Compounds for treating or inhibiting relapse of acute myeloid leukemia

Abstract

The present invention relates to compounds for treating acute myeloid leukemia or inhibiting the relapse of acute myeloid leukemia, and for inhibiting the proliferation and / or killing of leukemic stem cells.

Description

[Technical Field]

[0001] This application claims the benefit of International Patent Application No. PCT / CN20 / 79464, filed March 16, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Acute myeloid leukemia (AML) is a common hematologic malignancy in adults with a poor prognosis, with a predicted 5-year survival rate of 20%. In some cases, AML treatment can temporarily reduce the number of AML cells to undetectable levels. This state is called "complete remission." However, AML often relapses despite achieving complete remission, and many patients die from AML relapse. Therefore, there is an urgent need to develop more durable treatments for AML.

[0003] Although conventional chemotherapy can induce temporary remission of AML, recurrence remains a concern. In particular, the extremely low survival rate of relapsed cases is a serious concern. New approaches to treat AML and other hematological cancers are needed. Summary of the Invention

[0004] The present invention provides compounds that inhibit the proliferation of leukemic stem cells and / or treat acute myeloid leukemia or inhibit the relapse of acute myeloid leukemia.

[0005] In some embodiments, the present disclosure provides a compound of formula (I): [ka] A compound of the formula Each Q, Y, and Z is independently selected from N and C, and X is N or CR. a and (However, at least one of Q, X, Y, and Z is N, Each dashed bond shall be independently a single bond or a double bond, such that the two bicycles they form are heteroaryl; R1 is selected from alkyl, alkenyl, alkynyl, amino, acylamino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroaralkyl; a) W is N, R2 is absent, and A1 and A2 are each CH2; b) W is C, R2 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, and amino, and A1 and A2 are each independently selected from CH2 and O; or c) W is C, R1 and R2 together form =CH2-amido, cycloalkyl, and heterocyclyl, and A1 and A2 are each independently selected from CH2 and O; or Either; R a is selected from H, halo, CN, and alkyl; R9 is selected from H, halo, alkyl, alkoxy, hydroxy, acyloxy, and amino; R 10 is H or alkoxy; R 11 is aryloxy, heteroaryloxy, arylalkyl, alkoxycarbonyl, ureido, or —C(O)-aryl; R 12 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, and acyloxy (However, the compound of formula (I) [ka] shall not be; W is C, and R2, R9, and R 12 are hydrogen, and R 11 is unsubstituted phenyloxy, R1 is -NHCH2OH, -NHCH2COOH, -NHCH2CONH2, -NHCH2CH2NH2, -NH(CH2)2N(Me)2, -NHCH2-pyridinyl, -NHCO-pyridyl, -C(O)OEt, -NH-tetrahydropyran, -NH(CH2)3 imidazolyl, -NHCH2 pyrrolidinyl, -NHpyrrolidinonyl, [ka] rather than (In the formula, R 13 is selected from H, ethyl, isopropyl, t-butyl, -CH2OCH3, -CH2CH2OH, and -CH2CH2OCH3; W is N, and R and R 12 are hydrogen, and R 11 is unsubstituted phenyloxy, then R1 is not piperidinyl).

[0006] The present disclosure further relates to a method for simultaneously inhibiting HCK and BCL-2 in a cell, comprising contacting the cell with a compound disclosed herein and a BCL-2 inhibitor.

[0007] The present disclosure further relates to a method of killing a cell that has a FLT3-ITD mutation, comprising contacting the cell with a compound disclosed herein and a BCL-2 inhibitor.

[0008] The present disclosure further relates to a method of treating acute myeloid leukemia, comprising co-administering to a subject a compound disclosed herein and a BCL-2 inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art of this disclosure. The following references provide those of ordinary skill in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below unless otherwise specified.

[0010] In this disclosure, "comprises," "comprising," "containing," and "having" and the like may have the meaning ascribed to them in U.S. patent law, and "includes," "including," and the like, and "consisting essentially of" or "consisting essentially of," and the like, similarly have the meaning ascribed to them in U.S. patent law, and these terms are open-ended and permit the presence of more than what is recited (but excludes prior art embodiments) so long as the basic or novel characteristics of the recited thing are not changed by the presence of more than what is recited.

[0011] Unless expressly stated otherwise or clear from context, as used herein, the term "or" is understood to be inclusive. Unless expressly stated otherwise or clear from context, as used herein, the terms "a," "an," and "the" are understood to be singular or plural.

[0012] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0013] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0014] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0015] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0016] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0017] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter of which refers to an alkenyl moiety having substituents replacing hydrogen on one or more carbons of the alkenyl group. Such substituents may be on one or more carbons included or not included in one or more double bonds. Furthermore, such substituents include all of those contemplated for alkyl groups, as described below, except where stability precludes such substitution. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0018] An "alkyl" group or "alkane" is a fully saturated, straight-chain or branched non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group has from 1 to about 20, preferably from 1 to about 10, carbon atoms, unless otherwise defined. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also referred to as "lower alkyl" groups.

[0019] Furthermore, the term "alkyl" (or "lower alkyl"), as used throughout the specification, examples, and claims, is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to alkyl moieties having substituents in place of hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those of skill in the art will understand that moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, substituents of substituted alkyls can include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthio, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

[0020] "C x~y The term "C" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. For example, "C x~y The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups including straight-chain alkyl and branched-chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents a hydrogen when the group is in a terminal position and a bond when the group is internal. 2~y alkenyl" and "C 2~y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0021] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0022] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0023] The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter of which refers to an alkynyl moiety having substituents replacing hydrogen on one or more carbons of the alkynyl group. Such substituents may be on one or more carbons included or not included in one or more triple bonds. Furthermore, such substituents include all of those contemplated for alkyl groups as described above, except where stability prohibits. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0024] As used herein, the term "amide" refers to the group [ka] In the formula, each R 10 independently represent hydrogen or a hydrocarbyl group, or two R 10 together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure.

[0025] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, as well as salts thereof, e.g., [ka] wherein each R 10 independently represent hydrogen or a hydrocarbyl group, or two R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure. The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

[0026] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

[0027] The term "aryl," as used herein, includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0028] The term "carbamate" is art-recognized and refers to the following groups: [ka] In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R 9 and R 10 together with the intervening atom(s) complete a heterocyclic ring having from 4 to 8 atoms in the ring structure.

[0029] The terms "carbocycle" and "carbocyclic," as used herein, refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings that contain at least one double bond.

[0030] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or three or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, where valences permit, is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" can be substituted at any one or more positions capable of bearing a hydrogen atom.

[0031] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0032] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0033] The term "carbonate" is art-recognized and refers to the group -OCO-R 10 In the formula, R 10 represents a hydrocarbyl group.

[0034] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0035] The term "ester" as used herein refers to the group -C(O)OR 10 In the formula, R 10 represents a hydrocarbyl group.

[0036] The term "ether," as used herein, refers to a hydrocarbyl group bonded to another hydrocarbyl group via an oxygen atom. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0037] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0038] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0039] The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[0040] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, which ring structures contain at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heteroaromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0041] The term "heteroatom," as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0042] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, which ring structures contain at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heterocyclic; for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0043] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0044] The term "hydrocarbyl," as used herein, refers to a group that has no =0 or =5 substituents, typically at least one carbon-hydrogen bond, and a primarily carbon backbone, but may optionally contain heteroatoms, bonded through carbon atoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (having a =0 substituent on the bonded carbon) and ethoxy (bonded through an oxygen rather than a carbon) are not considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0045] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0046] The term "lower," when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer, preferably 6 or fewer, non-hydrogen atoms in the substituent. "Lower alkyl," for example, refers to alkyl groups containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether presented alone or in combination with other substituents, such as in descriptions of hydroxyalkyl and aralkyl (in which case, for example, atoms in the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0047] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0048] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0049] The term "substituted" refers to moieties having substituents in place of hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is based on the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound (e.g., not spontaneously altered by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In one broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those of skill in the art will understand that substituents can themselves be substituted, where appropriate. Unless specifically stated as "unsubstituted," references herein to chemical moieties are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0050] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0051] The term "sulfonamide" is art-recognized and can be represented by the general formula [ka] wherein R 9 and R 10 independently represent hydrogen or hydrocarbyl such as alkyl, or R 9 and R 10 together with the intervening atom(s) complete a heterocyclic ring having from 4 to 8 atoms in the ring structure.

[0052] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 10 In the formula, R 10 represents a hydrocarbyl.

[0053] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0054] The term “sulfone” is art-recognized and refers to the group —S(O)—R 10 In the formula, R 10 represents a hydrocarbyl.

[0055] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0056] The term "thioester" as used herein refers to the group -C(O)SR 10 or -SC(O)R 10 In the formula, R 10 represents a hydrocarbyl.

[0057] The term "thioether" as used herein is equivalent to an ether, where an oxygen has been replaced with a sulfur.

[0058] The term "urea" is art-recognized and has the general formula [ka] where R 9 and R 10 independently represent hydrogen or hydrocarbyl such as alkyl, or R 10 and R together with the intervening atom(s) 9 Any occurrence of completes a heterocycle having 4 to 8 atoms in the ring structure.

[0059] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during the course of a synthesis. Examples of protecting groups are found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY, and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated (e.g., benzyl and trityl ethers), as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers (e.g., ethylene glycol and propylene glycol derivatives), and allyl ethers.

[0060] In certain embodiments, the compounds of the present invention may be racemic. In certain embodiments, the compounds of the present invention may be enriched with one enantiomer. For example, the compounds of the present invention may have an ee of more than about 30%, an ee of more than about 40%, an ee of more than about 50%, an ee of more than about 60%, an ee of more than about 70%, an ee of more than about 80%, an ee of more than about 90%, or even an ee of more than about 95%. In certain embodiments, the compounds of the present invention may have multiple stereocenters. In certain such embodiments, the compounds of the present invention may be enriched with one or more diastereomers. For example, the compounds of the present invention may have an ee of more than about 30%, an ee of more than about 40%, an ee of more than about 50%, an ee of more than about 60%, an ee of more than about 70%, an ee of more than about 80%, an ee of more than about 90%, or even an ee of more than about 95%.

[0061] In certain embodiments, therapeutic preparations can be enriched to provide primarily one enantiomer of a compound (e.g., of Formula (I)). An enantiomerically enriched mixture can contain, for example, at least about 60 mole percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mole percent of one enantiomer. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the material accounts for, for example, less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% of the other enantiomer in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be considered to contain about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0062] In certain embodiments, therapeutic preparations can be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (I)). A diastereomerically enriched mixture can contain, for example, at least about 60 mole percent, or more preferably at least about 75, about 90, about 95, or even about 99 mole percent of one diastereomer.

[0063] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals (including commercially relevant mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs); and / or birds (including commercially relevant birds, e.g., chickens, ducks, geese, quail, and / or turkeys). A preferred subject is a human.

[0064] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence or delays the onset of the disorder or condition in a treated sample compared to an untreated control sample, or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0065] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is art-recognized and includes administering to a subject one or more of the compositions of the present disclosure. If the composition is administered prior to clinical manifestation of an undesired condition (e.g., a disease or other undesired condition in a subject), the treatment is prophylactic (i.e., protects the subject from the onset of the undesired condition), whereas if the composition is administered after the onset of the undesired condition, the treatment is therapeutic (i.e., intended to eliminate, ameliorate, or stabilize an existing undesired condition or its side effects).

[0066] The term "prodrug" is intended to encompass compounds that are converted under physiological conditions to the therapeutically active agents of the present invention (e.g., compounds of Formula (I)). A common method for making prodrugs is to include one or more selected moieties that are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of Formula (I) in the formulations depicted above can be replaced with the corresponding suitable prodrug, for example, a hydroxyl in the parent compound is presented as an ester, or carbonate, or carboxylic acid.

[0067] "Effective amount" as used herein refers to an amount sufficient to achieve a desired biological effect. "Therapeutically effective amount" as used herein refers to an amount sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount sufficient to improve at least one sign or symptom of cancer.

[0068] A "response" to a treatment method can include, inter alia, a decrease or alleviation of negative symptoms, a reduction in the progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of the disease, or partial or complete remission of the disease.

[0069] overview In certain embodiments, provided herein are compounds of formula (I): [ka] A compound of the formula Each Q, Y, and Z is independently selected from N and C, and X is N or CR. a and (However, at least one of Q, X, Y, and Z is N, Each dashed bond shall be independently a single bond or a double bond, such that the two rings they form are heteroaryl); R1 is selected from alkyl, alkenyl, alkynyl, amino, acylamino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroaralkyl; a) W is N, R2 is absent, and A1 and A2 are each CH2; b) W is C, R2 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, and amino, and A1 and A2 are each independently selected from CH2 and O; or c) W is C, R1 and R2 together form =CH2-amido, cycloalkyl, and heterocyclyl, and A1 and A2 are each independently selected from CH2 and O; or Either; R a is selected from H, halo, CN, and alkyl; R9 is selected from H, halo, alkyl, alkoxy, hydroxy, acyloxy, and amino; R 10 is H or alkoxy; R 11 is aryloxy, heteroaryloxy, arylalkyl, alkoxycarbonyl, ureido, or —C(O)-aryl; R 12 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, and acyloxy (However, the compound of formula (I) [ka] shall not be; W is C, and R2, R9, and R 12 are hydrogen, and R 11 is unsubstituted phenyloxy, R1 is -NHCH2OH, -NHCH2COOH, -NHCH2CONH2, -NHCH2CH2NH2, -NH(CH2)2N(Me)2, -NHCH2-pyridinyl, -NHCO-pyridyl, -C(O)OEt, -NH-tetrahydropyran, -NHCH2 pyrrolidinyl, -NH(CH2)3 imidazolyl, -NHpyrrolidinonyl, [ka] rather than (In the formula, R 13 is selected from H, ethyl, isopropyl, t-butyl, -CH2OCH3, -CH2CH2OH, and -CH2CH2OCH3; W is N, and R and R 12 are hydrogen, and R 11 is unsubstituted phenyloxy, then R1 is not piperidinyl).

[0070] In certain embodiments, the compound has the structure: [ka] wherein R2 is H.

[0071] In other embodiments, the compound has the structure: [ka] wherein R2 is H.

[0072] In other embodiments, the compound has the structure: [ka] wherein R2 is H.

[0073] In other embodiments, the compound has the structure: [ka] wherein R2 is H.

[0074] In some embodiments, at least two of Q, X, Y, and Z are N. In some such embodiments, at least three of Q, X, Y, or Z are N. In some such embodiments, all of Q, X, Y, and Z are N.

[0075] In some embodiments, at least Q is N.

[0076] In some embodiments, at least X is N. In some such embodiments, at least X and Z are N.

[0077] In some embodiments, at least Y is N. In some such embodiments, at least X and Y are N.

[0078] In some embodiments, at least Z is N.

[0079] In some embodiments, R1 is [ka] wherein V is N or CH; T is N or CH; R3 is alkyl; and R4 is H or alkyl.

[0080] In some embodiments, R1 is [ka] wherein V is N or CH; T is N or CH; R3 is alkyl; and R4 is H or alkyl.

[0081] In some embodiments, Q is C and X is CR a and R a is H, Y is N, and Z is C; Q is C, and X is CR a and R ais halo, Y is N, Z is C; Q is C, X is N, Y is C, Z is N; Q is C, X is N, Y is N, Z is C; Q is N, X is CR a and R a is H, Y is C, and Z is C; Q is C, and X is CR a and R a is H, Y is C and Z is N; or Q is C and X is CR a and R a is H, Y is N, and Z is C.

[0082] In some embodiments, Q is C, X is N, Y is C, and Z is N; or Q is C and X is CR a and R a is H, Y is N and Z is C; or Q is C, X is N, Y is N and Z is C.

[0083] In some embodiments, A1 and A2 are both CH2. In other embodiments, A1 and A2 are both O.

[0084] In some embodiments, W is N and R2 is absent. In other embodiments, W is C.

[0085] In some embodiments, R2 is selected from H, hydroxy, and amino.

[0086] In some embodiments, R is selected from alkyl, amino, cycloalkyl, heterocyclyl, heterocyclylalkyl, and heteroaryl. In certain preferred embodiments, R is a 6-membered heterocyclyl, preferably containing two nitrogen ring atoms. In particularly preferred embodiments, R is a 1,4-piperazinyl ring.

[0087] In certain such embodiments, R1 is [ka] wherein V is N or CH; T is N and R is either absent or T is C; J is selected from sulfonyl, C(H)sulfonamido, and >P(=O)-alkyl; R is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, amino, amido, cycloalkyl, heterocyclyl, carboxy, and alkoxycarbonyl; R is H or alkyl, or R and R together with the carbon atom to which they are attached form a cycloalkyl; R is selected from H, halo, CN, alkyl, alkoxy, acyloxy, amino, and amido; R is H or alkyl; R and R are each H; R and R are together with the carbon atom to which they are attached form an oxo; R is H or alkyl; and R is H, hydroxy, acyloxy, or amino.

[0088] In some such embodiments, R1 is [ka] In some such embodiments, V is N. In other such embodiments, V is CH.

[0089] In some such embodiments, T is N. In other such embodiments, T is C.

[0090] In certain embodiments, W is C, R2 is H, V is CH, and T is N. In other embodiments, W is C, R2 is H, V is N, and T is C. In yet other embodiments, W is C, R2 is H, V is N, and T is N. In still further embodiments, W is N, R2 is absent, V is CH, and T is N.

[0091] In some embodiments, R3 is selected from H, alkyl, amino, cycloalkyl, heterocyclyl, carboxy, and alkoxycarbonyl. In certain such embodiments, R3 is H. In other such embodiments, R3 is alkyl. In some such embodiments, R3 is methyl.

[0092] In some embodiments, each R4 is independently selected from H, alkyl, amino, and amido. In certain such embodiments, R4 is H. In other such embodiments, R4 is alkyl. In some such embodiments, R4 is methyl.

[0093] In some embodiments, R5 is H.

[0094] In certain embodiments, R9 is selected from halo, alkyl, alkoxy, hydroxy, acyloxy, and amino, preferably alkyl or halo, most preferably halo. In certain most preferred embodiments, R9 is F.

[0095] In some embodiments, R 12 is H or halo.

[0096] In some embodiments, R 11 is an amide, [ka] wherein B is selected from -O-, CH2, CHOH, NH, N(C 1~6 alkyl), and carbonyl; K1 and K2 are selected from N and CR 13 D is independently selected from -CH2-C(O)-, -NH-C(O)-, N(C 1~6 alkyl)-C(O), and -CHS(O)-; R 13 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, alkoxycarbonyl, amino, amido, and alkoxycarbonyl; R 14is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, alkoxycarbonyl, amino, amido, and alkoxycarbonyl; R 15 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, alkoxycarbonyl, amino, amido, and alkoxycarbonyl; R 16 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, amino, amido, and alkoxycarbonyl.

[0097] In some embodiments, B is —O—.

[0098] In some embodiments, K1 is CR 13 In some such embodiments, R 13 is selected from H, halo, CN, and alkyl. In certain such embodiments, R 13 is H or F.

[0099] In some embodiments, R 14 is H or alkyl.

[0100] In some embodiments, R 15 is H or halo.

[0101] In some embodiments, D is —NHC(O)—.

[0102] In some embodiments, R 16 is H or alkyl.

[0103] In some embodiments, R 11 teeth, [ka] wherein B is O; K1 and K2 are each CH; R 14 is H;R 15 is H. In other embodiments, R 11 teeth [ka] wherein K1 and K2 are each N; R 14 and R 15 are each H. In still other embodiments, R 11 teeth [ka] where D is NH; 16 is alkyl.

[0104] In certain preferred embodiments, the compound of formula (I) is [ka] [ka] In some such preferred embodiments, the compound of formula (I) is selected from: [ka] is selected from.

[0105] For example, the compound of formula (I) [ka] It could be.

[0106] Alternatively, the compound of formula (I) is [ka] It could be.

[0107] Alternatively, the compound of formula (I) is [ka] It could be.

[0108] Similarly, compounds of formula (I) [ka] It could be.

[0109] In certain embodiments, provided herein are methods for simultaneously inhibiting HCK and BCL-2 in a cell, the method comprising contacting the cell with a compound of Formula (I) and a BCL-2 inhibitor. In certain preferred embodiments, the compound is an HCK inhibitor. In some such embodiments, the HCK inhibitor is a dual HCK / FLT3-ITD inhibitor. In certain embodiments, the method further comprises contacting the cell with a FLT3-ITD inhibitor.

[0110] In certain embodiments, provided herein are methods of killing cells harboring a FLT3-ITD mutation, comprising contacting the cells with a compound of Formula (I) and a BCL-2 inhibitor. In certain preferred embodiments, the compound is an HCK inhibitor. In some such embodiments, the HCK inhibitor is a dual HCK / FLT3-ITD inhibitor. In certain embodiments, the method further comprises contacting the cells with a FLT3-ITD inhibitor.

[0111] In certain embodiments, provided herein are methods for treating acute myeloid leukemia, comprising co-administering a compound of Formula (I) and a BCL-2 inhibitor to a subject. In some such embodiments, the subject has FLT3-ITD+ acute myeloid leukemia. In certain such embodiments, the subject has malignant hematopoiesis and / or non-malignant multilineage hematopoiesis characterized by cells with one or more mutations in genes selected from DNMT3A, IDH2, IDH1, NPM1, TET2, CEBPA, ASXL1, EZH2, SETBP1, SMC3, KIT, NRAS, and WT1. In some such embodiments, the compound of Formula (I) is an HCK inhibitor. In certain such embodiments, the method further comprises co-administering a FLT3-ITD inhibitor. In other such embodiments, the HCK inhibitor is an HCK / FLT3-ITD dual inhibitor.

[0112] In certain embodiments, the HCK inhibitor, FLT3-ITD inhibitor, and BCL-2 inhibitor are administered simultaneously or sequentially in separate unit dosage forms. In other embodiments, the method comprises administering a single unit dosage form comprising an HCK inhibitor, a BCL-2 inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some such embodiments, the single unit dosage form further comprises an FLT3-ITD inhibitor, or the HCK inhibitor is a dual HCK / FLT3-ITD inhibitor.

[0113] In certain embodiments, the FLT3-ITD inhibitor is selected from AC220, sorafenib, PKC412, CEP-701, UNC2025, MLN518, KW-2449, and AMG-925, sunitinib, SU5614, AC2206, crenolanib, and PLX3397. In some such embodiments, the BCL-2 inhibitor is selected from AT-101, TW-37, TM-1206, gossypolic acid, gossypolonic acid, apogossypol, apogossypolone, A385358, ABT-737, ABT-263, ABT-199, WEHI-539, BXI-61, BXI-72, obatoclax, JY-1-106, and SAHB peptide. In some such embodiments, the BCL-2 inhibitor is selected from gossypol, obatoclax, ABT-737, ABT-199, and ABT-263. In some such embodiments, the BCL-2 inhibitor is ABT-199. In some such embodiments, the HCK inhibitor is (1) and the BCL-2 inhibitor is ABT-199. In other such embodiments, the HCK inhibitor is (2) and the BCL-2 inhibitor is ABT-199. In still other such embodiments, the HCK inhibitor is (3) and the BCL-2 inhibitor is ABT-199. In yet other such embodiments, the HCK inhibitor is (4) and the BCL-2 inhibitor is ABT-199. In still other such embodiments, the FLT3-ITD inhibitor is AC220 and the BCL-2 inhibitor is ABT-199. In other embodiments, the FLT3-ITD inhibitor is SU5614 and the BCL-2 inhibitor is ABT-737. In some such embodiments, the HCK inhibitor, and / or the FLT3-ITD inhibitor, and / or the BCL-2 inhibitor, each are present as a pharmaceutically acceptable salt, hi some such embodiments, the HCK inhibitor, and / or the FLT3-ITD inhibitor, and / or the BCL-2 inhibitor, each are present in a pharmaceutically acceptable composition.

[0114] Compositions and Salts In some embodiments, the disclosed compounds may be in the form of a pharmaceutically acceptable composition. Disclosed herein is a pharmaceutical composition comprising a FLT3-ITD inhibitor, and / or an HCK inhibitor, and / or a BCL-2 inhibitor described herein, and a pharmaceutically acceptable carrier.

[0115] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat. Other pharmaceutically acceptable carriers, adjuvants, or vehicles include water, saline, and dimethyl sulfoxide, as well as other hydrophobic or hydrophilic solvents.

