 100 mg / kg body weight / day.

[0174] In the case of these compositions containing additional therapeutic agents, the additional therapeutic agent and the compounds of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions is less than the amount required for monotherapy using only that therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dose of 0.001 to 1,000 μg / kg body weight / day.

[0175] The amount of additional therapeutic agent present in the compositions of this disclosure will not exceed the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions of this disclosure will be in the range of about 50% to about 100% of the amount that would normally be present in a composition containing that therapeutic agent as the sole active agent.

[0176] In some embodiments, the present disclosure provides methods for inhibiting Wee1A kinase in vitro. In some such embodiments, the amount of Wee1A kinase inhibition is evaluated based on a competitive ATP binding assay.

[0177] In some embodiments, the present disclosure provides methods for inhibiting Wee1A kinase in biological samples.

[0178] In some embodiments, the present disclosure provides methods for inhibiting both Wee1A kinase and Myt1 kinase in a biological sample.

[0179] In some embodiments, the disclosure provides methods for inhibiting both Wee1A kinase and Myt1 kinase in vitro. In some such embodiments, the levels of inhibition of Wee1A kinase and Myt1 kinase are evaluated based on a competitive ATP binding assay.

[0180] In some embodiments, the Disclosure provides a method for evaluating Cdk1 phosphorylation in cells, comprising contacting the cells with a compound described herein. In one embodiment, the contacting step comprises incubating the cells with the compound presented herein. In some embodiments, the cells are incubated for at least 4 hours. In some embodiments, the cells may include DAOY medulloblastoma cells. [Examples]

[0181] General method Reagents and solvents were purchased from suppliers and used as is unless otherwise noted. The solvent was dried using molecular sieves at 4 Å. The reaction mixture was stirred in glass vials or round-bottom flasks using a magnetic stirring rod and heated using a stirring plate. The solvent was removed by rotary evaporator, vacuum centrifuge, or freeze-drying. The reaction progress was monitored by LC-MS or thin-layer chromatography (TLC). Aluminum-backed TLC plate (60F) 254 ) was visualized using UV light (254nm).

[0182] 1 1H NMR and 13 The 13C NMR spectrum is at 500 MHz ( 1 1H NMR (500 MHz) and 13 ¹³C NMR (126MHz) Bruker Avance Neo spectrometer (equipped with 5mm iProbe BBF / H / D probe), or 400MHz ( 1 1H NMR (400MHz) and 13 ¹³C NMR (101 MHz) was recorded using a Varian Inova spectrometer (equipped with a 5 mm 1H / 13C automatically switchable gradient probe). Chloroform-d(δ H 7.27 ppm), Dimethyl sulfoxide-D6 (δ H 2.50 ppm), acetonitrile-d3 (δ H 1.95 ppm), or methanol-d4 (δ H The central peak at 3.31 ppm was used as the internal reference. The spectra were processed using commercially available software.

[0183] LC-MS was performed using a reversed-phase C18 column (eluted with acetonitrile and water (containing 0.1% TFA or 0.03% ammonia)) and a mass spectrometer (operating in ES (+ or -) ionization mode).

[0184] Flash chromatography was performed using an automated flash purification system equipped with a diode array detector (200-400 nm) using silica gel or C18-functionalized silica, and elution was performed with a gradient of ethyl acetate and petroleum ether, or methanol and dichloromethane (containing 0.03% ammonia).

[0185] Purity analysis was performed using a reversed-phase C18 column (eluted with acetonitrile and water (containing 0.1% TFA or 0.03% ammonia)). UV traces were recorded at 220 nm. Purification by preparative HPLC was performed using a reversed-phase C18 column eluted with acetonitrile and water (containing 0.1% TFA or 0.03% ammonia).

[0186] The stereochemical configurations of enantiomers or diastereomers separated using chiral chromatography were arbitrarily assigned. The absolute configurations are unknown.

[0187] Abbreviation: [Table 7-1] [Table 7-2]

[0188] Example 1 Synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-ylamino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one;trifluoroacetic acid (TFA salt of compound 124) and 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one;trifluoroacetic acid (TFA salt of compound 138) [ka]

[0189] tert-butyl 4-((6-bromopyridine-2-yl)amino)piperidine-1-carboxylate

[0190] N,N-diisopropylethylamine (3 equivalents) and tert-butyl 4-aminopiperidine-1-carboxylate (1 equivalent) were added at room temperature to a solution of 2,6-dibromopyridine (1 equivalent) in DMSO (0.8 mol / L). The reaction mixture was heated to 90°C and stirred for several days until complete conversion was observed by LCMS. The reaction mixture was diluted with brine and saturated aqueous NaHCO3 and extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was either used without further purification or purified by flash chromatography.

[0191] Alternatively, cesium carbonate (3 equivalents) and tert-butyl 4-aminopiperidine-1-carboxylate (1 equivalent) were added to a solution of 2,6-dibromopyridine (1 equivalent) in dry dimethylformamide (0.4 mol / L), and the mixture was stirred at 100°C until complete conversion was observed by LC-MS (typically overnight). The reaction mixture was diluted with brine, saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was either used without further purification or purified by flash chromatography.

[0192] tert-butyl4-((6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-yl)amino)piperidine-1-carboxylate

[0193] CuI (1.2 equivalents), followed by N,N'-dimethylethylenediamine (1 equivalent), was added at room temperature to a stirred, degassed suspension in dioxane (0.3 mol / L) containing tert-butyl 4-((6-bromopyridine-2-yl)amino)piperidine-1-carboxylate (1 equivalent), 6-(methylsulfanyl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (1 equivalent), and cesium carbonate (3 equivalents). The reaction mixture was heated overnight at 90°C in a sealed vial. The reaction mixture was diluted with water, a few drops of aqueous ammonia (28%) were added, and then extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was used without further purification or purified by flash chromatography.

[0194] 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-ylamino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 124)

[0195] mCPBA (approximately 75%, 1.2 equivalents) was added at room temperature to a solution of tert-butyl 4-((6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-yl)amino)piperidine-1-carboxylate (1 equivalent) stirred in dichloromethane (0.4 mol / L). The mixture was stirred until LCMS showed complete conversion to the corresponding sulfoxide (major) and sulfone (minor) (typically within 1 hour).

[0196] 1-amino-4-chlorobenzene (1 equivalent) was added to the reaction mixture, and the resulting mixture was heated to 40°C until LCMS showed complete conversion (typically overnight). Alternatively, dichloromethane was removed under reduced pressure, and the residue was redissolved in dry acetonitrile (0.6 mol / L). Then 1-amino-4-chlorobenzene (1 equivalent) was added, and the resulting mixture was heated to 60°C until LCMS showed complete conversion (typically overnight). The reaction mixture was concentrated, the residue was diluted with ethyl acetate, an aqueous solution of NaOH (1 M) was added, and the product was extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain the residue.

[0197] Trifluoroacetic acid (10-20% by volume) was added at room temperature to a solution of the above material (1 equivalent) stirred in dry dichloromethane (0.4 mol / L). The resulting solution was stirred until LC-MS showed complete conversion (typically within 1 hour). The reaction mixture was concentrated and purified by reverse-phase chromatography. The pure fraction was pooled and lyophilized to obtain compound 124. Yield: 29 mg, 49%, yellow solid. HPLC purity (220 nm) 100%.

[0198] 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 138)

[0199] Formaldehyde (38% in water, 2 equivalents) was added at room temperature to a solution of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-ylamino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 equivalent) stirred in THF (0.6 mol / L). If the starting material was in the form of a trifluoroacetate, diisopropylethylamine (1 equivalent) was added. The reaction mixture was stirred for 30 minutes, and then sodium triacetoxyborohydride (3 equivalents) was added gradually at room temperature. The mixture was stirred until LCMS showed complete conversion. This sometimes required the addition of further formaldehyde and sodium triacetoxyborohydride. The reaction mixture was concentrated and purified by reverse-phase chromatography. The pure fraction was pooled and lyophilized to obtain compound 128. Yield: 7.4 mg, 63%, yellow solid. HPLC purity (220 nm): 98%.

[0200] Example 2 Synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-yloxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one;trifluoroacetic acid (TFA salt of compound 141) and 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one;trifluoroacetic acid (TFA salt of compound 142) [ka]

[0201] tert-butyl 4-((6-bromopyridine-2-yl)oxy)piperidine-1-carboxylate

[0202] Sodium hydride was added at 0°C to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 equivalent) stirred in tetrahydrofuran (0.5 mol / mL). A solution of 2,6-dibromopyridine (1 equivalent) in THF (0.5 mol / mL) was added to the mixture, and once fully added, the mixture was allowed to return to room temperature and stirred until LCMS showed complete conversion (typically overnight). The reaction mixture was concentrated, diluted with brine and saturated aqueous solution of NaHCO3, and extracted with ethyl acetate (×3). The organic layer was washed with brine and then filtered through a phase separator. The organic layer was concentrated under reduced pressure to obtain the residue. The residue was purified by flash chromatography.

[0203] tert-butyl4-((6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-yl)oxy)piperidine-1-carboxylate

[0204] CuI (1.2 equivalents), followed by N,N'-dimethylethylenediamine (1 equivalent), was added at room temperature to a stirred, degassed suspension in dioxane (0.3 mol / L) containing tert-butyl 4-((6-bromopyridine-2-yl)oxy)piperidine-1-carboxylate (1 equivalent), 6-(methylsulfanyl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (1 equivalent), and cesium carbonate (3 equivalents). The reaction mixture was heated overnight at 90°C in a sealed vial. The reaction mixture was diluted with water, a few drops of aqueous ammonia (28%) were added, and then extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was used without further purification or purified by flash chromatography.

[0205] 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-yloxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 141)

[0206] mCPBA (approximately 75%, 1.2 equivalents) was added at room temperature to a solution of tert-butyl 4-((6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-yl)oxy)piperidine-1-carboxylate (1 equivalent) stirred in dichloromethane (0.4 mol / L). The mixture was stirred until LCMS showed complete conversion to the corresponding sulfoxide (major) and sulfone (minor) (typically within 1 hour).

[0207] 1-amino-4-chlorobenzene (1 equivalent) was added to the reaction mixture, and the resulting mixture was heated to 40°C until LCMS showed complete conversion (typically overnight). Alternatively, dichloromethane was removed under reduced pressure, and the residue was redissolved in dry acetonitrile (0.6 mol / L). Then 1-amino-4-chlorobenzene (1 equivalent) was added, and the resulting mixture was heated to 60°C until LCMS showed complete conversion (typically overnight). The reaction mixture was concentrated, the residue was diluted with ethyl acetate, an aqueous solution of NaOH (1 M) was added, and the product was extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain the residue.

[0208] Trifluoroacetic acid (10-20% by volume) was added at room temperature to a solution of the above material (1 equivalent) stirred in dry dichloromethane (0.4 mol / L). The resulting solution was stirred until LC-MS showed complete conversion (typically within 1 hour). The reaction mixture was concentrated and purified by reverse-phase chromatography. The pure fraction was pooled and lyophilized to obtain compound 141. Yield: 15 mg, 31%, solid. HPLC purity (220 nm): 98%.

[0209] 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 142)

[0210] Formaldehyde (38% in water, 2 equivalents) was added at room temperature to a solution of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-yloxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 equivalent) stirred in THF (0.6 mol / L). If the starting material was in the form of a trifluoroacetate, diisopropylethylamine (1 equivalent) was added. The reaction mixture was stirred for 30 minutes, and then sodium triacetoxyborohydride (3 equivalents) was added gradually at room temperature. The mixture was stirred until LCMS showed complete conversion. This sometimes required the addition of further formaldehyde and sodium triacetoxyborohydride. The reaction mixture was concentrated and purified by reverse-phase chromatography. The pure fraction was pooled and lyophilized to obtain compound 142. Yield: 42 mg, 63%, solid. HPLC purity (220nm) 97%.

[0211] Example 3 Synthesis of 1-{6-[(3R)-1-azabicyclo[2.2.2]octan-3-yloxy]pyridine-2-yl}-6-[(1-methyl-1H-pyrazole-4-yl)amino]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (TFA salt of compound 172) [ka]

[0212] (R)-3-((6-bromopyridine-2-yl)oxy)quinuclidine

[0213] N,N-diisopropylethylamine (3 equivalents) and (R)-quinuclidine-3-ol (1 equivalent) were added at room temperature to a solution of 2,6-dibromopyridine (1 equivalent) in DMSO (0.8 mol / L). The reaction mixture was heated to 90°C and stirred for several days until complete conversion was observed by LC-MS. The reaction mixture was diluted with brine and saturated aqueous solution of NaHCO3 and extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was either used without further purification or purified by flash chromatography.

[0214] Alternatively, cesium carbonate (3 equivalents) and (R)-quinuclidine-3-ol (1 equivalent) were added to a solution of 2,6-dibromopyridine (1 equivalent) in dry dimethylformamide (0.4 mol / L), and the mixture was stirred at 100°C until complete conversion was observed by LC-MS (typically overnight). The reaction mixture was diluted with brine and saturated aqueous solution of NaHCO3 and extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was either used without further purification or purified by flash chromatography.

[0215] (R)-2-allyl-6-(methylthio)-1-(6-(quinuclidin-3-yloxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0216] CuI (1.2 equivalents), followed by N,N'-dimethylethylenediamine (1 equivalent), was added at room temperature to a stirred, degassed suspension in dioxane (0.3 mol / L) containing (R)-3-((6-bromopyridine-2-yl)oxy)quinuclidine (1 equivalent), 6-(methylsulfanyl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (1 equivalent), and cesium carbonate (3 equivalents). The reaction mixture was heated overnight at 90°C in a sealed vial. The reaction mixture was diluted with water, a few drops of aqueous ammonia (28%) were added, and then extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was used without further purification or purified by flash chromatography.

[0217] (R)-2-allyl-6-((1-methyl-1H-pyrazole-3-yl)amino)-1-(6-(quinuclidin-3-yloxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 172)

[0218] mCPBA (approximately 75%, 1.2 equivalents) was added at room temperature to a solution of methanesulfonic acid (2 equivalents) and (R)-2-allyl-6-(methylthio)-1-(6-(quinuclidin-3-yloxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 equivalent) stirred in dichloromethane (0.6 mol / L). The mixture was stirred until LCMS showed complete conversion to the corresponding sulfoxide (major) and sulfone (minor) (typically within 1 hour).

[0219] 1-Methyl-1H-pyrazole-4-amine (1 equivalent) was added to the reaction mixture, and the resulting mixture was heated to 40°C until LC-MS showed complete conversion (typically overnight). Alternatively, dichloromethane was removed under reduced pressure, and the residue was redissolved in dry acetonitrile (0.6 mol / L). Then 1-methyl-1H-pyrazole-4-amine (1 equivalent) was added, and the resulting mixture was heated to 60°C until LC-MS showed complete conversion (typically overnight). The mixture was concentrated to dryness under reduced pressure and purified by reverse-phase chromatography. The pure fraction was pooled and lyophilized to obtain the product. Yield: 53 mg, 38%, yellow solid. HPLC purity (220 nm) 98%.

[0220] Other compounds of the present disclosure have been synthesized, or can be synthesized, using the synthetic routes described in Examples 1-3, by utilizing one or more of the following: a different reactive aromatic ring, a different amine in step 1A, a different alcohol in step 1B, or a different aromatic ring amine in step 3A or 3B relative to the starting material 2,6-dibromopyridine. Those skilled in the field of medicinal chemistry will be able to synthesize the compounds of the present disclosure without excessive experimentation by adapting the disclosed examples.

[0221] Example 4 Synthesis of 2-allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 370)

[0222] tert-butyl4-{6-[6-(4-bromophenylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazaiden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate

[0223] mCPBA (<77% purity) (83.1 mg, assumed 0.481 mmol) in DCM (0.5 mL) was added to a solution of tert-butyl 4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazaiden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (200 mg, 0.401 mmol) stirred in DCM (5 mL) at room temperature under nitrogen. The reaction was controlled by LC-MS. After 15 minutes, the DCM was removed under vacuum, the crude product was dissolved in MeCN (5 mL), and then p-bromoaniline (69 mg, 0.401 mmol) was added. The reaction mixture was stirred in a sealed vial at 60°C. After 96 hours, the reaction mixture was cooled to room temperature, and the mCPBA was quenched with 1 M NaOH (5 mL) added dropwise. The aqueous phase was extracted with ELISA (3 × 20 mL) and then washed with brine (20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the product as a yellow powder. The crude material was dissolved in DCM (5 mL), loaded onto a 10 g silica column, and purified by flash chromatography (0-100% EtOAC:PE) to obtain tert-butyl 4-{6-[6-(4-bromophenylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate [180 mg, 59%] as a pale yellow solid.

