Imidazole-containing inhibitors of ALK2 kinase

Abstract

To provide novel compositions that have ALK2 kinase inhibitory action and are useful in treating cancer (particularly a glioma), fibrodysplasia ossificans progressiva, and the like.SOLUTION: Specifically, the compound in the figure is presented, for example.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 520,150, filed June 15, 2017. [Background technology]

[0002] A single mutation (R206H) within the kinase domain of one of the four human bone morphogenetic protein (BMP) receptors (ACVR1 / ALK2) has been reported to be closely associated with a devastating disorder of secondary (ectopic) bone formation. As a result of this mutation, all children who exhibit features of classic fibrodysplasia ossificans progressiva (FOP) eventually become covered with secondary ectopic bone, thereby hindering their mobility. This disorder has been linked to dysregulation of BMP signaling in soft tissues (skeletal muscle, tendons, ligaments, and fascia), which are transformed into ribbons, sheets, and plates of heterotopic bone via endochondral processes. In addition to the common R206H mutation associated with the classic form of FOP, other dysregulating mutations in ACVR1 / ALK2 have been identified that lead to atypical and variant forms of FOP. Furthermore, compounds effective in modulating BMP signaling based on their ability to inhibit ALK2 have also been shown to inhibit kinases from diverse signaling pathways. Summary of the Invention [Problem to be solved by the invention]

[0003] Thus, there remains a need for additional compounds that inhibit ALK2 kinase, suitable for a variety of important therapeutic applications. [Means for solving the problem]

[0004] In certain embodiments, the present invention provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an optionally fused substituted aromatic ring, heteroaromatic ring, partially unsaturated cycloalkyl ring, or partially unsaturated heterocycloalkyl ring; W is C or N; R a represents H or alkyl, R 1 represents heteroarylene, R 1a is H, or optionally substituted —C(O)alkyl, —C(O)O(alkyl), —C(O)(heterocyclyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)NR x R y , alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; J, H, Halo, -OR 2 , -NR 2 R 3 , -C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl or heteroaryl, where the aryl or heteroaryl is selected from one or more R 2a may be replaced by occurrences of R 2 represents optionally substituted alkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl or hydroxyalkyl; R 3 represents H or alkyl, Or R 2 and R 3 together, one or more R 2a occurrences form an optionally substituted heterocycloalkyl ring, R 2a is independently at each occurrence halo, hydroxyl, -C(O)H, oxo, -NH2, -C(O)NH2, -C(O)OH, -C(O)R 5 , -C(O)OR 5 , -C(O)NH(R 5), or optionally substituted alkyl, alkoxyl, hydroxyalkyl, heteroaryl, aryl or -N(alkyl)2; Or R 2a any two geminal or vicinal occurrences of may be taken together to form a spiro or fused cycloalkyl ring; R 5 represents independently at each occurrence an optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R x and R y each independently represents H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

[0005] In a further aspect, the present invention provides a compound of formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an optionally fused substituted aromatic ring, heteroaromatic ring, partially unsaturated cycloalkyl ring, or partially unsaturated heterocycloalkyl ring; W is C or N; B is CH or N; D is CH or N; provided that when B is CH, D is N, or when D is CH, B is N; R a represents H or alkyl, R 1 represents heteroarylene, R 1ais H, or optionally substituted —C(O)alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)O(alkyl), —C(O)(heterocyclyl), —C(O)NR x R y , alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; J, H, Halo, -OR 2 , -NR 2 R 3 , -C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl or heteroaryl, where the aryl or heteroaryl is selected from one or more R 2a may be replaced by occurrences of R 2 represents optionally substituted alkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl or hydroxyalkyl; R 3 represents H or alkyl, Or R 2 and R 3 together, one or more R 2a occurrences form an optionally substituted heterocycloalkyl ring, R 2a is independently at each occurrence halo, hydroxyl, -C(O)H, oxo, -NH2, -C(O)NH2, -C(O)OH, -C(O)R 5 , -C(O)OR 5 , -C(O)NH(R 5 ), or optionally substituted alkyl, alkoxyl, hydroxyalkyl, heteroaryl, aryl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, or -N(alkyl)2, or R 2a any two geminal or vicinal occurrences of may be taken together to form a spiro or fused cycloalkyl ring; R 5represents independently at each occurrence an optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R x and R y each independently represents H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

[0006] In a further aspect, the present invention provides a compound selected from the group consisting of the following formulas or a pharmaceutically acceptable salt thereof: [ka]

[0007] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In certain embodiments, the present invention provides a method of inhibiting ALK2 kinase, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0009] The present invention also provides a method for treating fibrodysplasia ossificans progressiva, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0010] In a further aspect, the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, hi one embodiment, the cancer is glioma. DETAILED DESCRIPTION OF THE INVENTION

[0011] Provided herein are compounds of formula (I), (II), (III) and (IV), and pharmaceutically acceptable salts thereof, which are useful for inhibiting ALK2 kinase and for treating or preventing diseases or conditions that benefit from ALK2 kinase inhibition. For example, the disclosed inhibitors of ALK2 kinase are useful in therapeutic methods and compositions suitable for use in treating cancer or fibrodysplasia ossificans progressiva.

[0012] definition The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0013] The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or oxygen, nitrogen, or sulfur.

[0014] As used herein, the term "alkyl" is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C for straight chain). 30 , C3 to C for branched chains 30 ), or about 20 or fewer carbon atoms, or 10 or fewer carbon atoms. In some embodiments, the term "alkyl" refers to C1-C 10 In one embodiment, the term "alkyl" refers to a C1 to C6 alkyl group, for example, a C1 to C6 straight chain alkyl group. In one embodiment, the term "alkyl" refers to a C3 to C6 alkyl group, for example, a C3 to C6 straight chain alkyl group. 12It refers to a branched chain alkyl group. In one embodiment, the term "alkyl" refers to a C3 to C8 branched chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl (or isobutyl), tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0015] The term "cycloalkyl" refers to a monocyclic, bicyclic, or bridged saturated carbocyclic ring, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5 to 12 carbon atoms in their ring structure, and optionally 6 to 10 carbons in the ring structure. Preferably, a cycloalkyl is a (C3-C7)cycloalkyl, which refers to a monocyclic saturated carbocyclic ring having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings include monocyclic cycloalkyl rings in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge (i.e., -(CH2)) of 1 to 3 additional carbon atoms. w-type bridging group, where w is 1, 2, or 3. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. A bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group may be optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

[0016] The term "(cycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a (cycloalkyl)alkyl is a cyclohexylmethyl group.

[0017] The term "heterocycloalkyl" as used herein refers to a radical of a non-aromatic ring system having 3 to 12 atoms containing at least one heteroatom such as nitrogen, oxygen, sulfur, and the like, and the non-aromatic ring includes, but is not limited to, monocyclic, bicyclic, and tricyclic rings which may be fully saturated or may contain one or more units of unsaturation, but for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system. For illustrative purposes, which should not be construed as limiting the scope of the present invention, the following are examples of heterocyclic rings: Examples of rings are: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxa Heterocycloalkyl groups include zolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl. Heterocycloalkyl groups are optionally substituted with one or more of the following substituents:

[0018] As used herein, the term "(heterocycloalkyl)alkyl" refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0019] The term "alkenyl," as used herein, refers to a straight- or branched-chain hydrocarbon radical containing 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond in an alkenyl group can be located anywhere in the moiety and can be in either the (Z) or (E) configuration with respect to the double bond.

[0020] The term "alkynyl" as used herein means a straight or branched chain hydrocarbon radical containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0021] The term "alkylene" is art-recognized and, as used herein, refers to a diradical obtained by removing two hydrogen atoms from an alkyl group, as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like. That is, in one embodiment, a "substituted alkyl" is an "alkylene."

[0022] The term "amino" is a term of art and, as used herein, refers to both unsubstituted and substituted amines, for example, moieties that can be represented by the general formula: [ka] In the formula, R a , R b and R c are each independently hydrogen, alkyl, alkenyl, -(CH2) x -R d represents or R a and R b together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure; R d represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl; and x is 0 or an integer ranging from 1 to 8. In certain embodiments, R a or R b Only one of R a , R b and the nitrogen together do not form an imide. In other embodiments, R a and R b (and R c ) are each independently hydrogen, alkyl, alkenyl, or -(CH2) x -R d In certain embodiments, the term "amino" refers to -NH2.

[0023] In certain embodiments, the term "alkylamino" refers to --NH(alkyl).

[0024] In certain embodiments, the term "dialkylamino" refers to -N(alkyl)2.

[0025] The term "amide," as used herein, means -NHC(=O)-, where the amide group is attached to the parent molecular moiety through a nitrogen. Examples of amides include alkylamides such as CHC(=O)N(H)- and CHCHC(=O)N(H)-.

[0026] The term "acyl" is a term of art and, as used herein, refers to any group or radical of the form RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0027] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

[0028] The term "aminoacyl" is a term of art and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0029] The term "aminothionyl" as used herein refers to the analog of aminoacyl in which the O of RC(O)-- is replaced with sulfur, thus the form RC(S)--.

[0030] The term "phosphoryl" is a term of art and, as used herein, generally refers to a group having the formula: [ka] where Q50 represents S or O, and R59 represents hydrogen, lower alkyl, or aryl; for example, -P(O)(OMe)- or -P(O)(OH)2. When used to substitute, for example, an alkyl, the phosphoryl group of the phosphorylalkyl has the general formula: [ka] wherein Q50 and R59 are each independently as defined above, and Q51 represents O, S, or N; for example, -OP(O)(OH)OMe or -NH-P(O)(OH). When Q50 is S, the phosphoryl moiety is a "phosphorothioate."

[0031] The term "aminophosphoryl," as used herein, refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(O)(OH)Me2.

[0032] As used herein, the term "azide" or "azido group" refers to an -N3 group.

[0033] The term "carbonyl" as used herein refers to -C(=O)-.

[0034] The term "thiocarbonyl" as used herein refers to -C(=S)-.

[0035] The term "alkylphosphoryl," as used herein, refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(O)(OH)Me.

[0036] The term "alkylthio" as used herein refers to alkyl-S-. The term "(alkylthio)alkyl" refers to an alkyl group substituted with an alkylthio group.

[0037] The term "carboxy" as used herein means a -CO2H group.