[0116] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0117] These compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and / or antioxidants. Prevention of the action of microorganisms on the compounds described herein can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions.

[0118] Methods of preparing these formulations or compositions include the step of bringing into association a compound described herein with the carrier, and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound disclosed herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0119] The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw-Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw-Hill, 2001; Remington's Pharmaceutical Sciences, 20th Edition, Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties. Except insofar as any conventional excipient medium is incompatible with the compounds provided herein, such as by producing some undesirable biological effect or otherwise interacting deleteriously with any of the other component(s) of the pharmaceutically acceptable compositions, use of an excipient is contemplated within the scope of the present disclosure.

[0120] Provided herein are pharmaceutically acceptable salts, which refer to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein 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 with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of the salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0121] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or can be prepared separately, such as by reacting the free base or free acid of the compound with the appropriate base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-alkane salts. + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0122] Pharmaceutically acceptable acid addition salts may also exist as various solvates, for example with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be adventitious to such solvent.

[0123] Pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., in aqueous or non-aqueous solutions or suspensions, such as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds can also be formulated for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0124] The formulations can be conveniently provided in unit dosage form and prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0125] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier(s), and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0126] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), lyophilisates, powders, granules, each containing a predetermined amount of a compound of the present invention as an active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and gum arabic), and / or as a mouthwash, etc. The composition or compound may also be administered as a bolus, electuary, or paste.

[0127] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; and (4) disintegrating agents. Ingredients that may be used include, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, for example, paraffin; (6) absorption accelerators, for example, quaternary ammonium compounds; (7) wetting agents, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, for example, kaolin and bentonite clay; (9) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, for example, modified and unmodified cyclodextrins; and (11) coloring agents. For capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0128] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0129] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide delayed or controlled release of the active ingredient therein, for example, using hydroxypropyl methylcellulose in various proportions to provide the desired release profile, using other polymer matrices, using liposomes, and / or using microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0130] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0131] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0132] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0133] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0134] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0135] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0136] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0137] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0138] These compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0139] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the drug further depends on its dissolution rate, which may also depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0140] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0141] For use in the methods of the present invention, the active compound can be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient together with a pharmaceutically acceptable carrier.

[0142] Methods of introduction can also be provided by rechargeable or biodegradable devices. A variety of sustained-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0143] Actual dosage levels of the active ingredient in the pharmaceutical compositions may be varied to obtain an effective, without toxic effect on the patient, amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0144] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, used, the route of administration, the time of administration, the excretion rate of the particular compound(s) used, the duration of treatment, other drugs, compounds, and / or materials used in conjunction with the particular compound(s) used, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0145] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start by administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other therapeutic agents administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0146] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0147] If desired, the effective daily dose of active compound can be administered as 1, 2, 3, 4, 5, 6 or more sub-doses that are administered separately at appropriate intervals throughout the day, optionally in unit dosage form.In certain embodiments of the present invention, active compound can be administered 2 or 3 times a day.In a preferred embodiment, active compound is administered once a day.

[0148] Patients for this treatment may be any animal in need of treatment, including primates (especially humans); and other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and common pets.

[0149] In certain embodiments, the compounds of the present invention can be used alone or can be administered in combination with another type of therapeutic agent. As used herein, the phrase "co-administration" refers to any administration form of two or more different therapeutic compounds, such that the second compound is administered while the first therapeutic compound is still effective in the body (e.g., the two compounds are effective in the patient at the same time, which may include the synergistic effect of the two compounds). For example, different therapeutic compounds can be administered in the same formulation or in separate formulations, and can be administered simultaneously or sequentially. In certain embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or within 1 week of each other. Thus, individuals receiving such treatment can benefit from the combined effects of different therapeutic compounds.

[0150] In certain embodiments, the combined administration of a compound of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) improves efficacy compared to the administration of either the compound of the invention or the one or more additional therapeutic agent(s) individually. In certain such embodiments, the combined administration results in an additive effect, where additive effect refers to the sum of the respective effects of the compound of the invention and the one or more additional therapeutic agent(s) administered individually.

[0151] In certain preferred embodiments, the compounds of the present invention are administered in combination with a steroidal anti-inflammatory drug such as prednisolone, dexamethasone, prednisone, methylprednisolone, beclomethasone, betamethasone, fluticasone, or hydrocortisone. In certain preferred embodiments, the compounds of the present invention are administered in combination with dexamethasone. Without wishing to be bound by any particular theory, as described in U.S. Patent Application Publication No. 2018 / 0078567 (fully incorporated herein by reference), it is believed that steroidal anti-inflammatory drugs produce a synergistic effect when used in combination with the compounds of the present invention. The dosage forms of the compounds of the present invention and the steroidal anti-inflammatory drug can be appropriately modified by those skilled in the art. In certain preferred embodiments, the compounds of the present invention are administered in combination with a cell cycle inhibitor. Cell cycle inhibitors suitable for use with the compounds of the present invention include those known in the art (including, but not limited to, those described in Mills et al., "Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer," Cancer Research (2017) doi:10.158 / 0008-5472.CAN-17-2066). Exemplary cell cycle inhibitors suitable for use with the compounds of the present invention include, but are not limited to, palbociclib, ribociclib, abemaciclib, flavopiridol, AT9283, alisertib, and MK-1775. Dosage forms of the compounds of the present invention and cell cycle inhibitors can be appropriately prepared by those skilled in the art.

[0152] In certain preferred embodiments, the compounds of the present invention are administered in combination with one or more other anti-apoptotic agents, such as Mcl-1 inhibitors and inhibitors of apoptosis proteins (IAP) antagonists. Suitable Mcl-1 inhibitors include, but are not limited to, those described in Chen et al., "Mcl-1 Inhibitors: A Patent Review," Expert Opinion on Therapeutic Patents (2016) doi:10.1080 / 13543776.2017.1249848, which is incorporated herein by reference in its entirety. Such compounds include, but are not limited to, [ka] [ka] [ka] Includes:

[0153] Suitable IAP antagonists include, but are not limited to, those described in Hird et al., "Small Molecule Inhibitor of Apoptosis Proteins Antagonists: a Patent Review," Expert Opinion on Therapeutic Patents (2015) doi:10.1517 / 13543776.2015.1041922, which is incorporated herein by reference in its entirety. Such compounds include, but are not limited to, [ka] [ka] [ka] [ka] [ka] These include AT-406 / Debio 1143, GDC-0917 / CUDC-427, LCL161, and TL-32711.

[0154] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants may also be present in the composition.

[0155] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) fat-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0156] The compound represented by formula (I), its salt, or its prodrug can inhibit the proliferation of leukemia stem cells or kill leukemia stem cells.Therefore, such compound, its salt, or its prodrug can be used in pharmaceutical compositions for treating acute myeloid leukemia or inhibiting the recurrence of acute myeloid leukemia.

[0157] Leukemia stem cells are cells that meet at least one of the following requirements: 1: Cells that can selectively and exclusively generate leukemia in vivo; 2: Cells capable of generating the non-stem cell fraction of leukemia that are incapable of spontaneously generating leukemia; 3: Cells capable of engrafting in vivo; and / or 4: The cells are capable of self-renewal.

[0158] In certain embodiments, the leukemic stem cells express CD34 as a surface antigen. + CD38 - In this description, leukemia stem cells obtained from acute myeloid leukemia patients are referred to as "human AML CD34 + CD38 - Also called "cells."

[0159] When cells are capable of self-renewal, they can divide into two types of cells: stem cells and more differentiated progenitor cells.The concept of leukemia stem cells has been established and is generally accepted in the art (D. Bonnet, J. E. Dick, Nat. Med., 3, 730 (1997); T. Lapidot et al., Nature, 367, 645 (1994)).

[0160] In this description, all types of leukemia stem cells are within the scope of "leukemia stem cells." The term "leukemia stem cells" preferably refers to stem cells with high HCK gene expression levels, and more preferably refers to stem cells of acute myeloid leukemia cells.

[0161] The target leukemia stem cells in the present invention are generally derived from mammals.Examples of mammals include experimental animals, such as mice, rats, hamsters, guinea pigs, and other rodents, and rabbits; livestock animals, such as pigs, cows, goats, horses, sheep, and minks; companion animals, such as dogs and cats; and primates, such as humans, monkeys, cynomolgus monkeys, rhesus monkeys, marmosets, orangutans, and chimpanzees.The target leukemia stem cells in the present invention are preferably derived from primates, such as humans, or rodents, such as mice.

[0162] The pharmaceutical composition for killing leukemic stem cells and the pharmaceutical composition for treating or inhibiting relapse of acute myeloid leukemia according to the present invention (hereinafter referred to as "pharmaceutical composition(s) of the present invention") have the effect of killing leukemic stem cells. The effect of killing leukemic stem cells can be confirmed as the effect of inhibiting the proliferation of leukemic stem cells throughout the entire cell population.

[0163] Since leukemia stem cells are believed to cause relapsed leukemia, the use of the pharmaceutical composition of the present invention can inhibit and / or prevent the relapse of leukemia. Specifically, the pharmaceutical composition of the present invention is also useful for suppressing leukemia (preferably as a drug for inhibiting the relapse of leukemia). Relapse of leukemia is a state in which leukemia cells proliferate again and leukemia symptoms reappear or worsen after a patient has achieved partial or complete remission of leukemia symptoms through treatment. The onset (or relapse) of leukemia can be inhibited and / or prevented by administering the pharmaceutical composition of the present invention to a mammal at risk of developing leukemia (or experiencing relapse).

[0164] Acute myeloid leukemia can be brought into complete remission by using known cancer chemotherapy agents, such as alkylating agents (e.g., cyclophosphamide and ifosfamide), antimetabolites (e.g., cytarabine, 5-fluorouracil, and methotrexate), antitumor antibiotics (e.g., adriamycin and mitomycin), plant-derived anticancer agents (e.g., vinblastine, vincristine, vindesine, and taxol), cisplatin, carboplatin, or etoposide. However, AML often relapses after complete remission is achieved, and many patients die from the recurrence of AML.

[0165] By administering the pharmaceutical composition of the present invention to a patient in remission from acute myeloid leukemia, recurrence of acute myeloid leukemia can be prevented.

[0166] The compounds of formula (I) can inhibit HCK and / or FLT3 and retain inhibitory activity against cells harboring FLT3 / ITD mutations. Therefore, pharmaceutical compositions containing the compounds of the present invention, their salts, or prodrugs thereof can be useful for killing leukemia stem cells. Pharmaceutical compositions containing the compounds of the present invention, their salts, or prodrugs thereof can also kill leukemia stem cells harboring FLT3 / ITD mutations. Therefore, such pharmaceutical compositions can treat acute myeloid leukemia, including acute myeloid leukemia caused by leukemia stem cells harboring one or more FLT3 / ITD mutations.

[0167] The pharmaceutical composition of the present invention may further contain, in addition to the compound represented by formula (I), a salt thereof, or a prodrug thereof, an agent that exhibits an inhibitory effect on FLT3, for example, in order to enhance the efficacy against leukemic stem cells, including leukemic stem cells having an Flt3 / ITD mutation.

[0168] Examples of drugs having an inhibitory effect on FLT3 that can be used in the present invention include, but are not limited to, crenolanib, lestaurtinib (CEP-701 / KT5555), PKC412 (CGP41251), tandutinib (MLN518 / CT53518), sunitinib (SU11248), sorafenib (BA43-9006), linifanib (ABT-869), dovitinib (CHIR-258 / TKI-258), KW-2449, quizartinib (AC220), dovitinib dilactic acid, cabozantinib (XL-184), R406, TG101209, amuvatinib, and ENMD-2076.

[0169] If necessary, FLT3 ITD mutations can be detected and evaluated by detecting differences between the mutation site and the normal type by PCR, electrophoresis, sequencing, antibody detection (e.g., Western blotting or ELISA), or other means.In individuals in which FLT3 ITD mutations are detected in leukemia stem cells, the pharmacological efficacy can be evaluated as being enhanced compared to individuals in which normal FLT3 is detected in leukemia stem cells.If the pharmacological efficacy is evaluated as being enhanced, the pharmaceutical composition of the present invention can be administered to the individual.Therefore, treatment, inhibition, and / or prevention of relapse of acute myeloid leukemia can be achieved.

[0170] Administration The compositions of the present invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or intraperitoneally. In certain preferred embodiments, the disclosed methods include orally or parenterally administering any two or all three of a FLT3-ITD inhibitor, an HCK inhibitor, and a BCL-2 inhibitor.

[0171] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0172] The pharmaceutically acceptable compositions of the present invention can be orally administered 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 cornstarch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can also be added. In some embodiments, the provided oral formulations are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for buccal or sublingual administration and include tablets, lozenges, and pastilles. The compounds disclosed herein can also be in microencapsulated form.

[0173] The amount of the compounds of the present invention that can be combined with carrier materials to produce a composition in a single dosage form will vary depending on the subject being treated and the particular mode of administration. In certain embodiments, provided compositions should be formulated so that a dosage of about 0.01 to about 100 mg of compound per kg of body weight per day can be administered to a subject receiving these compositions. In other embodiments, dosages are about 0.5 to about 100 mg per kg of body weight, or about 1 mg to about 1000 mg per dose, about every 4 to 120 hours, or depending on the requirements of the particular drug. Typically, pharmaceutical compositions of the present invention are administered about once to about six times per day.

[0174] In some embodiments, the compound is formulated for oral administration at a dosage of about 5 mg / kg to about 10 mg / kg, preferably at a dosage of about 7.5 mg / kg.

[0175] It should also be understood that the specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, the patient's age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the specific compound in the composition.

[0176] When the condition of the subject improves, the maintenance dose of the compound, composition or combination of the present invention can be administered as needed.Then, depending on the symptoms, the dosage or the frequency of administration, or both, can be reduced to the level that maintains the improved condition when the condition is reduced to the desired level.However, when the condition of the subject recurs, the patient may need to be treated intermittently on a long-term basis.

[0177] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application will control, including any definitions herein. [Example]

[0178] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this invention and encompassed by the appended claims. For example, variations on reaction conditions using art-recognized substitutes and no more than routine experimentation will be understood to be within the scope of this application.

[0179] The following examples are presented so as to provide a complete disclosure and description to those of ordinary skill in the art for making and using the method of the present invention, and are not intended to limit the scope of what the inventors regard as their invention.

[0180] Unless otherwise noted, starting materials for the experiments described herein were obtained from commercial sources or known procedures and used without further modification.

[0181] General method compound General method All solvents and reagents were obtained from commercial sources and used without further purification unless otherwise noted. NMR spectra were obtained on a Bruker Neo 400M spectrometer operating at 400 MHz. Chemical shifts are reported in parts per million (δ) from the tetramethylsilane resonance in the designated solvent. LC-mass spectra were obtained on an Agilent 1260-6125B single quadrupole mass spectrometer using a Welch Biomate column (C18, 2.7 μm, 4.6 × 50 mm) eluted with a mixture of solvents A (ACN containing 0.05% FA) and B (water containing 0.05% FA) using gradient elution. Detection was by DAD (254 nm and 210 nm). Ionization was performed by ESI. Spectra were analyzed using Chemstation software. Analytical HPLC was performed on a Waters ARC system using gradient elution either under acid-containing conditions on a YMC Pack Pro column (C18 S-3 μm, 12 nm, 150 × 2.0 mm) eluting with a mixture of solvents A (ACN with 0.05% FA) and B (water with 0.05% FA) or under base-containing conditions on an Agilent Poroshell HPH C18 column (2.7 μm, 2.1 × 150 mm) eluting with a mixture of solvents C (water with 0.1% NH4OH) and D (ACN with 0.1% NH4OH). Detection was by DAD (254 nm and 210 nm). Preparative HPLC was performed on a Waters AutoP system coupled to a single quadrupole mass spectrometer using a Welch C18 column (5 μm, 25 × 150 mm) eluting with a mixture of solvents A and B. Flash chromatography was performed on a Biotage Isolera Prime system using a Welch WelFlash flash column (40-63 um) eluted with a mixture of solvents as indicated in the experimental procedures.

[0182] 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone [ka] 4-chloro-5-iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine To a stirred mixture of Ph3P (285.1 g, 1.07 mol) and THF (3.12 L), DEAD (170 mL, 1.07 mol) was added dropwise under ice bath. After the reaction mixture was warmed to room temperature, a solution of 4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (100 g, 0.36 mol) and 1,4-dioxaspiro[4.5]decan-8-ol (170 g, 1.07 mol) in THF (1.2 L) was added dropwise over 60 min. The reaction was stirred at room temperature for 3 h. TLC (EA:PE = 1:4) showed complete consumption of the starting material. The solvent was evaporated under vacuum. EA (1.78 L) was added to the residue, and the solid was collected by filtration. The solid was washed with EA (300 mL) and dried under reduced pressure to give the title compound as a white solid (139.8 g, 92.7% yield). LCMS: calculated exact mass = 419.0, found [M+H] + (ESI)=420.0; 1 H NMR(DMSO-d6)δ ppm:8.64(s,1H),8.12(s,1H),4.70-4.80(m,1H),3.88-3.95(m,4H),2.08-2.17(m,2H),1.88-1.96(m,2H),1.70-1.84(m,4H).

[0183] 4-Dichloro-5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine A reaction mixture of 4-dichloro-5-iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (60 g, 143 mmol), (4-phenoxyphenyl)boronic acid (60 g, 286 mmol), Pd(dppf)Cl (10 g, 14.3 mmol), and NaCO (45 g, 429 mmol) in dioxane-HO (10:1) (2.5 L) was heated to 80 °C and stirred for 3 h. TLC (PE:EA = 4:1) showed complete consumption of the starting material. The solvent was evaporated in vacuo. The residue was extracted with DCM (500 mL × 2). The combined organic layers were washed with water, dried over NaSO, and concentrated in vacuo. The crude product was purified by flash column chromatography (EA:PE=1:4) to give the title compound as a brown solid (42.0 g, 66% yield). LCMS: calculated exact mass=461.1, found [M+H] + (ESI)=462.2; 1 H NMR(DMSO-d6)δ ppm:8.66(s,1H),7.95(s,1H),7.54-7.56(m,2H),7.4-7.45(m,2H),7.03-7.21(m,5H),4.7 8-4.87(m,1H),3.89-3.96(m,4H),2.12-2.26(m,2H),1.94-2.02(m,2H),1.74-1.88(m,4H).

[0184] 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A reaction mixture of 4-dichloro-5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (20.3 g, 43.9 mmol), NHOH (200 mL), and dioxane (200 mL) was stirred in a high-pressure reactor at 120 °C for 48 h. The solid was filtered and dried to give the title compound as a white solid (10 g, 51.5% yield). LCMS: calculated exact mass = 442.2, found [M+H]. + (ESI)=443.2.

[0185] 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone A reaction mixture of 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 g, 22.6 mmol), HCl (6N, 160 mL), acetone (160 mL), and THF (36 mL) was stirred at 40° C. for 2 hours. Under ice bath cooling, NaOH (1 M, 980 mL) was added to the mixture until the pH reached 8. The solid was collected by filtration and dried under reduced pressure to give the title compound as a white solid (7.6 g, 84.4% yield). LCMS: calculated exact mass = 398.2, found [M+H]. + (ESI)=399.2; 1 H NMR(DMSO-d6)δ ppm:8.17(s,1H),7.40-7.47(m,5H),7.08-7.17(m,5H),6.12(br.s.,2H ),5.18(s,1H),2.73-2.78(m,2H),2.28-2.40(m,4H),2.15-2.25(m,2H).

[0186] 5-Iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] 5-Iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A mixture of 4-chloro-5-iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (13 g, 31 mmol), NHOH (200 mL), and dioxane (200 mL) was stirred in a high-pressure autoclave at 120 °C for 48 h. TLC (MeOH:DCM = 1:20) showed complete consumption of the starting material. The title compound was collected as a white solid by filtration and subsequently dried under reduced pressure (11.6 g, 93% yield). LCMS: calculated exact mass = 400.0, found [M+H].+ (ESI+)=401.0.

[0187] 5-Iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A mixture of 5-iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (11.6 g, 29 mmol), 6 M HCl (160 mL), acetone (160 mL), and THF (38 mL) was stirred at 40° C. for 2 hours. TLC (EA:PE=1:3) showed that the starting material was completely consumed. NaOH solution (980 mL, 1 mol / L) was added to the mixture until the pH reached 8.0 (under ice cooling). The title compound was collected as a white solid by filtration and subsequently dried under reduced pressure (7.6 g, 73% yield). LCMS: calculated exact mass=356.0, found [M+H]. + (ESI)=357.0; 1 H NMR(DMSO-d6)δ ppm:8.12(s,1H),7.60(s,1H),6.65(br.s.,2H),5.10(s,1H),2.68-2.74(m,2H),2.23-2.30(m,4H),2.09-2.14(m,2H).

[0188] 4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone [ka] 4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone A solution of 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (300 mg, 0.84 mmol), 2-(2-fluoro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (344.0 mg, 1.10 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (123.3 mg, 0.17 mmol), and sodium carbonate (178.6 mg, 1.65 mmol) in dioxane-water (11 mL, 10:1) was stirred at 90° C. under nitrogen for 12 hours. After cooling to room temperature, the mixture was filtered through Celite, concentrated, and purified by flash chromatography (DCM:MeOH=20:1) to give a brown oil (400 mg, 114.6% yield, approximately 80% purity). LCMS: calculated exact mass=416.2; found [M+H]+(ESI)=417.0.

[0189] 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone [ka] 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine NIS (1.99 kg, 8.88 mol) was added in three portions to a mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 kg, 7.4 mol) in DMF (6 L). The reaction was stirred at 80° C. overnight. The reaction was cooled to room temperature and allowed to settle. The solid was filtered and washed with EtOAc (12 L). The solid was filtered and dried under vacuum to give the product as a white solid (1.58 kg). LCMS: calculated exact mass=260.9; found [M+H] + (ESI)=262.2; 1 H NMR(DMSO-d6)δ ppm:8.18(s,1H).

[0190] 3-Iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine To an ice-bath cooled suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 g, 1.53 mol) in THF (5.5 L) was added 1,4-dioxaspiro[4.5]decan-8-ol (480 g, 3.06 mol), PPh3 (600 g, 2.3 mol), followed by dropwise addition of DEAD (400 g, 3 mol) over 4 h. The reaction was stirred at room temperature for 1 h and monitored by LCMS until complete conversion of the starting material. The reaction mixture was concentrated. The crude material was washed with THF (400 mL) and then EtOAc (4 L) to give the product (380 g, 62% yield). LCMS: calculated exact mass = 401.0; found [M+H]. + (ESI)=401.9; 1 H NMR (400MHz, DMSO-d6) δ ppm: 8.19 (s, 1H) 4.64-4.79 (m, 1H) 3.85-3.96 (m, 4H) 2.09-2.23 (m, 2H) 1.66-1.90 (m, 6H).

[0191] 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone To a suspension of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (660 g, 1.64 mol) in THF (1.2 L) and acetone (6 L) was added 6 N HCl (6 L, 36 mol). The reaction was heated at 60° C. for 1 h. It was neutralized with 7.5 N aqueous NaOH. After filtration, the solid product was collected (350 g) and used without further purification. LCMS: calculated exact mass = 357.0; found [M+H] + (ESI)=357.8; 1 H NMR (400MHz, DMSO-d6) δ ppm: 8.23 ​​(s, 1H) 5.10-5.23 (m, 1H) 2.61-2.76 (m, 2H) 2.25-2.40 (m, 5H) 2.14-2.23 (m, 2H).

[0192] 4-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-one [ka] 4-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-one A 50 mL round-bottom flask was charged with 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone (3 g, 8.4 mmol), 2-(2-fluoro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.16 g, 10.08 mmol), Pd(dppf)Cl (614 mg, 0.84 mmol), NaCO (3.6 g, 33.5 mmol), and 30 mL of dioxane-water (9-1, 20 mL). The reaction was stirred overnight at 85 °C under a N atmosphere. The reaction was cooled to room temperature, filtered, and concentrated. The crude was purified by flash column chromatography (MeOH in DCM, 0-5%) to give the product as a red solid (2.5 g, 71.3% yield), which was used without further purification. LC-MS: calculated exact mass: 417.16; found [M+H] + (ESI)=418.15.