[0224] 6-(4-bromophenylamino)-1-[6-(piperido-4-yloxy)pyrido-2-yl]-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one

[0225] A solution of tert-butyl 4-{6-[6-(4-bromophenylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate (150 mg, 0.236 mmol) in DCM (5 mL) was treated with TFA (2 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ELISA, washed with saturated NaHCO3 aqueous solution and brine, dried, (MgSO4) was used to concentrate the product, and the resulting material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 6-(4-bromophenylamino)-1-[6-(piperido-4-yloxy)pyrido-2-yl]-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one as a white solid [150 mg].

[0226] 6-(4-bromophenylamino)-1-[6-(1-methylpiperido-4-yloxy)pyrido-2-yl]-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one (compound 370)

[0227] 6-(4-bromophenylamino)-1-[6-(piperido-4-yloxy)pyrido-2-yl]-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one (150 mg, 0.236 mmol) was dissolved in anhydrous THF (5 mL). Formaldehyde (approximately 36% purity, 38.3 μL, 0.471 mmol) and STAB (150 mg, 0.707 mmol) were added in that order. The reaction mixture was stirred at room temperature while monitoring by LC-MS. After 2 hours, the reaction mixture was quenched by dropwise addition of saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the crude material as a yellow powder. The obtained material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain the title compound [50.9 mg, yield 33.2%].

[0228] Example 5 Synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 367)

[0229] tert-butyl4-{6-[6-(3-bromophenylamino)-2-ethyl-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidinecarboxylate

[0230] This intermediate was prepared by the same method as tert-butyl4-{6-[6-(4-bromophenylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate.

[0231] 2-Ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 367)

[0232] To a solution prepared by stirring tert-butyl 4-{6-[6-(3-bromophenylamino)-2-ethyl-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (230 mg, 376 μmol) in a mixture of 1,4-dioxane (7 mL) and water (2 mL), 2 M K2CO3 (600 μl) and hydroxy(5-pyrimidinyl) boranolate (46.6 mg, 376 μmol) were added. The reaction mass was degassed for 15 minutes. Iron bis[2-(diphenylphosphino)-2,4-cyclopentadiene-1-ido]-dichloro-paradametane (33 mg, 0.12 equivalents, 45.1 μmol) was added, and the screw cap of the sealed tube was tightened. The contents were heated to 100 °C and stirred overnight. The reaction mass was cooled to room temperature, diluted with ethyl acetate, and washed with water, followed by brine. The organic layer was dried over anhydrous Na₂SO₄, and the solvent was removed under reduced pressure to obtain a crude mass. The collected material (150 mg) was dissolved in DCM:TFA 4:1 v / v. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the residue was dissolved in anhydrous THF (5 mL). Formaldehyde (23.4 μL, 2 equivalents, 314 μmol) and sodium triacetoxyborohydride (99.8 mg, 3 equivalents, 471 μmol) were added in that order. The reaction mixture was stirred at room temperature while monitoring by LC-MS. After 2 hours, the reaction mixture was quenched by dropwise addition of saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were poured into a phase separator and concentrated under reduced pressure to obtain the product as a reddish-brown powder. The obtained material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain the title compound.

[0233] Example 6 Synthesis of 2-ethyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 366)

[0234] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0235] Example 7 Synthesis of 2-allyl-6-[m-(1-imidazolyl)phenylamino]-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 365)

[0236] tert-butyl4-(6-{2-allyl-6-[m-(1-imidazolyl)phenylamino]-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazaiden-1-yl}-2-pyridyloxy)-1-piperidinecarboxylate

[0237] 112 mg (estimated 0.493 mmol) of mCPBA (<77% purity) in 0.5 mL of DCM was added to a solution of tert-butyl 4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (205 mg, 0.411 mmol) stirred in 5 mL of DCM under nitrogen at room temperature. After 15 minutes, the DCM was evaporated under vacuum, and the crude product was dissolved in 5 mL of MeCN. Then, m-(1-imidazolyl)aniline (65.5 mg, 0.411 mmol) and methanesulfonic acid (79 mg, 0.822 mmol) were added. The reaction mixture was stirred in a sealed vial at 60°C. After 48 hours, the reaction mixture was cooled to room temperature, and mCPBA was quenched by dropwise addition of 1 M NaOH (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL) and then washed with brine (20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the product as a yellow powder. The crude material was dissolved in DCM (5 mL), loaded onto a 10 g silica column, and purified by flash chromatography (0-100%, ELISA:PE) to obtain tert-butyl 4-(6-{2-allyl-6-[m-(1-imidazolyl)phenylamino]-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl}-2-pyridyloxy)-1-piperidine carboxylate [160 mg, 62.7%] as a yellow solid.

[0238] 2-Allyl-6-[m-(1-imidazolyl)phenylamino]-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one, trifluoroacetate

[0239] A solution of tert-butyl 4-(6-{2-allyl-6-[m-(1-imidazolyl)phenylamino]-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl}-2-pyridyloxy)-1-piperidine carboxylate (160 mg, 0.307 mmol) in DCM (5 mL) was treated with TFA (2 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ELISA, washed with saturated NaHCO3 aqueous solution and brine, dried (MgSO4), and concentrated. The obtained material was purified by purification phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-[m-(1-imidazolyl)phenylamino]-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one as trifluoroacetate and as a white solid [150 mg].

[0240] 2-Allyl-6-[m-(1-imidazolyl)phenylamino]-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one, trifluoroacetate (compound 365)

[0241] 2-Allyl-6-[m-(1-imidazolyl)phenylamino]-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one (150 mg, 0.296 mmol) was dissolved in anhydrous THF (5 mL). Formaldehyde (approximately 36% purity, 44 μL, 0.591 mmol) and STAB (188 mg, 0.887 mmol) were added in that order. The reaction mixture was stirred at room temperature while monitoring by LC-MS. After 2 hours, the reaction mixture was quenched by dropwise addition of saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the crude material as a yellow powder. The obtained material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-[m-(1-imidazolyl)phenylamino]-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one as trifluoroacetate [26.9 mg, yield 28%].

[0242] Example 8 Synthesis of 2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 364)

[0243] tert-butyl4-(6-{3-oxo-2-(propa-2-enyl)-6-[3-(pyrazole-1-yl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-1-yl}pyrido-2-yloxy)piperidine-1-carboxylate

[0244] 114 mg (estimated 0.493 mmol) of mCPBA (<77% purity) in 0.5 mL of DCM was added to a solution of tert-butyl 4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (205 mg, 0.411 mmol) stirred in 5 mL of DCM under nitrogen at room temperature. After 15 minutes, the DCM was evaporated under vacuum, and the crude product was dissolved in 5 mL of MeCN. Then, m-(1-pyrazolyl)aniline (65.4 mg, 0.411 mmol) and methanesulfonic acid (79 mg, 0.822 mmol) were added. The reaction mixture was stirred in a sealed vial at 60°C. After 48 hours, the reaction mixture was cooled to room temperature, and mCPBA was quenched by dropwise addition of 1 M NaOH (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL), followed by 20 mL of brine. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the product as a yellow powder. The crude material was dissolved in DCM (5 mL), loaded onto a 10 g silica column, and purified by flash chromatography (0-100%, ELISA:PE) to obtain tert-butyl 4-(6-{3-oxo-2-(propa-2-enyl)-6-[3-(pyrazole-1-yl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl}pyrido-2-yloxy)piperidine-1-carboxylate [140 mg, 58.5%] as a white solid.

[0245] 2-Allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one, trifluoroacetate

[0246] A solution of tert-butyl 4-(6-{3-oxo-2-(propa-2-enyl)-6-[3-(pyrazole-1-yl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl}pyrido-2-yloxy)piperidine-1-carboxylate (140 mg, 0.275 mmol) in DCM (5 mL) was treated with TFA (2 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ELISA, washed with saturated NaHCO3 aqueous solution and brine, dried, (MgSO4) was used to concentrate the product, and the resulting material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one as trifluoroacetate and as a white solid [140 mg].

[0247] 2-Allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 364)

[0248] 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one (140 mg, 0.275 mmol) was dissolved in anhydrous THF (5 mL). Formaldehyde (approximately 36% purity, 40.9 μL, 0.549 mmol) and STAB (175 mg, 0.824 mmol) were added in that order. The reaction mixture was stirred at room temperature while monitoring by LC-MS. After 2 hours, the reaction mixture was quenched by dropwise addition of saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the crude material as a yellow powder. The obtained material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one [25 mg, yield 27%].

[0249] Example 9 Synthesis of 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 363)

[0250] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(1-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0251] Example 10 2-allyl-6-(1-isopropyl-1H-indazole-5-ylamino)-1-(6-{1-[( 2Synthesis of H3)methyl]-4-piperidyloxy}-2-pyridyl)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 354)

[0252] Methanol-d4 (31 μl, 0.76 mmol, 4.0 equivalents) and water (2 μl, 0.11 mmol, 0.58 equivalents) were added at room temperature to a suspension of dess-martin periodinane (129 mg, 0.30 mmol, 1.6 equivalents) in DCM (2 ml). The mixture was stirred for 20 minutes, and then filtered through a 0.45 μm syringe filter. A clear solution (1.6 equivalents) of the obtained formaldehyde-d2 was added to a solution of 1-[6-(piperidine-4-yloxy)pyridine-2-yl]-2-(propa-2-en-1-yl)-6-{[1-(propan-2-yl)-1H-indazole-5-yl]amino}-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (100 mg, 0.19 mmol, 1.0 equivalent) in THF (3 ml), followed by sodium triacetoxyboroduteride (81 mg, 0.38 mmol, 2.0 equivalents), and the mixture was stirred at room temperature. After 1 hour, the second portion (0.8 equivalents) of formaldehyde-d2 prepared in the same manner as above was added, followed by sodium triacetoxyboroduteride (50 mg, 0.23 mmol, 1.2 equivalents). After another hour, LC-MS showed complete conversion of the secondary amine. The mixture was diluted with SiO2 (30 ml), washed with NaCl (2 x 30 ml 15% aqueous solution), adjusted to pH 11 with NaOH aqueous solution, then washed with saturated brine (30 ml), filtered through a phase separator, and concentrated under reduced pressure. The crude material was purified by reverse-phase chromatography (Gemini NX-C18, 21 x 150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min), and the pure fraction was lyophilized to obtain the title compound. Yield: 91 mg of TFA salt (73%), pale yellow powder.

[0253] Example 11 Synthesis of 6-(4-biphenylamino)-2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 284)

[0254] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0255] Example 12 Synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(3-pyridyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 352)

[0256] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0257] Example 13 Synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[p-(1-methyl-4-pyrazolyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 277)

[0258] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0259] Example 14 Synthesis of 6-(4-biphenylamino)-2-ethyl-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 272)

[0260] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0261] Example 15 Synthesis of 2-ethyl-6-[p-(1-methyl-4-pyrazolyl)phenylamino]-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 271)

[0262] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0263] Example 16 Synthesis of 2-allyl-6-(m-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 269)

[0264] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0265] Example 17 Synthesis of 6-(p-bromophenylamino)-2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 268)

[0266] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0267] Example 18 Synthesis of 6-(p-bromophenylamino)-2-ethyl-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 267)

[0268] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0269] Example 19 Synthesis of 2-allyl-6-(1-isopropyl-1H-indazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 265)

[0270] This compound was prepared using the same method as that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. A crude free base intermediate (282 mg) was obtained as a brown solid, and 9% of it was purified by preparative HPLC. Yield: 20 mg of TFA salt (64%), a pale yellow powder.

[0271] Example 20 Synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 263)

[0272] tert-butyl4-(3-(2-allyl-6-amino-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0273] 400 mg, 0.755 mmol of tert-butyl 4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate was placed in a flask, and ammonia in THF (5 ml, 5.00 mmol) was added under an inert atmosphere at room temperature. The mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude compound, which was then purified by column chromatography (silica mesh 100-200, eluate: 80-100% ethyl acetate and hexane) to obtain the pure compound tert-butyl 4-(3-(2-allyl-6-amino-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (260 mg, 0.346 mmol, yield 45.7%) as a brown solid.

[0274] 2-Allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 263)

[0275] CuI (1.2 equivalents), followed by N,N'-dimethylethylenediamine (1 equivalent), was added at room temperature to a stirred, degassed suspension of tert-butyl 4-({6-[6-amino-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (200 mg), 4-bromo-2-methoxypyridine (1 equivalent), and cesium carbonate (3 equivalents) in dioxane. The reaction mixture was heated overnight at 90°C in a sealed vial. The reaction was monitored by LC-MS, and further CuI and ligands were added as needed to achieve complete conversion. The reaction mixture was diluted with water, a few drops of aqueous ammonia (28%) were added, and then extracted with ethyl acetate (×3). The combined organic layers were dried using a phase separator and concentrated under reduced pressure to obtain oil. This material was used without further refinement.

[0276] Trifluoroacetic acid (10-20% by volume) was added at room temperature to a solution of the above material (1 equivalent) stirred in dry dichloromethane (0.4 mol / L). The resulting solution was stirred (15 min, LC-MS) until the Boc-amine intermediate was consumed, then separated into siRNA and saturated brine, and adjusted with aqueous NaOH solution to approximately 12 pH. The organic phase was filtered through a phase separator and concentrated under reduced pressure to obtain the crude intermediate as a red solid. A portion of this material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min), and the pure fraction was freeze-dried to obtain the amine compound as a TFA salt.

[0277] This material was methylated using the same method as described for 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 178 mg of TFA salt (71%), pale yellow powder.

[0278] Example 21 Synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[2-(4-piperidyloxy)-4-pyrimidinyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 350)

[0279] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 157 mg of TFA salt (62%), yellow powder.

[0280] Example 222 Synthesis of 2-allyl-6-(2-methyl-1,3-benzothiazole-6-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 264)

[0281] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 15 mg of TFA salt (61%), yellow powder.

[0282] Example 23 Synthesis of 2-ethyl-6-[m-(1-methyl-4-pyrazolyl)phenylamino]-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 340)

[0283] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0284] Example 24 Synthesis of 6-(3-biphenylamino)-2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 339)

[0285] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0286] Example 25 Synthesis of 6-(3-biphenylamino)-2-ethyl-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 338)

[0287] This compound was prepared using a method similar to that used for the synthesis of 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-[m-(5-pyrimidinyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0288] Example 26 Synthesis of 2-allyl-6-(2-methyl-1,3-benzothiazole-6-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 260)

[0289] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 65 mg of TFA salt (62%), pale yellow powder.

[0290] Example 27 Synthesis of 2-allyl-6-(6-methoxy-3-pyridylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 251)

[0291] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0292] Example 28 Synthesis of 2-allyl-6-(6-methoxy-3-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 250)

[0293] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0294] Example 29 Synthesis of 2-allyl-6-(1,3,3a-triaza-5-indenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 249)

[0295] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 26 mg of TFA salt (56%), pale yellow powder.

[0296] Example 30 Synthesis of 2-allyl-6-(1-isopropyl-1H-indazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 248)

[0297] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 260 mg of TFA salt (81%), pale yellow powder.

[0298] Example 31 Synthesis of 2-allyl-6-(1,3,3a-triaza-5-indenylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 245)

[0299] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 53 mg of TFA salt (22%), yellow powder.

[0300] Example 32 Synthesis of 2-allyl-6-(2,1,3-benzothiadiazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 208)

[0301] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 58 mg of TFA salt (64%), pale yellow powder.