[0038] The term "aryl" is a term of art and, as used herein, includes monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene, and pyrene. Typically, aryl groups contain 6 to 10 carbon ring atoms (i.e., (C6-C8) 10) aryl). The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like. The term "aryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), and the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group.

[0039] The term "arylene" refers to a diradical obtained by removing two hydrogen atoms from the aryl group defined above. In certain embodiments, arylene refers to a disubstituted arene, i.e., an arene substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. That is, in certain embodiments, "substituted aryl" is "arylene."

[0040] The term "heteroaryl" is a term of art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 12 atoms in the ring structure, including one or more heteroatoms such as nitrogen, oxygen, or sulfur. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. A "heteroaryl" may be optionally substituted at one or more ring positions with one or more substituents such as halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), at least one of which is an aromatic group having one or more heteroatoms in the ring structure; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl.

[0041] The term "heteroarylene" refers to a diradical obtained by removing two hydrogen atoms from a heteroaryl group, as defined above. In certain embodiments, heteroarylene refers to a disubstituted heteroarene, i.e., a heteroarene substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like. That is, in certain embodiments, a "substituted heteroaryl" is a "heteroarylene."

[0042] The terms "aralkyl" or "arylalkyl" are terms of art and, as used herein, refer to an alkyl group substituted with an aryl group, the moiety being attached to the parent molecule through the alkyl group.

[0043] The terms "heteroaralkyl" or "heteroarylalkyl" are terms of art and, as used herein, refer to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through an alkyl group.

[0044] The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0045] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0046] The term "alkoxycarbonyl" means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group represented by -C(=O)-, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0047] The term "alkylcarbonyl," as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0048] The term "arylcarbonyl," as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0049] The terms "alkylcarbonyloxy" and "arylcarbonyloxy" as used herein refer to an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to, phenylcarbonyloxy.

[0050] The terms "alkenoxy" or "alkenoxyl" mean an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propene-1-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-).

[0051] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0052] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0053] The term "carbocyclyl," as used herein, means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms that is fully saturated or has one or more unsaturated bonds, but for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (such as phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0054] The term "cyano" is a term of art and as used herein refers to -CN.

[0055] The term "halo" is a term of art and, as used herein, refers to -F, -Cl, -Br, or -I.

[0056] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, in which some or all of the hydrogens have been replaced with halogen atoms.

[0057] The term "hydroxy" is a term of art and, as used herein, refers to --OH.

[0058] The term "hydroxyalkyl," as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0059] As used herein, the term "silyl" includes hydrocarbyl derivatives of the silyl (HSi-) group (i.e., (hydrocarbyl)Si-), where the hydrocarbyl group is a monovalent group formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl group may be a combination of different groups that can be varied to provide numerous silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0060] The term "silyloxy" as used herein means a silyl group, as defined herein, appended to the parent molecule through an oxygen atom.

[0061] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the compounds of the present invention may be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0062] For example, if a specific enantiomer (or mirror image) of a compound of this invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, and the diastereomers formed can then be resolved by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0063] It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the allowed valence of the substituted atom and substituent, and further includes the implicit proviso that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0064] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. 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 substituents of organic compounds described herein that satisfy the valence of the heteroatom. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0065] In certain embodiments, optional substituents include, for example, halogen, haloalkyl, hydroxyl, carbonyl (such as carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, alkenyloxy, alkynyloxy, phosphoryl, phosphate, phosphonate, phosphinate, amino (including alkylamino and dialkylamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, silyl, silyloxy, heterocycloalkyl, cycloalkyl, alkyl, alkenyl, alkynyl, aryl, aryloxy ... L , heteroaryl, aralkyl or heteroaralkyl groups.

[0066] As used herein, the phrase "protecting group" refers to a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals of aldehydes and ketals of ketones. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Protected forms of the compounds of the present invention are included within the scope of the present invention.

[0067] For purposes of this invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements, inside cover of the Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0068] Other chemical terms herein are used in accordance with conventional usage in the art as exemplified in the McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco (incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0069] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms can include salts in which the ratio of salt molecules is not 1:1. For example, a salt may contain more than one inorganic or organic acid molecule per base molecule, such as two hydrochloric acid molecules per compound of Formula I, II, III, or IV. As another example, a salt may contain less than one inorganic or organic acid molecule per base molecule, such as two tartaric acid molecules per compound of Formula I, II, III, or IV.

[0070] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration.Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oil; and solids such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, and urea.In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used.Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, the entire contents of which are incorporated herein by reference.

[0071] As used herein, the term "treating" means preventing, halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" means halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treating" means alleviating at least one objective symptom of a disease or condition in a subject.

[0072] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0073] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired therapeutic effect.

[0074] As used herein, the term "inhibit" refers to a decrease by an objectively measurable amount or degree. In various embodiments, "inhibit" refers to a decrease of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to a relevant control. In one embodiment, "inhibit" refers to a 100 percent decrease, i.e., cessation or elimination.

[0075] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0076] compound The present invention provides compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an optionally fused substituted aromatic ring, heteroaromatic ring, partially unsaturated cycloalkyl ring, or partially unsaturated heterocycloalkyl ring; W is C or N; R a represents H or alkyl, R 1 represents heteroarylene, R 1a is H, or optionally substituted —C(O)alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)O(alkyl), —C(O)(heterocyclyl), —C(O)NR x R y , alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; J, H, Halo, -OR 2 , -NR 2 R 3 , -C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl or heteroaryl, where the aryl or heteroaryl is selected from one or more R 2a may be substituted by occurrences of R 2 represents optionally substituted alkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl or hydroxyalkyl; R 3 represents H or alkyl, Or R 2 and R 3 together, one or more R 2a occurrences form an optionally substituted heterocycloalkyl ring, R 2a is independently at each occurrence halo, hydroxyl, -C(O)H, oxo, -NH2, -C(O)NH2, -C(O)OH, -C(O)R 5 , -C(O)OR 5 , -C(O)NH(R 5), or optionally substituted alkyl, alkoxyl, hydroxyalkyl, heteroaryl, aryl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, or -N(alkyl)2, or R 2a any two geminal or vicinal occurrences of may be taken together to form a spiro or fused cycloalkyl ring; R 5 represents independently at each occurrence an optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R x and R y each independently represents H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

[0077] In certain embodiments, the compounds of the present invention are represented by Formula (Ia) or Formula (IIa): [ka] During the ceremony, As valences permit, Q, T, U, and V each independently represent CH, CH, N, NH, O, or SO, where any hydrogen of a CH, CH, or NH group is R 4 can be replaced by the appearance of R 4is independently at each occurrence halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CHC(O)NH, —C(O)R 5 , -C(O)OR 5 or -S(O)2R 5 represents m is an integer from 0 to 4, as valence allows.

[0078] In certain embodiments, the compounds of the present invention are represented by Formula (Ib) or Formula (IIb): [ka] wherein Q represents CH or N and V represents CH or N. In one embodiment, Q is N and V is CH. In an alternative embodiment, Q is CH and V is N.

[0079] In certain embodiments, the compounds of the present invention are represented by Formula (Ic) or Formula (IIc). [ka]

[0080] In certain embodiments, the compounds of the present invention are represented by Formula (Id) or Formula (IId): [ka] wherein T represents CH, NH, O, or SO, and U represents CH, NH, O, or SO. In some embodiments, T is NH and U is CH. In other embodiments, T is CH and U is NH.

[0081] In certain embodiments, the compounds of the present invention are represented by Formula (Ie) or Formula (IIe). [ka]

[0082] In any of formulas (Ia), (IIa), (Ib), (IIb), (Ic), (IIc), (Id), (IId), (Ie), and (IIe), in certain embodiments, m is 0 or 1.

[0083] In certain embodiments, the compounds of the present invention are represented by formula (Ij) or (IIj): [ka] During the ceremony, W is C or N; As valences permit, X, Y, and Z each independently represent CH, CH, CO, N, NH, O, S, or SO, where any hydrogen of a CH, CH, or NH group is R 4 can be replaced by the appearance of R 4 is independently at each occurrence cyano, halo, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CHC(O)NH, —C(O)R 5 , -C(O)OR 5 or -S(O)2R 5 represents n is an integer from 0 to 4, as valence allows.

[0084] In one embodiment, R4 is independently at each occurrence halo, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, —CHC(O)NH, —C(O)R 5 , -C(O)OR 5 or -S(O)2R 5 Represents.

[0085] In one embodiment, R 4 represents independently at each occurrence halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, or heteroarylalkyloxy.

[0086] In one embodiment, one of X, Y, or Z is NR 4 is.

[0087] In some such embodiments, R 4 is selected from the group consisting of: [ka]

[0088] In certain embodiments, the compounds of the present invention are represented by formula (Ik) or (IIk): [ka] In the formula, X, Y, and Z each independently represent CH, N, NH, O, S, or SO2.

[0089] In certain embodiments, the compounds of the present invention are represented by formula (Ik') or (IIk'). [ka]

[0090] Alternatively, in certain embodiments, the compounds of the present invention are represented by formula (Ik") or (IIk"): [ka] wherein at least one of X and Z is selected from the group consisting of O, N, NH, and S.

[0091] In some embodiments of compounds of Formula (Ik") and (IIk"), one of X and Z is selected from the group consisting of O, NH, and S, and the other of X and Z is CH. For example, X may be selected from the group consisting of O, NH, and S. Alternatively, Z may be selected from the group consisting of O, NH, and S.

[0092] In other embodiments of compounds of Formula (Ik") and (IIk"), each of X and Z is selected from the group consisting of O, N, NH, and S. For example, one of X and Z can be N and the other of X and Z can be NH.

[0093] In certain embodiments, the compounds of the present invention are represented by formula (In) or (IIn): [ka] wherein each of Y and Z is selected from the group consisting of O, N, NH, and S.

[0094] In some such embodiments, Y is N and Z is NH.

[0095] In certain embodiments, the compounds of the present invention are represented by formula (Im) or (IIm): [ka] In the formula, X, Y, and Z each independently represent CH2, CO, NH, O, S, or SO2.

[0096] In some embodiments of the compound of Formula (Im) or (IIm), each of X, Y, and Z is CH. In alternative embodiments, one of X, Y, and Z is NH or O.