[0193] 5-Iodo-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-Iodo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] A mixture of 5-iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (6.3 g, 17.7 mmol), 1-methylpiperazine (11.71 g, 106.2 mmol), AcOH (0.63 mL, 10.62 mmol) and sieves in DCM (50 mL) was stirred at room temperature for 16 hours. NaCNBH (2.21 g, 35.4 mmol) was added to the mixture. The mixture was then stirred at 50 °C for 4 hours. TLC (MeOH:DCM = 1:15) showed that the starting material was completely consumed. The solvent was evaporated under vacuum. The residue was extracted with DCM (250 mL × 2). The combined organic layers were washed with water, dried over anhydrous NaSO, and concentrated under vacuum. The residue was purified by flash column chromatography (DCM:MeOH=10:1) to give 5-iodo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.3 g, 55.3% yield) along with the cis isomer. Analytical data for the trans isomer: LCMS: calculated exact mass = 440.1, found [M+H]. + (ESI)=441.1; 1 H NMR(DMSO-d6)δ ppm:8.08(s,1H),7.53(s,1H),6.58(br.s.,2H),4.47(s,1H),2.35(br.s.,4H),2.16(s,3H),1.81-1.90(m,6H),1.38-1.44(m,2H).

[0194] 5-Iodo-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrazolo[2,3-d]pyrimidin-4-amine and 5-Iodo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrazolo[2,3-d]pyrimidin-4-amine [ka] 5-Iodo-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrazolo[2,3-d]pyrimidin-4-amine A solution of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone (700 mg, 1.96 mmol), 1-methylpiperazine (0.65 mL, 11.76 mmol), acetic acid (0.1 mL, 1.96 mmol), and molecular sieves (2.0 g) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (1.2 g, 11.76 mmol) was then added, and stirring was continued at room temperature for 16 hours. Water (150 mL) and dichloromethane (150 mL) were added to the reaction mixture, and saturated aqueous sodium bicarbonate (120 mL) was added, and the mixture was partitioned. The organic layer was washed with brine (120 mL), dried over sodium sulfate, concentrated, and purified by flash chromatography (DCM:MeOH=10:1) to give 5-iodo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a white solid (530 mg, 61.6% yield) along with the corresponding cis isomer. Analytical data for the trans isomer: LCMS: calculated exact mass = 440.1; found [M+H]. + (ESI)=442.1.

[0195] (S)-tert-Butyl-4-((trans)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate and (S)-tert-Butyl-4-((cis)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate [ka] To a solution of the compound 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (1 g, 2.8 mmol), (S)-tert-butyl 2-methylpiperazine-1-carboxylate (3.36 g, 16.8 mmol), and AcOH (0.1 mL) in DCM (70 mL) was added NaBHCN (1 g, 16.8 mmol) at room temperature under a N atmosphere. The reaction was then stirred at 40 °C for 16 h. The reaction was extracted with DCM (150 mL) and water. The combined organic layer was washed with aqueous NH Cl (150 mL), dried over anhydrous Na SO , and concentrated in vacuo. The residue was purified by flash column chromatography (DCM:MeOH = 20:1) to give a mixture of the two title compounds (2 g), which was used without further purification. LCMS: Calculated exact mass = 540.17, actual value [M+H] + (ESI)=541.1.

[0196] 5-Iodo-7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] To a solution of (S)-tert-butyl 4-((trans)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate (1.0 g, 1.85 mmol) in DCM (20 mL) was added TFA (10 mL) dropwise. The reaction mixture was stirred at room temperature for 0.5 h. The mixture was evaporated and purified by flash column chromatography (MeOH in DCM, gradient 1-10%) to afford the title compound as an off-white solid (690 mg, 85% yield).

[0197] (S)-tert-Butyl-4-((trans)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate and (S)-tert-Butyl-4-((cis)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate [ka] A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone (2.5 g, 7 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.2 g, 21 mmol) in DCE (50 mL) was stirred at 55 °C under a N atmosphere for 90 min. After the mixture was cooled to room temperature, NaBH(OAc) (2076 mg, 9.8 mmol) was added in portions, and the mixture was stirred at 55 °C under a N atmosphere for 90 min, then cooled to room temperature and stirred at room temperature overnight. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography (MeOH in DCM 0–30%) to give the title compound as a yellow solid (1.4 g, 36% yield). LCMS: Calculated exact mass = 541.17; Actual value [M+H] + (ESI)=541.82.

[0198] 5-Iodo-7-((trans)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-iodo-7-((cis)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] 2-Oxopropane-1,3-diyldibenzoate To a stirred solution of 1,3-dihydroxypropan-2-one (30 g, 333 mmol) and DMAP (2.1 g, 16.65 mmol) in pyridine (133 mL) cooled in an ice bath, benzoyl chloride (85 mL, 732 mmol) was added dropwise, followed by pyridine (120 mL). After the addition, the mixture was warmed to room temperature and stirred overnight. The mixture was poured into HCl (6 M, 580 mL) at 0° C. The mixture was filtered and washed with water (150 mL × 2). The residue was suspended in MeOH (400 mL) and filtered to give the title compound as a white solid (64.6 g, 65% yield).

[0199] 2-Hydroxypropane-1,3-diyl dibenzoate To a stirred solution of 2-oxopropane-1,3-diyldibenzoate (15 g, 50 mmol) in THF (150 mL) cooled in an ice bath, NaBH (2.3 g, 60 mmol) was added portionwise. After the addition, the mixture was stirred at 0 °C for 30 min. The reaction was quenched with NH Cl solution and evaporated. The residue was diluted with EA (200 mL), washed with water (80 mL) and brine (80 mL), dried, concentrated in vacuo, and purified by flash column chromatography (EA in PE, gradient 0-20%) to give the title compound as a colorless oil (9.02 g, 60% yield).

[0200] 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diyl dibenzoate To a solution of PPh3 (15.5 g, 59.04 mmol) in THF (100 mL) cooled in an ice bath was added DEAD (10.3 g, 59.04 mmol). The mixture was stirred at room temperature. To the mixture was added a solution of 2-hydroxypropane-1,3-diyldibenzoate (7.7 g, 25.6 mmol) and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.5 g, 19.68 mmol) in THF (60 mL). The reaction was stirred at room temperature for 2 h. The mixture was evaporated. The residue was diluted with EA (30 mL), filtered, and the filtrate was concentrated in vacuo and purified by flash column chromatography (EA in PE, gradient 0-40%) to give the desired product as a white solid (7.1 g, 64% yield). LC-MS: calculated exact mass: 561.0 Found: [M+H] + (ESI)=561.9; 1 H NMR (400 MHz, chloroform-d) δ ppm: 8.61 (s, 1H), 7.90 (m, 4H), 7.52-7.66 (m, 3H), 7.37-7.48 (m, 4H), 5.66 (m, 1H), 4.77-4.99 (m, 4H).

[0201] 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diol A solution of 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diyldibenzoate (4.0 g, 7.12 mmol) in dioxane (50 mL) and concentrated aqueous ammonia (50 mL) was heated in a pressure vessel at 120° C. for 18 hours. The mixture was cooled to room temperature, and the solvent was removed under vacuum to give a yellow solid. The yellow solid was suspended in water (15 mL), filtered, and washed with water (5 mL) to give a white solid. The white solid was suspended in MeOH (15 mL), filtered, and washed with MeOH (5 mL) to give a white solid (2.0 g, 80% yield). LC-MS: Calculated exact mass: 334.0. Found: [M+H] + (ESI)=334.5.

[0202] 5-Iodo-7-((trans)-2-(piperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-Iodo-7-((cis)-2-(piperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diol (1.9 g, 5.69 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (15.8 g, 73.93 mmol), TsOH—HO (14.1 g, 73.93 mmol), and NaSO (40.4 g, 284.34 mmol) in toluene (250 mL) was stirred at 110° C. for 18 hours. After cooling to room temperature, NaCO solution was added and stirred for 15 minutes. The mixture was concentrated. The solid was suspended in DCM / MeOH (v / v=1:10, 400 mL), filtered, evaporated, and purified by flash column chromatography (MeOH in DCM, gradient 0-10%) to give a yellow solid (880 mg, 36% yield). LC-MS: Calculated exact mass: 429.1 Found: [M+H] + (ESI)=429.6.

[0203] 5-Iodo-7-((trans)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-Iodo-7-((cis)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of 5-iodo-7-((2r,5r)-2-(piperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (880 mg, 2.05 mmol), formaldehyde (369 mg, 12.3 mmol), and acetic acid (0.5 mL) in DCM / MeOH (v / v=1:2, 45 mL) was stirred at room temperature for 1 hour. NaBH(OAc) (3.9 g, 18.45 mmol) was added to the mixture. After stirring at room temperature for 16 hours, water (100 mL) and DCM (400 mL) were added to the mixture, followed by a saturated solution of NaHCO (200 mL). The organic layer was washed with brine (80 mL), dried over Na2SO4, evaporated, and purified by flash column chromatography (MeOH in DCM, gradient 0-10%) to give the mixture of title compounds as a yellow solid (460 mg, 51% yield). LC-MS: Calculated exact mass: 443.1 Found: [M+H] + (ESI)=443.6; 1 H NMR(400MHz,chloroform-d)δ ppm:8.22(s,1H),7.79(s,1H),5.70(br.s.,2H),4.72-4.81(m,1H),4.51(m,1H),4.15-4.27(m,4H), 3.11(d,J=10.4Hz,2H),2.40-2.52(m,4H),2.10-2.25(m,2H),1.86-1.96(m,2H),1.55-1.81(m,2H).

[0204] Example 1 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and Example 2 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] A solution of 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (500 mg, 1.25 mmol), 1-methylpiperazine (0.4 mL, 3.76 mmol), acetic acid (0.2 mL, 1.88 mmol), and molecular sieves (1.0 g) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (398 mg, 1.88 mmol) was then added, and stirring was continued at room temperature for 16 hours. Water (100 mL) and dichloromethane (100 mL) were added to the reaction mixture, and saturated aqueous sodium bicarbonate (100 mL) was added, and the mixture was partitioned. The organic layer was washed with brine (60 mL), dried over sodium sulfate, concentrated, and purified by flash chromatography (DCM:MeOH=10:1) to give 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a yellow solid (100 mg, 16.5% yield). LCMS: calculated exact mass=482.3; found [M+H] + (ESI)=483.3; 1 H NMR(400MHz,chloroform-d)δ ppm:8.34(s,1H),7.36-7.48(m,4H),7.15-7.20(m,1H),7.07-7.13(m,4H ),7.02(s,1H),5.18(br.s.,2H),4.70(tt,J=12.1,3.8Hz,1H),2.76(br. s.,4H),2.63(br.s.,2H),2.49-2.60(m,2H),2.36-2.45(m,3H),2.21-2. 33(m,2H),2.13(d,J=12.6Hz,2H),1.76-1.92(m,2H),1.57-1.69(m,2H).

[0205] Data for 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 13.2%): LCMS: calculated exact mass = 482.3; found [M+H] + (ESI)=483.3;1 H NMR(400MHz,chloroform-d)δ ppm:8.29-8.40(m,1H),7.45-7.54(m,2H),7.36-7.45(m,2H),7.17(t,J=7.4Hz,1H),7.07-7.15(m,5H),5.13(s,2H),4.80- 4.90(m,1H),2.58-2.73(m,7H),2.30-2.41(m,4H),2.16-2.28(m,5H),1.86(dd,J=8.6,3.8Hz,2H),1.68(t,J=13.7Hz,2H).

[0206] Using similar procedures the following compounds can be obtained: [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

[0207] Example 86 6-Bromo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] To a solution of 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (500 mg, 10.4 mmol) in dichloromethane (15 mL) was added NBS (368.8 mg, 2.07 mmol) portionwise at room temperature. The mixture was then stirred for 16 hours. The mixture was concentrated and purified by flash chromatography (DCM:MeOH=15:1) to give a yellow solid (280 mg, 48.3% yield). LCMS: calculated exact mass = 560.2; found [M+H]+ (ESI) = 561.8; 1 H NMR(400MHz,chloroform-d)δ ppm:8.23(br.s.,1H),7.33-7.45(m,4H),7.16-7.23(m,1H),7.11(dd,J=7.8,5.3Hz,4H),5.48(br.s.,2H),4.61(br.s.,1H),3.12 -3.35(m,6H),2.81-3.08(m,2H),2.75-2.80(m,2H),2.66(br.s.,3H),2.24(br.s.,2H),2.03(d,J=11.3Hz,2H),1.69-1.77(m,2H).

[0208] Example 87 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and Example 88 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol [ka] To a solution of 4-chloro-5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (885 mg, 1.92 mmol) in MeOH (20 mL) was added KOH (215 mg, 3.83 mmol) at room temperature under a N atmosphere and stirred at 80 °C for 4 h. TLC (PE:EA = 4:1) showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature, poured into ice water (50 mL), and extracted with EA (50 mL × 2). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give the crude product as a yellow solid, which was used in the next step without further purification (623 mg, 71% yield). LCMS: Calculated exact mass = 457.20, actual value [M+H] + (ESI)=458.2.

[0209] 4-(4-Hydroxy-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone A solution of 4-methoxy-5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d] (623 mg, 1.36 mmol) in THF (3 mL), acetone (15 mL), and 6 M HCl (11 mL) was stirred at 80° C. for 4 h. TLC (EA:PE=1:2) showed complete consumption of the starting material. The mixture was cooled in an ice bath. 1 M NaOH (80 mL, aq.) was added until pH 8. The light brown solid product was collected by filtration (465 mg, 85.5% yield) and used in the next step without further purification. LCMS: calculated exact mass = 399.16, found [M+H] + (ESI)=400.1.

[0210] 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol To a solution of the compound 4-(4-hydroxy-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (100 mg, 0.25 mmol), 1-methylpiperazine (200 mg, 2.00 mmol), and ZnCl (102 mg, 0.75 mmol) in MeOH (20 mL) was added NaBHCN (47 mg, 0.75 mmol) at room temperature, and AcOH (0.1 mL) was added under a N atmosphere. The reaction was then stirred at 40 °C for 16 h. After concentration, the residue was extracted with DCM (150 mL × 2) and water. The combined organic layer was washed with aqueous NHCl (200 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC followed by preparative HPLC to give 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol as a white solid (10 mg, 8.3% yield). LCMS: calculated exact mass = 483.26, found [M+H]. + (ESI)=484.2; 1 H NMR(400MHz,DMSO)δ11.99(s,1H),10.40(s,1H),7.94(dd,J=17.1,5.5Hz,3H),7.41(dd,J=14.4,5.9Hz,3H),7.14(t,J=7.4Hz,1H),7.02(dd,J=7.9,6 .6Hz,4H),4.64(s,1H),3.05(s,2H),2.65(s,3H),2.27(d,J=17.6Hz,2H), 2.03(dd,J=23.5,9.1Hz,4H),1.71(s,2H),1.59(s,2H),1.30-1.19(m,5H). Data for 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol: 1H NMR(400MHz,DMSO)δ8.92(s,1H),7.95(s,1H),7.42-7.32(m,7H),7.18-7.07(m,2H),7.05-6.93(m,7H),6.85(d ,J=8.1Hz,4H),4.83(s,1H),3.54-3.45(m,2H),2.79(s,3H),2.12(d,J=23.4Hz,7H),1.69(s,2H),1.23(s,5H).

[0211] Example 89 1-(4-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-1-yl)-2-methylpropan-2-ol [ka] 5-(4-phenoxyphenyl)-7-((trans)-4-(piperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl 4-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazine-1-carboxylate (170 mg, 0.3 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the product (50 mg, 35% yield). LCMS: calculated exact mass = 568.3; found [M+H] + (ESI)=569.2.

[0212] 1-(4-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-1-yl)-2-methylpropan-2-ol A reaction mixture of 5-(4-phenoxyphenyl)-7-((trans)-4-(piperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.21 mmol), 2,2-dimethyloxirane (30 mg, 0.43 mmol), and CsCO (208 mg, 0.64 mmol) in DMF (8 mL) was stirred at room temperature for 2 hours. NaBHCN (47 mg, 0.75 mol) was added. It was stirred at 100 °C overnight. After cooling to room temperature, DCM (20 mL) was added, and the mixture was washed with water (20 mL × 2). The organic layer was collected and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the desired product (6 mg, 5% yield). LCMS: Calculated exact mass = 540.2; Actual value [M+H] + (ESI)=540.3; 1 H NMR(400MHz,DMSO-d6)δ ppm:10.46(br.s.,1H)8.14(s,1H)7.38-7.50(m,6H)7.16(t,J=7.38Hz,2H)7.10(dd,J=8.07,6.07Hz,6H)6.15(s,1H)4.58-4.61 (m,1H)4.21-4.26(m,1H)3.01-3.09(m,4H)2.57-2.71(m,2H)2.20-2.36(m,4H)1.88-2.08(m,4H)1.75-1.82(m,2H)1.10(s,6H).

[0213] Example 90 1-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-2-one and Example 91 1-((cis)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-2-one [ka] tert-Butyl (tert-butoxycarbonyl)(7-(4-oxocyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate To a solution of 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-one (2 g, 5.01 mmol) in THF (10 mL) was added EtN (1.5 g, 15.06 mmol) and (Boc)O (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight. DMAP (122 mg, 1 mmol), EtN (1.5 g, 15.06 mmol), and (Boc)O (2.2 g, 10 mmol) were added, and the mixture was refluxed for 3 hours. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. Then, it was concentrated, washed with saturated NaHCO, extracted with DCM, and the organic layer was concentrated to give the crude product. The crude was purified by flash column chromatography (MeOH in DCM 0-0.5%) to give the product as a yellow solid (1.5 g, 50% yield). LCMS: calculated exact mass = 598.69; found [M+H] + (ESI)=599.11.

[0214] tert-Butyl (tert-butoxycarbonyl)(7-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate A solution of tert-butyl (tert-butoxycarbonyl)(7-(4-oxocyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (1250 mg, 2.088 mmol) and tert-butyl (2-aminoethyl)carbamate (2007 mg, 12.52 mmol) in DCE (15 mL) was stirred at 50 °C under a N atmosphere for 2 h. After it was cooled to room temperature, NaBH(OAc) (2655 mg, 12.527 mmol) was added in portions, and the mixture was stirred at room temperature under a N atmosphere overnight. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then filtered and concentrated, and the crude was purified by flash column chromatography (2-3% MeOH in DCM) to give the product as a white solid (1 g, 64.5% yield). LCMS: calculated exact mass = 742.41; found [M+H] + (ESI)=742.92.

[0215] tert-Butyl (tert-butoxycarbonyl)(7-(4-(N-(2-((tert-butoxycarbonyl)amino)ethyl)-2-chloroacetamido)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate To a solution of tert-butyl (tert-butoxycarbonyl)(7-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (500 mg, 0.67 mmol) in DCM (5 mL) was added EtN (430 mg, 2.05 mmol) and 2-chloroacetyl chloride (98.82 mg, 0.875 mmol) in DCM (0.5 mL) dropwise at 0° C. The mixture was allowed to warm to room temperature for 2 hours. The reaction was monitored by LCMS until the starting material was completely consumed. The reaction was quenched with ice / water and extracted with DCM (20 mL × 2). It was then concentrated to give the crude product. The crude was purified by flash column chromatography (1-1.5% MeOH in DCM) to give the product as a colorless solid (175 mg, 31.7% yield). LCMS: calculated exact mass = 818.38; found [M+H] + (ESI)=818.9.

[0216] tert-Butyl (tert-butyl) 4-(4-(4-((tert-butoxycarbonyl)amino)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-3-oxopiperazine-1-carboxylate To a solution of tert-butyl (tert-butoxycarbonyl)(7-(4-(N-(2-((tert-butoxycarbonyl)amino)ethyl)-2-chloroacetamido)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate (175 mg, 0.214 mmol) in DMF (2 mL) was added NaH (33 mg, 60% in oil, 0.854 mmol) at 0° C., then warmed to room temperature for 2 h. The reaction was monitored by TLC and LCMS until complete consumption of the starting material. The reaction was quenched with ice / water, extracted with DCM (50 mL×5), and the organic layer was concentrated to give the product as a yellow solid (150 mg, 89.5% yield). LCMS: calculated exact mass=782.4; found [M+H] + (ESI)=682.62.

[0217] 1-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-2-one, and 1-((cis)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-2-one To a solution of tert-butyl (tert-butyl) 4-(4-(4-((tert-butoxycarbonyl)amino)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-3-oxopiperazine-1-carboxylate (150 mg, 0.19 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. After concentration, 20 mL of 7.0 N NH3 in MeOH was added and the mixture was stirred at room temperature for 15 minutes. Concentration and preparative TLC afforded 1-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-2-one as a yellow solid (45 mg, 48.6% yield). LCMS: calculated exact mass = 482.24; found [M+H] + (ESI)=482.8; 1 H NMR(DMSO-d6)δ ppm:8.14(s,1H),7.38-7.52(m,5H),7.16(t,J=7.3Hz,1H),7.06-7.12(m,4H),6.03-6.24(m,1H),4.62(t,J=11.7Hz,1H),4.41-4.51(m,1H), 3.25(s,2H),3.21(t,J=5.0Hz,2H),2.88(t,J=5.2Hz,2H),2.05(d,J=9.5Hz,2H),1.99(br.s.,2H),1.72-1.86(m,2H),1.66(d,J=10.7Hz,2H) Data for 1-((cis)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)piperazin-2-one (300 mg, 48.6% yield): LCMS: calculated exact mass = 482.24; found [M+H] + (ESI)=482.79; 1 H NMR(DMSO-d6)δ ppm:8.14(s,1H),7.48-7.56(m,3H),7.38-7.46(m,2H),7.06-7.20(m,5H),6.12(br.s.,1H),4.80(d,J=3.7Hz,1H),4.30-4.40(m, 1H),3.23-3.28(m,4H),2.89(t,J=5.2Hz,2H),2.37(d,J=11.0Hz,2H),1.95-2.04(m,2H),1.80-1.91(m,2H),1.57(d,J=9.2Hz,2H).

[0218] Example 92 7-(3-amino-1,5-dioxaspiro[5.5]undecan-9-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] tert-Butyl (9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,5-dioxaspiro[5.5]undecan-3-yl)carbamate To a solution of 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (400 mg, 1 mmol) in toluene (10 mL) was added tert-butyl (1,3-dihydroxypropan-2-yl)carbamate (191 mg, 1 mmol), TsOH (12 mg, 0.06 mmol), and molecular sieves. The reaction mixture was heated to 150° C. and reacted under microwave irradiation for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (EA 100%) to give the product as a white solid (160 mg, 28% yield). LC-MS: calculated exact mass = 571.3, found [M+H]. + (ESI)=572.12.

[0219] 7-(3-amino-1,5-dioxaspiro[5.5]undecan-9-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl (9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,5-dioxaspiro[5.5]undecan-3-yl)carbamate (260 mg, 0.45 mmol) in DCM (20 mL) was added 2,6-lutidine (72 mg, 0.675 mmol) and TMSOTf (130 mg, 0.585 mmol) at −78 °C. The dry ice / acetone bath was replaced with an ice-water bath, and the reaction mixture was stirred for 2 h. NaHCO (20 mL aqueous solution) was then added, followed by extraction with EA (20 mL × 3). The organic layers were combined and dried over NaSO. After concentration, the crude was purified by preparative TLC (DCM:CHOH = 10:1) to give the product as a white solid (19 mg, 8.6% yield). LC-MS: Calculated exact mass = 471.2, actual value [M+H] + (ESI)=472.11; 1H NMR(DMSO-d6)δ ppm:8.14(s,1H),7.48(d,J=8.7Hz,2H),7.39-7.44(m,2H),7.36(s,1H),7.16(t, J=7.3Hz,1H),7.06-7.11(m,4H),4.60-4.73(m,1H),3.97(dd,J=11.7,3.4Hz,2H), 3.59-3.68(m,2H),2.96(br.s.,1H),2.45(d,J=13.5Hz,1H),2.37(d,J=13.5Hz,1 H),1.92-2.03(m,3H),1.86(d,J=9.8Hz,2H),1.54(ddt,J=17.3,13.6,3.7Hz,2H).