[0302] Example 33 Synthesis of 2-allyl-6-(6-isoquinolylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 244)

[0303] tert-butyl4-{6-[2-allyl-6-(6-isoquinolylamino)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidinecarboxylate

[0304] tert-butyl 4-[6-(2-allyl-6-amino-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl)-2-pyridyloxy]-1-piperidine carboxylate (100 mg, 0.214 mmol), 6-bromoisoquinoline (46.4 mg, 0.214 mmol), and Cs2CO3 (209 mg, 3 eq.) were mixed and stirred in dioxane (3 mL) under nitrogen for 15 minutes. A catalytic amount of CuI (48.9 mg, 1.2 eq) and 1,2-bis(methylamino)ethane (18.9 mg, 0.214 mmol) as a ligand were added. The reaction mixture was heated at 90°C for 18 hours. The progress of the reaction was observed by LC-MS. The reaction mixture was cooled to room temperature, and the crude residue was quenched with saturated aqueous ammonia to remove CuI. The mixture was then extracted with toluene (3 × 10 mL) and brine. The combined organic layer was dried (anhydrous Na₂SO₄), and the solvent was evaporated under reduced pressure. The crude product was dissolved in MeCN (2 mL) and crystallized over 1 hour by slowly adding water (2 mL). This yielded tert-butyl 4-{6-[2-allyl-6-(6-isoquinolylamino)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate [33 mg, yield 30%] as an off-white solid. LCMS (ESI+), measured m / z value: 596.

[0305] 2-Allyl-6-(6-isoquinolylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 244)

[0306] A solution of tert-butyl 4-{6-[2-allyl-6-(6-isoquinolylamino)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (33 mg, 0.055 mmol) in DCM (2 mL) was treated with TFA (0.5 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ELISA, washed with saturated NaHCO3 aqueous solution and brine, dried (MgSO4), and concentrated. The obtained material was purified by crystallization in MeCN (2 mL) with the slow addition of water (2 mL) over 1 hour. This yielded 2-allyl-6-(6-isoquinolylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one as a yellow solid [30 mg].

[0307] Example 34 Synthesis of 2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-(7-quinolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 335)

[0308] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0309] Example 35 Synthesis of 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-(6-quinolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 242)

[0310] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0311] Example 36 Synthesis of 2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-(6-quinoxalinylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 241)

[0312] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0313] Example 37 Synthesis of 2-allyl-6-(7-isoquinolylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 240)

[0314] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0315] Example 38 Synthesis of 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-(6-quinoxalinylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 239)

[0316] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0317] Example 39 Synthesis of 1-{6-[(S)-1-methyl-3-piperidyloxy]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 332)

[0318] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 61 mg of TFA salt (82%), pale yellow powder.

[0319] Example 40 Synthesis of 2-allyl-6-(5-fluoro-3-pyridylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 329)

[0320] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 157 mg of TFA salt (62%), yellow powder. Yield: 10 mg of TFA salt (46%).

[0321] Example 41 Synthesis of 6-(1,3a-diaza-5-indenylamino)-2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 328)

[0322] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 70 mg of TFA salt (80%), yellow solid.

[0323] Example 42 Synthesis of 2-allyl-6-(5-fluoro-3-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 327)

[0324] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 157 mg of TFA salt (62%), yellow powder. Yield: 125 mg of TFA salt (83%), yellow solid.

[0325] Example 43 Synthesis of 2-allyl-6-(7-isoquinolylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 326)

[0326] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0327] Example 44 Synthesis of 6-(1,3a-diaza-5-indenylamino)-2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 324)

[0328] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 100 mg of TFA salt (42%).

[0329] Example 45 Synthesis of 2-allyl-6-(5-chloro-3-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 323)

[0330] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0331] Example 46 Synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(1-propyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 322)

[0332] 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one was prepared using the same method as the method for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-yloxy)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one.

[0333] Propanol (37.7 μL, 0.502 mmol) was added to a suspension of des-martin periodinane (63.9 mg, 0.151 mmol) in DCM (4 mL), followed by 9 ml of H2O. The mixture was stirred for 30 minutes until it became a white suspension, and then filtered. 2 ml of the filtrate was added to a solution of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one (50 mg, 0.1 mmol) stirred in 2 ml of THF at room temperature. STAB (63.9 mg, 0.301 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was diluted with ELISA (20 ml) and washed with a brine mixture slightly basicized with NaOH (2 × 20 ml). The organic phase was dried using a phase separator and concentrated under vacuum. The crude material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(1-propyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one as trifluoroacetate (26 mg).

[0334] Example 47 Synthesis of 2-allyl-1-[6-(1-ethyl-4-piperidyloxy)-2-pyridyl]-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 321)

[0335] EtOH (29.3 μL, 0.502 mmol) was added to a suspension of des-martin periodinane (63.9 mg, 0.151 mmol) in DCM (4 mL), followed by 9 ml of H2O. The mixture was stirred for 30 minutes until it became a suspension, and then filtered. 2 ml of the filtrate was added to a solution of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one (50 mg, 0.1 mmol) stirred in 2 ml of THF at room temperature. STAB (42.6 mg, 0.201 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was diluted with ELISA (20 ml) and washed with a brine mixture slightly basicized with NaOH (2 × 20 ml). The organic phase was dried using a phase separator and concentrated under vacuum. The crude material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(1-propyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one as trifluoroacetate (25 mg).

[0336] Example 48 Synthesis of 2-allyl-6-(1,2-benzoisothiazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 320)

[0337] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 58 mg of TFA salt (64%), pale yellow powder.

[0338] Example 49 Synthesis of 2-allyl-1-[m-(1-methyl-4-piperidyloxy)phenyl]-6-(2-methyl-4-pyridylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 219)

[0339] 2-allyl-6-((2-methylpyridine-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (350 mg, 0.765 mmol) was stirred in THF (5 ml) to a solution to which formaldehyde (310 mg, 3.82 mmol) was added at 25°C, and the reaction mixture was stirred at 25°C for 5 minutes. Then STAB (486 mg, 2.295 mmol) was added little by little. After the STAB had been completely added, the reaction mixture was stirred at 25°C for 20 minutes. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was then quenched with TFA, followed by NH3 in MeOH, diluted with water, and extracted with 10% MeOH (2 × 100 mL) in DCM. The combined organic layers were washed with NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by preparative HPLC to obtain the pure compound 2-allyl-1-(3-((1-methylpiperidine-4-yl)oxy)phenyl)-6-((2-methylpyridine-4-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (66 mg, 0.136 mmol, yield 17.75%) as an off-white solid.

[0340] Example 50 Synthesis of 2-allyl-6-(p-fluorophenylamino)-1-[6-(1-methyl-4-azepanyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 317)

[0341] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0342] Example 51 Synthesis of 2-allyl-6-(2-methyl-1,3-benzoxazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 232)

[0343] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 13.5 mg of TFA salt (50%), yellow powder.

[0344] Example 52 Synthesis of 2-allyl-6-(2-methyl-1,3-benzoxazole-6-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 316)

[0345] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 17.6 mg of TFA salt (65%), yellow powder.

[0346] Example 53 Synthesis of 2-allyl-6-(2-methyl-1,3-benzoxazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 231)

[0347] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 19 mg of TFA salt (80%), pale yellow powder.

[0348] Example 54 Synthesis of 2-allyl-6-(2-methyl-4-pyridylamino)-1-[m-(4-piperidyloxy)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 222)

[0349] tert-butyl 4-(3-bromophenoxy)piperidine-1-carboxylate

[0350] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (7.48 g, 37.1 mmol) stirred in DMF (50 ml), NaH (2.285 g, 57.1 mmol) was added at 0°C under an inert atmosphere, and the mixture was stirred at 50°C for 1 hour. The flask was then cooled to room temperature, 1-bromo-3-fluorobenzene (5 g, 28.6 mmol) was dissolved in DMF (10 ml), and added to the reaction mass. The mixture was stirred at 70°C for 3 hours. The progress of the reaction was monitored by LC-MS and TLC. After the reaction was complete, the reaction mass was quenched with ice-cold water, extracted with siRNA (500 mL), washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica mesh 100-200, eluate: 10-20% ethyl acetate and hexane) to obtain tert-butyl 4-(3-bromophenoxy)piperidine-1-carboxylate (6.8 g, 14.89 mmol, yield 52.1%) as a yellow, rubbery liquid. LCMS m / z measured value: 300.0 (M-56).

[0351] N-(6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-yl)-2-cyano-N-methylacetamide

[0352] A solution of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (420 mg, 1.890 mmol), tert-butyl-4-(3-bromophenoxy)piperidine-1-carboxylate (808 mg, 2.268 mmol), K2CO3 (783 mg, 5.67 mmol), and N,N'-dimethylethylenediamine (0.203 ml, 1.890 mmol) was stirred in dioxane (5 ml) and degassed at room temperature for 20 minutes under an inert atmosphere. CuI (359 mg, 1.890 mmol) was added, the mixture was degassed again for 5 minutes, and then stirred at 110°C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was filtered through Celite and washed with 10% MeOH in DCM (150 mL). The collected fraction was concentrated under reduced pressure to obtain the crude compound, which was purified by flash column chromatography (SiO2 / 230-400 mesh; 20-50% ethyl acetate-petroleum ether) to obtain tert-butyl 4-(3-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (65 mg, 0.108 mmol, yield 5.74%) as an off-white solid.

[0353] tert-butyl-4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0354] 60 mg, 0.121 mmol of tert-butyl 4-(3-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (DCM) was stirred in 2 ml of DCM, and m-CPBA (41.6 mg, 0.241 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with aqueous sodium bicarbonate solution and then extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude tert-butyl-4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (60 mg, 0.113 mmol, yield 94%). This crude compound was used directly without further purification before proceeding to the next step.

[0355] tert-butyl-4-(3-(2-allyl-6-amino-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0356] 400 mg, 0.755 mmol of tert-butyl 4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate and 5 ml, 5.00 mmol of ammonia in THF were added to a flask and stirred at room temperature under an inert atmosphere for 16 hours. The reaction was monitored by TLC and LCMS. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude compound, which was purified by column chromatography (silica mesh 100-200, eluate: 80-100% ethyl acetate and hexane) to obtain tert-butyl 4-(3-(2-allyl-6-amino-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (260 mg, 0.346 mmol, yield 45.7%) as a brown solid.

[0357] tert-butyl-4-(3-(2-allyl-6-((2-methylpyridine-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrzolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0358] A solution of tert-butyl 4-(3-(2-allyl-6-amino-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (300 mg, 0.643 mmol), 4-bromo-2-methylpyridine (133 mg, 0.772 mmol), K2CO3 (267 mg, 1.929 mmol), and N,N'-dimethylethylenediamine (56.6 mg, 0.643 mmol) was stirred in dioxane (4 ml) and degassed with N2 for 30 minutes. Copper(I) iodide (122 mg, 0.643 mmol) was added to this mixture, and the mixture was degassed again for 5 minutes. The mixture was stirred at 110°C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mass was filtered through Celite, and the crude compound was washed with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum to obtain the crude compound. This was purified by column chromatography (silica mesh 100-200, eluate: 80-100% ethyl acetate and hexane) to obtain tert-butyl 4-(3-(2-allyl-6-((2-methylpyridine-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (140 mg, 0.208 mmol, yield 32.4%) as an off-white solid. LCMS m / z measured value: 558.5 (M+H).

[0359] 2-Allyl-6-((2-methylpyridine-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 222)

[0360] 40 mg, 0.071 mmol of tert-butyl 4-(3-(2-allyl-6-((2-methylpyridine-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (40 mg, 0.071 mmol) was stirred in 1 ml of dioxane, and 0.2 ml, 0.800 mmol of HCl in dioxane was added at 0°C under an inert atmosphere. The mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude compound, which was washed with n-hexane. The obtained crude compound was purified by preparative HPLC (column: X-select CSH C18, mobile phase A: water (0.1% AA), mobile phase B: acetonitrile, flow rate: 15.0 mL / min, Rt: 12.8) to obtain 2-allyl-6-((2-methylpyridine-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (14 mg, 0.030 mmol, yield 42.65%).

[0361] Example 55 Synthesis of 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-(3-pyridylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 230)

[0362] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 93 mg, white powder.

[0363] Example 56 Synthesis of 2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-(3-pyridylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 229)

[0364] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 96 mg of TFA salt (87%), pale yellow powder.

[0365] Example 57 Synthesis of 2-allyl-1-[6-(4-azepanyloxy)-2-pyridyl]-6-(p-fluorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 315)

[0366] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0367] Example 58 Synthesis of 2-allyl-6-(1,2-benzoisothiazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 228)

[0368] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0369] Example 59 Synthesis of 2-allyl-1-[2-(1-methyl-4-piperidylamino)-4-pyrimidinyl]-6-[p-(2,2,2-trifluoroethoxy)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 314)

[0370] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 49 mg of TFA salt (57%), white powder.

[0371] Example 60 Synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[2-(1-methyl-4-piperidylamino)-4-pyrimidinyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 313)

[0372] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 24.5 mg of TFA salt (40%), yellow powder.

[0373] Example 61 Synthesis of 2-allyl-6-(p-fluorophenylamino)-1-[2-(1-methyl-4-piperidylamino)-4-pyrimidinyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 312)

[0374] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 40 mg of TFA salt (54%), white powder.

[0375] Example 62 Synthesis of 2-allyl-1-[m-(1-methyl-4-piperidyloxy)phenyl]-6-(1-methyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 221)

[0376] tert-butyl4-(3-(2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrzolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0377] To a solution of tert-butyl 4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (80 mg, 0.151 mmol) stirred in acetic acid (3 mL), 1-methyl-1H-pyrazole-4-amine (14.67 mg, 0.151 mmol) was added at 25°C, and the reaction mixture was stirred at 25°C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with 10% aqueous sodium bicarbonate solution, and then extracted with 10% MeOH in DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica gel, mesh 100-200, eluate: 5-10% MeOH in DCM) to obtain tert-butyl 4-(3-(2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (60 mg, 0.082 mmol, yield 54.5%) as an off-white solid. LCMS m / z measured value: 547.6 (M+1).

[0378] 2-Allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0379] A solution of tert-butyl 4-(3-(2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (60 mg, 0.110 mmol) was stirred in 1,4-dioxane (5 mL). To this solution, 4M HCl (0.329 mL, 1.317 mmol) in dioxane was added at 0°C under an inert atmosphere. The reaction mixture was then stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mass was concentrated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC (column: X-select CSH C18, mobile phase A: water (0.1% FA), mobile phase B: acetonitrile (0.1% FA), flow rate: 15.0 mL / min, Rt: 12.8) to obtain 2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (8 mg, 0.018 mmol, yield 16%) as a brown solid.

[0380] 2-Allyl-1-[m-(1-methyl-4-piperidyloxy)phenyl]-6-(1-methyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 221)

[0381] 2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (100 mg, 0.224 mmol) was stirred in THF (5 mL) to a solution to which 37% formaldehyde aqueous solution (0.083 mL, 1.120 mmol) was added at 25°C, and the mixture was stirred for 10 minutes. Then, STAB (142 mg, 0.672 mmol) was added little by little. After the STAB had been completely added, the reaction mixture was stirred at 25°C for 3 hours. The progress of the reaction was monitored by UPLC. After the reaction was complete, the reaction mixture was quenched with TFA, followed by ammonia in MeOH. The reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic extracts were washed with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by preparative HPLC (column: X-select CSH C18, mobile phase A: ammonium acetate / water, mobile phase B: acetonitrile, flow rate: 15.0 mL / min, Rt: 10.8) to obtain 2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-1-(3-((1-methylpiperidine-4-yl)oxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one.

[0382] Example 63 Synthesis of 2-allyl-6-(2-methyl-1,3-benzoxazole-6-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 311)

[0383] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 184 mg of TFA salt (84%), pale yellow powder.

[0384] Example 64 Synthesis of 1-{m-[N-methyl(1-methyl-4-piperidyl)amino]phenyl}-2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 225)

[0385] 2-allyl-6-(methylthio)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0386] 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1.2 g, 5.40 mmol) was stirred in dichloromethane (15 mL) to which 3-nitrophenylboronic acid (1.352 g, 8.10 mmol), sodium carbonate (1.707 g, 16.20 mmol), and copper(II) acetate (0.49 g, 2.70 mmol) were added, followed by pyridine (0.169 g, 1.080 mmol) at room temperature. The mixture was heated to 70 °C and stirred for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. After the reaction was complete, the mixture was filtered through Celite and washed with 10% MeOH in DCM (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica mesh 100-200, eluate: 70-100% ethyl acetate and hexane) to obtain 2-allyl-6-(methylthio)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (700 mg, 1.794 mmol, yield 33.2%) as a white solid. LCMS m / z measured value: 344.2 (M+H).