[0097] In any of formulas (Ij), (IIj), (Ik), (IIk), (Ik'), (IIk'), (Ik"), (IIk"), (Im), and (IIm), in certain embodiments, n is 0 or 1.

[0098] In any of the preceding embodiments, R 4 When present, may be selected from the group consisting of optionally substituted alkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl and (heterocycloalkyl)alkyl.

[0099] In any of the preceding embodiments, R a can be H.

[0100] In one embodiment, R 1 is a nitrogen-containing heteroarylene, such as a 5-membered nitrogen-containing heteroarylene. 1 is an imidazolene.

[0101] In some embodiments, -R 1 -R 1a teeth [ka] Represents.

[0102] In one embodiment, R 1a is H.

[0103] Alternatively, R 1a may be an optionally substituted phenyl. Specifically, R 1amay be phenyl substituted by one or more occurrences of halo, hydroxyl, cyano, -C(O)NH, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, -C(O)alkyl, -C(O)O-alkyl, heterocycloalkyl, -C(O)NH(alkyl), -C(O)N(alkyl), -C(O)heterocycloalkyl, -C(O)(prolinol), -C(O)NH((cycloalkyl)alkyl), or -C(O)NH(cycloalkyl). In certain embodiments, R 1a is phenyl substituted with two or more occurrences of alkoxy. Preferably, R 1a is 3,4,5-trimethoxyphenyl.

[0104] In one embodiment, R 1a is a substituted phenyl, where two adjacent substituents on the phenyl, taken together with intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring. For example, R 1a may be phenyl in which two adjacent substituents form a fused, optionally substituted heterocycle such as 1,4-dioxane or 1,3-dioxolane.

[0105] In one embodiment, R 1a is an optionally substituted heteroaryl, such as quinoline.

[0106] In some embodiments, J is one or more R 2a is an optionally substituted aryl.

[0107] In an alternative embodiment, J is —NR 2 R 3 is.

[0108] In some such embodiments, R 2 and R 3 together, for example, one or more R 2a The occurrence of forms an optionally substituted heterocycloalkyl ring such as a pyrrolidine ring.

[0109] In some such embodiments, R 2a independently for each occurrence -C(O)NH2, -C(O)R 5 , hydroxyalkyl, heteroaryl or aryl, and preferably represents -C(O)NH2 or hydroxyalkyl.

[0110] In certain embodiments, A represents a fused, optionally substituted cycloalkyl ring, such as an optionally substituted cyclohexane or cycloheptane ring.

[0111] In certain embodiments, A represents a fused optionally substituted heterocycloalkyl ring, such as an optionally substituted tetrahydrofuran or pyrrolidine ring.

[0112] In certain embodiments, the compound of the present invention is selected from the group consisting of the compounds shown in the table below or a pharmaceutically acceptable salt thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0113] In a further aspect, the present invention provides a compound represented by formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is an optionally fused substituted aromatic ring, heteroaromatic ring, partially unsaturated cycloalkyl ring, or partially unsaturated heterocycloalkyl ring; W is C or N; B is CH or N; D is CH or N; with the proviso that when B is CH then D is N, or when D is CH then B is N; R a represents H or alkyl, R 1 represents heteroarylene, R 1a is H, or optionally substituted —C(O)alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)O(alkyl), —C(O)(heterocyclyl), —C(O)NR x R y , alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; J, H, Halo, -OR 2 , -NR 2 R 3 , -C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl or heteroaryl, where the aryl or heteroaryl is selected from one or more R 2a may be substituted by occurrences of R 2 represents optionally substituted alkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl or hydroxyalkyl; R3 represents H or alkyl, Or R 2 and R 3 together, one or more R 2a occurrences form an optionally substituted heterocycloalkyl ring, R 2a is independently at each occurrence halo, hydroxyl, -C(O)H, oxo, -NH2, -C(O)NH2, -C(O)OH, -C(O)R 5 , -C(O)OR 5 , -C(O)NH(R 5 ), or optionally substituted alkyl, alkoxyl, hydroxyalkyl, heteroaryl, aryl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, or -N(alkyl)2; Alternatively, R 2a any two geminal or vicinal occurrences of may be taken together to form a spiro or fused cycloalkyl ring; R 5 represents independently at each occurrence an optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R x and R y each independently represents H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

[0114] In certain embodiments, the compound is represented by Formula (IIIa) or Formula (IVa): [ka] wherein, as valences permit, Q, T, U, and V each independently represent CH, CH, N, NH, O, or SO, where any hydrogen on a CH, CH, or NH group is R 4 can be replaced by the appearance of R 4 is independently at each occurrence halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CHC(O)NH, —C(O)R 5 , -C(O)OR 5 or -S(O)2R 5 represents m is an integer from 0 to 4, as valence allows.

[0115] In certain embodiments, the compound is represented by Formula (IIIb) or Formula (IVb): [ka] wherein Q represents CH or N and V represents CH or N. In one embodiment, Q is N and V is CH. In an alternative embodiment, Q is CH and V is N.

[0116] In certain embodiments, the compound is represented by Formula (IIIc) or Formula (IVc). [ka]

[0117] In certain embodiments, the compound is represented by Formula (IIId) or Formula (IVd): [ka] wherein T represents CH, NH, O, or SO, and U represents CH, NH, O, or SO. In some embodiments, T is NH and U is CH. In other embodiments, T is CH and U is NH.

[0118] In certain embodiments, the compound is represented by Formula (IIIe) or Formula (IVe). [ka]

[0119] In any of formulas (IIIa), (IVa), (IIIb), (IVb), (IIIc), (IVc), (IIId), (IVd), (IIIe), and (IVe), in certain embodiments, m is 0 or 1.

[0120] In certain embodiments, the compound is represented by Formula (IIIj) or Formula (IVj): [ka] During the ceremony, W is C or N; As valences permit, X, Y, and Z each independently represent CH, CH, CO, N, NH, O, S, or SO, where any hydrogen of a CH, CH, or NH group is R 4 can be replaced by the appearance of R 4 is independently at each occurrence halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, —CHC(O)NH, —C(O)R5 , -C(O)OR 5 or -S(O)2R 5 represents n is an integer from 0 to 4, as valence allows.

[0121] In one embodiment, R 4 is independently at each occurrence halo, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, —CHC(O)NH, —C(O)R 5 , -C(O)OR 5 or -S(O)2R 5 Represents.

[0122] In one embodiment, R 4 represents independently at each occurrence halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, or heteroarylalkyloxy.

[0123] In some embodiments, one of X, Y, or Z is NR4.

[0124] In some such embodiments, R 4 is selected from the group consisting of: [ka]

[0125] In certain embodiments, the compound is represented by formula (IIIk) or (IVk): [ka] In the formula, X, Y, and Z each independently represent CH, N, NH, O, S, or SO2.

[0126] In further embodiments, the compound is represented by formula (IIIk') or (IVk'). [ka]

[0127] In certain embodiments, the compound is represented by formula (IIIk") or (IVk"): [ka] wherein at least one of X and Z is selected from the group consisting of O, N, NH, and S.

[0128] In some embodiments of compounds of Formula (IIIk") and (IVk"), one of X and Z is selected from the group consisting of O, NH, and S, and the other of X and Z is CH. For example, X may be selected from the group consisting of O, NH, and S. Alternatively, Z may be selected from the group consisting of O, NH, and S.

[0129] In further embodiments of compounds of Formula (IIIk") and (IVk"), each of X and Z is selected from the group consisting of O, N, NH, and S. For example, one of X and Z is N and the other of X and Z is NH.

[0130] In certain embodiments, the compounds of the present invention are represented by formula (IIIn) or (IVn): [ka] wherein each of Y and Z is selected from the group consisting of O, N, NH, and S.

[0131] In certain embodiments, Y is N and Z is NH.

[0132] In certain embodiments, the compounds of the present invention are represented by formula (IIIm) or (IVm): [ka] In the formula, X, Y, and Z each independently represent CH2, CO, NH, O, S, or SO2.

[0133] In some embodiments of a compound of Formula (IIIm) or (IVm), each of X, Y, and Z is CH. In alternative embodiments, one of X, Y, and Z is NH or O.

[0134] In any of formulas (IIIj), (IVj), (IIIk), (IVk), (IIIk'), (IVk'), (IIIk"), (IVk"), (IIIm), and (IVm), in certain embodiments, n is 0 or 1.

[0135] In any of the preceding embodiments, R 4 When present, may be selected from the group consisting of optionally substituted alkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl and (heterocycloalkyl)alkyl.

[0136] In any of the preceding embodiments, R a can be H.

[0137] In one embodiment, R 1 is a nitrogen-containing heteroarylene, such as a 5-membered nitrogen-containing heteroarylene. 1 is an imidazolene.

[0138] In some embodiments, -R 1 -R 1a teeth [ka] Represents.

[0139] In one embodiment, R 1a is H.

[0140] Alternatively, R 1amay be an optionally substituted phenyl. Specifically, R 1a may be phenyl substituted by one or more occurrences of halo, hydroxyl, cyano, -C(O)NH, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, -C(O)alkyl, -C(O)O-alkyl, heterocycloalkyl, -C(O)NH(alkyl), -C(O)N(alkyl), -C(O)heterocycloalkyl, -C(O)(prolinol), -C(O)NH((cycloalkyl)alkyl), or -C(O)NH(cycloalkyl). In certain embodiments, R 1a is phenyl substituted with two or more occurrences of alkoxy. Preferably, R 1a is 3,4,5-trimethoxyphenyl.

[0141] In one embodiment, R 1a is a substituted phenyl, where two adjacent substituents on the phenyl, taken together with intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring. For example, R 1a may be phenyl in which two adjacent substituents form a fused, optionally substituted heterocycle, such as 1,4-dioxane or 1,3-dioxolane.

[0142] In one embodiment, R 1a is an optionally substituted heteroaryl, such as quinoline.

[0143] In some embodiments, J is one or more R 2a is an optionally substituted aryl.

[0144] In an alternative embodiment, J is —NR 2 R 3 is.

[0145] In some such embodiments, R 2 and R 3 together, for example, one or more R 2aThe occurrence of forms an optionally substituted heterocycloalkyl ring such as a pyrrolidine ring.