[0220] Example 93 8-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(pyridin-4-yl)-1,3-diazaspiro[4.5]decane-2,4-dione [ka] 8-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,3-diazaspiro[4.5]decane-2,4-dione To a solution of 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-one (5 g, 12.6 mmol) in EtOH (50 mL) and water (50 mL) was added NaCN (926 mg, 18.9 mmol) and (NH)CO (3.63 g, 37.8 mmol). The mixture was stirred at 80 °C overnight. It was then cooled to room temperature, concentrated to remove EtOH, filtered, washed with water (10 mL), and the solid was dried to give the product (4.5 g, 76% yield). LCMS: calculated exact mass = 468.2; found [M+H] + (ESI)=469.2.

[0221] 8-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(pyridin-4-yl)-1,3-diazaspiro[4.5]decane-2,4-dione To a solution of 8-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,3-diazaspiro[4.5]decane-2,4-dione (230 mg, 0.5 mmol) and pyridin-4-ylboronic acid (95 mg, 0.75 mmol) in DCE (15 mL) was added Cu(OAc) (97 mg, 0.5 mmol) and EtN (0.15 mL, 1 mmol). The reaction mixture was stirred overnight at room temperature under an O atmosphere. The reaction was filtered through Celite, and the solid was washed with 10 mL of MeOH. The filtrate was concentrated and purified by preparative TLC (DCM:CHOH=10:1) to give 70 mg of crude product, which was further purified by preparative HPLC to give the product as a white solid (11 mg, 4% yield). LC-MS: Calculated exact mass = 545.2, actual value [M+H] + (ESI)=545.8; 1 H NMR(methanol-d4)δ ppm:8.78(br.s.,2H),8.48(d,J=5.8Hz,2H),8.27(s,1H),7.53(s,1H),7.42(d,J=8.5H) z,2H),7.28-7.35(m,2H),6.96-7.12(m,6H),1.97-2.25(m,9H),1.93(d,J=6.1Hz,1H).

[0222] Example 94 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetamide and Example 95 Methyl 2-(1-amino-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)acetate and Example 96 2-(1-amino-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)acetamide [ka] Ethyl 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetate A reaction mixture of 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (1.5 g, 3.76 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate (1.3 g, 3.76 mmol) in toluene (100 mL) was stirred at 110° C. overnight. The reaction mixture was cooled and concentrated. The residue was purified by flash column chromatography (DCM:EtOAc=1:1) to give the product (900 mg, 51% yield). LCMS: Calculated exact mass = 468.2; Actual value [M+H] + (ESI)=468.6.

[0223] 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetamide and Methyl 2-(1-amino-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)acetate and 2-(1-amino-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)acetamide A solution of ethyl 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetate (350 mg, 0.75 mmol) in NH-MeOH (14 mL) was reacted in a microwave reactor at 100° C. for 48 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography (DCM:MeOH=10:1) to give the following three products: 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetamide (2 mg, 0.6% yield). LCMS: calculated exact mass=439.2; found [M+H]. + (ESI)=439.6; 1 H NMR(400MHz,DMSO-d6)δ ppm:8.13(s,1H)7.47(d,J=8.55Hz,2H)7.38-7.45(m,3H)7.32(br.s.,1H)7.16(t,J=7.48Hz,1H)7.05-7.13(m,4H)6.85(br.s.,1H)5.50-5.60( m,1H)4.83(br.s.,1H)2.80(s,2H)2.45(br.s.,1H)2.33(br.s.,1H)2.24(br.s.,1H)2.15(d,J=14.65Hz,2H)1.89-2.06(m,2H)1.81(br.s.,1H).

[0224] 2-(1-amino-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)acetate (2 mg, 0.6% yield) LCMS: calculated exact mass = 471.2; found [M+H] + (ESI)=471.6; 1H NMR(400MHz,DMSO-d6)δ ppm:8.13(s,1H)7.67(s,1H)7.48(d,J=8.54Hz,2H)7.42(t,J=7.93Hz,2H)7.16(t,J=7.48Hz,1H)7.08(d,J=7.93Hz,2H) )7.11(d,J=8.54Hz,2H)6.14(br.s.,1H)4.61(br.s.,1H)3.68(s,3H)3.01(s,2H)1.95-2.14(m,4H)1.72-1.92(m,4H).

[0225] 2-(1-amino-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)acetamide (2 mg, 6% yield) LCMS: calculated exact mass = 456.2; found [M+H] + (ESI)=456.8; 1 H NMR(400MHz,DMSO-d6)δ ppm:8.13(s,1H)7.95(s,2H)7.99(s,1H)7.56-7.63(m,1H)7.48(d,J=8.24Hz,3H)7.42(t,J=7.78Hz,2H)7.17(d,J =7.32Hz,1H)7.03-7.15(m,4H)6.16(br.s.,1H)4.62(br.s.,1H)2.89(s,1H)2.70-2.80(m,2H)1.75-2.05(m,7H).

[0226] Example 97 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)-N-methylacetamide and Example 98 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(methylamino)cyclohexyl)-N-methylacetamide [ka] A solution of ethyl 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetate (40 mg, 0.085 mmol) and methylamine (40% in water, 0.5 mL) in MeOH (2 mL) was reacted in a microwave reactor at 100° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography (DCM:MeOH=10:1) to give the following two products: 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)-N-methylacetamide (3 mg, 7.8% yield). LCMS: calculated exact mass=453.2; found [M+H]. + (ESI)=453.8; 1 H NMR(400MHz,DMSO-d6)δ ppm:8.13(s,1H)7.79(d,J=4.27Hz,1H)7.44-7.50(m,3H)7.37-7.44(m,3H)7.16(t,J=7.17Hz,2H) 7.09(dd,J=8.09,4.43Hz,5H)7.01(br.s.,1H)5.55(br.s.,1H)4.81(br.s.,1H)2.81(s,2H)2.56-2 .61 (m, 3H) 2.44 (br.s., 2H) 2.22 (br.s., 1H) 2.04-2.18 (m, 2H) 1.89-2.04 (m, 3H); and 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(methylamino)cyclohexyl)-N-methylacetamide (3 mg, 7.2% yield). LCMS: calculated exact mass = 484.2; found [M+H] + (ESI)=484.8; 1 H NMR(400MHz,DMSO-d6)δ ppm:8.50(s,1H)8.14(s,1H)7.55(s,1H)7.49(d,J=8.54Hz,2H)7.42(t,J=7.63Hz,2H)7.03-7.21(m,5H)4.63(br .s.,1H)2.85(br.s.,2H)2.68(d,J=4.27Hz,3H)2.60(s,3H)1.90(s,2H)1.94(s,3H)1.81(br.s.,2H)1.75(s,1H).

[0227] Example 99 Ethyl 6-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)spiro[2.5]octane-1-carboxylate [ka] Ethyl 6-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)spiro[2.5]octane-1-carboxylate A solution of trimethylsulfoxonium iodide (92 mg, 0.42 mmol) and t-BuOK (47 mg, 0.42 mmol) in DMSO (2 mL) was stirred at room temperature for 3 hours, and then ethyl 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetate (100 mg, 0.21 mmol) was added. The reaction mixture was stirred overnight. Then, it was diluted with EtOAc, washed with water and brine, dried, and concentrated. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give the product (10 mg, 4.9% yield). LCMS: calculated exact mass=482.2; found [M+H] + (ESI)=483.1; 1 H NMR (400MHz, CDCl3-d6)δ ppm:8.30(s,1H)7.40-7.46(m,4H)2.15-2.19(m,3H)1.95-1.99(m,3H)1.57-1.60(m,2H)1.33(s,3H)1.10-1.31(m,3H).

[0228] Example 100 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-((4-methylpiperazin-1-yl)methyl)cyclohexanol [ka] 5-(4-phenoxyphenyl)-7-(1-oxaspiro[2.5]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of trimethylsulfoxonium iodide (220 mg, 1.00 mmol) and t-BuOK (110 mg, 1.00 mmol) in DMSO (10 mL) was stirred at room temperature for 0.5 h, after which ethyl 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylidene)acetate (200 mg, 0.50 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched with ice water, extracted with DCM, dried, and concentrated to give the crude product (250 mg), which was used without further purification. LCMS: calculated exact mass = 412.1; found [M+H]+ (ESI) = 412.8.

[0229] 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-((4-methylpiperazin-1-yl)methyl)cyclohexanol A solution of 5-(4-phenoxyphenyl)-7-(1-oxaspiro[2.5]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.12 mmol) and 1-methylpiperazine (50 mg, 0.50 mmol) in MeOH (10 mL) was heated at 70° C. for 5 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by flash column chromatography (DCM:MeOH=10:1) to give the product (20 mg, 39% yield over two steps). LCMS: calculated exact mass=512.2; found [M+H] + (ESI)=512.8; 1H NMR(400MHz,CDCl3-d6)δ ppm:8.13(s,1H)7.48(d,J=8.55Hz,2H)7.39-7.45(m,2H)7.37(s,1H)7.13-7.19(m,1H)7.09(d,J=8.55Hz,4H)6.12(br.s.,1H)4.53 (t,J=12.21Hz,1H)4.11(s,1H)2.54(br.s.,3H)2.35(br.s.,4H)2.26(s,3H)2.08-2.20(m,5H)1.63-1.79(m,4H)1.49-1.63(m,2H).

[0230] Example 101 1-((1H-imidazol-1-yl)methyl)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanol [ka] 1-((1H-imidazol-1-yl)methyl)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanol A solution of 5-(4-phenoxyphenyl)-7-(1-oxaspiro[2.5]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.10 mmol), 1H-imidazole (27 mg, 0.40 mmol), and K2CO3 (50 mg, 0.40 mmol) in DMF (5 mL) was heated at 100 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in DCM, washed with water, dried over Na2SO4, concentrated, and purified by preparative TLC (DCM:MeOH = 10:1) to give the product (10 mg, 20.8% yield). LCMS: calculated exact mass = 480.2; found [M+H] + (ESI)=480.8; 1H NMR(400MHz,CDCl3-d6)δ ppm:8.05(s,1H)7.60(s,1H)7.33-7.43(m,4H)7.32(s,1H)7.08-7.16(m,2H)7.01(d,J=7.63Hz,2H)7.04(d,J=8.54Hz,3H)6 .89(s,1H)4.5(s,3H)3.94(s,2H)1.87-2.07(m,3H)1.73(d,J=11.29Hz,2H)1.60(t,J=12.05Hz,2H)1.50(d,J=12.51Hz,3H).

[0231] Example 102 1-((1H-Tetrazol-1-yl)methyl)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanol [ka] 1-((1H-Tetrazol-1-yl)methyl)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanol A solution of 5-(4-phenoxyphenyl)-7-(1-oxaspiro[2.5]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.12 mmol), 1H-tetrazole (34 mg, 0.48 mmol), and K2CO3 (66 mg, 0.48 mmol) in DMF (5 mL) was heated at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in DCM, washed with water, dried over Na2SO4, concentrated, and purified by preparative TLC (DCM:MeOH = 10:1) to give the product (3 mg, 5% yield). LCMS: calculated exact mass = 482.2; found [M+H] + (ESI)=482.8; 1H NMR(400MHz, methanol-d4)δ ppm:9.07(s,1H)8.05(s,1H)7.37(d,J=8.85Hz,2H)7.28(t,J=7.93Hz,2H)7.17(s,1H)7.04(t,J=7.48Hz,1H)6.96(d,J=7.93Hz,2H)6.99( d,J=8.85Hz,2H)4.58(t,J=12.66Hz,1H)4.45(s,2H)1.99-2.14(m,3H)1.92(s,1H)1.84(s,2H)1.67-1.83(m,4H)1.58(d,J=13.12Hz,3H).

[0232] Example 103 3-(2-Fluoro-4-phenoxyphenyl)-1-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka] 3-(2-Fluoro-4-phenoxyphenyl)-1-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine A 500 mL round-bottom flask was charged with 3-iodo-1-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 g, 56.6 mmol), 2-(2-fluoro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21.35 g, 67.9 mmol), Pd(dppf)Cl (4.14 g, 5.6 mmol), NaCO (24 g, 226.5 mmol), and dioxane-water (9-1, 300 mL). The reaction was stirred at 85 °C overnight. It was cooled to room temperature, filtered, concentrated, and the crude was purified by flash column chromatography (MeOH in DCM, gradient 0-15%) to give the product as a white solid (15 g), which was further purified by preparative HPLC (acetonitrile-water gradient containing 0.1% TFA). After lyophilization, the product was obtained as a white powder (10.3 g, 41.2% yield). LC-MS: calculated exact mass: 501.27; found [M+H] + (ESI)=502.32; 1 H NMR(400MHz,DMSO-d6)δ ppm:8.32(s,1H),7.54(t,J=8.6Hz,1H),7.45-7.51(m,2H),7.22-7.29(m,1H),7.15-7.22(m,2H),7.03(dd,J=11.3,2.4Hz,1H),6.96(dd, J=8.5,2.4Hz,1H),4.75(dd,J=9.8,4.8Hz,1H),3.51(br.s.,4H),3.18(br.s.,5H),2.82(s,3H),1.98-2.24(m,6H),1.69(d,J=6.6Hz,2H).

[0233] Using similar procedures, the following compounds can be prepared: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15]

[0234] [ka] 4-chloro-5-(3-methoxy-4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-5-iodo-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 1.9 mmol), 2-(3-methoxy-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 3.98 mmol), Pd(dppf)Cl (140 mg, 0.19 mmol), and NaCO (600 mg, 5.7 mmol) in dioxane-HO (50 mL-5 mL) was heated at 80 °C for 3 h under an inert atmosphere. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography (EA in PE, gradient 0-33%) to give the product as a brown solid (350 mg, 37% yield).

[0235] 5-(3-Methoxy-4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A mixture of 4-chloro-5-(3-methoxy-4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.30 mmol) and NH3-HO (5 mL) in dioxane (5 mL) was heated at 120 °C for 16 h under microwave irradiation. After cooling to room temperature, the mixture was concentrated to give the title compound (170 mg, 100% yield). LC-MS: calculated exact mass: 472.5; found [M+H] + (ESI)=473.1.

[0236] 4-(4-amino-5-(3-methoxy-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone To a suspension of 5-(3-methoxy-4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (340 mg, 0.6 mmol) in acetone (20 mL) and THF (6 mL) was added 6N HCl (3 mL, 18 mmol). The reaction was heated at 40° C. for 3 h. Neutralized with 1N NaOH solution. Extraction with DCM, drying over sodium sulfate, evaporation, and purification by column chromatography (EA) afforded the desired product as a pale yellow solid (200 mg, 78% yield).

[0237] (S)-tert-Butyl 4-((trans)-4-(4-amino-5-(3-methoxy-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate A reaction mixture of 4-(4-amino-5-(3-methoxy-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (40 mg, 0.09 mol), (S)-tert-butyl 2-methylpiperazine-1-carboxylate (37 mg, 0.18 mol), and Ti(OiPr) (6 drops) in DCM (10 mL) was stirred at room temperature for 30 min. NaBH(OAc) (76 mg, 0.36 mol) was added. The reaction was stirred overnight at room temperature and then quenched with MeOH. Then, aqueous NaHCO and DCM were added. After filtration, the filtrate was extracted with DCM. The organic layer was collected and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to give the product (30 mg, 54% yield). LCMS: Calculated exact mass = 612.3; Actual value [M+H] + (ESI)=613.2.

[0238] Example 134 5-(3-Methoxy-4-phenoxyphenyl)-7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] To a solution of (S)-tert-butyl-4-((trans)-4-(4-amino-5-(3-methoxy-4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate (30 mg, 0.05 mmol) in DCM (10 mL) was added TFA (1 mL) dropwise. The reaction mixture was stirred at room temperature for 3 hours, then concentrated, and the residue was purified by preparative HPLC to give the product as a white solid (18 mg, 70% yield). LCMS: calculated exact mass = 512.2; found [M+H] + (ESI)=513.2; 1 H NMR(600MHz,DMSO-d6)δ ppm 8.14(s,1H)7.46-7.52(m,1H)7.33(t,J=7.78Hz,2H)7.19-7.23(m,1H)7.10(d,J=8.24Hz ,1H)7.01-7.08(m,2H)6.92(d,J=8.47Hz,2H)6.22(br.s.,1H)4.58(t,J=11.79Hz,1H)3.8 0(s,3H)3.20(d,J=11.22Hz,1H)3.12(br.s.,1H)2.85-3.00(m,3H)239(br.s.,1H)2.25(t ,J=10.99Hz,1H)1.98-2.05(m,2H)1.87-1.98(m,4H)1.44-1.58(m,2H)1.13-1.21(m,3H).

[0239] Example 135 (2S)-tert-butyl-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentyl)-2-methylpiperazine-1-carboxylate [ka] 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanol A 250 mL round-bottom flask was charged with 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 7.64 mmol), cyclopentane-1,3-diol (3.9 g, 38.2 mmol), triphenylphosphine (6.0 g, 22.9 mmol), and THF (50 mL). The mixture was stirred, and DEAD (3.98 g, 22.9 mmol) was added dropwise to the mixture in an ice bath. The resulting solution was stirred overnight at room temperature. The mixture was filtered, and the filter was concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with DCM-MeOH (100:1 to 10:1) to give the product as a brown solid (400 mg, 24% yield).

[0240] 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone A 100 mL round-bottom flask was charged with 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanol (316 mg, 0.92 mmol), PCC (236 mg, 1.1 mmol), and DCM (10 mL). The mixture was stirred overnight. The mixture was filtered, and the filter was concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with DCM-MeOH (100:1 to 20:1) to give the product as a white solid (100 mg, 31.8% yield).

[0241] 3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone A 100 mL round-bottom flask was charged with 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone (100 mg, 0.291 mmol), 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone (137 mg, 0.437 mmol), sodium carbonate (92.5 mg, 0.87 mmol), Pd(dppf)Cl2 (42.6 mg, 0.058 mmol, 0.2 equiv.), and dioxane-HO (10 mL-1 mL). The resulting mixture was stirred at 85 °C overnight. The mixture was filtered and the filter was concentrated. The residue was loaded onto a silica gel column and eluted with DCM / MeOH (50:1 to 20:1) to give the product (52 mg, 44% yield).

[0242] (2S)-tert-butyl-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentyl)-2-methylpiperazine-1-carboxylate To a 20 mL round-bottom flask were added 3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone (52 mg, 0.129 mmol), 1-methylpiperazine (25.8 mg, 0.258 mmol), and DCE (3 mL). The mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (41 mg, 0.193 mmol) was added to the mixture, and the mixture was then stirred at room temperature for 3 hours. The mixture was then filtered through Celite and concentrated. The residue was loaded onto a silica gel column and eluted with DCM-MeOH (50:1 to 10:1), then purified by preparative HPLC to give the product as a white solid (3.0 mg, 4.7% yield). LCMS: calculated exact mass = 487.25; found [M+H] + (ESI)=488.20; 1H NMR(CDCl3)δ ppm:8.32(s,1H),7.56(t,J=8.5Hz,1H),7.44(t,J=8.0Hz,2H),7.23(s,1H),7.12(d,J=7.7Hz,2H),6.96(dd,J=8. 5,2.2Hz,1H),6.86(dd,J=11.4,2.2Hz,1H),5.29-5.43(m,1H),3.13-3.39(m,8H),2.75(s,3H),2.08-2.56(m,7H).

[0243] [ka] tert-Butyl 7-((cis)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate and tert-Butyl 7-((trans)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate A reaction mixture of 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexanone (1.0 g, 2.81 mmol), tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (1.9 g, 8.43 mmol), and acetic acid (101 mg, 1.68 mmol) in THF (50 mL) was stirred at room temperature for 2 hours. NaBHCN (529 mg, 8.43 mol) was added. After stirring at room temperature for 3 hours, the mixture was quenched with MeOH (10 mL). Then, aqueous NaHCO and DCM were added, and the mixture was filtered. The filtrate was extracted with DCM. The organic layer was collected and concentrated. The residue was purified by column chromatography on silica (DCM:MeOH=10:1) to give tert-butyl 7-((trans)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (300 mg, 18% yield). LCMS: calculated exact mass=566.2; found [M+H]+ (ESI) = 567.0 and tert-butyl 7-((cis)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (330 mg, 21% yield). LCMS: calculated exact mass = 566.2; found [M+H] + (ESI)=567.0.

[0244] Example 136 7-((trans)-4-(2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] tert-Butyl 7-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate A mixture of tert-butyl 7-((trans)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (40 mg, 0.071 mmol), (4-phenoxyphenyl)boronic acid (18 mg, 0.085 mmol), Pd(dppf)Cl (15 mg, 0.013 mol), and NaCO (15 mg, 0.14 mmol) in dioxane (6 mL) and HO (0.6 mL) was heated at 85 °C for 2 h under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated and extracted with DCM (500 mL × 4). The organic layer was concentrated and purified by preparative TLC (DCM:MeOH=10:1) to give the product as a pale yellow solid (10 mg, 23% yield). LCMS: calculated exact mass=608.4; found [M+H] + (ESI)=609.1.

[0245] 7-((trans)-4-(2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl 7-((trans)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (20.0 mg, 0.03 mmol) in DCM (2 mL) was added TFA (1 mL) dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC to give the product as a white solid (3 mg, 17% yield). LCMS: calculated exact mass = 508.3; found [M+H] + (ESI)=509.1; 1 H NMR(400MHz,DMSO-d6)δ ppm:9.06(br.s.,2H)8.25(br.s.,1H)7.52(br.s.,1H)7.39-7.49(m,5H)7.23(s,2H )7.14-7.21(m,2H)7.07-7.14(m,6H)6.98(s,1H)5.33(t,J=4.63Hz,1H)4.58-4.63(m ,1H)3.57-3.62(m,6H)2.77(d,J=4.84Hz,1H)2.63-2.69(m,1H)2.31-2.37(m,1H)2.2 6(br.s.,1H)2.18(br.s.,2H)1.89-2.15(m,13H)1.77(br.s.,3H)1.41-1.51(m,2H).

[0246] Example 137 7-((cis)-4-(2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] tert-Butyl 7-((cis)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate A mixture of tert-butyl 7-((cis)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (450 mg, 0.80 mmol), (4-phenoxyphenyl)boronic acid (204 mg, 0.95 mmol), Pd(dppf)Cl (116 mg, 0.16 mmol), and NaCO (169 mg, 0.59 mmol) in dioxane (30 mL) and HO (3 mL) was heated at 85 °C for 2.5 h under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography (DCM:MeOH = 20:1) to give the product (20 mg, 4% yield). LCMS: Calculated exact mass = 608.4; Actual value [M+H] + (ESI)=609.1.

[0247] 7-((cis)-4-(2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl 7-((cis)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (20 mg, 0.033 mmol) in DCM (2 mL) was added TFA (1 mL) dropwise. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC to give the product as a white solid (2 mg, 12% yield). LCMS: calculated exact mass = 508.3; found [M+H] + (ESI)=509.1; 1H NMR(400MHz,DMSO-d6)δ 10.06(br.s.,2H),8.92(br.s.,2H),8.31(br.s.,1H),7.52(br.s.,1H),7.39-7.50(m,3H),7.18(t,J=7.3Hz,1H),7.04-7.16(m,3H) ),4.84(br.s.,1H),3.79(br.s.,2H),3.29(br.s.,5H),2.34(br.s.,2H),2.25(br.s.,2H),2.05(d,J=8.1Hz,4H),1.94(br.s.,3H).

[0248] [ka] Ethyl 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-4-carboxylate To an ice-bath-cooled suspension of ethyl 1H-pyrazole-4-carboxylate (1 g, 7.14 mmol) in THF (10 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (2.26 g, 14.3 mmol), PPh3 (3.75 g, 14.3 mmol), followed by dropwise addition of DEAD (2.49 g, 14.3 mmol) over 20 min. The reaction was stirred overnight at room temperature. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (EA in PE, gradient 0-20%) to give the desired product as a colorless oil (1.0 g, 50% yield).

[0249] Ethyl 1-(4-oxocyclohexyl)-1H-pyrazole-4-carboxylate To a suspension of ethyl 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-4-carboxylate (1 g, 3.57 mmol) in acetone (15 mL) was added 6 N HCl (15 mL, 9 mmol). The reaction was heated at 50 °C for 1 h. Neutralized with 1 N aqueous NaOH. Extraction with EA (100 mL × 2), washing with brine, drying over sodium sulfate, evaporation, and purification by column chromatography (EA in PE, gradient 0-30%) afforded the desired product as a colorless oil (470 mg, 56% yield).