[0387] 2-allyl-6-(methylsulfonyl)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0388] 2-allyl-6-(methylthio)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (50 mg, 0.146 mmol) was stirred in 10 ml of DCM, and mCPBA (53.7 mg, 0.218 mmol) was added at room temperature under an inert atmosphere. The mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC and ULC. After the reaction was complete, the reaction mixture was quenched with 10% aqueous sodium bicarbonate solution (10 mL) and extracted with 10% MeOH (2 × 50 mL) in DCM. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 2-allyl-6-(methylsulfonyl)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (30 mg, 0.024 mmol, yield 16.47%) as an off-white solid. This crude compound was proceeded to the next step without further purification.

[0389] 2-Allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0390] 2-allyl-6-(methylsulfonyl)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (0.7 g, 2.039 mmol) was stirred in AcOH (5 mL), and 1-methyl-1H-indazole-5-amine (0.3 g, 2.039 mmol) was added to the solution and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and ULC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the resulting residue was quenched with 10% aqueous sodium bicarbonate (100 mL). The resulting mixture was extracted with ethyl acetate (2 × 300 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica mesh 100-200, eluate: 10-20% ethyl acetate and hexane) to obtain 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (600 mg, 1.221 mmol, yield 66.51%) as a yellow solid.

[0391] tert-butyl(2-allyl-1-(3-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate

[0392] 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (0.2 g, 0.452 mmol) was stirred in DCM (5 mL) and TEA (0.452 mmol) and Boc anhydrous (0.148 g, 0.678 mmol) were added. The mixture was stirred at room temperature under an inert atmosphere for 16 hours. The progress of the reaction was monitored by TLC and ULC. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound tert-butyl(2-allyl-1-(3-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate (250 mg, 0.424 mmol, yield 94%) as a white solid. LCMS m / z measured value: 443.4 (M-100).

[0393] tert-butyl(2-allyl-1-(3-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate

[0394] 250 mg, 0.461 mmol of tert-butyl(2-allyl-1-(3-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate was stirred in EtOH (3.0 mL) and water (10 mL). Iron (257 mg, 4.61 mmol) and NH4Cl (246 mg, 4.61 mmol) were added to the solution, and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC and ULC. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica gel mesh 100-200, eluate: 50-80% ethyl acetate / hexane) to obtain tert-butyl(2-allyl-1-(3-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate (0.150 g, 0.234 mmol, yield 50.8%) as a brown solid compound. LCMS m / z measured value: 513.4 (M+H).

[0395] tert-butyl-(2-allyl-1-(3-((1-methylpiperidine-4-yl)amino)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate

[0396] tert-butyl(2-allyl-1-(3-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate (0.15 g, 0.293 mmol) and 1-methylpiperidine-4-one (0.033 g, 0.293 mmol) were stirred in dichloroethane (5 mL), and AcOH (1 mL) was added under an inert atmosphere. The mixture was stirred at room temperature for 4 hours and then cooled to 0°C. STAB (0.311 g, 0.293 mmol) was added, and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC and ULC. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by flash column chromatography (silica mesh 100-200, eluate: 0-20% MeOH and DCM) to obtain tert-butyl(2-allyl-1-(3-((1-methylpiperidine-4-yl)amino)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate (140 mg, 0.204 mmol, yield 69.8%) as a yellow solid compound.

[0397] tert-butyl-(2-allyl-1-(3-(methyl(1-methylpiperidine-4-yl)amino)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate

[0398] To a solution of tert-butyl(2-allyl-1-(3-((1-methylpiperidine-4-yl)amino)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate (0.130 g, 0.213 mmol) stirred in THF (2 mL), NaH (0.012 g, 0.533 mmol) was added, and the mixture was stirred at 0°C for 30 minutes under an inert atmosphere. Then MeI (0.030 g, 0.213 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and ULC. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound tert-butyl(2-allyl-1-(3-(methyl(1-methylpiperidine-4-yl)amino)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate (120 mg) as a yellow solid. This crude compound was proceeded to the next step without purification.

[0399] 2-Allyl-1-(3-(methyl(1-methylpiperidine-4-yl)amino)phenyl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 225)

[0400] A solution of tert-butyl(2-allyl-1-(3-(methyl(1-methylpiperidine-4-yl)amino)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)(1-methyl-1H-indazole-5-yl)carbamate (90 mg, 0.144 mmol) was stirred in DCM (5 mL). 4M HCl (0.3 mL, 1.200 mmol) in 1,4-dioxane was added to the solution, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC and UPLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC (column: X-select CSH C18, mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile, flow rate: 15.0 mL / min, Rt: 10.8) to obtain 2-allyl-1-(3-(methyl(1-methylpiperidine-4-yl)amino)phenyl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (7.7 mg, 0.015 mmol, yield 10.09%) as an off-white solid.

[0401] Example 65 Synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidyloxy)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 220)

[0402] 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (210 mg, 0.423 mmol) was stirred in THF (5 mL) to a solution to which 37% formaldehyde aqueous solution (172 mg, 2.114 mmol) was added at 25°C, and the resulting mixture was stirred for 10 minutes. Then, STAB (269 mg, 1.269 mmol) was added little by little. After the STAB had been completely added, the reaction mixture was stirred at 25°C for 16 hours. The progress of the reaction was monitored by UPLC. After the reaction was complete, the reaction mixture was quenched with TFA, followed by ammonia in MeOH. The reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic extracts were washed with an aqueous sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by preparative HPLC to obtain 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-((1-methylpiperidine-4-yl)oxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (21.22 mg, 0.040 mmol, yield 9.53%) as a white solid.

[0403] Example 66 Synthesis of p-{2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-6-ylamino}benzonitrile (compound 310)

[0404] This compound was prepared using the same method as that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 37.1 mg (44%).

[0405] Example 67 Synthesis of 2-allyl-6-(1-benzofuran-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 309)

[0406] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 154 mg of TFA salt (84%), pale yellow powder.

[0407] Example 68 Synthesis of 2-allyl-6-(1-benzofuran-6-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 308)

[0408] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 114 mg of TFA salt (62%), pale yellow powder.

[0409] Example 69 Synthesis of 2-allyl-6-(2H-1,3-benzodioxol-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 307)

[0410] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 130 mg of TFA salt (70%), pale yellow powder.

[0411] Example 70 Synthesis of m-{2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazaidene-6-ylamino}benzonitrile (compound 305)

[0412] This compound was prepared using the same method as that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 25 mg (27%).

[0413] Example 71 Synthesis of 2-allyl-6-(1,3-benzothiazole-6-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 303)

[0414] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 19 mg of TFA salt (80%), pale yellow powder.

[0415] Example 72 Synthesis of p-{2-ethyl-3-oxo-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazainden-6-ylamino}benzonitrile (compound 302)

[0416] This compound was prepared using p-bromobenzonitrile and tert-butyl4-[(6-{6-amino-2-ethyl-3-oxo-1H,2H,3H-pyrzolo[3,4-d]pyrimidine-1-yl}pyridine-2-yl)oxy]piperidine-1-carboxylate by a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one]. Yield: 7.8 mg (9%).

[0417] Example 73 Synthesis of p-{2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazaidene-6-ylamino}benzonitrile (compound 301)

[0418] This compound was prepared using p-bromobenzonitrile by a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one.

[0419] Example 74 p-{2-allyl-3-oxo-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazainden-6-ylamino}benzonitrile (compound 300)

[0420] 4-{6-[2-allyl-6-(p-cyanophenylamino)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidinecarboxylate

[0421] tert-butyl-4-[6-(2-allyl-6-amino-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl)-2-pyridyloxy]-1-piperidine carboxylate (200 mg, 0.428 mmol), p-bromobenzonitrile (155.8 mg, 0.856 mmol), and Cs2CO3 (418 mg, 3 equivalents) were mixed and stirred in dioxane (5 mL) under nitrogen for 15 minutes. A catalytic amount of CuI (252.6 mg, 3.1 equivalents) and 1,2-bis(methylamino)ethane (41.5 mg, 0.471 mmol) as a ligand were added. The reaction mixture was heated at 90°C for 48 hours. The progress of the reaction was observed by LC-MS. The reaction mixture was cooled to room temperature, the crude residue was quenched with saturated aqueous ammonia solution, then extracted with siRNA (3 × 10 mL), and washed with brine. The combined organic layer was dried (anhydrous Na₂SO₄), and the solvent was evaporated under reduced pressure. The crude product was dissolved in MeCN (5 ml), and the product was crystallized over 1 hour by slowly adding water (5 ml). The pale brown crude material was dissolved in DCM (5 ml), loaded onto a 10 g silica column, and purified by flash chromatography (0-100%, siRNA:PE) to obtain tert-butyl 4-{6-[2-allyl-6-(p-cyanophenylamino)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate [175 mg, yield 72%] as a yellow solid.

[0422] p-{2-allyl-3-oxo-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-6-ylamino}benzonitrile, trifluoroacetate (compound 300)

[0423] A solution of tert-butyl 4-{6-[2-allyl-6-(p-cyanophenylamino)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (175 mg, 0.308 mmol) in DCM (3 mL) was treated with TFA (1.5 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and brine, dried, (MgSO4) was used to concentrate the product, and the resulting material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain p-{2-allyl-3-oxo-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaindene-6-ylamino}benzonitrile as trifluoroacetate and as a white solid [165 mg].

[0424] Example 75: 2-Allyl-6-(1,2-benzoisoxazole-6-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 299)

[0425] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 55 mg (42%), white powder.

[0426] Example 76: 2-Allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(4-piperidyloxy)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 223)

[0427] tert-butyl-4-(3-bromophenoxy)piperidine-1-carboxylate

[0428] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (7.48 g, 37.1 mmol) stirred in DMF (50 mL), NaH (2.285 g, 57.1 mmol) was added at 0°C under an inert atmosphere, and the mixture was then stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, and a solution of 1-bromo-3-fluorobenzene (5 g, 28.6 mmol) dissolved in DMF (5 mL) was added. After the addition, the reaction mixture was stirred at 70°C for 3 hours. The progress of the reaction was monitored by LC-MS and TLC. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2 × 400 mL). The organic phases were combined, washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica mesh 100-200, eluate: 10-20% ethyl acetate and hexane) to obtain tert-butyl 4-(3-bromophenoxy)piperidine-1-carboxylate (6.8 g, 14.89 mmol, yield 52.1%) as a yellow, rubbery liquid. The isolated product was then used to proceed to the next step.

[0429] tert-butyl-4-(3-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0430] A solution of tert-butyl 4-(3-bromophenoxy)piperidine-1-carboxylate (481 mg, 1.350 mmol), 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (250 mg, 1.125 mmol), K2CO3 (466 mg, 3.37 mmol), and N,N'-dimethylethylenediamine (99 mg, 1.125 mmol) was stirred in dioxane (10 mL) and degassed at room temperature for 20 minutes under an inert atmosphere. Then CuI (214 mg, 1.125 mmol) was added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was diluted with DCM and filtered through a Celite pad. The collected organic fraction was concentrated under reduced pressure to obtain a crude compound, which was purified by flash column chromatography (SiO2 / 230-400 mesh; 20-50% ethyl acetate-petroleum ether) to obtain tert-butyl-4-(3-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (80 mg, 0.154 mmol, yield 13.72%) as an off-white solid.

[0431] tert-butyl-4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0432] To a solution of tert-butyl 4-(3-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (80 mg, 0.161 mmol) stirred in DCM (5 mL), m-CPBA (55.5 mg, 0.322 mmol) was added at room temperature, and the mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the solution was quenched with aqueous sodium bicarbonate and extracted with 10% MeOH (2 × 50 mL) in DCM. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to obtain tert-butyl 4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (85 mg, 0.053 mmol, yield 32.9%). This compound was proceeded to the next step without further purification.

[0433] tert-butyl-4-(3-(2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-3-oxo-2,3-dihydro-1H-pyramido[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0434] To a solution of tert-butyl 4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (65 mg, 0.123 mmol) stirred in AcOH (3 mL), 1-methyl-1H-indazole-5-amine (18.06 mg, 0.123 mmol) was added at room temperature. The reaction mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mass was quenched with aqueous sodium bicarbonate solution and extracted with 10% MeOH (2 × 100 mL) in DCM. The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (SiO2 / 230-400 mesh; 0-20% MeOH-DCM) to obtain tert-butyl-4-(3-(2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (30 mg). The isolated product was then used directly in the next step.

[0435] 2-Allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 223)

[0436] To a solution of tert-butyl-4-(3-(2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (30 mg, 0.050 mmol) stirred in dioxane (1 mL), 4 M HCl (0.2 ml) was added to the dioxane under an inert atmosphere at 0°C, and the mixture was then stirred for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the solvent was evaporated under reduced pressure, washed with n-hexane (2 × 5 mL), and then purified by preparative HPLC (column: X-select CSH C18, mobile phase A: water (0.1% AA), mobile phase B: acetonitrile, flow rate: 15.0 mL / min, Rt: 12.8) to obtain 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (4 mg, 7.97 μmol, yield 15.86%) as a brown solid.

[0437] Example 77: 2-Allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 226)

[0438] 2-allyl-6-(methylthio)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0439] 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1, 1.2 g, 5.40 mmol) was stirred in dichloroethane (15 mL). To this solution, 3-nitrophenylboronic acid (1.352 g, 8.10 mmol), sodium carbonate (1.707 g, 16.20 mmol), and copper(II) acetate (0.490 g, 2.70 mmol) were added, followed by pyridine (0.169 g, 1.080 mmol) at room temperature. The temperature was raised to 70 °C and the mixture was stirred for 16 hours. The reaction was monitored by TLC and LC-MS. After the reaction was complete, the reaction mixture was filtered through Celite and extracted with 10% MeOH (2 × 100 mL) in DCM. The combined organic layers were dried over anhydrous Na2SO4 and then evaporated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica mesh 100-200, eluate: 70-100% ethyl acetate and hexane) to obtain 2-allyl-6-(methylthio)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (700 mg, 1.794 mmol, yield 33.2%) as a white solid.

[0440] 2-allyl-6-(methylsulfonyl)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0441] 2-allyl-6-(methylthio)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (50 mg, 0.146 mmol) was stirred in 10 ml of DCM, and mCPBA (53.7 mg, 0.218 mmol) was added at room temperature under an inert atmosphere, followed by continued stirring for 2 hours. The progress of the reaction was monitored by TLC and ULC. After the reaction was complete, the reaction mixture was quenched with 10% aqueous sodium bicarbonate solution (10 mL) and extracted with 10% MeOH (2 × 50 mL) in DCM. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 2-allyl-6-(methylsulfonyl)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (30 mg, 0.024 mmol, yield 16.47%) as an off-white solid. This crude compound was then used directly without further purification before proceeding to the next step.

[0442] 2-Allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0443] 2-allyl-6-(methylthio)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (0.7 g, 2.039 mmol) was stirred in AcOH (5 mL), and 1-methyl-1H-indazole-5-amine (0.3 g, 2.039 mmol) was added to the solution and stirred at room temperature for 16 hours. The reaction was monitored by TLC and ULC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was quenched with 10% aqueous sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (2 × 300 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica gel, mesh 100-200, eluate: 10-20% ethyl acetate and hexane) to obtain 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (600 mg, 1.221 mmol, yield 66.51%) as a yellow solid.

[0444] 2-allyl-1-(3-aminophenyl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0445] 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (50 mg, 0.113 mmol) was stirred in EtOH (3.0 mL) and water (10 mL). Iron (63.1 mg, 1.130 mmol) and NH4Cl (60.4 mg, 1.130 mmol) were added to the solution, and the temperature was raised to 60°C. The mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC and UPLC. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by flash column chromatography (silica mesh 100-200, eluate: 50-80% ethyl acetate and hexane) to obtain 2-allyl-1-(3-aminophenyl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (200 mg, 0.023 mmol, yield 20.38%) as a white solid compound.

[0446] 2-Allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-((1-methylpiperidine-4-yl)amino)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 226)

[0447] 2-allyl-1-(3-aminophenyl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (0.2 g, 0.485 mmol) and 1-methylpiperidine-4-one (55 mg, 0.485 mmol) were stirred together, and AcOH (1 mL) was added at room temperature. The resulting mixture was stirred for 2 hours. This was then cooled to 0°C, STAB (0.617 g, 2.91 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with ice-cold water and extracted with DCM (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the crude compound. This was purified by preparative HPLC (column: X-select CSH C18, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 15.0 mL / min, Rt: 10.8) to obtain 2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(3-((1-methylpiperidine-4-yl)amino)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (14 mg, 0.026 mmol, yield 5.44%) as an off-white solid.