[0146] In some such embodiments, R 2a independently for each occurrence -C(O)NH2, -C(O)R 5 , hydroxyalkyl, heteroaryl or aryl, and preferably represents -C(O)NH2 or hydroxyalkyl.

[0147] In certain embodiments, the compound of the present invention is selected from the group consisting of the compounds shown in the table below. [ka]

[0148] Pharmaceutical Composition The present invention provides a pharmaceutical composition comprising one or more compounds of the present invention or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0149] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than a compound of the present invention. The at least one additional pharmaceutically active agent may be an agent useful in the treatment of a disease or condition that would benefit from inhibition of ALK2 kinase.

[0150] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention, or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0151] How to use The present invention provides compounds and pharmaceutically acceptable salts thereof that are useful for treating or preventing diseases or conditions whose treatment would benefit from ALK2 kinase inhibition.

[0152] In certain aspects, the present invention provides a method of inhibiting ALK2 kinase, comprising administering to a subject in need thereof an effective amount of a compound of the present invention (e.g., a compound of Formula (I), (II), (III), or (IV)), or a pharmaceutically acceptable salt thereof.

[0153] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0154] In certain aspects, the present invention provides a method of treating fibrodysplasia ossificans progressiva, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0155] The present invention also provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the cancer includes central nervous system tumors, breast cancer, prostate cancer, skin cancer (including basal cell carcinoma, squamous cell carcinoma, and melanoma), cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular tumor, thyroid cancer, astrocytoma, glioma, pancreatic cancer, gastric cancer, liver cancer, colon cancer, kidney cancer, bladder cancer, esophageal cancer, laryngeal cancer, parotid cancer, biliary tract cancer, rectal cancer, endometrial cancer, adenocarcinoma, small cell carcinoma, neuroblastoma, mesothelioma, adrenocortical carcinoma, epithelial cancer, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, Ewing's sarcoma family of tumors, germ cell tumor, hepatoblastoma, hepatocellular carcinoma, non-rhabdomyosarcoma, soft tissue sarcoma, osteosarcoma, peripheral primitive neuroectodermal tumor, retinoblastoma, rhabdomyosarcoma, and Wilms' tumor.

[0157] In some embodiments, the cancer is a glioma, such as diffuse intrinsic pontine glioma.

[0158] The compounds of the present invention are useful for treating any disease or condition whose treatment would benefit from inhibition of ALK2 kinase, meaning that it is desirable to reduce ALK2 kinase activity in such a disease or condition. For example, it may be desirable to reduce ALK2 kinase activity in situations of inappropriate activation or overactivation of ALK2 kinase.

[0159] Formulations, Routes of Administration, and Dosage The compounds of the present invention and their pharmaceutically acceptable salts can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the selected route of administration, for example, oral or parenteral, intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes, etc. Additional routes of administration are also contemplated by the present invention.

[0160] Thus, the compounds of the present invention or their pharmaceutically acceptable salts can be combined with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier, and administered systemically, for example, orally. They can be enclosed in hard or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compound (i.e., the compounds of the present invention or their pharmaceutically acceptable salts) can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations may, of course, vary and may conveniently be between about 2% and about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0161] Tablets, troches, pills, capsules, and the like may contain the following diluents and carriers: binders such as tragacanth gum, acacia, cornstarch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as cornstarch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame; or flavorings such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, in addition to the above-mentioned materials, a liquid carrier such as vegetable oil or polyethylene glycol may be included. Various other materials may be present as coatings or to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. Moreover, the active compounds may be incorporated into sustained-release preparations and devices.

[0162] Active compound can also be administered intravenously or intraperitoneally by infusion or injection.The solution of active compound can be prepared in water or physiologically acceptable aqueous solution, and optionally mixed with non-toxic surfactant.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and their mixture, and in oil.Under normal storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0163] Pharmaceutical dosage forms suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the active compound, optionally encapsulated in liposomes, suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the final dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage. Liquid carriers or vehicles can be solvents or liquid dispersion media, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the required particle size in the case of dispersions, or by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0164] Sterile injectable solutions are prepared by incorporating the required amount of active compound into a suitable solvent with various other ingredients as listed above, as needed, and then filter sterilization. In the case of sterile powders for preparing sterile injectable solutions, methods for preparation include vacuum drying and freeze-drying techniques, which yield a powder of the active compound and any additional desired ingredients present in a previously sterile-filtered solution.

[0165] For topical administration, the compounds of the present invention or their pharmaceutically acceptable salts can be applied in pure form (if they are liquids), however, it is generally desirable to combine them with a dermatologically acceptable carrier (which can be solid or liquid) and administer them to the skin as a composition or formulation.

[0166] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohols, or glycols, or water-alcohol / glycol blends, in which the compound of the present invention or a pharmaceutically acceptable salt thereof can be dissolved or dispersed at effective levels, optionally with the aid of a nontoxic surfactant. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from absorbent pads, used to impregnate bandages or other dressings, or sprayed onto the affected area using a pump-action or aerosol sprayer.

[0167] Thickening agents such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified mineral materials may also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like for application directly to the user's skin.

[0168] Examples of useful dermatological compositions that can be used to deliver the compounds of the invention, or pharmaceutically acceptable salts thereof, to the skin are known in the art: see, e.g., Jacquet et al. (U.S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U.S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Pat. No. 4,559,157; ​​incorporated herein by reference), and Wortzman (U.S. Pat. No. 4,820,508; incorporated herein by reference).

[0169] Useful dosages of the compounds of the present invention or their pharmaceutically acceptable salts can be determined, at least initially, by comparing their in vitro activity with their in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949 (incorporated herein by reference).

[0170] The amount of the compound or pharmaceutically acceptable salt thereof required for therapeutic use will vary not only with the particular compound or salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician.

[0171] However, in general, suitable doses range from about 0.5 to about 100 mg / kg of recipient body weight / day, e.g., from about 3 to about 90 mg / kg body weight / day, from about 6 to about 75 mg / kg body weight / day, from about 10 to about 60 mg / kg body weight / day, or from about 15 to about 50 mg / kg body weight / day.

[0172] The compounds of the invention, or pharmaceutically acceptable salts thereof, can be conveniently formulated into unit dosage forms; for example, each unit dosage form contains 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active compound. In one embodiment, the invention provides a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, formulated into such a unit dosage form. The desired dose can conveniently be presented in a single dose or as divided doses administered at appropriate intervals (e.g., two, three, four or more sub-doses per day). The sub-dose itself may be further divided, for example, into a number of discrete loosely spaced administrations.

[0173] The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be administered in combination with other therapeutic agents, for example, other agents useful in treating or preventing diseases or conditions whose treatment would benefit from ALK2 kinase inhibition.

[0174] Other delivery systems include sustained-release, delayed-release, or sustained-release delivery systems, as are well known in the art. Such systems can avoid repeated administration of active compounds, and can increase the convenience of patients and physicians. Many types of release delivery systems are available and known to those skilled in the art. It may be desirable to use long-term sustained-release implants. As used herein, long-term release means that the delivery system is an implant that is configured and arranged to deliver therapeutic levels of active compounds for at least 30 days, preferably 60 days.

[0175] In certain embodiments, the compounds of the invention or pharmaceutically acceptable salts thereof are formulated for intraocular administration, e.g., formulated for direct injection or insertion within or in connection with an intraocular medical device.

[0176] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be formulated for deposition within medical devices, including various conventional grafts, stents (including stent-grafts), catheters, balloons, baskets, or other devices that can be deployed or permanently implanted within a body lumen. As a particular example, it is desirable to have devices and methods that can deliver the compounds of the present invention, or pharmaceutically acceptable salts thereof, to areas of the body treated by interventional techniques.

[0177] In an exemplary embodiment, a compound of the invention or a pharmaceutically acceptable salt thereof may be deposited within a medical device, such as a stent, and delivered to a treatment site for treatment of a part of the body.

[0178] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are typically permanently implanted in coronary or peripheral vessels. Stent designs include those described in U.S. Pat. No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062 (Wiktor). Such designs include both metallic and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents can also be used to deliver drugs to sites of contact with the vascular system, as disclosed, for example, in U.S. Pat. No. 5,102,417 (Palmaz), U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634 (Narciso, Jr.), and WO 91 / 12779 (Medtronic, Inc.) and WO 90 / 13332 (Cedars-Sanai Medical Center).

[0179] The term "deposited" means that the active compound is coated, adsorbed, disposed on, or incorporated into the device by methods known in the art. For example, the active compound can be embedded within and released from a polymeric material coating or spanning the medical device ("matrix type"), or surrounded by and released through such a polymeric material ("reservoir type"). In the latter example, the active compound can be encapsulated within or bonded to the polymeric material using one or more techniques for creating such materials known in the art. In other formulations, the active compound can be attached to the surface of the medical device without the need for a coating, e.g., by a removable bond, and released over time or removed by active mechanical or chemical processes. In other formulations, the active compound can be in a permanently immobilized form that provides the active compound at the implantation site.

[0180] In certain embodiments, active compounds can be incorporated into polymer compositions during the formation of biocompatible coatings for medical devices such as stents. Coatings made from these components are generally homogeneous and useful for coating many devices designed for implantation.

[0181] The polymer may be either a biostable or bioabsorbable polymer depending on the desired release rate or desired degree of polymer stability, although bioabsorbable polymers are often preferred for this embodiment because, unlike biostable polymers, they typically do not persist long enough after implantation to cause adverse chronic local responses. Bioabsorbable polymers that can be used include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoesters , polyphosphoester urethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonates), copoly(ether esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes; biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid; polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinked or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art.Biostable polymers with relatively low chronic tissue reaction, such as polyurethane, silicone, and polyester, can also be used, as can other polymers, provided they can be dissolved and cured or polymerized in the medical device. Examples of such polymers include polyolefins, polyisobutylene, and ethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatics, such as polystyrene; polyvinyl esters, such as polyvinyl acetate; ethylene-methyl methacrylate copolymers, and acrylonitrile. copolymers of vinyl monomers and copolymers of vinyl monomers with olefins, such as tolyl-styrene copolymer, ABS resin, and ethylene-vinyl acetate copolymer; pyran copolymers; polyhydroxypropyl methacrylamide phenol; polyhydroxyethyl-aspartamide-phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

[0182] The polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, tubes, prostheses, and the like.