[0250] Ethyl 1-((trans)-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate and Ethyl 1-((cis)-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate To a stirred mixture of ethyl 1-(4-oxocyclohexyl)-1H-pyrazole-4-carboxylate (470 mg, 1.99 mmol) in MeOH (15 mL) was added NaBH (91 mg, 2.39 mmol). After stirring for 1 h, the mixture was concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with DCM (20 mL). The organic layer was concentrated in vacuo to give a mixture of ethyl 1-((trans)-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate and ethyl 1-((cis)-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate as a colorless oil (400 mg, 84% yield).

[0251] Ethyl 1-((trans)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate and Ethyl 1-((cis)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate To an ice-bath cooled suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (240 mg, 0.924 mmol) in THF (5 mL) was added a mixture of ethyl 1-((trans)-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate and ethyl 1-((cis)-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate (220 mg, 0.924 mmol), PPh3 (363 mg, 1.38 mmol), followed by the dropwise addition of DEAD (241 mg, 1.38 mmol) over 5 min. The reaction was stirred at room temperature overnight. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH in DCM, gradient 0-10%) to give the crude product (540 mg). The crude material was purified by preparative HPLC to give a mixture of ethyl 1-((trans)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate and ethyl 1-((cis)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate as a white solid (160 mg, 36% yield).

[0252] Ethyl 1-((trans)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate and Ethyl 1-((cis)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate A mixture of ethyl 1-((trans)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate and ethyl 1-((cis)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate (as a white solid) (50 mg, 0.104 mmol), (4-phenoxyphenyl)boronic acid (37 mg, 0.125 mmol), Pd(dppf)Cl (15 mg, 0.0208 mmol), and NaCO (33 mg, 0.312 mmol) in dioxane-HO (3 mL-0.3 mL) was heated at 85 °C overnight under an inert atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo and purified by preparative HPLC to give ethyl 1-((trans)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate as a white solid (20 mg, 37% yield). LC-MS: Calculated exact mass: 523.2. Found: [M+H]. + (ESI) = 524.1 and ethyl 1-((cis)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate (as a white solid) (6 mg, 11% yield) LC-MS: Calculated exact mass: 523.2 Found: [M+H] + (ESI)=524.1.

[0253] Example 138 (1-((trans)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)methanol [ka] To a stirred mixture of ethyl 1-((trans)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-1H-pyrazole-4-carboxylate (15 mg, 0.0287 mmol) in THF (2 mL) cooled in an ice bath was added LAH (2 mg, 0.0574 mmol). The mixture was purged with N. After stirring for 2 h, LAH (10 mg, 0.263 mmol) was added to the mixture. After TLC monitoring and complete disappearance of the starting material, the mixture was quenched with HO (2 mL) and extracted with DCM (5 mL). The organic layer was concentrated under vacuum and purified by preparative HPLC to give the title compound as a white solid (3 mg, 21.7% yield). LC-MS: calculated exact mass: 481.2; found [M+H] + (ESI)=482.1; 1 H NMR(400MHz,CDCl3)δ 11.55(s,1H),8.25(s,1H),7.58(d,J=10.9Hz,3H),7.42(t,J=7.8Hz,2H),7.22(t,J=7.4Hz,1H),7.16(d,J=7.9Hz,2H),7.10(d,J=7 .9Hz,2H),6.26(s,1H),5.05(s,1H),4.63(s,2H),4.47(s,1H),2.61(s,2H),2.44(s,2H),2.14(dd,J=20.5,9.7Hz,4H),1.26(s,1H).

[0254] Example 139 N-(4-(4-amino-7-(4-(5-amino-1,3-dioxan-2-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-phenylpropanamide [ka] 5-Iodo-7-(4-(methoxymethylene)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of (methoxymethyl)triphenylphosphonium chloride (3451 mg, 11.231 mmol) in THF (15 mL) was added potassium tert-butanolate (1.26 g, 11.2 mmol) in THF (10 mL) dropwise over 30 minutes at 0° C. 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-one (2.0 g, 5.61 mmol) was added to the mixture, which was then stirred at room temperature overnight. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then filtered. The filtrate was concentrated to give the crude product. The crude product was purified by flash column chromatography (MeOH in DCM 0-3%) to give the product as a yellow solid (1.9 g, 88% yield). LCMS: calculated exact mass = 384.04; found [M+H] + (ESI)=385.61; 1 H NMR(DMSO-d6)δ ppm:8.08(s,1H),7.54(s,1H),6.59(br.s.,1H),5.95(s,1H),4.56-4.67(m,1H),3.51(s,3H),2.78 (d,J=11.3Hz,1H),2.14-2.24(m,1H),2.00-2.11(m,1H),1.89(t,J=12.1Hz,2H),1.68-1.79(m,3H).

[0255] 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carbaldehyde To a solution of 5-iodo-7-(4-(methoxymethylene)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1900 mg, 4.945 mmol) in THF (15 mL) was added 6N HCl (20 mL, 120 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. Then it was filtered, and the filtrate was adjusted to pH=10 and extracted with EtOAc (30 mL×3). The organic layer was dried with brine and anhydrous Na2SO4. Then it was concentrated to give the crude product as a yellow solid (1.15 g, 62.8% yield). LCMS: calculated exact mass=307.03; found [M+H] + (ESI)=307.6; 1H NMR(DMSO-d6)δ ppm:9.62(s,1H),8.44(s,1H),7.94(s,1H),4.57(br.s.,1H),2.37(br.s.,1 H),2.08(d,J=12.5Hz,2H),1.89-2.01(m,4H),1.41(dd,J=12.7,4.1Hz,2H).

[0256] tert-Butyl (2-(4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-1,3-dioxan-5-yl)carbamate A solution of 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carbaldehyde (1.1 g, 2.97 mmol), tert-butyl (1,3-dihydroxypropan-2-yl)carbamate (5.68 g, 29.7 mmol), p-toluenesulfonic acid monohydrate (5.65 g, 29.7 mmol), and Na2CO3 (8.43 mg, 59.4 mmol) in chloroform (50 mL) was refluxed overnight. It was then cooled to room temperature and filtered. The solid was washed with DCM (10 mL × 3). The filtrate was concentrated, and the crude product was purified by flash column chromatography (MeOH in DCM 0.5–2.5%) to give the product as a white solid (350 mg, 21.7% yield). LCMS: Calculated exact mass = 543.13; Actual value [M+H] + (ESI)=543.7.

[0257] tert-Butyl (2-(4-(4-amino-5-(4-(3-phenylpropanamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-1,3-dioxan-5-yl)carbamate A 50 mL round-bottom flask was charged with tert-butyl (2-((trans)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-1,3-dioxan-5-yl)carbamate (150 mg, 0.27 mmol), 3-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (193 mg, 0.55 mmol), Pd(dppf)Cl (101 mg, 0.13 mmol), NaCO (143 mg, 0.82 mmol), and 10% water in 1,4-dioxane (5 mL). The mixture was stirred at 80 °C overnight. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The crude material was purified by flash column chromatography (MeOH in DCM 5-25%) to give the crude product as a yellow solid (150 mg, 80% yield). LCMS: calculated exact mass = 640.34; found [M+H] + (ESI)=640.81.

[0258] N-(4-(4-amino-7-(4-(5-amino-1,3-dioxan-2-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-phenylpropanamide To a solution of tert-butyl (2-((trans)-4-(4-amino-5-(4-(3-phenylpropanamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-1,3-dioxan-5-yl)carbamate (150 mg, 0.22 mmol) in DCM (5 mL) was added TFA (2 mL), and the mixture was stirred at room temperature for 40 min. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then concentrated, and the crude was purified by flash column chromatography (MeOH in DCM, 1-5%) and preparative HPLC (acetonitrile / water, 0.1% TFA) and lyophilized to give the title compound as a white solid (55 mg, 43% yield). LCMS: calculated exact mass = 540.28; found [M+H] + (ESI)=540.79;1 H NMR(DMSO-d6)δ ppm:10.10(s,1H),8.43(s,1H),8.19(br.s.,3H),7.70-7.77(m,3H),7.37-7.45(m, 2H),7.23-7.31(m,4H),7.20(d,J=6.7Hz,1H),4.53-4.67(m,1H),4.46(d,J=5.8Hz,1 H),3.94-4.05(m,3H),3.29(br.s.,1H),2.93(t,J=7.5Hz,2H),2.67(t,J=7.6Hz,2H) ,1.97(d,J=7.6Hz,4H),1.80-1.93(m,2H),1.67(br.s.,1H),1.30(d,J=11.0Hz,2H).

[0259] Benzyl 9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate [ka] Benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate A solution of 3-azaspiro[5.5]undecan-9-one hydrochloride (260 mg, 1.28 mmol) and triethylamine (0.4 mL, 3.19 mmol) in THF (40 mL) was stirred at room temperature for 10 minutes. The mixture was then cooled to 0°C, and benzyl carbonochloridate (0.4 mL, 2.55 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature for 12 hours. The reaction was diluted with ethyl acetate (120 mL), washed with water (50 mL), dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (PE:EA = 3:1) to give the product as a yellow solid (350 mg, 91.1% yield). LCMS: calculated exact mass = 301.2; found [M+H] + (ESI)=302.1.

[0260] Benzyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate A stirred solution of benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (350 mg, 1.16 mmol) in methanol (15 mL) maintained at 0° C. was treated with sodium borohydride (66.3 mg, 1.74 mmol). After 10 minutes, the reaction mixture was warmed to room temperature and stirred at this temperature for an additional 1.5 hours. The solvent was then removed under reduced pressure, and the resulting residue was partitioned between water (50 mL) and dichloromethane (50 mL). The separated aqueous phase was extracted with dichloromethane (50 mL), and the combined organic fractions were then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product as a colorless oil (400 mg, quantitative). LCMS: calculated exact mass = 303.2; found [M+H]+ (ESI) = 304.1; 1 H NMR(400MHz,chloroform-d)δ ppm:7.30-7.45(m,5H),5.14(s,2H),3.63-3.76(m,1H),3.43-3.50(m,4H),1.74-1.8 3(m,2H),1.65-1.73(m,2H),1.40-1.60(m,4H),1.35-1.40(m,2H),1.17-1.31(m,2H).

[0261] Benzyl 9-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate Diethyl azodicarboxylate (0.5 mL, 3.45 mmol) was added dropwise to a solution of triphenylphosphine (904.9 mg, 3.45 mmol) in tetrahydrofuran (15 mL) under ice cooling. The mixture was then allowed to warm to room temperature, and a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (338.5 mg, 1.21 mmol) and benzyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (350 mg, 1.21 mmol) in tetrahydrofuran (10 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The solvent was then evaporated. The residue was purified by flash chromatography (PE:EA = 3:1) to give the product as a yellow solid (260 mg, 39.9% yield). LCMS: Calculated exact mass = 564.1; Actual value [M+H]+(ESI) = 564.9.

[0262] Benzyl 9-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate A solution of benzyl 9-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate (240 mg, 0.43 mmol), (4-phenoxyphenyl)boronic acid (182.8 mg, 0.85 mmol), Pd(dppf)Cl (30.3 mg, 0.04 mmol), and sodium carbonate (135.8 mg, 1.28 mmol) in dioxane-water (27.5 mL, 10:1) was stirred at 80° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with ethyl acetate (120 mL), washed with water (200 mL) and brine (50 mL), dried over sodium sulfate, and concentrated. The crude was purified by flash column chromatography (PE:EA=3:1) to give the product as a yellow solid (220 mg, 85.3% yield). LCMS: calculated exact mass=606.2; found [M+H]+(ESI)=607.2.

[0263] Benzyl 9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate A mixture of benzyl 9-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 0.16 mmol), 1,4-dioxane (1.5 mL), and concentrated aqueous ammonia (1.5 mL) was reacted in a microwave reactor at 120° C. for 9 hours. The mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound as a yellow solid (70 mg, 72.8% yield). LCMS: Calculated exact mass = 587.3; Actual value [M+H]+(ESI) = 588.2.

[0264] Example 140 4-(9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecan-3-yl)butan-1-ol [ka] 4-(9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecan-3-yl)butan-1-ol A mixture of benzyl 9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate (70 mg, 0.12 mmol) and Pd / C (70 mg, 1.0 equivalent (w / w)) in tetrahydrofuran (10 mL) was stirred under a hydrogen atmosphere at room temperature for 12 hours. The solution was then filtered, concentrated, and purified by preparative TLC (DCM:MeOH=15:1) to give the product as a yellow solid (23 mg, 36.7% yield). LCMS: calculated exact mass=525.3; found [M+H]+(ESI)=526.2; 1H NMR(400MHz,chloroform-d)δ ppm:8.30(s,1H),7.33-7.53(m,4H),6.94-7.24(m,6H),5.25(br.s.,2H),4.66(t,J=11.6Hz,1H),3.64(t,J=5.2 Hz,2H),2.78(br.s.,4H),2.69(t,J=6.0Hz,2H),1.77-2.05(m,10H),1.61-1.76(m,4H),1.44(t,J=12.1Hz,2H).

[0265] Example 141 5-(4-phenoxyphenyl)-7-(3-azaspiro[5.5]undecan-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] 5-(4-phenoxyphenyl)-7-(3-azaspiro[5.5]undecan-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of benzyl 9-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-azaspiro[5.5]undecane-3-carboxylate (50 mg, 0.09 mmol) in dichloromethane (10 mL) was cooled to 0° C. Then, boron tribromide (1.0 mL, 1.0 M in dichloromethane) was added dropwise. After the addition, the mixture was continued to stir at 0° C. for 0.5 h. The reaction was quenched with methanol (2 mL), concentrated, and purified by preparative TLC (DCM:MeOH=15:1) to give the product as a yellow solid (36 mg, 93.2% yield). LCMS: calculated exact mass=453.3; found [M+H]+(ESI)=454.2; 1H NMR(400MHz,DMSO-d6)δ ppm:8.47(br.s.,2H),8.14(s,1H),7.56(s,1H),7.37-7.51(m,4H),7.05-7.22(m,5H),6.14(br.s.,2H),4.51-4.66(m, 1H),3.08(br.s.,4H),1.96-2.14(m,2H),1.82-1.93(m,4H),1.75(d,J=9.9Hz,2H),1.54(br.s.,2H),1.32-1.46(m,2H).

[0266] Example 142 7-(3-methyl-3-azaspiro[5.5]undecan-9-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] 7-(3-methyl-3-azaspiro[5.5]undecan-9-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of 5-(4-phenoxyphenyl)-7-(3-azaspiro[5.5]undecan-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 mg, 0.04 mmol), formaldehyde (7.9 mg, 0.26 mmol), acetic acid (2.4 mg, 0.04 mmol), and molecular sieves (300 mg) in dichloroethane / methanol (5 mL / 2 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (55.1 mg, 0.26 mmol) was then added, and stirring was continued at room temperature for 16 hours. Water (50 mL) and dichloromethane (50 mL) were added to the reaction mixture, and saturated aqueous sodium bicarbonate (25 mL) was then added, and the mixture was then heated. The organic layer was washed with brine (25 mL), dried over sodium sulfate, concentrated, and purified by preparative TLC (DCM:MeOH=15:1) to give the title compound as a white solid (9 mg, 43.7% yield). LCMS: calculated exact mass=467.3; found [M+H]+(ESI)=468.2; 1H NMR(400MHz,DMSO-d6)δ ppm:8.13(s,1H),7.56-7.61(m,1H),7.37-7.52(m,4H),7.04-7.22(m,5H),6.13(br.s.,1H),4.59 (t,J=12.1Hz,1H),2.95-3.20(m,4H),2.71(s,3H),2.01(d,J=12.2Hz,2H),1.75(d,J=11.0Hz,2H).

[0267] Example 143 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-4-methylmorpholin-3-one and Example 144 7-(4-(4-methylmorpholin-2-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] 2-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-4-methylmorpholin-3-one To a solution of 4-methylmorpholin-3-one (1.88 g, 16.3 mmol) in THF (20 mL) was added LDA (2 mmol / L, 19.6 mmol, 9.8 M) under a N atmosphere at −78 °C. The reaction was then stirred at −78 °C for 60 min. After that, 1,4-dioxaspiro[4.5]decan-8-one (92.5 g, 16.3 mmol) in THF (10 mL) was added dropwise at −78 °C. The reaction was slowly warmed to room temperature and stirred at 20 °C for 2 h. Consumption of the starting material was detected by LC-MS and TLC. It was quenched with saturated NH Cl solution (20 mL) and extracted with EA (30 mL × 3). The organic layer was washed with brine (40 mL), dried over Na SO , and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with DCM-MeOH (200 / 1 to 50 / 1) to give the desired product as a yellow solid (2.8 g, 64% yield). LC-MS: calculated exact mass = 271.14; found [M+H] + (ESI)=272.1; 1 H NMR(400MHz,chloroform-d)δ ppm:4.06(dd,J=4.16,11.69Hz,1H),3.95-4.01(m,4H),3.93(s,1H),3.75-3.84(m,1H),3.65(dt,J=4.43,11.75Hz,1H), 3.13(dd,J=2.82,11.95Hz,1H),1.97-2.20(m,3H),1.88(dt,J=4.03,13.43Hz,1H),1.54-1.65(m,3H),1.42-1.50(m,1H).

[0268] 4-Methyl-2-(4-oxocyclohexylidene)morpholin-3-one To a solution of 2-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-4-methylmorpholin-3-one (2.3 g, 8.5 mmol) and TEA (17.2 g, 170 mmol) in DCM (30 mL) was added POCl (13.0 g, 85 mmol) at 0 °C under a N atmosphere. The reaction was then stirred at 20 °C for 6 h. The reaction was monitored by LC-MS and TLC until the starting material was consumed. The reaction was quenched with ice water (20 mL) and extracted with DCM (30 mL × 3). The organic layer was washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with PE-EA (5 / 1-1 / 1) to give the product as a colorless oil (1.0 g, 57% yield). LC-MS: Calculated exact mass = 209.11; Actual value [M+H] + (ESI)=210.1; 1 H NMR(400MHz,chloroform-d)δ ppm:4.08(t,J=5.04Hz,2H),3.50(t,J=5.04Hz,2H),3.32(t,J=6.87Hz,2H),3.00-3.09(m,3H),2.72(t,J=6.87Hz,2H),2.37-2.49(m,4H).

[0269] 4-Methyl-2-(4-oxocyclohexyl)morpholin-3-one To a solution of 4-methyl-2-(4-oxocyclohexylidene)morpholin-3-one (84 mg, 0.3 mmol) in THF (15 mL) was added Pd / C (100 mg, 10%). The reaction was then hydrogenated at 30 psi for 4 hours at 20° C. Consumption of the starting material was detected by LC-MS and TLC. Filtration and concentration in vacuo afforded the desired product as a pale yellow oil (1.0 g, 98% yield). LC-MS: calculated exact mass = 211.12; found [M+H] + (ESI)=212.1; 1H NMR(400MHz,chloroform-d)δ ppm:4.11(d,J=1.88Hz,1H),4.02(dd,J=3.76,11.82Hz,1H),3.78(dt,J=3.09,11.62Hz,1H),3.58-3.71(m,1H ),3.13(dd,J=2.55,11.95Hz,1H),2.99-3.05(m,3H),2.57-2.70(m,1H),2.31-2.48(m,4H),1.73-2.05(m,4H).

[0270] 2-(4-hydroxycyclohexyl)-4-methylmorpholin-3-one To a solution of the compound 4-methyl-2-(4-oxocyclohexyl)morpholin-3-one (0.5 g, 2.5 mmol) in THF (20 mL) was added NaBH (380 mg, 10 mmol) at 0 °C under a N atmosphere. The reaction was then stirred at 20 °C for 2 h. The reaction was monitored by LC-MS and TLC until the starting material was consumed. It was quenched with saturated NH Cl solution (20 mL) and extracted with DCM (30 mL × 5). The organic layer was washed with brine (20 mL), dried over Na SO and concentrated. The crude product was purified by flash column chromatography eluting with PE-EA (10 / 1-1 / 5) to give the product as a colorless oil (126 mg, 24% yield). LC-MS: calculated exact mass = 213.14; found [M+H] + (ESI)=214.1; 1 H NMR(400MHz,chloroform-d)δ ppm:3.97-4.02(m,2H),3.76(dt,J=2.55,11.48Hz,1H),3.45-3.67(m,2H),3.10(d,J =11.28Hz,1H),3.00(s,3H),1.93-2.18(m,3H),1.69-1.76(m,1H),1.22-1.57(m,5H).

[0271] 2-(4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-4-methylmorpholin-3-one To a solution of 2-(4-hydroxycyclohexyl)-4-methylmorpholin-3-one (84 mg, 0.3 mmol), 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (63 mg, 0.3 mmol), and PPh3 (236 mg, 0.9 mmol) in THF (12 mL) was added dropwise DIAD (182 mg, 0.9 mmol) at 0 °C under a N2 atmosphere. The reaction was then stirred at 20 °C for 16 h. Near consumption of the starting material was detected by LC-MS and TLC. The reaction was concentrated and purified by preparative TLC eluting with PE-EA (3:1) to give the desired product as a yellow solid (120 mg, 80% yield). LC-MS: calculated exact mass = 474.03; found [M+H]. + (ESI)=475.0.

[0272] 2-(4-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-4-methylmorpholin-3-one A suspension of the compound 2-(4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-4-methylmorpholin-3-one (150 mg, 0.3 mmol), (4-phenoxyphenyl)boronic acid (67 mg, 0.3 mmol), NaCO (102 mg, 0.9 mmol), and Pd(dppf)Cl (22 mg, 0.03 mmol) in THF and water (15 mL-3 mL) was stirred at 65 °C under a N atmosphere for 4 h. Near consumption of the starting material was detected by LC-MS and TLC. The reaction was concentrated and purified by flash column chromatography eluting with DCM-MeOH (100 / 1 to 20 / 1) to give the desired product as a yellow solid (130 mg, 84% yield). LC-MS: Calculated exact mass = 516.19; Actual value [M+H] + (ESI)=517.2; 1H NMR (400 MHz, chloroform-d) δ ppm: 8.63 (s, 1H), 7.63-7.71 (m, 3H), 7.52-7.59 (m, 2H), 7.43-7.51 (m, 6H), 7.33-7.41 (m, 3H), 6.95-7.18 (m, 6H), 4.94-5.04 (m, 1H), 4.17 (d, J = 4.03 Hz, 1H), 4.04 (td, J = 2.08, 9.81 Hz, 1H) ),3.77(dt,J=3.22,11.15Hz,1H),3.61(dt,J=4.30,11.28Hz,1H),3.16(d,J=11.82Hz,1H),3 .00(s,3H),2.45(d,J=4.57Hz,1H),2.18-2.35(m,2H),1.91-2.09(m,3H),1.77-1.90(m,2H).

[0273] 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-4-methylmorpholin-3-one To a solution of the compound 2-(4-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-4-methylmorpholin-3-one (130 mg, 0.25 mmol) in 1,4-dioxane (5 mL) was added NH3·H2O (8 mL) in a sealed tube. The reaction was then stirred at 120 °C for 48 h. Near consumption of the starting material was detected by LC-MS and TLC. Extraction with EA (30 mL × 3), washing with brine (40 mL), drying over Na2SO4, concentration under vacuum, and purification by preparative TLC eluting with DCM / MeOH (20 / 1) gave the desired product as a yellow solid (100 mg, 80% yield). LC-MS: calculated exact mass = 497.24; found [M+H] + (ESI)=498.2; 1H NMR(400MHz, methanol-d4)δ ppm:8.29(s,1H),7.57(s,1H),7.47(d,J=8.60Hz,2H),7.32-7.40(m,2H ),7.02-7.16(m,5H),4.21(d,J=4.57Hz,1H),3.98-4.10(m,1H),3.70-3. 84(m,1H),3.52-3.66(m,1H),3.29-3.31(m,1H),3.22(d,J=12.09Hz,1H ),2.95(s,3H),2.21-2.43(m,3H),1.74-2.08(m,5H),1.49-1.65(m,1H).