[0448] Example 78: 2-Ethyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 298)

[0449] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 55 mg (42%), white powder. Yield: 92.5 mg, 80%, off-white solid.

[0450] Example 79: 2-Ethyl-6-(p-fluorophenylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 297)

[0451] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 55 mg (42%), white powder. Yield: 50.0 mg, 43%, off-white solid.

[0452] Example 80: 2-Allyl-6-(1-methyl-4-pyrazolylamino)-1-[m-(4-piperidyloxy)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 224)

[0453] tert-butyl-4-(3-(2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrzolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate

[0454] To a solution of tert-butyl 4-(3-(2-allyl-6-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (80 mg, 0.151 mmol) stirred in acetic acid (3 mL), 1-methyl-1H-pyrazole-4-amine (14.67 mg, 0.151 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with 10% sodium bicarbonate aqueous solution, and then extracted with 10% MeOH in DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (silica gel, mesh 100-200, eluate: 5-10% MeOH in DCM) to obtain tert-butyl 4-(3-(2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (60 mg, 0.082 mmol, yield 54.5%) as an off-white solid.

[0455] 2-Allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 224)

[0456] A solution of tert-butyl 4-(3-(2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)phenoxy)piperidine-1-carboxylate (60 mg, 0.110 mmol) was stirred in 1,4-dioxane (5 mL). To this solution, 4M HCl (0.329 mL, 1.317 mmol) in dioxane was added under an inert atmosphere at 0°C. The reaction mixture was stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction product was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: X-select CSH C18, mobile phase A: water (0.1% FA), mobile phase B: acetonitrile (0.1% FA), flow rate: 15.0 mL / min, Rt: 12.8) to obtain 2-allyl-6-((1-methyl-1H-pyrazole-4-yl)amino)-1-(3-(piperidine-4-yloxy)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (8 mg, 0.018 mmol, yield 16%) as a brown solid.

[0457] Example 81: 2-Allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-[p-(2,2,2-trifluoroethoxy)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 227)

[0458] tert-butyl-4-(6-{2-allyl-3-oxo-6-[p-(2,2,2-trifluoroethoxy)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl}-2-pyridyloxy)-1-piperidinecarboxylate

[0459] 166 mg (estimated 0.722 mmol) of mCPBA (<77% purity) in 0.5 mL of DCM was added to a solution of tert-butyl 4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (300 mg, 0.602 mmol) stirred in 2.5 mL of DCM under nitrogen at room temperature. After 15 minutes, the DCM was concentrated under vacuum, and the crude product was dissolved in 3 mL of MeCN. Then, p-(2,2,2-trifluoroethoxy)aniline (115 mg, 0.602 mmol) was added, and the reaction mixture was stirred in a sealed vial at 60°C. After 18 hours, the reaction mixture was cooled to room temperature, and the mCPBA was quenched by dropwise addition of 1 M NaOH (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL) and washed with brine (20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain a yellow powder. The crude material was dissolved in DCM (5 mL), loaded onto a 10 g silica column, and purified by flash chromatography (0-100%, ELISA:PE) to obtain tert-butyl 4-(6-{2-allyl-3-oxo-6-[p-(2,2,2-trifluoroethoxy)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl}-2-pyridyloxy)-1-piperidine carboxylate [210 mg, 94%] as a pale yellow solid.

[0460] 2-Allyl-6-[p-(2-fluoroethoxy)phenylamino]-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one, trifluoroacetate (compound 227)

[0461] A solution of tert-butyl 4-(6-{2-allyl-3-oxo-6-[p-(2,2,2-trifluoroethoxy)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl}-2-pyridyloxy)-1-piperidine carboxylate (210 mg, 0.360 mmol) in DCM (5 mL) was treated with TFA (2.5 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ELISA, washed with saturated NaHCO3 aqueous solution and brine, dried, (MgSO4) was used to concentrate the solution, and the obtained material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-[p-(2-fluoroethoxy)phenylamino]-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one as trifluoroacetate and a white solid (1.4 mg).

[0462] Example 82: 5-{2-allyl-3-oxo-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazainden-6-ylamino}-2-toluonitrile (Compound 293)

[0463] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 27 mg, 47%.

[0464] Example 83: 2-Ethyl-6-(p-fluorophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 290)

[0465] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 55 mg (42%), white powder. Yield: 156 mg, 43%, yellow solid.

[0466] Example 84: 2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 289)

[0467] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 55 mg (42%), white powder. Yield: 82 mg, 53%, off-white solid.

[0468] Example 85 2-Allyl-1-(6-(methyl(1-methylpiperidine-4-yl)amino)pyridine-2-yl)-6-((1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (Compound 201)

[0469] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 28 mg (25.2%).

[0470] Example 86: 2-Allyl-6-(1-isobutyl-4-pyrazolylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 200)

[0471] tert-butyl4-{6-[6-(1-isobutylpyrazole-4-ylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate

[0472] 108 mg (estimated 0.469 mmol) of mCPBA (<77% purity) in 0.5 mL of DCM was added to a solution of tert-butyl 4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (123 mg, 0.247 mmol) stirred in 5 mL of DCM under nitrogen at room temperature. After 15 minutes, the DCM was concentrated under vacuum, and the crude product was dissolved in 5 mL of MeCN. Then, 54.4 mg (0.391 mmol) of 1-isobutyl-4-pyrazolylamine was added. The reaction mixture was stirred in a sealed vial at 60°C. After 22 hours, the reaction mixture was cooled to room temperature, and the mCPBA was quenched by dropwise addition of 1 M NaOH (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure to obtain the crude product as a yellow powder. The crude material was dissolved in DCM (5 ml), loaded onto a 10 g silica column, and purified by flash chromatography (0-100%, EtOAC:PE) to obtain tert-butyl 4-{6-[6-(1-isobutylpyrazole-4-ylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate as a pale yellow solid (100 mg, 84%).

[0473] 2-Allyl-6-(1-isobutyl-4-pyrazolylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one

[0474] A solution of tert-butyl 4-{6-[6-(1-isobutylpyrazole-4-ylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate (100 mg, 0.205 mmol) in DCM (5 mL) was treated with TFA (2 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ELISA, washed with saturated NaHCO3 aqueous solution and brine, dried, (MgSO4) was used to concentrate the product, and the obtained material was purified by HPLC (Phenomenex Gemini 5 μm NX-C18 110 Å 150 × 21, 2 mm, buffer 0.2% NH4OH, water (0.2% NH4OH) / acetonitrile, gradient for 9 minutes, 30 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-(1-isobutyl-4-pyrazolylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one as a white solid (100 mg).

[0475] 2-Allyl-6-(1-isobutyl-4-pyrazolylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 200)

[0476] 2-allyl-6-(1-isobutyl-4-pyrazolylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (100 mg, 0.205 mmol) was dissolved in anhydrous THF (5 mL). Formaldehyde (approximately 36% purity, 30.4 μL, 0.408 mmol) and STAB (86.5 mg, 0.408 mmol) were added in that order. The reaction mixture was stirred at room temperature while monitoring by LC-MS. After 2 hours, the reaction mixture was quenched by dropwise addition of saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the crude material as a yellow powder. The crude product was dissolved in MeOH (5 ml) and purified by HPLC (Phenomenex Gemini 5 μm NX-C18 110 Å 150 × 21, 2 mm, buffer 0.2% NH4OH, water (0.2% NH4OH) / acetonitrile, gradient for 6 minutes, 30 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-(1-isobutyl-4-pyrazolylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (60 mg, 60%).

[0477] Example 87: 2-Allyl-6-(1-isopropyl-4-pyrazolylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 198)

[0478] This compound was prepared using the same method as that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 60 mg (24%).

[0479] Example 88: 2-Allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-(6-methyl-3-pyridylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 197)

[0480] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 29 mg of TFA salt (83%), pale yellow powder.

[0481] Example 89: 2-Allyl-6-(2H-1,3-benzodioxol-5-ylamino)-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 196)

[0482] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. The purified material was converted to free base by solid-phase extraction (1 g SCX-2, MeOH, NH3 / MeOH 1.4 M). Yield: 41 mg of free base (33%), a brown solid.

[0483] Example 90: 2-Allyl-6-(1-benzofuran-6-ylamino)-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 195)

[0484] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 110 mg of TFA salt (74%), yellow solid.

[0485] Example 91: 2-allyl-1-{6-(9-methyl-9-azabicyclo[3.3.1]non-3-yloxy)-2-pyridyl}6-(1-methyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 194)

[0486] This compound was prepared using the same method as that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 40 mg (31.7%).

[0487] Example 92: 1-{6-[(R)-3-piperidyloxy]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 192)

[0488] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one.

[0489] Example 93: 2-Allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 191)

[0490] tert-butyl4-{6-[6-(3-methylphenylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazaiden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate

[0491] mCPBA (<77% purity) (167.2 mg, assumed 0.727 mmol) in DCM (0.5 mL) was added to a solution of tert-butyl 4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (300 mg, 0.602 mmol) stirred in DCM (5 mL) at room temperature under nitrogen. After 15 minutes, the DCM was concentrated under vacuum, the crude product was dissolved in MeCN (5 mL), and then m-toluidine (96.7 mg, 0.903 mmol) was added. The reaction mixture was stirred in a sealed vial at 60°C. After 22 hours, the reaction mixture was cooled to room temperature, and the mCPBA was quenched by dropwise addition of 1 M NaOH (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), then dried (MgSO4), and concentrated under reduced pressure to obtain the product as a yellow powder. The crude material was dissolved in DCM (5 mL), loaded onto a 10 g silica column, and purified by flash chromatography (0-100% EtOAC:PE) to obtain tert-butyl 4-{6-[6-(3-methylphenylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate [300 mg, 87.2%] as a pale yellow solid.

[0492] 2-Allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one, trifluoroacetate

[0493] A solution of tert-butyl 4-{6-[6-(3-methylphenylamino)-3-oxo-2-(propa-2-enyl)-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]pyrido-2-yloxy}piperidine-1-carboxylate (300 mg, 0.525 mmol) in DCM (5 mL) was treated with TFA (2 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in ELISA, washed with saturated NaHCO3 aqueous solution and brine, dried, (MgSO4) was used to concentrate the product, and the obtained material was purified by HPLC (Phenomenex Gemini 5 μm NX-C18 110 Å 150 × 21, 2 mm, buffer 0.2% NH4OH, water (0.2% NH4OH) / acetonitrile, gradient for 9 minutes, 30 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one as trifluoroacetate and as a white solid [120 mg].

[0494] 2-Allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 191)

[0495] 2-Allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one (120 mg, 0.21 mmol) was dissolved in anhydrous THF (5 mL). Formaldehyde (approximately 36% purity, 31 μL, 0.21 mmol) and STAB (89 mg, 0.21 mmol) were added in that order. The reaction mixture was stirred at room temperature while monitoring by LC-MS. After 2 hours, the reaction mixture was quenched by the dropwise addition of saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the crude material as a yellow powder.

[0496] The crude product was dissolved in MeOH (5 ml) and purified by HPLC (Phenomenex Gemini 5 μm NX-C18 110 Å 150 × 21, 2 mm, buffer 0.2% NH4OH, water (0.2% NH4OH) / acetonitrile, gradient for 6 minutes, 30 ml / min). The pure fraction was pooled and concentrated to obtain [100 mg, yield 33%] 2-allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (40 mg, 33%) as a white solid.

[0497] Example 94: 2-Allyl-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 188)

[0498] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 144 mg, 56%.

[0499] Example 95: 2-Allyl-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-6-[4-(2,2,2-trifluoroethoxy)-3-toluidino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 181)

[0500] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 105 mg, 68%.

[0501] Example 96: 2-Allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-(1-propyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 180)

[0502] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 75 mg, 70%.

[0503] Example 97: 2-Allyl-1-[6-(4-piperidylamino)-2-pyridyl]-6-[4-(2,2,2-trifluoroethoxy)-3-toluidino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 178)

[0504] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 220 mg, 81%.

[0505] Example 98: 1-{6-[N-methyl(1-methyl-4-piperidyl)amino]-2-pyridyl}2-allyl-6-(1-propyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 177)

[0506] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 8 mg, 10%.

[0507] Example 99 1-{6-[N-(S)-3-piperidyl-N-methylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 173)

[0508] This compound was prepared starting from tert-butyl(S)-3-amino-1-piperidine carboxylate using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 7.0 mg of TFA salt (31%).

[0509] Example 100 1-{6-[N-(R)-3-piperidyl-N-methylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 171)

[0510] This compound was prepared starting from tert-butyl(R)-3-amino-1-piperidine carboxylate using a method similar to that used for the synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[m-(1-methyl-4-piperidylamino)phenyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 6.6 mg of TFA salt (25%).

[0511] Example 101: 1-{6-[(R)-1-methyl-3-piperidylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 168)

[0512] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, starting from 1-{6-[(R)-3-piperidylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 93 mg, 76%.

[0513] Example 102 1-{6-[(S)-1-methyl-3-piperidylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 167)

[0514] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, starting from 1-{6-[(S)-3-piperidylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 91 mg, 34%.

[0515] Example 103: 1-{6-[(R)-3-piperidylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 166)

[0516] This compound was prepared starting from tert-butyl(R)-3-amino-1-piperidinecarboxylate using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 150 mg, 63%.

[0517] Example 104 1-{6-[(S)-3-piperidylamino]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 165)

[0518] This compound was prepared starting from tert-butyl(S)-3-amino-1-piperidinecarboxylate using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 310 mg, 39%.

[0519] Example 105 1-(6-{[(S)-1-methyl-3-piperidyl]-N-methylamino}-2-pyridyl)-2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 164)

[0520] This compound was prepared starting from tert-butyl(S)-3-amino-1-piperidinecarboxylate using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 40 mg of TFA salt (43%), pale yellow solid.

[0521] Example 106 (R)-2-allyl-6-((4-chlorophenyl)amino)-1-(6-(methyl(1-methylpiperidine-3-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 163)

[0522] This compound was prepared starting from tert-butyl(R)-3-amino-1-piperidinecarboxylate using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 38 mg of TFA salt (35%), pale yellow solid.

[0523] Example 107: 2-Allyl-6-(3-fluoro-5-toluidino)-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 161)

[0524] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 54 mg, 62%.

[0525] Example 108: 2-allyl-6-(3-fluoro-5-toluidino)-1-[6-(4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 160)

[0526] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 78 mg, 63%.

[0527] Example 109: 2-Allyl-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-6-(3-phenyl-5-isothiazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 158)

[0528] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 1.8 mg, 37%.

[0529] Example 110: 6-(4-fluoro-3-toluidino)-2-methyl-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 154)

[0530] This compound was prepared using tert-butyl4-({6-[2-methyl-6-(methylsulfanyl)-3-oxo-1H,2H,3H-pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one) and 4-fluoro-3-methylaniline (1 equivalent) in the same manner as the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (81 mg) and 4-fluoro-3-methylaniline (1 equivalent) to obtain a crude free base intermediate (77 mg), of which 20% was purified by preparative HPLC. Yield: 9.3 mg of TFA salt (60%).

[0531] Example 111: 6-(p-chlorophenylamino)-2-methyl-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 153)

[0532] This compound was prepared using tert-butyl 4-({6-[2-methyl-6-(methylsulfanyl)-3-oxo-1H,2H,3H-pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one) and 4-chloroaniline (1 equivalent) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (81 mg) and 4-chloroaniline (1 equivalent) to obtain a crude free base intermediate (78 mg), of which 20% was purified by preparative HPLC. Yield: 8.7 mg of TFA salt (56%).

[0533] Example 112: 6-(4-fluoro-3-toluidino)-2-methyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 152)

[0534] This compound was prepared using 6-[(4-fluoro-3-methylphenyl)amino]-2-methyl-1-[6-(piperidine-4-yloxy)pyridine-2-yl]-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (62 mg) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(6-methylpiperidine-4-yloxy)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 57 mg of TFA salt (71%), powder.

[0535] Example 113: 2-Allyl-6-(3,4-dichlorophenylamino)-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 151)

[0536] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 33 mg, 84%.

[0537] Example 114: 6-(p-chlorophenylamino)-2-methyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 150)

[0538] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 45 mg of TFA salt (57%), powder.

[0539] Example 115: 1-{6-[(S)-1-methyl-3-pyrrolidinyloxy]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 148)

[0540] This compound was prepared using tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 94 mg of TFA salt (82%), pale yellow powder.