[0183] In one embodiment of the invention, a compound of the invention, or a pharmaceutically acceptable salt thereof, is bound to a polymer or semipermeable polymer matrix that is formed into a stent or stent-graft device.

[0184] Typically, the polymer is applied to the surface of the implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be used for this purpose. Spraying methods include conventional methods as well as microdeposition techniques using inkjet-type dispensers. Additionally, photopatterning can be used to deposit the polymer onto the implantable device to place it only in specific portions of the device. This coating of the device provides a uniform layer around the device and improves the diffusion of various analytes through the coating of the device.

[0185] In one embodiment of the present invention, the compound of the present invention or its pharmaceutically acceptable salt is formulated for release from a polymer coating into the environment in which the medical device is placed.Preferably, the active compound is released in a controlled manner over an extended period of time (e.g., several months) using at least one of several well-known techniques, including a polymer carrier or layer for controlling elution.Some of these techniques are described in U.S. Patent Application Publication No. 2004 / 0243225, the entire disclosure of which is incorporated herein in its entirety.

[0186] Additionally, the reagents and reaction conditions of the polymer composition can be manipulated to control the release of the active compound from the polymer coating, as described, for example, in U.S. Pat. No. 6,770,729, which is incorporated herein in its entirety. For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of the active compound from the polymer coating. In a variation on this theme, the diffusion coefficient of one or more polymer coatings can be controlled to regulate the ability of analytes present in the environment in which the medical device is placed (e.g., analytes that promote the degradation or hydrolysis of a portion of the polymer) to access one or more components within the polymer composition (and, for example, thereby, regulate the release of the active compound from the polymer coating). Yet another embodiment of the present invention includes a device having multiple polymer coatings, each with multiple diffusion coefficients. In such an embodiment of the present invention, the release of the active compound from the polymer coating can be regulated by the multiple polymer coatings.

[0187] In yet another embodiment of the present invention, the release of the active compound from the polymer coating is controlled by adjusting one or more properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds or the pH of the polymer composition. For example, a polymer composition can be designed to release the active compound in response to a decrease in the pH of the polymer composition.

[0188] kit The invention also provides a kit comprising a compound of the invention or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent to a mammal to treat or prevent a disease or condition that benefits from ALK2 inhibition. In one embodiment, the mammal is a human.

[0189] Those skilled in the art will appreciate that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in view of the information known to those skilled in the art, and can be made without departing from the scope of the invention or any embodiment thereof. [Example]

[0190] Having described the invention in detail, the same will be more clearly understood by reference to the following examples, which are included for illustrative purposes only and are not intended to limit the invention. Part 1 shows the synthesis of exemplary compounds of the invention. Part 2 shows the preparation of various exemplary 3-substituted-(4-amino-1H-imidazol-1-yl) reagents. Part 3 presents biological assay data for exemplary compounds of the invention.

[0191] For purposes of the present invention, the numerical descriptors "pyrrolo[2,1-f][1,2,4]triazine" and "pyrrolo[1,2-f][1,2,4]triazine," etc., are understood to be synonymous in the context of the chemical names provided for the compounds disclosed herein and, therefore, may and often are used interchangeably. As a non-limiting example, the chemical names "2,4-dichloropyrrolo[2,1-f][1,2,4]triazine" and "2,4-dichloropyrrolo[1,2-f][1,2,4]triazine" are both understood to refer to compounds having the structure: [ka]

[0192] As another non-limiting example, the chemical names "2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine" and "2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine" are both understood to refer to a compound having the structure: [ka]

[0193] Part 1: Synthesis of imidazole-containing inhibitors of ALK2 kinase Scheme 1 [ka] Preparation of 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) To a solution of 2,4-dichlorofuro[3,2-d]pyrimidine (1a) (0.71 g, 3.74 mmol; CAS number 956034-07-4) in 2-propanol (20 mL), DIPEA (1.63 mL, 9.36 mmol) and 1-methyl-1H-imidazol-4-amine hydrochloride (0.5 g, 3.74 mmol) were added and heated to reflux for 24 hours (h). The reaction mixture was concentrated to dryness under vacuum, and the resulting residue was triturated with water. The resulting solid was collected by filtration and dried under vacuum to give 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (550 mg, 59% yield) as a brown solid. 1 H NMR(300MHz,DMSO-d6)δ10.89(s,1H,D2O exchangeable),8.35(d,J=2.1Hz,1H),7.52(d,J=1.6Hz,1H),7.39(d,J=1.3 Hz,1H),7.03(d,J=2.1Hz,1H),3.71(s,3H);MS(ES+):250.3(M+1),272.3,274.3(M+Na),(ES-):248.2(M-1).

[0194] Scheme 2 [ka] Preparation of (S)-(1-(4-((1-methyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (2a) A stirred suspension of 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (100 mg, 0.40 mmol), (S)-pyrrolidin-2-ylmethanol (122 mg, 1.20 mmol) in N-methyl-2-pyrrolidinone (1 mL) was microwaved for 2 h at 150° C. The reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (2×20 mL), dried, filtered, and concentrated in vacuo. The crude residue was purified by combiflash (silica gel, 12 g, eluted with chloroform / CMA80) to give (S)-(1-(4-((1-methyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (2a) (43 mg, 34% yield) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6)δ9.90(s,1H,D2O exchangeable),8.00(d,J=2.1Hz,1H),7.44(s, 1H),7.42(d,J=1.4Hz,1H),6.71(d,J=2.1Hz,1H),4.94(s,1H,D2O exchangeable),4.13 (s,1H),3.83-3.69(m,1H),3.64(s,3H),3.62-3.49(m,1H),3.48-3.23(m,2H) ,2.07-1.83(m,4H);MS(ES+):315.4(M+1),337.5(M+Na),(ES-):313.4(M-1). HPLC purity: 98.70%.

[0195] Scheme 3 [ka] Preparation of (R)-(1-(4-((1-methyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (3a) Following the procedure reported in Scheme 2, 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (100 mg, 0.40 mmol) was reacted with (R)-pyrrolidin-2-ylmethanol (122 mg, 1.20 mmol) in NMP (1 mL) to give, after workup and purification, (R)-(1-(4-((1-methyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (3a) (65 mg, 52% yield) as a buff-colored solid; 1 H NMR (300MHz, DMSO-d6) δ9.91 (s, 1H, D2O exchangeable), 8.00 (d, J=2.2Hz, 1H), 7.44 (s, 1H),7.42(d,J=1.4Hz,1H),6.71(d,J=2.1Hz,1H),4.93(s,1H,D2O exchangeable),4.13 (s,1H),3.82-3.69(m,1H),3.64(s,3H),3.61-3.48(m,1H),3.48-3.23(m,2H) ,2.06-1.80(m,4H);MS(ES+):315.4(M+1),337.4(M+Na),(ES-):313.3(M-1).

[0196] Scheme 4 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4c)

[0197] Step 1: Preparation of 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) Compound 4b was prepared from compound 4a according to the procedure reported by Mastalerz, Harold et al. in the international patent application published on January 10, 2008 as WO 2008 / 005956 (incorporated by reference), which gave 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) as a pale solid; 1 H NMR(300MHz,DMSO-d6)δ11.15(s,1H),7.75-7.67(m,1H),7.54(s,1H),7.44(s,1H),7.35(dd,J=4.5,1.5Hz ,1H),6.68(dd,J=4.4,2.6Hz,1H),3.70(s,3H);MS(ES+):249.3(M+1),271.3(M+Na);MS(ES-):247.2(M-1).

[0198] Step 2: Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4c) Compound 4c was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4b) (100 mg, 0.40 mmol), 2-(pyrrolidin-2-yl)pyridine (179 mg, 1.21 mmol) and DIPEA (0.21 mL, 1.21 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography [silica (24 g), eluting with 0–20% CMA 80 in CHCl 3 ], N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4c) (50 mg, 35% yield) as a yellow solid; 1H NMR(300MHz,DMSO-d6)δ10.24(s,1H),8.67-8.56(m,1H),7.67(td,J=7.7,1.8Hz,1H),7.4 4-7.32(m,2H),7.28-7.15(m,2H),7.06(dd,J=4.4,1.7Hz,1H),6.86-6.67(m,1H),6.36(d d,J=4.4,2.5Hz,1H),5.29(d,J=8.3Hz,1H),3.81(t,J=9.0Hz,1H),3.67-3.54(m,1H),3.5 3(s,3H),2.46-2.24(m,1H),2.09-1.75(m,3H);MS(ES+):361.5(M+1);MS(ES-)3594(M-1).

[0199] Scheme 5 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (5a) Compound 5a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (100 mg, 0.40 mmol), DIPEA (155 mg, 1.20 mmol), and 2-(pyrrolidin-2-yl)pyridine hydrochloride (148 mg, 0.8 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by flash chromatography [silica (12 g), eluting with 0–20% CMA 80 in CHCl], N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (5a) (22 mg, 15% yield) as an off-white solid; 1H NMR(300MHz,DMSO-d6)δ9.83(s,1H,D2O exchangeable),8.61(s,1H),8.00(s,1H),7.66(td,J=7. 6,1.8Hz,1H),7.38-7.27(m,1H),7.26-7.18(m,1H),7.15(d,J=7.8Hz,1H),6.84-6.67( m,1H),6.67-6.44(m,1H),5.29(d,J=8.2Hz,1H),3.99-3.81(m,1H),3.78-3.60(m,1H), 3.52(s,3H),2.46-2.27(m,1H),2.06-1.74(m,3H);MS(ES+):362.4(M+1),384.5(M+Na).

[0200] Scheme 6 [ka] Preparation of (S)-(1-(4-(1-methyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (6a) Compound 6a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4b) (50 mg, 0.2 mmol), (S)-pyrrolidin-2-ylmethanol (61 mg, 0.6 mmol), and DIPEA (0.11 mL, 0.6 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography [silica (24 g), eluting with 0–40% CMA80 in CHCl3], (S)-(1-(4-(1-methyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (6a) (34 mg, 54% yield); 1H NMR(300MHz,DMSO-d6)δ10.32(s,1H),7.47(s,2H),7.35(dd,J=2.4,1.7Hz,1 H),7.08(d,J=3.5Hz,1H),6.36(dd,J=4.4,2.4Hz,1H),4.81(t,J=5.0Hz,1H), 4.16-4.07(m,1H),3.82-3.70(m,1H),3.65(s,3H),3.54-3.42(m,1H),3.36- 3.25(m,2H),2.12-1.79(m,4H);MS(ES+):314.4(M+1);MS(ES-):312.4(M-1).