[0274] 7-(4-(4-methylmorpholin-2-yl)cyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)-4-methylmorpholin-3-one (50 mg, 0.1 mmol) in THF (5 mL) was added LAH (2 mL) at 0 °C under a N atmosphere. The reaction was then stirred at 20 °C for 2 h. Consumption of the starting material was monitored by LC-MS and TLC. The reaction was quenched sequentially with saturated water (0.076 mL), NaOH (0.076 mL, 15%), and water (0.228 mL). NaSO was then added, and the mixture was stirred for 30 min. The mixture was filtered through Celite and washed with MeOH (20 mL). The filtrate was concentrated and purified by preparative HPLC to give the desired product as a white solid (10 mg, 10% yield). LC-MS: Calculated exact mass = 483.26; Actual value [M+H] + (ESI)=484.3; 1H NMR(600MHz, methanol-d4)δ ppm:8.30(s,1H),7.59(s,1H),7.49(d,J=8.59Hz,2H),7.39(t,J=8.01Hz,2H),7.16(t,J=7.43Hz,1H),7.12(d ,J=8.59Hz,2H),7.07(d,J=7.76Hz,2H),4.15(d,J=11.06Hz,1H),4.02-4.10(m,1H),3.87(t,J=12.39Hz,1H), 3.70(d,J=12.06Hz,1H),3.45(d,J=12.22Hz,1H),3.32-3.33(m,1H),3.09(t,J=10.82Hz,1H),2.94(s,3H),2. 87(t,J=11.48Hz,1H),2.08-2.25(m,3H),1.93(dt,J=4.38,8.30Hz,2H),1.80-1.87(m,3H),1.65-1.76(m,1H).

[0275] [ka] 2-Hydroxypropane-1,3-diyl dibenzoate To a solution of 2-oxopropane-1,3-diyldibenzoate (2.5 g, 8.4 mmol) in THF (50 mL) was added NaBH (352 mg, 9.6 mmol) at 0 °C and stirred at 0 °C for 10 min. The reaction was monitored by TLC until the starting material was consumed. It was quenched with NH Cl solution and extracted with EA. The organic layer was washed with brine (40 mL), dried over Na SO and concentrated. The crude was purified by flash column chromatography (PE:EA = 10:1 to 3:1) to give the desired product as a colorless oil (1.8 g, 75.6% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm:8.00(d,J=7.25Hz,4H),7.61-7.73(m,2H),7.45-7.56(m,4H),5.57(d,J=5.64Hz,1H),4.32-4.44(m,4H),4.15-4.25(m,1H).

[0276] 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diyl dibenzoate To a solution of 2-hydroxypropane-1,3-diyldibenzoate (1.4 g, 5 mmol), 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.8 g, 6 mmol), and PPh3 (3.93 g, 15 mmol) in THF (40 mL) was added DEAD (2.61 g, 15 mmol) dropwise at 0 °C under a N2 atmosphere. The reaction was then stirred at 20 °C for 18 h. The reaction was concentrated, and the crude material was purified by preparative TLC eluting with PE / EA (100 / 1 to 3 / 1) to give the desired product as a white solid (2 g, 71% yield). LC-MS: calculated exact mass = 561.00; found [M+H]. + (ESI)=562.0.

[0277] 2-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diyl dibenzoate A suspension of 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diyldibenzoate (2.2 g, 3.9 mmol), (4-phenoxyphenyl)boronic acid (1.0 g, 4.7 mmol), NaCO (2.48 g, 23.4 mmol), and Pd(dppf)Cl (571 mg, 0.78 mmol) in THF and water (30 mL-6 mL) was stirred at 65 °C under a N atmosphere for 3 h. The reaction was concentrated, and the crude material was purified by flash column chromatography (PE:EA = 20:1 to 3:1) to give the desired product as a yellow solid (2.0 g, 85% yield). LC-MS: calculated exact mass = 603.16; found [M+H]. + (ESI)=604.2.

[0278] 2-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diol To a solution of 2-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diyldibenzoate (2 g, 3.3 mmol) in 1,4-dioxane (30 mL) was added NH₃·H₂O (30 mL) in a sealed tube. The reaction was then stirred at 120°C for 60 h. The reaction mixture was extracted with EA (30 mL × 3). The organic layer was washed with brine (40 mL), dried over Na₂SO₄, and concentrated. The crude was purified by preparative TLC (DCM:MeOH = 100:1 to 10:1) to give the desired product as a yellow solid (750 mg, 60% yield). LC-MS: Calculated exact mass = 376.15; Actual value [M+H] + (ESI)=377.2; 1 H NMR(400MHz,DMSO-d6)δ ppm:8.13(s,1H),7.47(d,J=8.53Hz,2H),7.41(t,J=7.91Hz,2H),7.32(s,1H),7.16(t,J =7.40Hz,1H),7.07-7.13(m,4H),5.93(br.s.,2H),4.69-4.90(m,3H),3.84(br.s.,4H).

[0279] 5-(4-phenoxyphenyl)-7-((2r,5r)-2-(piperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and 5-(4-phenoxyphenyl)-7-((2s,5s)-2-(piperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A suspension of 2-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane-1,3-diol (50 mg, 0.13 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (360 mg, 1.69 mmol), TSOH·HO (321 mg, 1.69 mmol), and NaSO (1.85 g, 13 mmol) in CHCl (15 mL) was stirred at reflux under a N atmosphere for 48 h. The reaction was quenched with NaCO solution (40 mL) and extracted with EA (40 mL × 3). The organic layer was washed with brine (40 mL), dried over NaSO, and concentrated. The crude was purified by preparative TLC (PE:EA=10:1) and preparative HPLC to give 5-(4-phenoxyphenyl)-7-((2r,5r)-2-(piperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 mg, 16% yield). LC-MS: calculated exact mass=471.23; found [M+H]. + (ESI)=472.1; 1 H NMR(600MHz, methanol-d4)δ ppm8.26(s,1H),7.84(s,1H),7.50(d,J=8.47Hz,2H),7.40(t,J=7.90Hz,2H),7.17(t,J=7.44Hz,1H),7.13(d ,J=8.47Hz,2H),7.08(d,J=8.01Hz,2H),4.83-4.84(m,1H),4.74(d,J=4.58Hz,1H),4.38-4.46(m,2H),4.31(d , J = 12.59 Hz, 2H), 3.41 (d, J = 12.36 Hz, 2H), 2.98 (t, J = 12.02 Hz, 2H), 2.01-2.08 (m, 3H), 1.57-1.72 (m, 2H); and 5-(4-phenoxyphenyl)-7-((2s,5s)-2-(piperidin-4-yl)-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg, 8% yield). LC-MS: calculated exact mass = 603.16; found [M+H]. + (ESI)=472.1; 1H NMR(600MHz, methanol-d4)δ ppm8.34(s,1H),7.55(s,1H),7.48(d,J=8.47Hz,2H),7.39(t,J=7.90Hz,2H),7.16(t,J=7.32Hz,1H),7.12(d, J=8.47Hz,2H),7.07(d,J=8.01Hz,2H),5.08(td,J=5.52,10.70Hz,1H),4.65(d,J=4.35Hz,1H),4.30-4.35(m, 2H), 4.22-4.29 (m, 2H), 3.43 (d, J=12.59 Hz, 2H), 2.96-3.06 (m, 2H), 1.95-2.12 (m, 3H), 1.62-1.74 (m, 2H); and tert-butyl 4-(5-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,3-dioxan-2-yl)piperidine-1-carboxylate.

[0280] Example 145 7-((2r,5r)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine and Example 146 7-((2s,5s)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] To a solution of tert-butyl 4-(5-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,3-dioxan-2-yl)piperidine-1-carboxylate (130 mg, 0.28 mmol) in THF (5 mL) was added LAH (2 mL, 2 mmol) at 0° C. under a N atmosphere. The reaction was then stirred at 20° C. for 16 h. The reaction was quenched sequentially by adding saturated water (0.076 mL), NaOH (0.076 mL, 15%), and water (0.228 mL). NaSO was then added, and the mixture was stirred for 30 min. It was filtered through Celite and washed with MeOH. The filtrate was concentrated. The crude was purified by preparative HPLC to give: 7-((2r,5r)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (15 mg, 11% yield). LC-MS: calculated exact mass = 471.23; found [M+H] + (ESI)=486.2; 1 H NMR (600MHz, methanol-d4)ppm:8.33(s,1H),7.92(s,1H),7.50(d,J=8.47Hz,2H),7.40(t,J=7.90Hz,2H),7.17(t,J=7.44Hz,1H),7.14( d,J=8.47Hz,2H),7.09(d,J=8.24Hz,2H),4.92(br.s.,1H),4.75(d,J=4.58Hz,1H),4.42(d,J=12.36Hz,2H),4.31(d,J=12.36Hz,2H) , 3.53 (d, J = 12.36 Hz, 2H), 2.97 (t, J = 12.13 Hz, 2H), 2.83 (s, 3H), 2.08 (d, J = 13.96 Hz, 2H), 1.98 (ddd, J = 3.89, 8.35, 16.14 Hz, 1H), 1.65-1.75 (m, 2H); and 7-((2s,5s)-2-(1-methylpiperidin-4-yl)-1,3-dioxan-5-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10 mg, 7%) LC-MS: calculated exact mass = 471.23; found [M+H] + (ESI)=486.2; 1H NMR (600MHz, methanol-d4)ppm:8.34(s,1H),7.56(s,1H),7.48(d,J=8.47Hz,2H),7.39(t,J=7.78Hz,2H ),7.17(t,J=7.44Hz,1H),7.12(d,J=8.47Hz,2H),7.07(d,J=8.24Hz,2H),5.05-5.14(m,1H),4.66(d ,J=4.35Hz,1H),4.30-4.35(m,2H),4.23-4.29(m,2H),3.55(d,J=12.36Hz,2H),3.00(t,J=12.13Hz, 2H),2.86(s,3H),2.09(d,J=14.42Hz,2H),1.97(tdd,J=3.98,8.13,12.07Hz,1H),1.66-1.77(m,2H).

[0281] 5-Iodo-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] tert-Butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate To an ice-bath cooled suspension of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (50 g, 179 mmol) in THF (900 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (54.1 g, 29 mmol), PPh3 (78 g, 448 mmol), followed by dropwise addition of DEAD (117.4 g, 448 mmol) over 60 min. The reaction was stirred overnight at room temperature. The mixture was evaporated. The residue was diluted with EA (900 mL). The solid thus obtained was collected by filtration. Drying under reduced pressure gave the title compound (35 g, 42% yield).

[0282] tert-Butyl 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (25 g, 54.1 mmol) in dioxane (200 mL) and NH3-H2O (200 mL) was reacted in a sealed vessel at 120 °C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated to give the product as a pale yellow solid (20 g, 84% yield). LCMS: calculated exact mass = 443.1; found [M+H] + (ESI)=443.6.

[0283] 5-Iodo-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl tert-butyl 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (15 g, 33.9 mmol) in DCM (80 mL) was added dropwise TFA (50 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and adjusted to pH 8 by adding 1 M sodium hydroxide. The solid formed was filtered to give the product as a white solid (12 g, 100% yield). LCMS: calculated exact mass = 343.0; found [M+H] + (ESI)=343.6.

[0284] 3-Iodo-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Method-1 [ka] tert-Butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate To an ice-bath cooled suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20.0 g, 76.6 mmol) in THF (600 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (38.5 g, 191.6 mmol), PPh3 (50.2 mg, 191.6 mmol), followed by dropwise addition of DEAD (33.4 g, 191.6 mmol) over 1 h. The reaction was stirred at room temperature for 3 h and monitored by LCMS until complete conversion of the starting material. The reaction mixture was concentrated. The crude was washed with THF (100 mL), then EtOAc (250 mL), and filtered to give the product (11.1 g, 32% yield). LCMS: calculated exact mass = 444.1; found [M+H] + (ESI)=445.0.

[0285] 3-Iodo-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a solution of tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (11.1 g, 25.0 mmol) in DCM (100 mL) was added TFA (25 mL) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by column chromatography on silica (DCM:MeOH=10:1) to give the product (7.5 g, 87% yield). LCMS: calculated exact mass=344.0; found [M+H] + (ESI)=344.9.

[0286] Method-2 [ka] tert-Butyl 4-(4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate Diethyl azodicarboxylate (16.8 mL, 106.97 mmol) was added dropwise to a solution of triphenylphosphine (28.1 g, 106.97 mmol) in tetrahydrofuran (200 mL) under ice cooling. The mixture was then allowed to warm to room temperature, and a solution of 4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (10 g, 35.66 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (9.3 g, 46.35 mmol) in tetrahydrofuran / dimethyl sulfoxide (150 mL / 50 mL) was added dropwise to the mixture. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (200 mL), washed with water (350 mL) and brine (300 mL), dried over sodium sulfate, concentrated, and purified by flash chromatography (PE:EA=3:1) to give tert-butyl 4-(4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a pink solid (2.4 g, 14% yield). LCMS: calculated exact mass=463.0; found [M+H] + (ESI)=463.6.

[0287] tert-Butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.4 g, 5.18 mmol), 1,4-dioxane (35 mL), and concentrated aqueous ammonia (35 mL) was heated in a pressure vessel at 120° C. for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was suspended in water (20 mL), filtered, and washed with water (10 mL) to give a white solid (2.0 g, 87% yield). LCMS: calculated exact mass = 444.1; found [M+H]+ (ESI) = 444.6.

[0288] 3-Iodo-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine A solution of tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.0 g, 4.50 mmol) in TFA-DCM (4 mL-4 mL) was stirred at room temperature for 0.5 hours. The mixture was concentrated to give the crude product, which was used in the next step without further purification. LCMS: calculated exact mass = 344.0; found [M+H] + (ESI)=344.6.

[0289] 5-(4-phenoxyphenyl)-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] tert-Butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate To an ice-bath cooled suspension of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 35.8 mmol) in THF (250 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (11 g, 53.7 mmol), PPh3 (21 mg, 82.3 mmol), followed by dropwise addition of DEAD (14.3 g, 82.3 mmol) over 1 h. The reaction was stirred at room temperature for 3 h and monitored by LCMS until complete conversion of the starting material. The reaction mixture was concentrated. The crude was washed with THF (100 mL) followed by EtOAc (250 mL) to give the product (9.3 g, 37% yield). LCMS: calculated exact mass = 462.0; found [M+H] + (ESI)=463.1.

[0290] tert-Butyl 4-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (8.9 g, 19.26 mmol), (4-phenoxyphenyl)boronic acid (8.2 g, 38.52 mmol), Pd(dppf)Cl (1.4 g, 1.93 mmol), and NaCO (4.1 g, 38.52 mmol) in dioxane (150 mL) and HO (15 mL) was heated at 85 °C for 3 h under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated and extracted with DCM (500 mL × 4). The organic layer was concentrated and purified by flash column chromatography (PE:EA = 6:1) to give the product as a pale yellow solid (6.2 g, 65% yield). LCMS: Calculated exact mass = 504.2; Actual value [M+H] + (ESI)=505.0.

[0291] tert-Butyl 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate A mixture of tert-butyl 4-(4-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (500 mg, 0.99 mmol) in dioxane (2.5 mL) and NH4OH (2.5 mL) was reacted in a microwave reactor at 120 °C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated to give the product as a pale yellow solid (450 mg, 93% yield). LCMS: calculated exact mass = 485.2; found [M+H] + (ESI)=486.0.

[0292] 5-(4-phenoxyphenyl)-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To a solution of tert-butyl 4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (960 mg, 1.98 mmol) in DCM (8 mL) was added dropwise TFA (8 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and 2 M sodium hydroxide was added thereto to adjust the pH to 8, and the mixture was extracted with DCM (15 mL x 2). The organic layer was concentrated to give the product as a white solid (890 mg). LCMS: calculated exact mass = 385.3; found [M+H] + (ESI)=386.3; 1 H NMR(400MHz,DMSO-d6)δ 8.95(d,J=10.7Hz,1H),8.68(d,J=9.8Hz,1H),8.50(s,1H),7.65(s,1H),7.51(d,J=8.5Hz,2H),7.41-7.47(m,2H),7. 07-7.22(m,5H),4.92-5.06(m,2H),3.48(d,J=12.5Hz,2H),2.23-2.36(m,2H),2.11-2.23(m,2H),2.02-2.11(m,3H).

[0293] Example 147 3-(2-Fluoro-4-phenoxyphenyl)-1-(1'-methyl-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka] 3-(2-Fluoro-4-phenoxyphenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine A mixture of 3-iodo-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.453 mmol), 2-(2-fluoro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (639 mg, 2.034 mmol), Pd(dppf)Cl (212 mg, 0.291 mmol), and NaCO (461 mg, 4.358 mmol) in dioxane-HO (8 mL-1 mL) was heated at 85 °C overnight under an inert atmosphere. After cooling to room temperature, the reaction mixture was concentrated and purified by flash column chromatography (MeOH in DCM, gradient 0-10%) to give the product as a semi-solid (300 mg, 51% yield).

[0294] 3-(2-Fluoro-4-phenoxyphenyl)-1-(1'-methyl-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a mixture of 3-(2-fluoro-4-phenoxyphenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.37 mol) and 1-methylpiperidin-4-one (126 mg, 1.11 mmol) in DCE (6 mL) was added 5 g of 4 Å molecular sieves and 10 mL of AcOH. The mixture was stirred at 50 °C under a N atmosphere for 50 min. After cooling to room temperature, NaBH(OAc) (157 mg, 0.74 mmol) was added in portions, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then filtered, concentrated, and purified by preparative TLC (15% MeOH in DCM) and preparative HPLC (acetonitrile / water, 0.1% TFA) to give the product (10 mg, 5.4% yield). LCMS: Calculated exact mass = 501.27; Actual value [M+H] + (ESI)=502.41; 1H NMR(DMSO-d6)δ ppm:10.01(br.s.,1H),8.29-8.35(m,1H),7.44-7.58(m,3H),7.25(t,J=7.4Hz ,1H),7.19(d,J=8.0Hz,2H),7.04(dd,J=11.3,2.1Hz,1H),6.96(dd,J=8.4,1.9H z,1H),5.13(br.s.,1H),4.39(br.s.,3H),3.59-3.67(m,4H),3.34(br.s.,2H) ,3.02(br.s.,2H),2.79(br.s.,3H),2.17-2.39(m,4H),1.94(d,J=10.0Hz,2H).

[0295] Example 148 1-(4-(4-amino-1-(1'-methyl-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea [ka] 3-iodo-1-(1'-methyl-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine A solution of 3-iodo-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.45 mmol) and 1-methylpiperidin-4-one (493.2 mg, 4.36 mmol) in tetrahydrofuran (60 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (923.8 mg, 4.36 mmol) was then added, and stirring was continued for 16 hours. The mixture was concentrated and diluted with DCM-MeOH (250 mL, 10:1). The solution was filtered, concentrated, and purified by flash chromatography (DCM-MeOH-NH3 (7.0 N in methanol): 100:10:1) to give the product as a brown solid (400 mg, 62% yield). LCMS: calculated exact mass = 441.1; found [M+H] + (ESI)=441.7.

[0296] 1-(4-(4-amino-1-(1'-methyl-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea A solution of 3-iodo-1-(1'-methyl-[1,4'-bipiperidin]-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.45 mmol), (4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)boronic acid (206 mg, 0.68 mmol), Pd(dppf)Cl (66 mg, 0.09 mmol), and sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was reacted in a microwave reactor at 80 °C for 1 hour under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated and purified by flash chromatography (DCM:MeOH:NH3 (7.0 N in methanol) = 100:10:1) to give a yellow solid (250 mg, 80% purity), which was further purified by preparative HPLC to give the title compound as a white solid (105 mg, 40% yield). LCMS: calculated exact mass = 572.3; found [M+H] + (ESI)=572.8; 1 H NMR(400MHz,DMSO-d6)δ ppm:9.71(s,2H),9.17(s,1H),8.30(s,1H),7.66(d,J=8.5Hz,1H),7.60(d,J=8.5Hz,2H),6.52(s,1H),5.11-5.25 (m,1H),3.35-3.72(m,9H),3.02(d,J=8.9Hz,2H),2.80(s,3H),2.22-2.33(m,4H),1.88-2.15(m,2H),1.30(s,9H).

[0297] Using similar procedures, the following compounds were prepared: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0298] Example 161 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)propane-1,3-diol [ka] 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)propane-1,3-diyl dibenzoate A solution of 5-(4-phenoxyphenyl)-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (800 mg, 2.07 mmol) and 2-oxopropane-1,3-diyldibenzoate (1.23 g, 4.15 mmol) in DCE (8 mL) was stirred at 50 °C for 2 h under a N atmosphere. After cooling to room temperature, NaBH(OAc) (1.3 g, 6.22 mmol) was added in portions, and the mixture was stirred overnight at room temperature under a N atmosphere. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. Then, it was filtered, and saturated NaHCO was added to the filtrate and extracted with DCM (30 mL × 3). The organic layer was dried over anhydrous NaSO and concentrated to give the crude product. The crude was purified by flash column chromatography (2-5% MeOH in DCM) to give the product as a white solid (150 mg, 10.8%). LCMS: calculated exact mass = 667.28; found [M+H] + (ESI)=667.71.

[0299] 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)propane-1,3-diol A solution of 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)propane-1,3-diyl dibenzoate (150 mg, 0.22 mmol) dissolved in 7.0 N NH3 / MeOH (10 mL) was stirred at 30 °C for 3 days. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then concentrated and purified by flash column chromatography (5-10% MeOH in DCM) to give the product as a white solid (75 mg, 72.5% yield). LCMS: calculated exact mass = 459.23; found [M+H] + (ESI)=459.8; 1 H NMR(DMSO-d6)δ ppm:8.13(s,1H),7.38-7.49(m,5H),7.13-7.19(m,1H),7.06-7.12(m,4H),6.12(br.s.,1H),4.55(t,J=12.1Hz,1H),4.29(br.s.,2 H),3.43-3.57(m,4H),2.97(d,J=10.7Hz,2H),2.67(t,J=11.4Hz,2H),2.55-2.62(m,1H),1.98-2.06(m,2H),1.87(d,J=10.7Hz,2H).

[0300] Example 162 7-(1-(2-(aminomethyl)-1,3-dioxan-5-yl)piperidin-4-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ka] 2-((5-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)-1,3-dioxan-2-yl)methyl)isoindoline-1,3-dione To a solution of 2-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)propane-1,3-diol (100 mg, 0.218 mmol) and 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (411 mg, 2.17 mmol) in chloroform (5 mL) was added anhydrous NaSO (927 mg, 6.53 mmol) and p-toluenesulfonic acid monohydrate (414 mg, 2.17 mmol). The mixture was refluxed overnight. Then it was cooled to room temperature, saturated NaHCO was added, and extracted with DCM (25 mL × 3). The organic layer was concentrated to give the crude product. The crude was purified by flash column chromatography (3-7% MeOH in DCM) to give the product as a white solid (30 mg, 21.8% yield). LCMS: calculated exact mass = 510.31; found [M+H] + (ESI)=511.3.

[0301] 7-(1-(2-(aminomethyl)-1,3-dioxan-5-yl)piperidin-4-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine A solution of 2-((5-(4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)-1,3-dioxan-2-yl)methyl)isoindoline-1,3-dione (30 mg, 0.048 mmol) in 7.0 N NH3 / MeOH (20 mL) was stirred at 30 °C overnight. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then concentrated and subjected to preparative TLC (MeOH:DCM=40:3) to give the product as a white solid (7 mg, 29% yield). LCMS: calculated exact mass=500.25; found [M+H] + (ESI)=500.81; 1H NMR(DMSO-d6)δ ppm:8.14(s,1H),7.40-7.52(m,5H),7.16(t,J=7.3Hz,1H),7.10(t,J=6.9Hz,4H), 6.14(br.s.,1H),4.76(d,J=5.5Hz,1H),4.59(br.s.,1H),4.13(br.s.,1H),3.70-3 .81(m,1H),3.58(d,J=6.7Hz,2H),3.49(d,J=11.9Hz,1H),3.17(s,3H),3.04(d,J= 10.4Hz, 1H), 2.89-2.98 (m, 2H), 2.57-2.73 (m, 1H), 1.88-2.10 (m, 4H), 1.75 (s, 1H).