[0541] Example 116: 2-allyl-6-(3,4-dichlorophenylamino)-1-[6-(4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 146)

[0542] This compound was prepared using 3,4-dichloroaniline and tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate. Yield: 46 mg, 24%.

[0543] Example 117: 1-{6-[(S)-3-pyrrolidinyloxy]-2-pyridyl}2-allyl-6-(p-chlorophenylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 145)

[0544] This compound was prepared using tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 177 mg of TFA salt (62%), yellow powder.

[0545] Example 118: 2-allyl-6-(p-chlorophenylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 141)

[0546] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (99 mg) and 4-chloroaniline (1 equivalent) in a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (99 mg) and 4-chloroaniline (1 equivalent). After deprotection, the reaction mixture was concentrated to obtain a yellow oil (175 mg, crude), half of which was purified by preparative HPLC and then converted to free base by solid-phase extraction (1 g SCX-2, MeOH, 1.4 M MeOH / NH3). Yield: 15 mg of free base (31%), powder.

[0547] Example 119: 2-Allyl-6-(p-chlorophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 142)

[0548] 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0549] A solution of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 g, 4.50 mmol), 2-bromo-6-fluoropyridine (0.871 g, 4.95 mmol), trans-N,N-dimethylethylenediamine (0.397 g, 4.50 mmol), and K2CO3 (1.865 g, 13.50 mmol) was stirred in DMSO (4 ml), degassed for 5 minutes, and then copper(I) iodide (0.857 g, 4.50 mmol) was added at 25°C. The resulting mixture was stirred at 100°C for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite pad and washed with ethyl acetate (250 mL). The filtrate was concentrated under reduced pressure. The obtained crude material was purified by flash chromatography (SiO2 / 100-200 mesh; 20-30% ethyl acetate-hexane) to obtain 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (700 mg, 2.089 mmol, yield 46.4%) as a light brown solid.

[0550] 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylsulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0551] 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 g, 3.15 mmol) was stirred in dichloromethane (30 mL) to which m-CPBA (1.554 g, 6.30 mmol) was added at 0°C, and the mixture was stirred at 25°C for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with DCM (300 mL) and washed with sodium bicarbonate aqueous solution (2 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylsulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 g, 2.63 mmol, yield 84%) as a pale yellow solid.

[0552] 2-allyl-6-((4-chlorophenyl)amino)-1-(6-fluoropyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0553] 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylsulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 g, 2.86 mmol) was stirred in acetic acid (10 mL) and 4-chloroaniline (0.438 g, 3.44 mmol) was added under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. The obtained residue was basicized with sodium bicarbonate and extracted with ethyl acetate (10 × 2 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude material was purified by flash chromatography (SiO2 / 100-200 mesh; 7-8% methanol-DCM) to obtain 2-allyl-6-((4-chlorophenyl)amino)-1-(6-fluoropyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (800 mg, 1.774 mmol, yield 62.0%) as a light brown solid.

[0554] 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 142)

[0555] NaH (60% in oil) (121 mg, 2.77 mmol) was added to a solution of 1-methylpiperidine-4-ol (218 mg, 1.890 mmol) stirred in tetrahydrofuran (10 ml). The resulting mixture was stirred at 60°C for 1 hour. Then, 2-allyl-6-((4-chlorophenyl)amino)-1-(6-fluoropyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (6, 500 mg, 1.260 mmol) was added, and the mixture was stirred at 60°C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water (150 mL) and extracted with 10% methanol-DCM (2 × 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained crude material was purified by flash chromatography (SiO2 / 230-400 mesh; 20-25% methanol-DCM) to obtain 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (175 mg, 0.352 mmol, yield 27.9%) as an off-white solid.

[0556] Example 120: 2-allyl-6-(4-fluoro-3-toluidino)-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 140)

[0557] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 129 mg, 75%.

[0558] Example 121: 2-Allyl-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-6-[p-(2,2,2-trifluoroethoxy)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 139)

[0559] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 80 mg, 66.6%.

[0560] Example 122: 2-Allyl-6-(p-chlorophenylamino)-1-[6-(1-methyl-4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 138)

[0561] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 7.4 mg, 63%.

[0562] Example 123: 2-Allyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-(1-methyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 137)

[0563] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one. Yield: 20 mg, 17%.

[0564] Example 124: 2-allyl-6-(4-chloro-3-toluidino)-1-[6-(4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 133)

[0565] This compound was prepared using 4-chloro-3-methylaniline and tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate. Yield: 24 mg, 38%.

[0566] Example 125: 2-Ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-6-(1-methyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 132)

[0567] This compound was prepared using 1-methyl-1H-pyrazole-4-amine and 2-ethyl-1-{6-[(1-methylpiperidine-4-yl)oxy]pyridine-2-yl}-6-(methylsulfanyl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one, using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 35 mg, 56%.

[0568] Example 126: 2-allyl-1-[6-(4-piperidylamino)-2-pyridyl]-6-[p-(trifluoromethyl)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 131)

[0569] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 18 mg, 29%.

[0570] Example 127: 2-Allyl-1-[6-(4-piperidylamino)-2-pyridyl]-6-[p-(2,2,2-trifluoroethoxy)phenylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 130)

[0571] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 6.9 mg.

[0572] Example 128: 2-allyl-6-(4-fluoro-3-toluidino)-1-[6-(4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 128)

[0573] This compound was prepared using 4-fluoro-3-methylaniline and tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate. Yield: 153 mg, 61%.

[0574] Example 129 1-{6-[N-methyl(1-methyl-4-piperidyl)amino]-2-pyridyl}2-ethyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 287)

[0575] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 35 mg, 60%.

[0576] Example 130: 2-Allyl-6-(4-methoxy-3-toluidino)-1-[6-(4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 127)

[0577] This compound was prepared using 4-methoxy-3-methylaniline and tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate. Yield: 43 mg, 71%.

[0578] Example 131: 2-Allyl-1-[6-(4-piperidylamino)-2-pyridyl]-6-m-toluidino-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 126)

[0579] This compound was prepared using 3-methylaniline and tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate. Yield: 39 mg, 67%.

[0580] Example 132: 2-allyl-6-(p-chlorophenylamino)-1-[6-(4-piperidylamino)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 124)

[0581] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 4-chloroaniline (1 equivalent) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 4-chloroaniline (1 equivalent). Yield: 29 mg of TFA salt (49%), yellow powder.

[0582] Example 133: 1-[6-(N-methyl-N-4-piperidylamino)-2-pyridyl]-2-ethyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 286)

[0583] This compound was prepared using 1-methyl-1H-indazole-5-amine and tert-butyl4-({6-[2-ethyl-6-(methylsulfanyl)-3-oxo-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}(methyl)amino)piperidine-1-carboxylate, using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}(methyl)amino)piperidine-1-carboxylate. Yield: 70 mg, 54%.

[0584] Example 134: 2-methyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 121)

[0585] This compound was prepared using 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (69 mg) and 1-methyl-1H-indazole-5-amine (1 equivalent), using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)oxy]pyridine-2-yl)-6-(methylsulfanyl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (1 equivalent). Yield: 49 mg of TFA salt (46%), yellow powder.

[0586] Example 135 1-{6-[N-methyl(1-methyl-4-piperidyl)amino]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 118)

[0587] This compound was prepared using the same method as that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 9.8 mg, 68%.

[0588] Example 136: 6-anilino-2-ethyl-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 117)

[0589] This compound was prepared using 2-ethyl-1-{6-[(1-methylpiperidine-4-yl)oxy]pyridine-2-yl}-6-(methylsulfanyl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (102 mg) and aniline (1 equivalent) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (102 mg) and aniline (1 equivalent). Yield: 69 mg of TFA salt (48%), yellow powder.

[0590] Example 137 1-[6-(N-methyl-N-4-piperidylamino)-2-pyridyl]-2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 116)

[0591] This compound was prepared using 1-methyl-1H-indazole-5-amine and tert-butyl4-[methyl({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl})amino]piperidine-1-carboxylate, using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl})amino]piperidine-1-carboxylate. Yield: 22 mg, 40%.

[0592] Example 138: 2-Ethyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 114)

[0593] This compound was prepared using 2-ethyl-1-{6-[(1-methylpiperidine-4-yl)oxy]pyridine-2-yl}-6-(methylsulfanyl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (103 mg) and 1-methyl-1H-indazole-5-amine (2.5 equivalents) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl}-6-(methylsulfanyl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (2.5 equivalents). Yield: 64 mg of TFA salt (41%), yellow powder.

[0594] Example 139: 2-allyl-6-(2-methyl-4-pyridylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 113)

[0595] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 2 mg.

[0596] Example 140 1-{6-[(S)-1-methyl-3-pyrrolidinylamino]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 108)

[0597] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 6.5 mg of TFA salt (24%), yellow powder.

[0598] Example 141 Synthesis of 1-{6-[(S)-3-pyrrolidinylamino]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 107)

[0599] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 73 mg of TFA salt (66%), yellow powder.

[0600] Example 142 Synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 106)

[0601] This compound was prepared using tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (184 mg) and 1-methyl-1H-indazole-5-amine (1 equivalent) by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (184 mg) and 1-methyl-1H-indazole-5-amine (1 equivalent). Yield: 140 mg of TFA salt (62%), yellow powder.

[0602] Example 143 Synthesis of 2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 109)

[0603] This compound was prepared using 6-[(1-methyl-1H-indazole-5-yl)amino]-1-[6-(piperidine-4-yloxy)pyridin-2-yl]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetate (15 mg) by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridin-2-yl]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetate (15 mg). Yield: 9 mg of TFA salt (60%), pale yellow powder.

[0604] Example 144 Synthesis of 1-{6-[(S)-1-methyl-3-pyrrolidinyloxy]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 105)

[0605] This compound was prepared using tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one. Yield: 10.4 mg, 62%.

[0606] Example 145 Synthesis of 1-{6-[(S)-3-piperidyloxy]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 104)

[0607] This compound was prepared using a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one, using 1-methyl-1H-indazole-5-amine (1 equivalent) and tert-butyl(3S)-3-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate (135 mg) (prepared from tert-butyl(3S)-3-hydroxypiperidine-1-carboxylate). Yield: 92 mg of TFA salt (56%), yellow powder.

[0608] Example 146 Synthesis of 1-{6-[(R)-3-pyrrolidinyloxy]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 101)

[0609] This compound was prepared using 1-methyl-1H-indazole-5-amine and tert-butyl(3R)-3-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)pyrrolidine-1-carboxylate (prepared from tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate) by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)pyrrolidine-1-carboxylate (prepared from tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate). Yield: 8.1 mg, 21%.

[0610] Example 147 Synthesis of 1-{6-[(S)-3-pyrrolidinyloxy]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 100)

[0611] This compound was prepared using 1-methyl-1H-indazole-5-amine and tert-butyl(3S)-3-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)pyrrolidine-1-carboxylate (prepared from tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate) by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)pyrrolidine-1-carboxylate (prepared from tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate). Yield: 55.1 mg, 60%.

[0612] Example 148 Synthesis of 2-allyl-6-(1-methyl-1H-1,3-benzimidazole-5-ylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 211)

[0613] mCPBA (<77% purity) (41.5 mg, assumed 0.241 mmol) in DCM (0.5 mL) was added to a solution of tert-butyl 4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidine carboxylate (100 mg, 0.201 mmol) stirred in DCM (2.5 mL) at room temperature under nitrogen. The reaction was controlled by LC-MS. After 15 minutes, the DCM was removed under vacuum, and the crude product was dissolved in MeCN (3 mL). Then, 1-methyl-1H-1,3-benzimidazole-5-ylamine (29.5 mg, 0.201 mmol) and methanesulfonic acid (26 μL, 0.401 mmol) were added. The reaction mixture was stirred in a sealed vial at 60°C. After 18 hours, the reaction mixture was cooled to room temperature, and mCPBA was quenched by dropwise addition of 1M NaOH (5 mL). The aqueous phase was extracted with Depositphotos (3 × 20 mL), followed by brine (20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to obtain the product as a yellow powder. The crude material was dissolved in DCM (5 mL), loaded onto a 10 g silica column, and purified by flash chromatography (0-100%, Depositphotos:PE) to obtain the Boc-protected compound [85 mg, 94%] as a pale yellow solid. This material (85 mg, 0.131 mmol) in DCM (5 mL) was treated with TFA (2.5 mL) for 2 hours. The solvent was removed under vacuum, the crude product was dissolved in Depositphotos, washed with saturated NaHCO3 aqueous solution and brine, dried (MgSO4), and concentrated. The obtained material was purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 2-allyl-6-(1-methyl-1H-1,3-benzimidazole-5-ylamino)-1-[6-(4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one as trifluoroacetate and a white solid [85 mg].

[0614] Example 149 Synthesis of 2-allyl-6-((1-methyl-1H-indole-5-yl)amino)-1-(6-((1-methylpiperidine-4-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 186)

[0615] This compound was prepared using 1-{6-[(1-methylpiperidine-4-yl)oxy]pyridine-2-yl}-6-(methylsulfanyl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (100 mg) and 1-methyl-1H-indole-5-amine (1.5 equivalents) by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridinyl}-6-(methylsulfanyl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyramido[3,4-d]pyrimidine-3-one (100 mg) and 1-methyl-1H-indole-5-amine (1.5 equivalents). Yield: 77 mg of TFA salt (51%), powder.

[0616] Example 150 Synthesis of 1-{6-[(R)-3-pyrrolidinylamino]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 102)

[0617] tert-butyl(3R)-3-[(6-bromopyridine-2-yl)amino]pyrrolidine-1-carboxylate

[0618] 2-bromo-6-fluoropyridine (0.37 g, 2.1 mmol), DIPEA (6.3 mmol, 1.1 ml), and tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate hydrochloride (0.52 g, 2.1 mmol) were mixed in 10 ml of DMSO. The reaction mixture was stirred at 100°C for 2 days and divided into ethyl acetate and water. The organic phase was washed with water, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated. The residue was slurryed with a mixture of heptane and ethyl acetate and collected by filtration to obtain 0.42 g (58%) of tert-butyl(3R)-3-[(6-bromopyridine-2-yl)amino]pyrrolidine-1-carboxylate.

[0619] Step 2

[0620] 6-(methylsulfanyl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (56 mg, 0.25 mmol), copper(I) iodide (52 mg, 0.27 mmol), potassium carbonate (104 mg, 0.75 mmol), 1,2-dimethylethylenediamine (44 mg, 0.50 mmol), and tert-butyl(3R)-3-[(6-bromopyridine-2-yl)amino]pyrrolidine-1-carboxylate (86 mg, 0.25 mmol) were mixed under nitrogen in 20 ml of dioxane. The reaction mixture was stirred overnight at 90°C, diluted with ethyl acetate, filtered through Celite, and concentrated. The residue was purified by flash chromatography (silica, 10-40% ethyl acetate / petroleum ether).

[0621] 1-{6-[(R)-3-pyrrolidinylamino]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one

[0622] The compound from Step 2 and MCPBA (77%, 31 mg, 0.14 mmol) were mixed in 5 ml of DCM. After 2 hours, 1-methyl-1H-indazole-5-amine (37 mg, 0.25 mmol) was added. The reaction mixture was stirred overnight at room temperature. TFA (2 ml) was added, and after 3 hours, the solvent was removed under reduced pressure. The residue was dissolved in methanol / water and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient for 12 minutes, 25 ml / min). The pure fraction was pooled and concentrated to obtain 13 mg (7% in 2 steps) of the title compound.

[0623] Example 151 Synthesis of 6-[(1-methyl-1H-indazole-5-yl)amino]-1-{6-[(3R)-piperidine-3-yloxy]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one;bis(trifluoroacetic acid) (compound 103)

[0624] This compound was prepared using 1-methyl-1H-indazole-5-amine and tert-butyl(3R)-3-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate by a method similar to that used for the synthesis of allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}oxy)piperidine-1-carboxylate. Yield: 130 mg, 56%.