[0201] Scheme 7 [ka] Preparation of (R)-(1-(4-(1-methyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (7a) Compound 7a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4b) (50 mg, 0.2 mmol), (R)-pyrrolidin-2-ylmethanol (61 mg, 0.6 mmol), and DIPEA (0.11 mL, 0.6 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography [silica (24 g), eluted with 0–40% CMA 80 in CHCl], (R)-(1-(4-(1-methyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (7a) (27 mg, 43% yield); 1H NMR(300MHz,DMSO-d6)δ10.32(s,1H),7.47(s,2H),7.35(dd,J=2.5,1.7Hz,1 H),7.08(dd,J=4.5,1.7Hz,1H),6.36(dd,J=4.4,2.4Hz,1H),4.81(t,J=5.0H z,1H),4.20-4.04(m,1H),3.82-3.69(m,1H),3.65(s,3H),3.54-3.42(m,1H) ,3.35-3.24(m,2H),2.11-1.78(m,4H);MS(ES+):314.5(M+1),336.5(M+Na).

[0202] Scheme 8 [ka] Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (8c)

[0203] Step 1: Preparation of 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (8b) Compound 8b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (240 mg, 1.28 mmol; CAS number 918538-05-3) in 2-propanol (5 mL) using DIPEA (0.67 mL, 3.83 mmol) and 1-phenyl-1H-imidazol-4-amine, HCl (8a) (250 mg, 1.28 mmol; prepared according to the procedure reported by Sakamoto, T. et al. in Bioorganic & Medicinal Chemistry, 17(14), 5015-5026; 2009, and by Francini, Cinzia Maria et al. in Chem. Med. Chem., 10(12), 2027-2041) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (8b) (302 mg, 76% yield); 1 H NMR(300MHz,DMSO-d6)δ11.35(s,1H),8.35-8.18(m,1H),7.95-7.87(m,1H),7.81-7.73(m,1H),7.65(d,J=7.9Hz ,2H),7.56(t,J=7.7Hz,2H),7.46-7.35(m,2H),6.80-6.66(m,1H);MS(ES+):311.3(M+1);MS(ES-):309.3(M-1).

[0204] Step 2: Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (8c) Compound 8c was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (8b) (100 mg, 0.32 mmol), (S)-pyrrolidin-2-ylmethanol (98 mg, 0.97 mmol), and DIPEA (0.17 mL, 0.97 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography [silica (24 g), eluting with 0–40% CMA 80 in CHCl 3 ], the TFA salt of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (8c) (29 mg, 24% yield) as a pale off-white solid (obtained by reverse-phase column purification of the final compound using 0.1% TFA in acetonitrile / water as the mobile phase); 1 H NMR(300MHz,DMSO-d6)δ10.58(s,1H),8.32(s,1H),7.98(s,1H),7.76(d,J=7.8Hz,2H),7.51(t,J=7.7Hz,2H),7.43-7.37(m,1H),7.37-7.31(m,1H) ,7.23-7.09(m,2H),7.00(s,1H),6.48-6.31(m,1H),4.26-4.09(m,1H),3. 84-3.68(m,1H),3.59-3.44(m,1H),3.44-3.28(m,2H),2.15-1.78(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-74.29; MS(ES+): 376.5(M+1); MS(ES-): 374.4(M-1), 410.4(M+Cl).

[0205] Scheme 9 [ka] Preparation of N-(1-phenyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (9a) Compound 9a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (8b) (100 mg, 0.32 mmol), 2-(pyrrolidin-2-yl)pyridine hydrochloride (149 mg, 0.81 mmol), and DIPEA (0.28 mL, 1.61 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography [silica (24 g), eluting with 0–40% CMA 80 in CHCl 3 ], N-(1-phenyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (9a) (27 mg, 20% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.55(s,1H),8.43(s,1H),8.26-8.08(m,1H),8.04-7.76(m,1H),7.67-7.52(m,6H),7.49-7.34(m,3H),7.20-7.1 0(m,1H),6.42(dd,J=4.4,2.5Hz,1H),5.47(d,J=8.3Hz,1H),3.91-3.78(m,1H),3.70-3.62(m,1H),2.53-2.36(m,1H),2.14-1.73(m,3H); 19 F NMR (282MHz, DMSO-d6) δ-74.26; MS(ES+): 423.5(M+1), 445.5(M+Na); MS(ES-): 421.4(M-1).

[0206] Scheme 10 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (10a) Compound 10a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4b) (80 mg, 0.32 mmol), 2-phenylpyrrolidine (142 mg, 0.97 mmol), and DIPEA (0.17 mL, 0.97 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by flash chromatography [silica (24 g), eluting with 0–40% CMA 80 in CHCl], N-(1-methyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (10a) (31 mg, 27% yield) as a pale off-white solid; 1 H NMR(300MHz,DMSO-d6)δ10.20(s,1H),7.41-7.25(m,6H),7.24-7.15(m,1H),7.05(dd,J= 4.4,1.7Hz,1H),6.78-6.66(m,1H),6.35(dd,J=4.4,2.4Hz,1H),5.32(d,J=8.0Hz,1H),3. 84-3.70(m,1H),3.64-3.54(m,1H),3.49(s,3H),2.41-2.30(m,1H),2.01-1.76(m,3H);M S(ES+): 360.5(M+1), 382.5(M+Na); MS(ES-): 358.4(M-1), 394.5(M+Cl); HPLC purity: 95.75%.

[0207] Scheme 11 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-3-yl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (11a) Compound 11a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (100 mg, 0.4 mmol) and 3-(pyrrolidin-2-yl)pyridine (119 mg, 0.8 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-3-yl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (11a) (23 mg, 16% yield) as an off-white solid after workup and purification by reverse-phase flash chromatography (silica gel C-18, 24 g, eluted with 0.1% TFA in acetonitrile and 0.1% TFA in water, 0% to 100%). 1 H NMR(300MHz,DMSO-d6)δ9.83(s,1H,D2O exchangeable),8.54(s,1H),8.41(dd,J=4.8,1.6Hz,1H),8.01( d,J=2.2Hz,1H),7.62(d,J=8.0Hz,1H),7.32(dd,J=7.8,4.7Hz,2H),6.72(s,1H),6.70-6.30(m, 1H),5.35(d,J=7.9Hz,1H),3.98-3.81(m,1H),3.77-3.60(m,1H),3.51(s,3H),2.47-2.33(m,1 H),2.02-1.73(m,3H);MS(ES+):362.5(M+1),384.5(M+Na),745.8(2M+Na),(ES-):360.4(M-1).

[0208] Scheme 12 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)thieno[3,2-d]pyrimidin-4-amine (12c)

[0209] Step 1: Preparation of 2-chloro-N-(1-methyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (12b) Compound 12b was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (0.31 g, 1.5 mmol; CAS No. 16234-14-3) in 2-propanol (10 mL) using 1-methyl-1H-imidazol-4-amine hydrochloride (0.2 g, 1.5 mmol) and DIPEA (0.65 mL, 3.74 mmol) according to the procedure described in Scheme 1. This afforded 2-chloro-N-(1-methyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (12b) (165 mg, 42% yield) as a yellow solid after workup and purification by flash column chromatography (silica gel, 24 g, eluted with CMA80 in chloroform); 1 H NMR(300MHz,DMSO-d6)δ10.82(s,1H),8.21(d,J=5.4Hz,1H),7.55(s,1H),7.41(s,1H),7. 36(d,J=5.4Hz,1H),3.71(s,3H);MS(ES+):266.3(M+1),288.3(M+Na),(ES-):264.2(M-1).

[0210] Step 2: Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)thieno[3,2-d]pyrimidin-4-amine (12c) Compound 12c was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (12b) (100 mg, 0.38 mmol) and 2-(pyrrolidin-2-yl)pyridine (167 mg, 1.13 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica C-18, 30 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)thieno[3,2-d]pyrimidin-4-amine (12c) (86 mg, 61% yield) as an off-white solid; 1H NMR(300MHz,DMSO-d6)δ9.81(s,1H,D2O exchangeable),8.62(s,1H),8.02-7.80(m,1H),7 .66(td,J=7.6,1.8Hz,1H),7.31(s,1H),7.27-7.05(m,3H),6.62(s,1H),5.34(d, J=8.2Hz,1H),4.01-3.84(m,1H),3.79-3.64(m,1H),3.64-3.43(m,3H),2.44(s, 1H),2.08-1.77(m,3H);MS(ES+):378.5(M+1),400.5(M+Na),(ES-):376.4(M-1).

[0211] Scheme 13 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (13a) Compound 13a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (100 mg, 0.4 mmol) and 2-phenylpyrrolidine (147 mg, 1.0 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, N-(1-methyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (13a) (8 mg, 6% yield) was obtained as a colorless solid. 1H NMR(300MHz,DMSO-d6)δ11.50(s,1H,D2O exchangeable),8.33(s,1H),7.68(s,1H),7.36(d,J=5.6Hz,4H),7.32-7.20(m,1H),6.97(s,1H),6.58(s,1H), 5.47(d,J=7.2Hz,1H),3.96(s,1H),3.74-3.63(m,1H),3.54(s,3H),2. 49-2.34(m,1H),2.08(s,1H),2.01-1.83(m,2H);MS(ES+):361.5(M+1).

[0212] Scheme 14 [ka] Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (14b)

[0213] Step 1: Preparation of 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (14a) Compound 14a was prepared from 2,4-dichlorofuro[3,2-d]pyrimidine (1a) (400 mg, 2.12 mmol) in 2-propanol (30 mL) using DIPEA (0.92 mL, 5.29 mmol) and 1-phenyl-1H-imidazol-4-amine,HCl (8a) (414 mg, 2.12 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (14a) (267 mg, 41% yield) as a light brown solid; 1H NMR(300MHz,DMSO-d6)δ11.01(s,1H),8.38(d,J=2.2Hz,1H),8.23(d,J=1.6Hz,1H),7.88(d,J=1.7Hz,1H),7.70-7.63( m,2H),7.63-7.50(m,2H),7.45-7.35(m,1H),7.06(d,J=2.2Hz,1H);MS(ES+):312.3(M+1),334.3(M+Na),310.3(M-1).