[0302] 4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanone [ka] Ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-imidazole-5-carboxylate To a solution of NHOH-HCl (447 g, 6.42 mol) in water (700 mL), NaHCO (787 g, 9.41 mol) was added portionwise. Subsequently, 1,4-dioxaspiro[4.5]decane-8-carbonitrile (716 g, 4.28 mol) and EtOH (7 L) were added. The mixture was stirred at room temperature for 1 hour and then heated to 80 °C for 22 hours. It was then cooled to room temperature, and ethyl propiolate (660 g, 6.73 mol) was added. The reaction was heated to 80 °C for 7.5 hours. After cooling to room temperature, the reaction was filtered, and the filtrate was concentrated and extracted with EtOAc. The organic layer was washed with brine and concentrated to give an orange solid (1.4 kg). Diphenyl ether (7 kg) was added, and the reaction was heated to 200 °C for 2 hours. The mixture was cooled to room temperature, and PE (21 L) was added. After filtration, a black crude product (2 kg) was obtained, which was purified by flash column chromatography (EtOAc 100%) to give the product as a yellow solid (850 g, 62% yield). 1H NMR(400MHz,CDCl3)δ ppm:7.63(s,1H),4.34(q,J=7.1Hz,2H),3.90-4.02(m,5H),2.89(br.s.,1H),2.09(dd ,J=13.2,3.2Hz,2H),1.86(d,J=12.3Hz,3H),1.63-1.71(m,2H),1.36(t,J=7.1Hz,3H).

[0303] 7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-imidazole-5-carboxylate (312 g, 1.11 mol) in DMF (5 L) cooled in an ice bath, LiHMDS (1.0 M, 1.11 L, 1.11 mol) was added dropwise. The mixture was stirred for 2 hours, and then diphenylaminooxyphosphonate (260 g, 1.11 mol) was added. The reaction mixture was stirred overnight at room temperature. DCM was added, and the mixture was filtered. The filtrate was partially concentrated to give a DMF solution. Formamidine acetate (1.16 kg, 11.1 mol) and ethanol (5 L) were added. The reaction was heated to 85° C. under a N atmosphere for 2 days. The reaction was heated to 100° C. for 3.5 hours. The mixture was concentrated to give 1 kg of crude product, which was purified by flash column chromatography (MeOH in DCM, gradient 0-10%) to give the crude product as a pale yellow wax (255 g), which was used without further purification. LC-MS: Calculated exact mass: 276.12; Found [M+H] + (ESI)=277.1.

[0304] 5-Bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one To a solution of 7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (100 g, 0.362 mol) in DMF (1.25 L) cooled in an ice bath, NBS (77.3 g, 0.434 mol) was added portionwise. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. The reaction was quenched by adding 1 L of water. The solid was filtered and washed with water (200 mL x 3). The white solid was dried under reduced pressure to give a white powder product (98 g, 76.2% yield). LC-MS: calculated exact mass: 354.03; found [M+H] + (ESI)=355.13; 1 H NMR(400MHz,DMSO-d6)δ ppm:11.85(br.s.,1H),7.90(s,1H),3.83-3.92(m,4H),3.17(ddd,J=10.8 ,6.6,4.3Hz,1H),1.81-1.90(m,3H),1.73-1.81(m,3H),1.56-1.65(m,2H).

[0305] 5-Bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4-amine To a suspension of 1H-1,2,4-triazole (97 g, 1.4 mol) in ACN (1.5 L) cooled in an ice bath, POCl (64 g, 0.42 mol) was added dropwise, followed by EtN (170 g, 1.68 mol) and 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (50 g, 0.14 mol) at room temperature. The reaction was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure. NH in MeOH (7.0 N, 1 L) was added, and the reaction was heated to 80 °C for 1 hour and then left at room temperature overnight. It was filtered, and the residue was suspended in water and aqueous NaOH. After filtration, a pale yellow solid product (141 g, 82% yield) was obtained. LC-MS: Calculated exact mass: 353.05; Actual value [M+H] + (ESI)=354.2.

[0306] 5-(2-fluoro-4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4-amine A mixture of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4-amine (40 g, 0.11 mol), 2-(2-fluoro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (48 g, 0.127 mol), Pd(dppf)Cl (8 g, 0.011 mol), NaCO (35 g, 0.33 mol), and 700 mL of 1,4-dioxane (containing 10% water) was heated to 100 °C overnight. The mixture was cooled to room temperature, filtered, concentrated, and the residue was extracted with DCM and HO (1 L), dried, and concentrated. The crude material was purified by flash column chromatography (MeOH in DCM, gradient 0-2%) to give a yellow solid product (42 g, 81% yield). LC-MS: Calculated exact mass: 461.19; Actual value [M+H] + (ESI)=462.1.

[0307] 4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanone To a solution of 5-(2-fluoro-4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[5,1-f][1,2,4]triazin-4-amine (42 g, 0.091 mol) in acetone (400 mL) and THF (800 mL) was added 6N HCl (400 mL). The reaction was stirred at 40° C. for 5 hours. The mixture was cooled to room temperature and neutralized with aqueous NaOH. After concentration, the residue was extracted with DCM (300 mL×3). The organic layer was washed with water, dried, and concentrated. The crude was purified by flash column chromatography to give a yellow solid product (14 g, 36.8% yield). LC-MS: calculated exact mass: 417.16; found [M+H] + (ESI)=418.31.

[0308] Example 163 5-(2-Fluoro-4-phenoxyphenyl)-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine and Example 164 5-(2-fluoro-4-phenoxyphenyl)-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine [ka] A round-bottom flask was charged with 4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanone (150 mg, 0.36 mmol), 1-methylpiperazine (180 mg, 1.8 mmol), DCM (30 mL), and 4 Å molecular sieves. The mixture was stirred at room temperature for 15 minutes, and NaBH(OAc) (156 mg, 0.72 mol) was added portionwise. The reaction was stirred at room temperature for 3 hours. Additional NaBH(AcO) (156 mg, 0.72 mol) was added portionwise. The reaction was stirred at room temperature for 3.5 hours. The reaction was quenched with saturated aqueous NaHCO. It was then filtered and extracted with DCM. The organic layer was concentrated and the crude was purified by flash column chromatography (MeOH in DCM, 0-10%) to give: 5-(2-fluoro-4-phenoxyphenyl)-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine (as a pale yellow solid) (10 mg, 5.5% yield). LC-MS: calculated exact mass: 501.27; found [M+H]. + (ESI)=502.2; 1H NMR(DMSO-d6)δ ppm:7.89(s,1H),7.41-7.53(m,3H),7.15-7.25(m,3H),6.97(dd,J=11.1,2.4Hz,1H),6.91(dd,J=8.5,2.4 Hz,1H),3.12-3.20(m,1H),2.63-2.78(m,2H),2.60(br.s.,2H),2.53-2.57(m,1H),2.21-2.44(m,5H),1.94 -2.16 (m, 4H), 1.91 (br.s., 2H), 1.59-1.74 (m, 2H), 1.42 (br.s., 2H), 1.34 (d, J = 7.3 Hz, 1H); and 5-(2-fluoro-4-phenoxyphenyl)-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine (40 mg, 22% yield); 1 H NMR(400MHz,DMSO)δ 9.79(s,1H),8.16(s,1H),7.89(s,1H),7.54-7.43(m,3H),7.23(t,J=7.4Hz,1H),7.20-7.15(m,2H),6.96(ddd,J=10.8,9. 8,2.3Hz,2H),3.42(s,1H),2.99(s,4H),2.67(s,3H),2.27(d,J=47.5Hz,4H),2.13-1.93(m,4H),1.72(s,2H),1.59(s,2H).

[0309] Example 165 5-(2-Fluoro-4-phenoxyphenyl)-7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine and Example 166 5-(2-Fluoro-4-phenoxyphenyl)-7-((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine [ka] (S)-tert-Butyl 4-((trans)-4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate and (S)-tert-Butyl 4-((cis)-4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate To a mixture of 4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanone (250 mg, 0.60 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (250 mg, 1.2 mmol) in DCM (30 mL) was added 4A molecular sieves. The mixture was stirred at room temperature for 2 h, and then NaBH(OAc)3 (31.67 g, 0.50 mol) was added portionwise. The reaction was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3. It was then filtered and extracted with DCM. The organic layer was collected and concentrated. The crude product was purified by flash column chromatography (MeOH in DCM, gradient 0–5%) to give a mixture of two products as a white solid (300 mg, 83% yield). LC-MS: Calculated exact mass: 601.32; Actual value [M+H] + (ESI)=602.1.

[0310] 5-(2-Fluoro-4-phenoxyphenyl)-7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine and 5-(2-Fluoro-4-phenoxyphenyl)-7-((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine To a solution of (S)-tert-butyl 4-(4-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate (300 mg, 0.50 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 3 hours, after which it was concentrated. Saturated aqueous NaHCO3 and DCM were added and extracted. The organic layer was collected, dried, and concentrated. The crude material was purified by flash column chromatography (MeOH in DCM, gradient 0-10%) to give: 5-(2-fluoro-4-phenoxyphenyl)-7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine (25 mg, 10% yield). LC-MS: calculated exact mass: 501.27; found [M+H] + (ESI)=502.1; 1 H NMR(400MHz,DMSO-d6)δ ppm:8.31(br.s.,1H),7.89(s,1H),7.42-7.52(m,3H),7.15-7.26(m,3H),6.98(dd,J=11.1,2.4Hz,1H),6.9 2(dd,J=8.5,2.3Hz,1H),3.18(d,J=12.5Hz,3H),2.95(br.s.,3H),2.20-2.35(m,2H),2.08(d,J=12.9Hz,2H) , 1.89 (d, J = 9.6 Hz, 2H), 1.61-1.75 (m, 2H), 1.43 (d, J = 12.0 Hz, 2H), 1.19 (d, J = 6.5 Hz, 3H); and 5-(2-fluoro-4-phenoxyphenyl)-7-((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)imidazo[5,1-f][1,2,4]triazin-4-amine (150 mg, 60% yield): 1H NMR (400 MHz, DMSO) δ 8.74(s,1H),8.26(s,1H),7.89(s,1H),7.54-7.42(m,3H),7.23(t,J=7.4Hz, 1H),7.20-7.15(m,2H),6.96(ddd,J=10.9,9.8,2.4Hz,2H),5.76(s,1H),4.0 9(s,1H),3.44(s,1H),3.17(s,3H),3.07-2.90(m,3H),2.25(s,1H),2.05(d, J=11.4Hz,2H),1.92(s,2H),1.72(s,2H),1.59(s,2H),1.18(d,J=6.5Hz,3H).

[0311] 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-one [ka] 7-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (0.6 g, 2.82 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (0.9 g, 3.38 mmol), Pd(dppf)Cl (0.2 g, 0.28 mmol), and NaCO (0.9 g, 8.46 mmol) in 1,4 dioxane (containing 10% water) (50 mL) was stirred at 100 °C overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The crude material was purified by flash column chromatography (PE:EtOAc = 1:1) to give the product as a yellow solid (400 mg, 52% yield). LCMS: Calculated exact mass = 272.1; Actual value [M+H] + (ESI)=273.0.

[0312] 7-(1,4-Dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine To a mixture of 7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (400 mg, 1.47 mmol) in MeOH / EtOAc (100 mL) was added Pd (80 mg, 10% in activated carbon). The mixture was stirred overnight at room temperature under an H atmosphere. It was then filtered, and the filtrate was concentrated to give the product as a yellow solid (290 mg, 72% yield). LCMS: calculated exact mass = 274.1; found [M+H] + (ESI)=275.2.

[0313] 5-Bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine To a solution of 7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (290 mg, 1.06 mmol) in DCM (100 mL) was added NBS (226 mg, 1.27 mmol). The mixture was stirred at room temperature for 2.5 hours. The mixture was quenched with saturated aqueous NaHCO3, extracted with DCM, dried, and concentrated. The residue was purified by flash column chromatography (PE: EtOAc = 2:1) to give the product as a pale yellow solid (250 mg, 67%). LCMS: calculated exact mass = 352.0; found [M+H] + (ESI)=353.1.

[0314] 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (230 mg, 0.65 mmol), (4-phenoxyphenyl)boronic acid (418 mg, 1.95 mmol), Pd(dppf)Cl (95 mg, 0.13 mmol), and NaCO (276 mg, 2.6 mmol) in 1,4 dioxane (containing 10% water) (20 mL) was stirred at 100 °C overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The crude material was purified by flash column chromatography (PE: EtOAc = 1:1) to give the product as a yellow solid (125 mg, 42% yield). LCMS: calculated exact mass = 442.2; found [M+H] + (ESI)=443.1.

[0315] 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-one A mixture of 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (120 mg, 0.27 mmol) in THF (2 mL), acetone (5 mL), and 6.0 N HCl (1 mL) was stirred at room temperature for 4 hours. It was then quenched with aqueous NaOH, extracted with DCM, dried, and concentrated to give the crude product as a pale yellow solid (95 mg, 88% yield). LCMS: calculated exact mass = 398.2; found [M+H] + (ESI)=399.1.

[0316] 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone [ka] 7-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (1.6 g, 7.5 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (2.4 g, 9.0 mmol), Pd(dppf)Cl (550 mg, 0.75 mmol), and NaCO (2.4 g, 22.5 mmol) in dioxane-HO (50 mL-5 mL) was heated at 100 °C overnight under an Ar atmosphere. After cooling to room temperature, the reaction mixture was concentrated and extracted with DCM (200 mL × 4). The organic layer was concentrated. The crude product was purified by flash column chromatography (PE:EA = 1:1) to give the product (900 mg, 36.7% yield). LCMS: Calculated exact mass = 272.1; Actual value [M+H] + (ESI)=272.8.

[0317] 7-(1,4-Dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of 7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (900 mg, 3.3 mmol) and Pd / C (180 mg) in MeOH-EtOAc (200 mL) was hydrogenated overnight under a balloon. The reaction mixture was filtered through Celite and washed with (DCM / MeOH=10 / 1). The filtrate was concentrated to give the product as a pale yellow solid (900 mg, 99% yield). LCMS: calculated exact mass=274.1; found [M+H] + (ESI)=274.8.

[0318] 5-Bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine To a mixture of 7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (900 mg, 3.3 mmol) in DCM (200 mL) was added NBS (700 mg, 3.9 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with NaHCO3, extracted with DCM, dried, and concentrated to give the crude product (1.15 g), which was used without further purification. LCMS: calculated exact mass = 452.1; found [M+H] + (ESI)=452.8.

[0319] 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone To a suspension of 5-bromo-7-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.1 g, 3.1 mol) in THF (25 mL) and acetone (25 mL) was added 6N HCl (10 mL). The reaction was heated at 50 °C for 2 h. It was neutralized with aqueous NaHCO3, extracted with DCM, dried, and concentrated. The residue was purified by flash column chromatography (PE:EA = 1:1) to give the product (600 mg, 62.6% yield). LCMS: calculated exact mass = 308.0; found [M+H] + (ESI)=308.8.

[0320] [ka] 5-Bromo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and 5-Bromo-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone (200 mg, 0.67 mmol), 1-methylpiperazine (134 mg, 1.34 mmol), and titanium tetraisopropanolate (758 mg, 2.67 mmol) in DCM (30 mL) was stirred at room temperature. After stirring for 2 hours, sodium tris(acetoxy)borohydride (560 mg, 2.67 mmol) was added. It was stirred at room temperature for 16 hours and then diluted with DCM. NaHCO3 solution was then added. The mixture was filtered. The organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (DCM:MeOH=10:1) to give 5-bromo-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine as a white solid (80 mg, 30% yield) and 5-bromo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine as a light yellow solid (60 mg, 22% yield).

[0321] 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone [ka] 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone A mixture of tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone (60 mg, 0.19 mmol), (4-phenoxyphenyl)boronic acid (82 g, 0.38 mmol), Pd(dppf)Cl (14 mg, 0.019 mmol), and NaCO (41 mg, 0.38 mmol) in dioxane-HO (10 mL-1 mL) was heated at 85 °C for 2 h under an Ar atmosphere. After cooling to room temperature, the reaction mixture was concentrated and extracted with DCM (50 mL × 4). The organic layer was concentrated and purified by flash column chromatography (PE:EA = 6:1) to give the product as a pale yellow solid (60 mg, 79% yield). LCMS: calculated exact mass = 398.1; found [M+H] + (ESI)=398.9.

[0322] Example 167 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Example 168 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ka] A mixture of 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexan-1-one (90 mg, 0.22 mmol) and 1-methylpiperazine (110 mg, 1.1 mmol) in 1,2-dichloroethane (5 mL) containing 2 drops of AcOH was stirred at room temperature under a N atmosphere for 1 hour. NaBH(OAc) (370 mg, 1.76 mmol) was then added in portions. The mixture was stirred at room temperature under a N atmosphere for 3 hours. The reaction was monitored by TLC and LCMS until the starting material was completely consumed. It was then filtered, concentrated and the crude was purified by flash (MeOH in DCM 1-10%) to give: 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (as a colorless solid) (28 mg, 26% yield), LCMS: calculated exact mass = 442.2; found [M+H] + (ESI)=443.1; 1 H NMR(DMSO-d6)δ 7.89 (s, 1H), 7.38-7.51 (m, 4H), 7.17 (t, J = 7.3 Hz, 1H), 7.10 (dd, J = 7.9, 3.7 Hz, 4H), 6.54 (br.s., 1H), 2.67 (br.s., 3H), 2.32 (br.s., 5H), 1.88 (br.s., 5H), 1.75 (br.s., 3H), 1.58 (br.s., 2H)); and 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (as a colorless solid) (25 mg, 23% yield). LCMS: calculated exact mass = 442.2; found [M+H]. + (ESI)=443.1; 1H NMR(DMSO-d6)δ 7.89(s,1H),7.39-7.47(m,4H),7.17(t,J=7.3Hz,1H),7.09(t,J=8.4Hz,4H),6.50(s,1H),3.04(d,J=7.9Hz,1H),2 .58(br.s.,3H),2.33(br.s.,4H),2.18-2.28(m,4H),2.13(d,J=11.6Hz,3H),1.92(br.s.,2H),1.37-1.56(m,4H).

[0323] 7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ka] (S)-tert-Butyl 4-((trans)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate A reaction mixture of 4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanone (50 mg, 0.12 mol), (S)-tert-butyl-2-methylpiperazine-1-carboxylate (50 mg, 0.24 mol), and Ti(OiPr) (142 mg, 0.48 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. NaBH(OAc) (100 mg, 0.48 mol) was added. It was stirred at room temperature overnight and quenched with MeOH. Then, aqueous NaHCO and DCM were added, and it was filtered. The filtrate was extracted with DCM. The organic layer was collected and concentrated. The residue was purified by flash column chromatography (DCM:MeOH=10:1) to give (S)-tert-butyl 4-((trans)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate (25 mg, 36% yield). LCMS: calculated exact mass=582.3; found [M+H]+ (ESI) = 583.1; and (S)-tert-butyl 4-((cis)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate (as a white solid) (21 mg, 30% yield) LCMS: calculated exact mass = 582.3; found [M+H] + (ESI)=583.1.

[0324] Example 169 7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ka] 7-((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine To a solution of (S)-tert-butyl 4-((trans)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate (25 mg, 0.04 mmol) in DCM (10 mL) was added TFA (0.5 mL) dropwise. The reaction was stirred at room temperature for 3 hours, then concentrated and the residue purified by preparative HPLC to give the product as a white solid (18 mg, 93% yield). LCMS: calculated exact mass = 482.3; found [M+H] + (ESI)=483.1; 1H NMR (400MHz, methanol-d4)δppm 7.94(s,1H)7.41(d,J=8.54Hz,2H)7.31(t,J=7.93Hz,2H)7.08(t,J=7.32Hz,1H)7.00(d,J=7.93Hz,2H)7.04(d,J=8.55Hz,2H) 6.68(s,1H)3.55-3.68(m,4H)3.29-3.41(m,1H)2.99(t,J=12.05Hz,1H)2.12-2.29(m,4H)1.58-1.76(m,4H)1.30-1.36(m,3H).

[0325] Example 170 7-((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ka] 7-((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine To a solution of (S)-tert-butyl 4-((cis)-4-(4-amino-5-(4-phenoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)-2-methylpiperazine-1-carboxylate (21 mg, 0.04 mmol) in DCM (10 mL) was added TFA (0.5 mL) dropwise. The reaction mixture was stirred at room temperature for 4 hours. The mixture was evaporated, dissolved in DCM, and washed with NaHCO3 solution and water. The organic layer was dried and concentrated in vacuo to give the title compound as a pale yellow solid (16 mg, 82% yield). LC-MS: calculated exact mass: 482.3; found [M+H] + (ESI)=483.7; 1H NMR(400MHz,MeOD)δ8.03(s,1H),7.54(d,J=8.7Hz,2H),7.46-7.40(m,2H),7.20(t,J=7.4Hz,1H),7.13(dd,J=15.3,8.1Hz,4H),6.86(s ,1H),3.52(d,J=14.0Hz,6H),2.83(s,1H),2.74-2.62(m,1H),2.48(s,1H),2.18(s,2H),1.95(d,J=19.6Hz,7H),1.37(d,J=6.5Hz,3H).

[0326] Example 171 1-(4-(4-amino-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl))phenyl)-3-(5-(tert-butyl)furan-3-yl)urea and Example 172 1-(4-(4-amino-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(5-(tert-butyl)furan-3-yl)urea [ka] A mixture of 5-bromo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and 5-bromo-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.2 mmol), (4-(3-(5-(tert-butyl)furan-3-yl)ureido)phenyl)boronic acid (74 mg, 0.24 mmol), sodium carbonate (64 mg, 0.6 mmol), and Pd(dppf)Cl (30 mg, 0.04 mmol) in dioxane-HO (10 mL-1 mL) was heated at 100 °C for 3 h under an inert atmosphere. The reaction was concentrated in vacuo. The residue was dissolved in DCM, washed with water, dried, evaporated and purified by preparative TLC (DCM:MeOH=10:1) to give: 1-(4-(4-amino-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(5-(tert-butyl)furan-3-yl)urea (as a white solid) (5 mg, 4% yield). LC-MS: calculated exact mass: 571.3; found [M+H]. + (ESI)=572.3; 1 H NMR(400MHz,MeOD)δ 7.82(s,1H),7.61(d,J=8.5Hz,2H),7.45(d,J=8.5Hz,2H),6.52(s,1H),6.42(s,1H),3.20(s, 2H),2.78(d,J=65.6Hz,10H),2.42(s,3H),2.28(d,J=10.8Hz,3H),2.14(d,J=10.2Hz,2H),1. 68-1.50 (m, 5H), 1.38 (s, 10H); and 1-(4-(4-amino-7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(5-(tert-butyl)furan-3-yl)urea (as a white solid) (21 mg, 18% yield) LC-MS: calculated exact mass: 571.3; found [M+H] + (ESI)=572.3; 1H NMR(400MHz,MeOD)δ 7.70(s,1H),7.50(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),6.52(s,1H),6.30(s,1H), 3.37(s,1H),2.72(s,8H),2.40(s,4H),2.07(s,2H),1.82-1.67(m,6H),1.26(s,9H).

[0327] 8-chloro-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine and 8-chloro-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine [ka] N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide To a solution of 4-oxocyclohexanecarboxylic acid (0.7 g, 3.9 mmol) and TEA (1.1 mL, 7.8 mmol) in DCM (10 mL) was added HATU (1.77 g, 4.67 mL) and (3-chloropyrazin-2-yl)methanamine (1.77 g, 4.67 mmol). The reaction was stirred at room temperature for 18 h, then quenched with water (20 mL) and extracted with DCM (20 mL x 3). The organic layer was collected, washed with brine (20 mL), and dried over Na2SO4. After concentration, the crude was purified by flash column chromatography (EA 100%) to give the desired product as a yellow solid (680 mg, 65% yield). LCMS: calculated exact mass = 267.08; found [M+H] + (ESI)=268.0; 1H NMR(400MHz,DMSO-d6)δ ppm:8.63(d,J=2.42Hz,1H),8.50(t,J=5.24Hz,1H),8.44(d,J=2.42Hz,1H),4.53(d,J=5.37Hz,2H),2.72(tt,J =3.59,10.64Hz,1H),2.34-2.45(m,2H),2.23-2.33(m,2H),2.05(dd,J=3.76,13.16Hz,2H),1.73-1.88(m,2H).

[0328] N-((3-chloropyrazin-2-yl)methyl)-4-(4-methylpiperazin-1-yl)cyclohexanecarboxamide To a solution of N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (2.2 g, 8.1 mmol) and 1-methylpiperazine (1.2 g, 10.6 mmol) in DCM (30 mL) was added NaBHCN (1023 mg, 16.2 mmol) and AcOH (292 mg, 4.87 mmol) under a N atmosphere at 0 °C. The reaction was stirred at 20 °C for 3 h. The reaction was quenched with aqueous NaHCO (20 mL) and extracted with DCM (20 mL × 3). The organic layer was washed with brine (20 mL) and dried over NaSO. After concentration, the crude was purified by flash column chromatography (DCM:MeOH = 100:1 to 5:1) to give the desired product as a yellow solid (1.4 g, 60% yield). LCMS: Calculated exact mass = 351.18; Actual value [M+H] + (ESI)=352.0.