[0625] Example 152 Synthesis of 6-[(1-methyl-1H-indazole-5-yl)amino]-1-[6-(piperidine-4-yloxy)pyridine-2-yl]-2-propyl-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 110)

[0626] 6-[(1-methyl-1H-indazole-5-yl)amino]-1-[6-(piperidine-4-yloxy)pyridine-2-yl]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (60 mg, 0.098 mmol) was dissolved in ethanol (5 mL), to which 10% palladium carbon (4.4 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). The solution was filtered through Celite to remove the catalyst, and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to obtain the crude product as a colorless oil. The crude product was purified by reverse-phase chromatography, and the pure fraction was pooled and lyophilized to obtain the title compound. Yield: 20 mg of TFA salt (33%).

[0627] Example 153 Synthesis of 6-[(1-methyl-1H-indazole-5-yl)amino]-1-{6-[(1-methylpiperidine-4-yl)oxy]pyridine-2-yl}-2-propyl-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 111)

[0628] 6-[(1-methyl-1H-indazole-5-yl)amino]-1-{6-[(1-methylpiperidine-4-yl)oxy]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (41 mg, 0.066 mmol) was dissolved in ethanol (4 mL), to which 10% palladium carbon (2.95 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). The solution was filtered through Celite to remove the catalyst, and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to obtain the crude product as a colorless oil, which was dissolved in acetonitrile and water, and lyophilized to obtain the title compound. Yield: 33 mg of TFA salt (80%).

[0629] Example 154 Synthesis of 1-{6-[(1-methylpiperidine-4-yl)oxy]pyridine-2-yl}-6-[(2-methylpyridine-4-yl)amino]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 112)

[0630] This compound was prepared using 6-[(2-methylpyridine-4-yl)amino]-1-[6-(piperidine-4-yloxy)pyridine-2-yl]-2-propyl-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one, using a method similar to that used for the synthesis of 6-[(2-methylpyridine-4-yl)amino]-1-[6-(piperidine-4-yloxy)pyridine-2-yl]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one. Yield: 31 mg of TFA salt (28%), powder.

[0631] Example 155 Synthesis of 1-{6-[(R)-1-methyl-3-pyrrolidinyloxy]-2-pyridyl}2-allyl-6-(1-methyl-1H-indazole-5-ylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 115)

[0632] 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0633] 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 g, 3.15 mmol) was stirred in DCM (10 ml), and m-CPBA (1.088 g, 6.30 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with sodium bicarbonate and extracted with DCM to obtain a crude product (1 g, 1.920 mmol, yield 60.9%), which was then used directly in the next step.

[0634] 2-allyl-1-(6-fluoropyridine-2-yl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0635] 2-allyl-1-(6-fluoropyridine-2-yl)-6-(methylsulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (1 g, 2.86 mmol) was stirred in acetic acid (10 ml), and 1-methyl-1H-indazole-5-amine (3, 0.421 g, 2.86 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated, quenched with ice-cold water, filtered, and washed with MTBE (20 mL) to obtain the pure compound 2-allyl-1-(6-fluoropyridine-2-yl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (800 mg, 1.767 mmol, yield 61.7%) as a brown solid.

[0636] (R)-2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(6-((1-methylpyrrolidine-3-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

[0637] (R)-1-methylpyrrolidine-3-ol (5,300 mg, 2.97 mmol) was stirred in THF (5 ml), and NaH (60% in oil) (214 mg, 8.90 mmol) was added at 60°C and stirred for 1 hour. Then, 2-allyl-1-(6-fluoropyridine-2-yl)-6-((1-methyl-1H-indazole-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (4,300 mg, 0.720 mmol) was added to the above reaction mixture and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction product was quenched with ice-cold water and extracted with DCM to obtain the crude product. This product was concentrated under reduced pressure and then subjected to preparative HPLC (X-SELECT C18 150M, 0.1% FA / H2O). After lyophilization, the fraction was collected to obtain pure (R)-2-allyl-6-((1-methyl-1H-indazole-5-yl)amino)-1-(6-((1-methylpyrrolidine-3-yl)oxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (90 mg, 0.179 mmol, yield 6.04%).

[0638] Example 156 Synthesis of 1-(6-{[(3R)-1-ethylpyrrolidine-3-yl]amino}pyridine-2-yl)-6-[(1-methyl-1H-indazole-5-yl)amino]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 119)

[0639] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one, using 6-[(1-methyl-1H-indazole-5-yl)amino]-2-(propa-2-en-1-yl)-1-(6-{[(3R)-pyrrolidine-3-yl]amino}pyridin-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (45 mg) and acetaldehyde (excess). Yield: 15 mg of TFA salt (32%), powder.

[0640] Example 157 Synthesis of 6-[(1-methyl-1H-indazole-5-yl)amino]-2-(propa-2-en-1-yl)-1-(6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]amino}pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 120)

[0641] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-(p-bromophenylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1,2-dihydro-3H-1,2,5,7-tetraazaiden-3-one, with 6-[(1-methyl-1H-indazole-5-yl)amino]-2-(propa-2-en-1-yl)-1-(6-{[(3R)-pyrrolidine-3-yl]amino}pyridin-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (45 mg) and acetone (excess). Yield: 30 mg of TFA salt (63%), powder.

[0642] Example 158 Synthesis of 6-[(1-methyl-1H-indazole-5-yl)amino]-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 122)

[0643] This compound was prepared using tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (182 mg) and 1-methyl-1H-indazole-5-amine (1 equivalent) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-ylamino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyrimidine-2-yl}amino)piperidine-1-carboxylate (182 mg) and 1-methyl-1H-indazole-5-amine (1 equivalent). Yield: 107 mg of TFA salt (48%), yellow powder.

[0644] Example 159 Synthesis of 6-(phenylamino)-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 123)

[0645] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (50 mg) and aniline (3 equivalents) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-ylamino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate (50 mg) and aniline (3 equivalents). Yield: 31 mg of TFA salt (55%), yellow powder.

[0646] Example 160 Synthesis of 6-[(4-fluorophenyl)amino]-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 125)

[0647] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 4-fluoroaniline (2 equivalents) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-(piperidine-4-ylamino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 4-fluoroaniline (2 equivalents). Yield: 37 mg of TFA salt (64%), powder.

[0648] Example 161 Synthesis of 6-[(1-methyl-1H-indazole-5-yl)amino]-1-{6-[(1-methylpiperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 129)

[0649] This compound was prepared using 6-[(1-methyl-1H-indazole-5-yl)amino]-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (38 mg), using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (38 mg). Yield: 20 mg (52%), powder.

[0650] Example 162 Synthesis of 2-methyl-4-[(3-oxo-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-6-yl)amino]benzonitrile (compound 134)

[0651] This compound was prepared using tert-butyl4-[(6-{6-[(4-cyano-3-methylphenyl)amino]-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl}pyridine-2-yl)oxy]piperidine-1-carboxylate, followed by deprotection of the boc group, using a method similar to that used for the synthesis of 2-allyl-6-(2-methoxy-4-pyridylamino)-1-[6-(1-methyl-4-piperidyloxy)-2-pyridyl]-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl}pyridine-2-yl)oxy]piperidine-1-carboxylate. Yield: 15.3 mg of TFA salt (39%), white powder.

[0652] Example 163 Synthesis of 1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-6-{[4-(trifluoromethoxy)phenyl]amino}-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 135)

[0653] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 4-(trifluoromethoxy)aniline (2 equivalents), using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyrimidine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 4-(trifluoromethoxy)aniline (2 equivalents). Yield: 27 mg (51%), powder.

[0654] Example 164 Synthesis of 6-{[3-methyl-4-(trifluoromethoxy)phenyl]amino}-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 136)

[0655] This compound was prepared using tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 3-methyl-4-(trifluoromethoxy)aniline (2 equivalents) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyrimidine-2-yl}amino)piperidine-1-carboxylate (50 mg) and 3-methyl-4-(trifluoromethoxy)aniline (2 equivalents). Yield: 29 mg of TFA salt (44%), powder.

[0656] Example 165 Synthesis of 6-[(4-bromophenyl)amino]-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 143)

[0657] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (60 mg) and 4-bromoaniline (2 equivalents), using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate (60 mg) and 4-bromoaniline (2 equivalents). Yield: 27.5 mg (44%), white powder.

[0658] Example 166 Synthesis of 6-[(3-bromo-5-chlorophenyl)amino]-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 144)

[0659] This compound was prepared using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, using tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate (50 mg), 3-bromo-5-chloroaniline (2 equivalents), and methanesulfonic acid (1 equivalent). Yield: 25 mg of TFA salt (37%), powder.

[0660] Example 167 Synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 149)

[0661] tert-butyl 4-[(6-bromopyridine-2-yl)(propyl)amino]piperidine-1-carboxylate

[0662] 60% sodium hydride (113 mg, 2.82 mmol, 1.3 equivalents) in mineral oil was added at 0°C to a solution of tert-butyl 4-[(6-bromopyridine-2-yl)amino]piperidine-1-carboxylate (773 mg, 2.17 mmol, 1 equivalent) and propylmethanesulfonate (360 mg, 2.6 mmol, 1.2 equivalents) stirred in DMF (8 mL). After complete addition, the mixture was allowed to return to room temperature and stirred for 40 minutes. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 120 mL). The organic layer was washed with water (4 × 100 mL) and brine (100 mL), and then dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the residue. The residue was purified by flash chromatography using silica and eluted with a 5-70% ethyl acetate / petroleum ether gradient to obtain the title compound (470 mg, 54%) as a colorless oil.

[0663] tert-butyl4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridin-2-yl}(propyl)amino)piperidine-1-carboxylate

[0664] This intermediate was prepared using tert-butyl 4-[(6-bromopyridine-2-yl)(propyl)amino]piperidine-1-carboxylate (475 mg) by the same method as the method used for the synthesis of tert-butyl 4-((6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-yl)amino)piperidine-1-carboxylate. Yield: 519 mg (81%).

[0665] 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one

[0666] The title compound was prepared using 6-[(4-chlorophenyl)amino]-1-{6-[(piperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (85 mg), by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (85 mg). Yield: 65 mg of TFA salt (75%), powder.

[0667] Example 168 Synthesis of 6-{[3-methyl-5-(trifluoromethoxy)phenyl]amino}-1-{6-[(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 155)

[0668] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (100 mg) and 3-methyl-5-(trifluoromethoxy)aniline (1.5 equivalents) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyrimidine-2-yl}amino)piperidine-1-carboxylate (100 mg) and 3-methyl-5-(trifluoromethoxy)aniline (1.5 equivalents). Yield: 60 mg of TFA salt (46%), powder.

[0669] Example 169 Synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[methyl(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 156)

[0670] This compound was prepared using tert-butyl 4-[methyl({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one] and 4-chloroaniline (1 equivalent) by a method similar to that used for the synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl}pyridine-2-yl})amino]piperidine-1-carboxylate (200 mg) and 4-chloroaniline (1 equivalent). Yield: 112 mg (58%), white powder.

[0671] Example 170 Synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[methyl(1-methylpiperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 157)

[0672] This compound was prepared using 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (65 mg) by a method similar to that used for the synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[methyl(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (65 mg). Yield: 68 mg of TFA salt (83%), pale yellow powder.

[0673] Example 171 Synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[(3R)-piperidine-3-yloxy]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 159)

[0674] This compound was prepared using tert-butyl 4-({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-2-yl}amino)piperidine-1-carboxylate (166 mg) and 4-chloroaniline (1 equivalent) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl}amino)piperidine-1-carboxylate (166 mg) and 4-chloroaniline (1 equivalent). Yield: 150 mg of TFA salt (76%), yellow powder.

[0675] Example 172 Synthesis of 6-[(4-chlorophenyl)amino]-1-(6-{[(3S)-1-methylpiperidine-3-yl]oxy}pyridine-2-yl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 162)

[0676] This compound was prepared using 6-[(4-chlorophenyl)amino]-1-{6-[(3R)-piperidine-3-yloxy]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (kdh-0088) (150 mg) by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (kdh-0088) (150 mg). Yield: 82 mg of free base (53%), powder.

[0677] Example 173 Synthesis of 1-{6-[methyl(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazole-4-yl]amino}-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 169)

[0678] This compound was prepared using tert-butyl4-[methyl({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one] using a method similar to that used for the synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl})amino]piperidine-1-carboxylate (200 mg) and 1-isopropyl-4-pyrazoleamine (1.5 equivalents). Yield: 139 mg of TFA salt (59%), powder.

[0679] Example 174 Synthesis of 1-{6-[methyl(piperidine-4-yl)amino]pyridine-2-yl}-6-{[1-(2-methylpropyl)-1H-pyrazole-4-yl]amino}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 170)

[0680] This compound was prepared using tert-butyl4-[methyl({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one] using a method similar to that used for the synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl})amino]piperidine-1-carboxylate (200 mg) and 1-isobutyl-4-pyrazoleamine (1.5 equivalents). Yield: 153 mg of TFA salt (63%), powder.

[0681] Example 175 Synthesis of 1-{6-[methyl(1-methylpiperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazole-4-yl]amino}-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 174)

[0682] This compound was prepared using 1-{6-[methyl(piperidine-4-yl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazole-4-yl]amino}-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (110 mg), using a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (110 mg). Yield: 37 mg of TFA salt (33%), powder.

[0683] Example 176 Synthesis of 1-{6-[methyl(1-methylpiperidine-4-yl)amino]pyridine-2-yl}-6-{[1-(2-methylpropyl)-1H-pyrazole-4-yl]amino}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 175)

[0684] This compound was prepared using 1-{6-[methyl(piperidine-4-yl)amino]pyridine-2-yl}-6-{[1-(2-methylpropyl)-1H-pyrazole-4-yl]amino}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (126 mg), by a method similar to that used for the synthesis of 2-allyl-6-((4-chlorophenyl)amino)-1-(6-((1-methylpiperidine-4-yl)amino)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one; trifluoroacetic acid (126 mg). Yield: 67 mg of TFA salt (52%), powder.

[0685] Example 177 Synthesis of 1-{6-[(3R)-1-azabicyclo[2.2.2]octan-3-yloxy]pyridine-2-yl}-6-[(4-chlorophenyl)amino]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 176)

[0686] This compound was prepared using 1-{6-[(3R)-1-azabicyclo[2.2.2]octan-3-yloxy]pyridine-2-yl}-6-(methylsulfanyl)-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (100 mg) and 4-chloroaniline (2 equivalents) by a method similar to that used for the synthesis of (R)-2-allyl-6-((1-methyl-1H-pyrazole-3-yl)amino)-1-(6-(quinuclidinyl-3-yloxy)pyridine-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (100 mg) and 4-chloroaniline (2 equivalents). Yield: 67 mg of TFA salt (46%), yellow powder.

[0687] Example 178 Synthesis of 2-allyl-1-[6-(4-piperidyloxy)-2-pyridyl]-6-(1-propyl-4-pyrazolylamino)-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (Compound 179)

[0688] This compound was prepared using tert-butyl4-{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-yl]-2-pyridyloxy}-1-piperidinecarboxylate (123 mg) and 1-propyl-4-pyrazolylamine (48.9 mg) by a method similar to that used for the synthesis of 2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyloxy}-1-piperidinecarboxylate (123 mg) and 1-propyl-4-pyrazolylamine (48.9 mg). Yield: 12 mg of TFA salt.

[0689] Example 179 Synthesis of 1-{6-[methyl(piperidine-4-yl)amino]pyridine-2-yl}-6-[(1-methyl-1H-pyrazole-4-yl)amino]-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 182)

[0690] This compound was prepared using tert-butyl4-[methyl({6-[6-(methylsulfanyl)-3-oxo-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one] using a method similar to that used for the synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-1-yl]pyridine-2-yl})amino]piperidine-1-carboxylate (200 mg) and 1-methyl-4-pyrazoleamine (1 equivalent) to obtain a crude free base intermediate (227 mg) as a brown oil, of which 13% was purified by preparative HPLC. Yield: 13.4 mg of TFA salt (45%), powder.

[0691] Example 180 Synthesis of 1-[6-(N-methyl-N-4-piperidylamino)-2-pyridyl]-2-allyl-6-[1-(2-fluoro-2-methylpropyl)-4-pyrazolylamino]-1,2-dihydro-3H-1,2,5,7-tetraazaidene-3-one (compound 183)

[0692] This compound was prepared using a method similar to that used for the synthesis of 6-[(4-chlorophenyl)amino]-1-{6-[(1-methylpiperidine-4-yl)(propyl)amino]pyridine-2-yl}-2-(propa-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidine-3-one, by using tert-butyl4-({6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-1,2,5,7-tetraazainden-1-yl]-2-pyridyl}-N-methylami...