[0214] Step 2: Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (14b) Compound 14b was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (14a) (100 mg, 0.32 mmol) and (S)-pyrrolidin-2-ylmethanol (81 mg, 0.8 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (14b) (65 mg, 54% yield) as a brown solid after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO. 1H NMR(300MHz,DMSO-d6)δ10.13(s,1H,D2O exchangeable),8.18(d,J=1.6Hz,1H),8.04(d,J=2.1Hz,1 H),7.95(d,J=1.7Hz,1H),7.80-7.64(m,2H),7.51(t,J=7.7Hz,2H),7.34(t,J=7.4Hz,1H) ,6.74(d,J=2.1Hz,1H),5.00(s,1H,D2O exchangeable),4.20(s,1H),3.85-3.69(m,1H),3.66-3.54 (m,1H),3.55-3.41(m,2H),2.09-1.83(m,4H);MS(ES+):377.5(M+1),(ES-):375.4(M-1).

[0215] Scheme 15 [ka] Preparation of (S)-N-(1-methyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (15a) Compound 15a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4b) (80 mg, 0.32 mmol), (S)-2-phenylpyrrolidine (142 mg, 0.97 mmol), DIPEA (0.17 mL, 0.97 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-N-(1-methyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (15a) (42 mg, 36% yield) as an off-white solid; 1H NMR(300MHz,DMSO-d6)δ10.20(s,1H,D2O exchangeable),7.40-7.34(m,2H),7.34-7.26(m,4 H),7.25-7.15(m,1H),7.05(dd,J=4.3,1.7Hz,1H),6.73(s,1H),6.36(dd,J=4.4,2 .4Hz,1H),5.33(d,J=8.0Hz,1H),3.86-3.70(m,1H),3.66-3.50(m,1H),3.49(s,3H) ),2.42-2.28(m,1H),2.02-1.71(m,3H);MS(ES+):360.5(M+1),(ES-):358.5(M-1).

[0216] Scheme 16 [ka] Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (16b)

[0217] Step 1: Preparation of 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (16a) Compound 16a was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (500 mg, 2.44 mmol) in 2-propanol (30 mL) using DIPEA (1.07 mL, 6.1 mmol) and 1-phenyl-1H-imidazol-4-amine,HCl (8a) (477 mg, 2.45 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (16a) (340 mg, 43% yield) as a pale pink solid; 1H NMR(300MHz,DMSO-d6)δ10.97(s,1H,D2O exchangeable),8.27(s,1H),8.24(d,J=5.4Hz,1H),7.96(d,J=1.7Hz,1 H),7.73-7.65(m,2H),7.62-7.52(m,2H),7.46-7.36(m,2H);MS(ES+):328.3(M+1)(ES-):326.3(M-1).

[0218] Step 2: Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (16b) Compound 16b was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (16a) (100 mg, 0.31 mmol) and (S)-pyrrolidin-2-ylmethanol (77 mg, 0.76 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (16b) (95 mg, 79% yield) as a brown solid after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO. 1H NMR(300MHz,DMSO-d6)δ10.14(s,1H,D2O exchangeable),8.20(d,J=1.6Hz,1H),7.98(d,J=1.6Hz,1H ),7.93(d,J=5.4Hz,1H),7.72(s,2H),7.51(t,J=7.8Hz,2H),7.35(t,J=7.4Hz,1H),7.10(d, J=5.4Hz,1H),5.03(s,1H,D2O exchangeable),4.24(s,1H),3.87-3.70(m,1H),3.70-3.45(m,1H),3.4 3-3.36(m,2H),2.12-1.78(m,4H);MS(ES+):393.5(M+1),415.5(M+Na),(ES-):391.4(M-1).

[0219] Scheme 17 [ka] Preparation of (S)-N4-(1-phenyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)thieno[3,2-d]pyrimidine-2,4-diamine (17a) Compound 17a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (16a) (100 mg, 0.31 mmol), (S)-1-phenylethanamine (111 mg, 0.92 mmol) and DIPEA (0.2 mL, 1.2 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-N4-(1-phenyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)thieno[3,2-d]pyrimidine-2,4-diamine (17a) (65 mg, 52% yield) as an off-white solid; 1H NMR (300MHz, DMSO-d6) δ10.10 (s, 1H, D2O exchangeable), 8.33-8.16 (m, 1H), 8.14 (s, 1H), 7.97-7.87(m,1H),7.76-7.63(m,2H),7.57(t,J=7.8Hz,2H),7.48-7.30(m,3H),7 .33-7.19(m,3H),7.22-7.07(m,1H),7.04(d,J=5.4Hz,1H),5.32-5.16(m,1H),1 .50(d,J=7.0Hz,3H);MS(ES+):413.5(M+1),(ES-):411.5(M-1);HPLC purity:91.57%.

[0220] Scheme 18 [ka] Preparation of (S)-N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (18a) Compound 18a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) (100 mg, 0.4 mmol), (S)-2-(pyrrolidin-2-yl)pyridine dihydrochloride (98 mg, 0.44 mmol) and DIPEA (0.17 mL, 0.97 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (18a) (11 mg, 8% yield) as a pale yellow solid; 1H NMR (300MHz, DMSO-d6) δ10.24 (s, 1H, D2O exchangeable), 8.66-8.56 (m, 1H), 7.67 (td, J=7.7, 1.8H z,1H),7.43-7.31(m,2H),7.27-7.16(m,2H),7.06(dd,J=4.5,1.7Hz,1H),6.75(bs,1H), 6.36(dd,J=4.4,2.4Hz,1H),5.29(d,J=8.2Hz,1H),3.87-3.74(m,1H),3.66-3.56(m,1H) ,3.53(s,3H),2.44-2.31(m,1H),2.05-1.79(m,3H);MS(ES+):361.5(M+1),383.5(M+Na).

[0221] Scheme 19 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-3-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (19a) Compound 19a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) (100 mg, 0.4 mmol), 3-(pyrrolidin-2-yl)pyridine (119 mg, 0.804 mmol), and DIPEA (0.21 mL, 1.21 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-3-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (19a) (11 mg, 8% yield) as a pale yellow solid; 1H NMR (300MHz, DMSO-d6) δ10.24 (s, 1H, D2O exchangeable), 8.66-8.56 (m, 1H), 7.67 (td, J=7.7, 1.8H z,1H),7.43-7.31(m,2H),7.27-7.16(m,2H),7.06(dd,J=4.5,1.7Hz,1H),6.75(bs,1H), 6.36(dd,J=4.4,2.4Hz,1H),5.29(d,J=8.2Hz,1H),3.87-3.74(m,1H),3.66-3.56(m,1H) ,3.53(s,3H),2.44-2.31(m,1H),2.05-1.79(m,3H);MS(ES+):361.5(M+1),383.5(M+Na).

[0222] Scheme 20 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-4-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (20a) Compound 20a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) (100 mg, 0.4 mmol), 4-(pyrrolidin-2-yl)pyridine (119 mg, 0.8 mmol) and DIPEA (0.21 mL, 1.21 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-methyl-1H-imidazol-4-yl)-2-(2-(pyridin-4-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (20a) (23 mg, 16% yield) as a light brown solid; 1H NMR (300MHz, DMSO-d6) δ10.26 (s, 1H, D2O exchangeable), 8.55-8.42 (m, 2H), 7.37 (s, 2H), 7.34 -7.30(m,2H),7.07(dd,J=4.4,1.7Hz,1H),6.74(s,1H),6.36(dd,J=4.5,2.4Hz,1H), 5.30(d,J=8.3Hz,1H),3.86-3.73(m,1H),3.68-3.58(m,1H),3.52(s,3H),2.47-2.30 (m,1H),2.01-1.73(m,3H);MS(ES+):361.5(M+1),383.5(M+Na),(ES-):359.4(M-1).

[0223] Scheme 21 [ka] Preparation of (S)-N4-(1-methyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)quinazoline-2,4-diamine (21c)

[0224] Step 1: Preparation of 2-chloro-N-(1-methyl-1H-imidazol-4-yl)quinazolin-4-amine (21b) Compound 21b was prepared according to the procedure reported by Su, Qibin et al. in Journal of Medicinal Chemistry, 57(1), 144-158; 2014, which gave 2-chloro-N-(1-methyl-1H-imidazol-4-yl)quinazolin-4-amine (21b) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.97(s,1H,D2O exchangeable),8.72(dd,J=8.3,1.3Hz,1H),7.84(ddd,J=8.3,6.9,1.3Hz,1H),7.6 8(dd,J=8.4,1.2Hz,1H),7.62-7.50(m,3H),3.73(s,3H);MS(ES+):260.3(M+1),282.3(M+Na),(ES-):258.3(M-1).

[0225] Step 2: Preparation of (S)-N4-(1-methyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)quinazoline-2,4-diamine (21c) Compound 21c was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)quinazolin-4-amine (21b) (100 mg, 0.39 mmol), (S)-1-phenylethanamine (140 mg, 1.16 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, (S)-N-(1-methyl-1H-imidazol-4-yl)-N-(1-phenylethyl)quinazoline-2,4-diamine (21c) (24 mg, 18% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ9.96(s,1H,D2O exchangeable),8.36(d,J=8.2Hz,1H),7.96(s,1H),7.55-7.39(m,4H),7.37-7.3(m,5H),7.08-6.9 3(m,1H),5.29(s,1H),3.69(s,3H),1.50(d,J=7.0Hz,3H);MS(ES+):345.5(M+1),367.5(M+Na),(ES-):343.4(M-1),379.5(M+Cl).

[0226] Scheme 22 [ka] Preparation of (S)-(1-(6-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (22c)

[0227] Step 1: Preparation of 2-chloro-6-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (22b) Compound 22b was prepared from 2,4-dichloro-6-methylthieno[2,3-d]pyrimidine (22a) (500 mg, 2.28 mmol, CAS No. 76872-23-6) in 2-propanol (30 mL) using DIPEA (1.0 mL, 5.71 mmol) and 1-phenyl-1H-imidazol-4-amine,HCl (8a) (363 mg, 2.28 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-6-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (22b) (340 mg, 44% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ10.88(s,1H,D2O exchangeable),8.25(d,J=1.7Hz,1H),7.91(d,J=1.7Hz,1H),7.72(s,1H),7.70-7.63(m ,2H),7.57(dd,J=8.7,7.1Hz,2H),7.46-7.36(m,1H),2.56(d,J=1.2Hz,3H);MS(ES+):364.3(M+Na),(ES-):340.3(M-1).