[0329] 8-chloro-3-(4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine To a solution of N-((3-chloropyrazin-2-yl)methyl)-4-(4-methylpiperazin-1-yl)cyclohexanecarboxamide (1.4 g, 4 mmol) in ACN (30 mL) was added DMI (1.37 g, 12 mmol) and POCl (2.5 g, 16 mmol) dropwise at 0 °C under a N atmosphere. The reaction was stirred under reflux for 3 h. It was carefully quenched with NH H O (20 mL) and ice and extracted with DCM (20 mL × 3). The organic layer was washed with brine (20 mL) and dried over Na SO . After concentration, the crude was purified by flash column chromatography (DCM:MeOH=100:1 to 10:1) to give 8-chloro-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (240 mg, 18% yield). LCMS: calculated exact mass=333.17; found [M+H]. + (ESI) = 334.1; and 8-chloro-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (340 mg, 25% yield) LCMS: calculated exact mass = 333.17; found [M+H] + (ESI)=334.1.

[0330] Example 173 3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine [ka] 1-Bromo-8-chloro-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine To a solution of 8-chloro-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (240 mg, 0.72 mmol) in DCM (10 mL) was added NBS (192 mg, 1.08 mmol) at 20 °C under a N atmosphere. The reaction was then stirred at reflux for 3 h. Consumption of the starting material was detected by LC-MS and TLC. The reaction was quenched with NaHCO (20 mL) and extracted with DCM (20 mL × 3). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the desired product as a yellow solid, which was used in the next step without further purification (300 mg, 98% yield). LCMS: calculated exact mass = 411.08; found [M+H] + (ESI)=412.1.

[0331] 1-Bromo-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-8-amine To a solution of 1-bromo-8-chloro-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (300 mg, 0.70 mmol) in 1,4-dioxane (10 mL) was added NH₃·HO (10 mL) in a sealed tube. The reaction was then stirred at 120 °C for 48 h. Near consumption of the starting material was detected by LC-MS and TLC. It was extracted with EA (30 mL × 3). The organic layer was washed with brine (40 mL), dried over Na₂SO₄, concentrated in vacuo, and purified by silica gel chromatography (DCM:MeOH = 100:1 to 10:1) to give the desired product as a yellow solid (100 mg, 34% yield).

[0332] 3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine A suspension of 1-bromo-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-8-amine (100 mg, 0.25 mmol), 4-phenoxyphenylboronic acid (65 mg, 0.30 mmol), NaCO (81 mg, 0.76 mmol), and Pd(dppf)Cl (37 mg, 0.05 mmol) in THF (15 mL) and water (3 mL) was stirred at 80 °C under a N atmosphere for 3 h. Consumption of the starting material was detected by LC-MS and TLC. The reaction was concentrated in vacuo and purified by flash column chromatography (PE:EA = 10:1 to 3:1) and preparative HPLC to give the desired product as a white solid (26 mg, 22% yield). LCMS: Calculated exact mass = 482.28; Actual value [M+H] + (ESI)=483.3; 1 H NMR(600MHz, methanol-d4)δ ppm:7.74(d,J=5.72Hz,1H),7.62(d,J=8.47Hz,2H),7.41(t,J=7.78Hz,2H),7.19( t,J=7.32Hz,1H),7.15(d,J=8.47Hz,2H),7.10(d,J=8.24Hz,2H),6.99(d,J=5.49Hz ,1H),3.35(s,1H),3.32(br.s.,4H),3.18(t,J=11.79Hz,1H),2.71(br.s.,3H),2.1 5(d,J=9.84Hz,4H),1.85(q,J=12.05Hz,2H),1.58-1.70(m,2H),1.26-1.37(m,2H).

[0333] Example 174 3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine [ka] 1-Bromo-8-chloro-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine To a solution of 8-chloro-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (200 mg, 0.6 mmol) in DCM (10 mL) was added NBS (128 mg, 0.72 mmol) under a N atmosphere at 20 °C. The reaction was then stirred under reflux for 3 h. Consumption of the starting material was detected by LC-MS and TLC. The reaction was quenched with NaHCO solution (20 mL), extracted with DCM (20 mL × 3), washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the desired product as a yellow solid, which was used in the next step without further purification (240 mg, 98% yield). LCMS: calculated exact mass = 411.08; found [M+H] + (ESI)=412.1.

[0334] 1-Bromo-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-8-amine To a solution of 1-bromo-8-chloro-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (190 mg, 0.46 mmol) in 1,4-dioxane (10 mL) was added NH₃·H₂O (10 mL) in a sealed tube. The reaction was then stirred at 120 °C for 48 h. Near consumption of the starting material was detected by LC-MS and TLC. It was extracted with EA (30 mL × 3). The organic layer was washed with brine (40 mL), dried over Na₂SO₄, and concentrated in vacuo. The crude was purified by flash column chromatography (DCM:MeOH = 100:1 to 10:1) to give the desired product as a yellow solid (160 mg, 80% yield).

[0335] 3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine A suspension of 1-bromo-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-8-amine (160 mg, 0.4 mmol), 4-phenoxyphenylboronic acid (100 mg, 0.48 mmol), NaCO (128 mg, 1.2 mmol), and Pd(dppf)Cl (60 mg, 0.08 mmol) in THF (15 mL) and water (3 mL) was stirred at 80 °C under a N atmosphere for 3 h. Consumption of the starting material was detected by LC-MS and TLC. The reaction was concentrated in vacuo and purified by flash column chromatography and preparative HPLC eluting with PE:EA (10:1 to 3:1) to give the desired product as a white solid (40 mg, 40% yield). LCMS: Calculated exact mass = 482.28; Actual value [M+H] + (ESI)=483.3; 1 H NMR(600MHz, methanol-d4)δ ppm:7.76(d,J=5.95Hz,1H),7.69(d,J=8.47Hz,2H),7.42(t,J=7.90Hz,2H),7.20(t,J=7.32Hz,1H),7.15(d,J=8.47Hz,2H),7.11( d,J=8.01Hz,2H),6.97(d,J=5.95Hz,1H),3.31-3.60(m,9H),3.21(br.s.,1H),2.90(s,3H),2.17-2.29(m,4H),1.88-2.06(m,4H).

[0336] Example 175 1-(4-(8-amino-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea [ka] A mixture of 5-bromo-7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (60 mg, 0.153 mmol), (4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)boronic acid (70 mg, 0.23 mmol), Pd(dppf)Cl (11 mg, 0.015 mmol), and NaCO (49 mg, 0.459 mmol) in dioxane-HO (10:1, 22 mL) was heated to 80 °C. The reaction mixture was stirred for 2 h. TLC (MeOH:DCM = 1:10) showed complete consumption of the starting material. The solvent was evaporated in vacuo. The residue was extracted with DCM (100 mL). The combined organic layers were washed with 1M NaOH (200 mL), dried over anhydrous NaSO, and concentrated in vacuo. The crude was purified by preparative HPLC to give the product as a white solid (16 mg, 18% yield). LCMS: calculated exact mass = 574.3, found [M+H] + (ESI)=575.3; 1 H NMR(DMSO-d6)δ ppm:9.82(s,1H),9.36(s,1H),7.95(s,1H),7.56-7.67(m,4H),7.10-7.12 (m,1H),6.52(s,1H),3.05-3.25(m,5H),1.50-2.25(m,8H),1.30(s,12H).

[0337] Example 176 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine and Example 177 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine [ka] 4-Methoxy-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine A mixture of 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (650 mg, 4.36 mmol), 1-bromo-4-phenoxybenzene (1.3 g, 5.22 mmol), CuI (1.66 g, 8.72 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.24 g, 8.72 mmol), and K2CO3 (1.8 g, 13.08 mmol) in DMSO (50 mL) was heated at 140 °C under an Ar atmosphere for 3 h. After cooling to room temperature and filtering, the filtrate was quenched with water, extracted with EtOAc, dried, and concentrated. The residue was purified by column chromatography (PE:EA = 3:1) to give the product (750 mg, 53% yield). LCMS: calculated exact mass = 317.1; found [M+H] + (ESI)=318.0.

[0338] 7-Bromo-4-methoxy-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine To a mixture of 4-methoxy-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine (1 g, 3.2 mmol) in DCM (50 mL) was added NBS (670 mg, 3.8 mmol). The mixture was stirred at room temperature for 2 hours. Quenched with saturated NaHCO3, extracted with DCM, dried, concentrated, and the residue was purified by column chromatography (PE:EA = 2:1) to give the product (1 g, 79% yield) as a yellow solid. LCMS: calculated exact mass = 395.0; found [M+H] + (ESI)=395.9.

[0339] 7-Bromo-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol A mixture of 7-bromo-4-methoxy-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine (1 g, 2.5 mmol) in MeOH (20 mL) containing 6N HCl (20 mL) was refluxed overnight. It was then cooled to room temperature and concentrated. The residue was neutralized with saturated NaHCO3 and filtered. The filter cake was dried to give the product as a pale yellow solid (850 mg, 88% yield). LCMS: calculated exact mass = 381.0; found [M+H] + (ESI)=382.2.

[0340] 7-Bromo-4-chloro-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine A suspension of 7-bromo-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol (850 mg, 2.2 mmol) in POCl was stirred at 100 °C for 1.5 h. Then, after cooling to room temperature and concentration, the residue was quenched with saturated NaHCO, extracted with DCM, dried, and concentrated to give the product as a pale yellow solid (900 mg, 100% yield). LCMS: calculated exact mass = 399.0; found [M+H] + (ESI)=399.9.

[0341] 7-Bromo-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine To a suspension of 7-bromo-4-chloro-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine (900 mg, 2.24 mmol) in 1,4-dioxane (20 mL) was added NH3·H2O (20 mL), and the mixture was stirred in a sealed tube at 130 °C overnight. It was then cooled to room temperature and concentrated. The suspension was filtered to give the product (900 mg, 100% yield). LCMS: calculated exact mass = 380.0; found [M+H] + (ESI)=380.8.

[0342] 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine A mixture of 7-bromo-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (750 mg, 1.97 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (2.6 g, 9.84 mol), Pd(dppf)Cl (288 mg, 0.39 mmol), and NaCO (1.04 g, 9.84 mmol) in dioxane-HO (40 mL-4 mL) was heated at 100 °C for 4 h under an Ar atmosphere. After cooling to room temperature, the reaction mixture was concentrated and extracted with DCM. The organic layer was concentrated and purified by flash column chromatography (EtOAc, 100%) to give the product (50 mg, 6% yield). LCMS: Calculated exact mass = 440.2; Actual value [M+H] + (ESI)=440.9.

[0343] 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine To a solution of 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (40 mg, 0.092 mmol) in EtOAc / MeOH (50 mL) was added Pd / C (20 mg, 10% in activated carbon). The mixture was stirred overnight at room temperature under an H atmosphere. It was then filtered, and the filtrate was concentrated to give the product (40 mg, 100% yield). LCMS: calculated exact mass = 442.2; found [M+H] + (ESI)=442.8.

[0344] 4-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexan-1-one To a mixture of 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4.5]decan-8-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (50 mg, 0.11 mmol) in acetone (5 mL) was added 6N HCl in THF (2 mL). The mixture was stirred at 40° C. for 3 hours. Then, after cooling to room temperature, the mixture was neutralized with aqueous NaOH, extracted with DCM, dried, and concentrated. The residue was purified by flash column chromatography (EtOAc, 100%) to give the product (15 mg, 30% yield). LCMS: calculated exact mass = 398.17; found [M+H] + (ESI)=398.9.

[0345] 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine and 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine To a mixture of 4-(4-amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexan-1-one (15 mg, 0.038 mmol) and 1-methylpiperazine (19 mg, 0.19 mmol) in DCE (5 mL) was added AcOH (1 drop). The reaction was stirred at room temperature for 2 hours. NaBH(OAc) (64 mg, 0.304 mmol) was added in portions. The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO, extracted with DCM, dried, and concentrated. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the following product: 7-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (3 mg, 16% yield). LCMS: calculated exact mass=482.3; found [M+H] + (ESI)=483.3; 1H NMR (chloroform-d) δ 8.40 (s, 1H), 7.41-7.44 (m, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.19-7.25 (m, 1H), 7.11 (dd, J = 7.9, 6.1 Hz, 5H), 4.90 (br.s., 2H), 3.03 (br.s., 9H), 2.53 (br.s., 3H), 2.30 (d, J = 16.2 Hz, 4H), 1.60-1.71 (m, 6H); and 7-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (2 mg, 11% yield). LCMS: Calculated exact mass = 482.3; Actual value [M+H] + (ESI)=483.3; 1 H NMR(chloroform-d)δ 8.40(s,1H),7.35-7.52(m,5H),7.17-7.23(m,1H),7.11(t,J=9.3Hz,4H),4.82-5.01(m,2H),3.00(br.s. ,6H),2.54(br.s.,3H),2.03(br.s.,2H),1.87(br.s.,2H),1.77(d,J=10.7Hz,2H),1.63(d,J=7.6Hz,2H).

[0346] HCK kinase assay: 10 μL of HCK kinase reaction mixture (containing 4 nM N-terminally GST-tagged HCK(75-526) purified from an insect expression system) in kinase reaction buffer (40 mM Tris-HCl (pH 7.5), 20 mM MgCl, 0.1 mg / mL BSA, 1 mM MnCl, 0.1 mM sodium vanadate), 5 μM control AMC substrate, 2 μM Src family kinase R110 substrate, and 50 μM ATP, along with test compounds serially diluted 1:3 starting at 1 μM, were incubated at room temperature (22–25°C) for 60 min in a 384-well plate (Corning, catalog no. 4514). The procedure for the ProFluor Src-Family Kinase Assay (Promega, catalog no. V1271) was then followed. Five microliters of protease solution was added to the reaction mixture, and the mixture was incubated at room temperature (22–25°C) for 60 minutes. Five microliters of stabilization solution was then added. Fluorescence signals were read using an Envision multilabel plate reader (Perkin Elmer). R110 was then read at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. AMC signals were read at an excitation wavelength of 355 nm and an emission wavelength of 460 nm. [Table 4] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0347] Evaluation of in vitro metabolic stability Dog liver microsomes (0.5 mg / mL) were purchased from Corning. Stock solutions for test compounds were prepared at 10 mM in DMSO. Aliquots of the stock solution were diluted to 0.5 mM with acetonitrile and then further diluted to 1.5 μM by adding liver microsomes / buffer. A 30 μL aliquot of the 1.5 μM solution was mixed with 15 μL of 6 mM NADPH. The final concentration of NADPH was 2 mM, which was preheated to 37°C. The final concentrations of test compound and ketanserin were 1 μM. The plate was kept in a 37°C water bath for the duration of the experiment. At each time point (0, 5, 15, 30, and 45 minutes), 135 μL of acetonitrile was added to the corresponding well. After quenching the final time point with acetonitrile, the assay plate was shaken (IKA, MTS2 / 4) for 10 minutes (600 rpm) and then centrifuged (Thermo Multifuge x3R) at 5,594 g for 15 minutes. An aliquot of the supernatant was collected, diluted 1:1 with distilled water, and analyzed by LC-MS / MS. The peak area response ratio (PARR) of the compound relative to the internal standard at 5, 15, 30, and 45 minutes was compared with the PARR at time 0 to determine the percent of test compound remaining at each time point. Half-lives were calculated using Excel software by fitting to a single-phase exponential decay equation.

[0348] In vivo pharmacokinetic evaluation A total of six male non-naive beagle dogs (Beijing Marshall Biotechnology Co., Ltd.) weighing approximately 8.00-10.00 kg were administered 1 mg / kg or 3 mg / kg by intravenous injection (iv) or oral gavage (po). The IV and PO vehicles were 100% saline and 100% (0.5% MC in water), respectively. IV administration was via cephalic vein injection, and PO administration was via gavage. Animals were manually restrained, and approximately 0.5 mL of blood was collected from the cephalic vein into pre-chilled K2EDTA tubes per time point. Blood samples were placed on wet ice and centrifuged at 4°C (2000 g, 5 min) to obtain plasma within 15 min of sample collection. Plasma samples were analyzed by UPLC / MS-MS. PK parameters were estimated using a noncompartmental model using WinNonlin 6.4.

[0349] Inhibitory activity against HCK and circulating half-life (t 1 / 2 The following compounds were evaluated for the following: The compounds were synthesized as described above. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0350] As shown in the data table above, the compounds of Examples 127, 103, 165, 163, 19, and 21 have higher t 1 / 2 The compound of Example 1 had a half-life of 11 minutes, whereas the compound of Example 19 surprisingly had a half-life of t 1 / 2 In the compound of Example 21, when the pyrrole ring of Example 19 was replaced with a pyrazole ring, t 1 / 2Alternatively, when the pyrrole ring of the compound of Example 1 was replaced with a pyrazole ring and an ortho-fluorine substituent was added, the compound of Example 103 showed a t 1 / 2 In the compound of Example 127, the piperazinyl-methyl group of the compound of Example 103 was shifted by one position, and the t 1 / 2 The pyrazole ring of the compound of Example 127 was replaced with imidazole, and the compound of Example 165 showed the highest t 1 / 2 For the compound of Example 163, when the piperazinyl-methyl group of the compound of Example 165 was returned to the terminal piperazinyl nitrogen, the t 1 / 2 The long t of Examples 103, 127, and 163 decreased slightly to 108 minutes. 1 / 2 This was confirmed by reduced plasma clearance and increased bioavailability in vivo.

[0351] Furthermore, the test compounds also demonstrated a surprising effect of substitution on potency. For example, compounds of Examples 127 and 21 differ only in the fluorine group, yet compound of Example 127 surprisingly exhibits nearly an order of magnitude higher potency. As another example, compounds of Examples 127 and 17 differ only in the stereochemistry of the methyl group, yet compound of Example 127 exhibits nearly three times higher potency. The present invention includes the following embodiments. (Embodiment 1) Formula (I): [ka] A compound of the formula Each Q, Y, and Z is independently selected from N and C, and X is N or CR. a where at least one of Q, X, Y, and Z is N; Each dashed bond shall be independently a single bond or a double bond, such that the two bicycles they form are heteroaryl; R 1 is selected from alkyl, alkenyl, alkynyl, amino, acylamino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroaralkyl; a) W is N and R 2 does not exist, and A 1 and A 2 are CH 2 Is it; b) W is C and R 2 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, and amino; A 1 and A 2 is CH 2 and O; or c) W is C and R 1 and R 2 Let's get together =CH 2 -amide, cycloalkyl, and heterocyclyl, A 1 and A 2 is CH 2 and O, Either; R a is selected from H, halo, CN, and alkyl; R 9 is selected from H, halo, alkyl, alkoxy, hydroxy, acyloxy, and amino; R 10 is H or alkoxy; R 11 is aryloxy, heteroaryloxy, arylalkyl, alkoxycarbonyl, ureido, or —C(O)-aryl; R 12 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, and acyloxy (However, the compound of formula (I)

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof [In the formula, Each Q, Y, and Z is independently selected from N and C, and X is N or C—R ａ and (However, at least one of Q, X, Y, and Z is N, Each dashed bond is intended to be independently a single or double bond, such that the two bicycles they form are heteroaryl; R １ teeth, 【Chemistry 2】 and V is N or CH; T is N and either R 4 ' is absent or T is C; R 3 is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, amino, amido, cycloalkyl, heterocyclyl, carboxy, and alkoxycarbonyl; R 3 ' is H or alkyl, or R 3 and R 3 ' together with the carbon atom to which they are attached form a cycloalkyl; R 4 is selected from H, halo, CN, alkyl, alkoxy, acyloxy, amino, and amido; R 4 ' is H or alkyl; R 5 is H or alkyl; a) W is N and R ２ does not exist, and A １ and A ２ are CH ２ or b) W is C and R ２ is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, and amino; A １ and A ２ is CH ２ and O; is one of: R ａ is selected from H, halo, CN, and alkyl; R ９ is selected from H, halo, alkyl, alkoxy, hydroxy, acyloxy, and amino; R １０ is H or alkoxy; R １１ is aryloxy, heteroaryloxy, arylalkyl, alkoxycarbonyl, ureido, or —C(O)-aryl; R １２ is selected from H, halo, CN, alkyl, alkoxy, hydroxy, and acyloxy with the proviso that either R 3 is alkyl or R 9 is halo.

2. structure: 【Chemistry 3】 wherein R ２ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

3. Q is C, X is N, Y is C, and Z is N; Q is C, X is C—R a , R a is H, Y is N, and Z is C; or 3. The compound of claim 1 or 2, wherein Q is C, X is N, Y is N, and Z is C, or a pharmaceutically acceptable salt thereof.

4. A １ and A ２ But both are CH ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. W is C, R ２ is H, V is N; T is N, 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R ３ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is methyl.

7. R ４ The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is H or methyl.

8. R ９ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is H or F.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 12 is H or halo.

10. R １１ but, 【Chemistry 4】 Selected from: B is —O—, CH ２ , CHOH, NH, N(C １～６ alkyl), and carbonyl; K １ and K. ２ However, N and CR １３ are independently selected from D is -CH ２ -C(O)-, -NH-C(O)-, N(C １～６ alkyl)-C(O), and —CH ２ S (O) ２ Selected from: R １３ is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, amino, amido, and alkoxycarbonyl; R １４ is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, amino, amido, and alkoxycarbonyl; R １５ is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, amino, amido, and alkoxycarbonyl; R １６ is selected from H, halo, CN, alkyl, alkoxy, hydroxy, acyloxy, amino, amido, and alkoxycarbonyl; 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R １１ but, 【Chemistry 5】 and B is O; K １ and K. ２ are each CH; R １４ is H; R １５ is H, 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 9 is halo.

13. The compound according to any one of claims 1 to 12, wherein R 9 is F, or a pharmaceutically acceptable salt thereof.

14. below: 【Chemistry 6】 【change】 or a pharmaceutically acceptable salt thereof.

15. 15. An in vitro method for simultaneously inhibiting HCK and BCL-2 in a cell or killing a cell harboring a FLT3-ITD mutation, the method comprising contacting the cell with a compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a BCL-2 inhibitor.

16. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating acute myeloid leukemia in combination with a BCL-2 inhibitor.

17. The use according to claim 16, wherein the acute myeloid leukemia is FLT3-ITD+ acute myeloid leukemia.

18. The use according to claim 17, wherein the medicament is for co-administration with an FLT3-ITD inhibitor.

19. 19. The use of claim 18, wherein the FLT3-ITD inhibitor is selected from AC220, sorafenib, PKC412, CEP-701, UNC2025, MLN518, KW-2449, and AMG-925, sunitinib, SU5614, AC2206, crenolanib, and PLX3397.

20. 20. The use of any one of claims 16 to 19, wherein the BCL-2 inhibitor is selected from AT-101, TW-37, TM-1206, gossypol, gossypolic acid, gossypolonic acid, apogossypol, apogossypolone, A385358, ABT-737, ABT-263, ABT-199, WEHI-539, BXI-61, BXI-72, obatoclax, JY-1-106, and SAHB peptide.

21. The compound 【Chemistry 7】 【change】 and the BCL-2 inhibitor is ABT-199.

22. The use according to any one of claims 16 to 21, wherein the medicament is for administration in combination with dexamethasone, an anti-apoptotic agent, an Mcl-1 inhibitor, an IAP antagonist, or a cell cycle inhibitor.

23. the anti-apoptotic agent is tretinoin, GGTI 298 TFA salt, BTSA1, AT406, SM-406, elesclomol, STA-4783, ganetespib, STA-9090, NQDI-1, or zoledronic acid; and / or The Mcl-1 inhibitor is 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 and / or The IAP antagonist is 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 【Chemistry 9-5】 AT-406 / Debio1143, GDC-0917 / CUDC-427, LCL161, and TL-32711; and / or the cell cycle inhibitor is palbociclib, ribociclib, abemaciclib, flavopiridol, AT9283, alisertib, or MK-1775; 23. The use according to claim 22.

Images