Claims

1. Compounds having structural formula AA: 【Chemistry 74】 or its solvates, enantiomers, tautomers, or diastereomers, or any pharmaceutically acceptable salt thereof. [In the formula, Each of X, Y, and Z is independently CH or N. R １ is -O-, -NH-, or -N(C １ -C ３ Alkyl)-, Each R ２ is independently fluoro, -CN, unsubstituted C １ -C ５ alkyl, fluoro-substituted C １ -C ５ alkyl, or cyano-substituted C １ -C ５ alkyl, and two Rs bonded to the same carbon atom ２ may optionally combine together to form a spiro-fused C ３ -C ７ cycloalkyl ring, or two Rs bonded to different carbon atoms ２ may optionally combine together to form a crosslinked or fused C ３ -C ５ cycloalkyl ring, or one R ２ and R ８ may optionally combine together to form a crosslinked or fused 3- to 5-membered ring, R ３ is, -C １ -C ３ Alkyl or -CH ２ -CH=CH ２ And, R ４ teeth, 【Chemistry 75】 【Transformation 76】 And, 【Chemical 77】 R ４ This represents the bonding point between the compound and the other compound. Each R ５ and each R ６ These are independently hydrogen, halo, -CN, and optionally -C substituted with halo. １ -C ４ Alkyl, optionally substituted with a halo -O-(C １ -C ４ Alkyl), C ３ -C ６ Cycloalkyl-substituted -O-(C １ -C ４ Alkyl), N-bonded saturated 3-7 member heterocyclyl, 5-6 member heteroaryl, or phenyl, with two or fewer R ６ It is something other than hydrogen, and R on the adjacent ring atom ５ and R ６ R is an optional choice to join together. ４ It forms a 4- to 7-membered saturated heterocyclic or cycloalkyl ring through condensation, R ７ is hydrogen, -C １ -C ４ Alkyl, -C １ -C ４ Alkylene-OC １ -C ４ Alkyl, -C(O)-C １ -C ４ Alkyl, or C ３ -C ６ It is a cycloalkyl, R ７ Any C １ -C ４ Alkyl or C １ -C ４ The alkylene moiety is optionally substituted with one or more substituents independently selected from the halo and -CN groups. R ８ is hydrogen, -C １ -C ４ Alkyl or 4-6 member saturated heterocycle, R ９ This is hydrogen, halo, -CN, and optionally -C substituted with halo. １ -C ４ Alkyl, optionally substituted with a halo -O-C １ -C ４ Alkyl, or optionally substituted phenyl, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. m+n is 1, 2, 3, or 4. Any hydrogen atom is optionally replaced by deuterium.

2. Each of X, Y, and Z is independently CH or N. R １ However, -O-, -NH-, or -N(C １ -C ３ Alkyl)-, Each R ２ However, independently, fluoro, -CN, and unsubstituted C １ -C ５ Alkyl and fluorosubstituted C １ -C ５ Alkyl or cyano-substituted C １ -C ５ It is an alkyl group, and has two R's bonded to the same carbon atom. ２ However, they can be optionally combined and undergo spirocondensation C ３ -C ７ Two R atoms that form a cycloalkyl ring or are bonded to different carbon atoms ２ However, by optional choice, they become bridge C ３ -C ５ Forms a cycloalkyl ring, or one R ２ and R ８ However, they can optionally combine to form cross-linked or condensed 3-5 membered rings. R ３ However, -C １ -C ３ Alkyl or -CH ２ -CH=CH ２ And, R ４ but, 【Transformation 78】 【Chemistry 79】 And, 【Chemistry 80】 However, R ４ This represents the bonding point between the compound and the aforementioned compound. Each R ５ and each R ６ is independently hydrogen, halo, -CN, -C optionally substituted with halo １ -C ４ alkyl, or -O-(C optionally substituted with halo １ -C ４ alkyl), and no more than two R ６ are other than hydrogen, and R ５ and R ６ on adjacent ring atoms together form a 4- to 7-member saturated heterocyclic or cycloalkyl ring fused with R ４ ​ R ７ However, hydrogen, -C １ -C ４ Alkyl, or -C １ -C ４ Alkylene-OC １ -C ４ It is alkyl, R ７ Any C １ -C ４ Alkyl or C １ -C ４ The alkylene moiety is optionally substituted with one or more substituents independently selected from the halo and -CN. R ８ However, hydrogen or -C １ -C ４ It is alkyl, R ９ However, hydrogen, halo, -CN, and optionally -C substituted with halo １ -C ４ Alkyl, optionally substituted with a halo -O-C １ -C ４ Alkyl, or optionally substituted phenyl, m is 0 or 1, The compound according to claim 1, wherein n is 0, 1, 2, or 3, and m and n are not both 0.

3. The compound according to claim 1 or 2, wherein each of X, Y, and Z is CH.

4. The compound according to claim 1 or 2, wherein X is N and each of Y and Z is CH.

5. The compound according to claim 2, wherein each of X and Y is N and Z is CH.

6. R ４ but, 【Chemistry 81】 The compound according to any one of claims 1 to 5.

7. R ４ but, 【Chemistry 82】 And, R ５ However, hydrogen, halo, -CN, and optionally C substituted with halo １ -C ４ -O-(C) substituted with alkyl or optionally halo １ -C ４ It is alkyl, Each R ６ However, hydrogen, halo, -CN, and optionally -C substituted with halo were considered independently. １ -C ４ Alkyl, optionally substituted with a halo -O-(C １ -C ４ Alkyl), C ３ -C ６ Cycloalkyl-substituted -O-(C １ -C ４ Alkyl), N-bonded saturated 3-7 member heterocyclyl, 5-6 member heteroaryl, or phenyl, or R bonded to adjacent ring atoms ５ and R ６ The compound according to claim 6, wherein the two elements combine to form methylenedioxy.

8. Each R ６ However, independently, hydrogen, fluoro, bromo, chloro, -CN, -CF ３ ien-CH ３ , -OCH ３ , -OCF ３ , -OCH ２ CF ３ , -OCH ２ CH ３ , -OCH ２ CH ２ F, -OCH ２ CH (CH ３ )CH ３ , cyclopropylmethoxy, morpholine-4-yl, thiomorpholine-4-yl, 1-methyl-1H-pyrazolyl, or phenyl substituted with a halo of any choice, Each R ５ However, hydrogen, fluoro, chloro, -CN, -CF ３ ien-CH ３ , or -OCH ３ The compound according to any one of claims 1 to 7.

9. One or fewer R ６ A compound according to any one of claims 1 to 8, wherein the compound is other than hydrogen.

10. R ４ but, 【Chemistry 83】 And, R ６ However, it is hydrogen or chloroform, R ７ However, hydrogen, -CH ３ ien-CH ２ CH ３ ien-CH ２ C (CH ３ ) ２ F, -CH ２ CH ２ CF ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH (CH ３ ) ２ ien-CH ２ CH (CH ３ ) ２ , -C(CH ３ ) ３ ien-CH ２ CH ２ CH ２ F, -OCH ２ CF ３ The compound according to claim 6, which is either cyclopropyl or otherwise.

11. R ４ but, 【Chemical 84】 And, Each R ６ However, hydrogen or -CH ３ And, R ９ The compound according to claim 6, wherein the phenyl is optionally substituted.

12. R ４ but 【Chemical 85】 And in the formula, each R ６ The compound according to claim 6, wherein the compound is hydrogen.

13. R ４ but 【Chemical 86】 And each R ６ The compound according to claim 6, wherein is hydrogen or methyl.

14. R ４ but 【Transformation 87】 And in the formula, each R ６ If it is hydrogen and present, R ７ The compound according to claim 6, wherein isopropyl.

15. R ４ but 【Chemical 88】 And R ７ is methyl or -C(O)CH ３ And each R ６ The compound according to claim 6, wherein is hydrogen.

16. R ４ but, 【Chemical 89】 And each R ６ The compound according to claim 6, wherein is hydrogen.

17. R ４ However, phenyl, 3-methylphenyl, 3-chloro-5-bromophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-(1-methylpiperidine-4-yl)-5-methylphenyl, 4-trifluoromethoxyphenyl, 3-methyl-4-trifluoromethoxyphenyl, 4-(2,2,2-trifluoroethane-1-yl)oxyphenyl, 3-methyl-4-(2,2,2-trifluoroethane-1-yl)oxyphenyl, 4-trifluoromethylphenyl, 3-methyl-4-chlorophenyl, 3-methyl-4-fluorophenyl, 3-methyl-5-fluorophenyl, 3-methyl-4-cyanophenyl, 3-methyl-4-methoxyphenyl, 3-methyl-4-(2,2,2-trifluoroethane-1-yloxy)phenyl, 3,4-methylenedioxyphenyl 4-(cyclopropylmethyloxy)phenyl, 4-(morpholine-4-yl)phenyl, 4-(thiomorpholine-4-yl)phenyl, 4-(2-methylpropane-1-yloxy)phenyl, 3-(1-methyl-1H-pyrazole-4-yl)phenyl, 4-(1-methyl-1H-pyrazole-4-yl)phenyl, 3-methyl-4-(morpholine-4-yl)phenyl, 4-(phenyl)phenyl, 3-bromophenyl, 3-cyanophenyl, 4-(2-fluoroethane-1 -yloxy)phenyl, 4-cyanophenyl, 4-(1,1-dioxothiazinane-4-yl)phenyl, 3-(pyridine-3-yl)phenyl, 3-(pyrimidine-5-yl)phenyl, 3-(1H-imidazole-1-yl)phenyl, 3-(1H-pyrazole-1-yl)phenyl, 3-(d3-methyl)phenyl, 4-(3-fluoropropane-1-yloxy)phenyl, 4-ethoxyphenyl, 2-methylpyridine-4-yl, 6-methylpyridine-3-yl, 2,6-dimethylpyridine-4-yl, 2-trifluoromethyl-6-methylpyridine-4-yl, 2-trifluoromethylpyridine-4-yl, pyridine-3-yl, 2-methylpyridine-5-yl, 2-methoxypyridine-4-yl, 2-methoxypyridine-5-yl, 3-chloropyridine-5-yl, 3-fluoropyridine-5-yl, 3-cyanopyridine-5-yl, 3-methylpyridine-5-yl, 3-methoxypyridine-5- Il, 1-methyl-1H-pyrazole-4-yl, 1-propyl-1H-pyrazole-4-yl, 1-isopropyl-1H-pyrazole-4-yl, 1-(2,2-dimethylethane-1-yl)pyrazole-4-yl, 1-(2-fluoro-2,2-dimethylethane-1-yl)-1H-pyrazole-4-yl, 1-(3,3,3-trifluoropropane-1-yl)-1H-pyrazole-4-yl, 1H-indazole-5-yl, 1 -Methyl-1H-indazole-5-yl, 1-ethyl-1H-indazole-5-yl, 1-propyl-1H-indazole-5-yl, 1-(3-fluoropropan-1-yl)-1H-indazole-5-yl, 1-isopropyl-1H-indazole-5-yl, 1-isobutyl-1H-indazole-5-yl, 1-cyclopropyl-1H-indazole-5-yl, 3-chloro-1H-indazole-5-yl, 3-methyl Lu-1H-indazole-5-yl, 1,3-dimethyl-1H-indazole-5-yl, 1H-indazole-4-yl, 2-methyl-2H-indazole-5-yl, 2-ethyl-2H-indazole-5-yl, 3-phenylisothiazoloid-5-yl, benzofuran-6-yl, benzofuran-5-yl, 1-methyl-1H-indole-5-yl, 1-acetyl-1H-indole-5-yl, 1,2,4-triazolo[1,5-a] Pyridine-6-yl, quinoxaline-6-yl, quinoline-6-yl, quinoline-7-yl, isoquinoline-6-yl, isoquinoline-7-yl, 2-methylbenzo[d]oxazole-5-yl, 2-methylbenzo[d]oxazole-6-yl, benzo[d]isoxazole-6-yl, benzo[d]thiazole-6-yl, 2-methylbenzo[d]thiazole-6-yl, 1-methyl-1H-benzo[d]imidazole-5-yl, benzo[d]thiazole-5-yl, 1-methyl The compound according to claim 6, which is -1H-indazole-6-yl, 2-methyl-2H-indazole-6-yl, imidazo[1,2-a]pyridine-6-yl, 2-(2-fluoroethoxy)pyridine-5-yl, 2-(t-butyl)-2H-indazole-5-yl, 1-isopropyl-1H-benzo[d]imidazole-5-yl, 1-isopropyl-1H-pyrazolo[3,4-b]pyridine-5-yl, or 1-isopropyl-1H-benzo[d][1,2,3]triazole-5-yl.

18. structure: 【Chemistry 90】 The compound according to any one of claims 1 to 17, wherein the ring represented by is selected from pyrrolidine-3-yl, 1-methylpyrrolidine-3-yl, 1-ethylpyrrolidine-3-yl, 1-isopropylpyrrolidine-3-yl, piperidine-4-yl, piperidine-3-yl, 1-methylpiperidine-4-yl, 1-methylpiperidine-3-yl, quinuclidin-3-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, and 9-methyl-9-azabicyclo[3.3.1]nonane-3-yl

19. structure: 【Chemistry 91】 The compound according to any one of claims 1 to 17, wherein the ring represented by is selected from pyrrolidine-3-yl, 1-methylpyrrolidine-3-yl, 1-ethylpyrrolidine-3-yl, 1-isopropylpyrrolidine-3-yl, piperidine-4-yl, piperidine-3-yl, 1-methylpiperidine-4-yl, 1-methylpiperidine-3-yl, 1-(methyl-d3)piperidine-4-yl, azepan-4-yl, quinuclidin-3-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, and 9-methyl-9-azabicyclo[3.3.1]nonane-3-yl.

20. R ３ However, methyl, ethyl, n-propyl, or -CH ２ -CH=CH ２ The compound according to any one of claims 1 to 19.

21. R ３ ga-CH ２ -CH=CH ２ The compound according to claim 20.

22. R １ However, -O-, -N(CH ３ )-,-N(CH ２ CH ２ CH ３ The compound according to any one of claims 1 to 21, wherein the compound is - or -NH-.

23. R １ The compound according to claim 22, wherein is -O-.

24. The compound according to claim 1, wherein the compound is one of the following compounds. Table 8-1 Table 8-2 Table 8-3 Table 8-4 Table 8-5 Table 8-6 Table 8-7 Table 8-8 Table 8-9 Table 8-10 Table 8-11 Table 8-12 Table 8-13 Table 8-14 Table 8-15 Table 8-16 Table 8-17 Table 8-18 Table 8-19

25. The compound according to claim 1, wherein the compound is one of the following compounds. Table 9

26. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier.

27. A method for inhibiting Wee1A kinase activity in a subject, comprising the step of administering an effective amount of a compound according to any one of claims 1 to 25 or a composition according to claim 26 to the subject.

28. A method for treating a subject suffering from cancer or other disordered cell growth characterized by abnormal Wee1A kinase activity, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 25 or a composition according to claim 26.

29. The method according to claim 28, wherein the subject is suffering from cancer related to the inactivation of p53.

30. A method for inhibiting both Wee1A kinase activity and Myt1 kinase activity in a subject, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 25 that is a dual inhibitor, or a composition according to claim 26 that contains a dual inhibitor.

31. A method for treating a subject suffering from cancer or other disordered cell growth characterized by both abnormal Wee1A kinase activity and abnormal Myt1 kinase activity, the method comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 25 or a composition according to claim 26.

32. The method according to any one of claims 28, 29, or 31, wherein the cancer is selected from brain tumors, cervical brain tumors (cervicocerebral cancer), cardiac tumors, gastrointestinal cancers, esophageal cancers, thyroid cancers, small cell carcinomas, non-small cell carcinomas, breast cancers, lung cancers, stomach cancers, gallbladder / bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, endometrial cancers, cervical cancers, renal pelvis / ureteral cancers, bladder cancers, prostate cancers, penile cancers, testicular cancers, fetal cancers, Wilms' tumors, skin cancers, malignant melanomas, neuroblastomas, osteosarcomas, Ewing's tumors, soft tissue sarcomas, acute leukemias, chronic lymphocytic leukemias, chronic myeloid leukemias, polycythemia vera, malignant lymphomas, multiple myelomas, Hodgkin lymphomas, and non-Hodgkin lymphomas.

33. The method according to claim 32, wherein the subject is suffering from a cancer selected from uterine serous carcinoma or kidney carcinoma.

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