[0228] Step 2: Preparation of (S)-(1-(6-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (22c) Compound 22c was prepared from 2-chloro-6-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (22b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (89 mg, 0.88 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(6-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (22c) (65 mg, 55% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ9.98(s,1H,D2O exchangeable),8.20(s,1H),7.96(d,J=1.6Hz ,1H),7.84-7.60(m,2H),7.57-7.42(m,3H),7.40-7.29(m,1H),4.94(s,1H,D2 (O exchangeable), 4.42-4.02 (m, 1H), 3.87-3.39 (m, 2H), 2.63-2.51 (m, 1H), 2.49-2.35 ( m,4H),2.13-1.76(m,4H);MS(ES+):407.5(M+1),429.5(M+Na),(ES-):405.4.

[0229] Scheme 23 [ka] Preparation of (S)-(1-(6-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (23c)

[0230] Step 1: Preparation of 2-chloro-6-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (23b) Compound 23b was prepared from 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (23a) (500 mg, 2.28 mmol, CAS number 35265-82-8) in 2-propanol (30 mL) using DIPEA (1.00 mL, 5.71 mmol) and 1-phenyl-1H-imidazol-4-amine,HCl (8a) (363 mg, 2.28 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-6-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (23b) (340 mg, 44% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ10.75(s,1H,D2O exchangeable),8.27(d,J=1.6Hz,1H),7.92(d,J=1.6Hz,1H),7.68(dd,J=7.9,1.6Hz,2H),7.57(d d,J=8.6,7.1Hz,2H),7.45-7.36(m,1H),7.17-7.08(m,1H),2.60(s,3H);MS(ES+):342.3(M+1),364.3(M+Na),(ES-):340.3(M-1).

[0231] Step 2: Preparation of (S)-(1-(6-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (23c) Compound 23c was prepared from 2-chloro-6-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (23b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (89 mg, 0.88 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. The workup and reverse-phase flash chromatography [(silica gel)] afforded the compound 23c. C-18, 24 g), eluted with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3 to give (S)-(1-(6-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (23c) (65 mg, 55% yield) as an off-white solid; 1 H NMR(300MHz,DMSO-d6)δ9.95(s,1H,D2O exchangeable),8.19(d,J=1.6Hz,1H),7.96(d,J=1.6Hz, 1H),7.72(s,2H),7.51(t,J=7.7Hz,2H),7.34(t,J=7.4Hz,1H),6.83(d,J=1.5Hz,1H),5 .37-4.71(m,1H,D2O exchangeable),4.36-4.05(m,1H),3.85-3.69(m,1H),3.70-3.38(m,3H),2. 52(s,3H),2.10-1.80(m,4H);MS(ES+):407.5(M+1),429.5(M+Na),(ES-):405.5(M-1).

[0232] Scheme 24 [ka] Preparation of (S)-N4-(1-phenyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)quinazoline-2,4-diamine (24b)

[0233] Step 1: Preparation of 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)quinazolin-4-amine (24a) Compound 24a was prepared from 2,4-dichloroquinazoline 21a (180 mg, 0.9 mmol; CAS number 607-68-1) in 2-propanol (5 mL) using DIPEA (0.51 mL, 2.92 mmol) and 1-phenyl-1H-imidazol-4-amine, HCl 8a (177 mg, 0.9 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)quinazolin-4-amine 24a (125 mg, 43% yield) as an off-white solid; 1 H NMR(300MHz,DMSO-d6)δ11.18(s,1H,D2O exchangeable),8.77(d,J=8.2Hz,1H),8.29( d,J=1.7Hz,1H),8.04(d,J=1.7Hz,1H),7.87(ddd,J=8.3,7.0,1.3Hz,1H),7.7 3(dd,J=8.4,1.2Hz,1H),7.70-7.65(m,2H),7.60(tdd,J=8.5,6.9,1.5Hz,3H) ,7.46-7.37(m,1H);MS(ES+):322.4(M+1),344.4(M+Na),(ES-):320.3(M-1).

[0234] Step 2: Preparation of (S)-N4-(1-phenyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)quinazoline-2,4-diamine (24b) Compound 24b was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)quinazolin-4-amine (24a) (100 mg, 0.31 mmol), (S)-1-phenylethanamine (113 mg, 0.93 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, (S)-N-(1-phenyl-1H-imidazol-4-yl)-N-(1-phenylethyl)quinazoline-2,4-diamine (24b) (86 mg, Yield 68%) as an off-white solid; 1 H NMR(300MHz,DMSO-d6)δ11.47-10.14(m,1H,D2O exchangeable),8.66-8.36(m,2H),8.22(d,J=1.7Hz,1H),7.82-7.63(m,1H),7.59(t,J=7.6Hz ,2H),7.51-7.28(m,9H),7.26-7.15(m,2H),5.35(q,J=7.2Hz,1H),1.57(d,J=6.9Hz,3H);MS(ES+):407.5(M+1),(ES-):405.6(M-1).

[0235] Scheme 25 [ka] Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (25c)

[0236] Step 1: Preparation of 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (25b) Compound 25b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (323 mg, 1.72 mmol) in 2-propanol (20 mL) using DIPEA (0.9 mL, 5.15 mmol) and 1-(4-fluorophenyl)-1H-imidazol-4-amine (25a) (440 mg, 2.06 mmol; prepared according to the procedure reported by Sakamoto, T. et al. in Bioorganic & Medicinal Chemistry, 17(14), 5015-5026; 2009, and by Francini, Cinzia Maria et al. in Chem. Med. Chem., 10(12), 2027-2041). This gave 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (25b) (381 mg, 68% yield) as a pale off-white solid; 1 H NMR(300MHz,DMSO-d6)δ11.35(s,1H,D2O exchangeable),8.21(d,J=1.6Hz,1H),7.87(d,J=1.6Hz,1H),7 .77(dd,J=2.6,1.5Hz,1H),7.74-7.65(m,2H),7.49-7.35(m,3H),6.72(dd,J=4.5,2.6Hz,1H); 19 F NMR (282MHz, DMSO) δ-114.97; MS(ES+): 329.3(M+1); MS(ES-): 327.3(M-1).

[0237] Step 2: Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (25c) Compound 25c was prepared from 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (25b) (100 mg, 0.32 mmol), (S)-pyrrolidin-2-ylmethanol (154 mg, 1.52 mmol) and DIPEA (0.16 mL, 0.91 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography [silica (24 g), eluting with 0–40% CMA80 in CHCl3], (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (25c) (40 mg, 33% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.53(s,1H,D2O exchangeable),8.20(d,J=1.6Hz,1H),7.93(d,J=1.6H z,1H),7.86-7.74(m,2H),7.39(dd,J=2.4,1.6Hz,1H),7.38-7.29(m,2H),7.15(dd,J= 4.5,1.7Hz,1H),6.39(dd,J=4.4,2.4Hz,1H),4.91(t,J=5.0Hz,1H,D2O exchangeable),4.26-4. 12(m,1H),3.83-3.69(m,1H),3.55-3.44(m,1H),3.39-3.25(m,2H),2.12-1.81(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-115.67; MS(ES+): 394.5(M+1), 416.5(M+Na); MS(ES-): 392.5(M-1).

[0238] Scheme 26 [ka] Preparation of (S)-(1-(4-((1-cyclopropyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (26c)

[0239] Step 1: Preparation of 2-chloro-N-(1-cyclopropyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (26b) Compound 26b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (268 mg, 1.43 mmol) in 2-propanol (5 mL) using DIPEA (1.25 mL, 7.14 mmol) and 1-cyclopropyl-1H-imidazol-4-amine hydrochloride (26a) (1.4 g, 7.14 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-cyclopropyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (26b) (225 mg, 57% yield) as a brownish solid; 1 H NMR(300MHz,DMSO-d6)δ11.19(s,1H,D2O exchangeable),7.73(dd,J=2.6,1.5Hz,1H),7.65(d,J=1.5Hz,1H),7.50(d,J=1.5Hz,1H ),7.35(dd,J=4.5,1.6Hz,1H),6.68(dd,J=4.5,2.6Hz,1H),3.62-3.46(m,1H),1.14-0.89(m,4H);MS(ES-):273.3(M-1).

[0240] Step 2: Preparation of (S)-(1-(4-((1-cyclopropyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (26c) Compound 26c was prepared from 2-chloro-N-(1-cyclopropyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (26b) (70 mg, 0.26 mmol), (S)-pyrrolidin-2-ylmethanol (129 mg, 1.27 mmol), and DIPEA (0.13 mL, 0.76 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by flash chromatography [silica (24 g), eluting with 0–40% CMA80 in CHCl3], (S)-(1-(4-((1-cyclopropyl-1H-imidazol-4)-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (26c) (22 mg, 25% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.31(s,1H,D2O exchangeable),7.60(d,J=1.4Hz,1H),7.49(d,J=1.6Hz, 1H),7.35(dd,J=2.4,1.6Hz,1H),7.09(dd,J=4.5,1.7Hz,1H),6.36(dd,J=4.4,2.4Hz,1H) ,4.77(t,J=5.1Hz,1H,D2O exchangeable),4.21-4.01(m,1H),3.80-3.64(m,1H),3.59-3.38(m,2H) ,3.39(s,2H),2.13-1.77(m,4H),1.07-0.83(m,4H);MS(ES+):340.5(M+1),362.5(M+Na).

[0241] Scheme 27 [ka] Preparation of N-(1-cyclopropyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (27a) Compound 27a was prepared from 2-chloro-N-(1-cyclopropyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (26b) (70 mg, 0.26 mmol), 2-(pyrrolidin-2-yl)pyridine (113 mg, 0.76 mmol), and DIPEA (0.13 mL, 0.76 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-cyclopropyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (27a) (48 mg, 51% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.19(s,1H,D2O exchangeable),8.59(s,1H),7.78-7.60(m,1H),7.52-7.43(m, 1H),7.41-7.32(m,1H),7.29-7.11(m,2H),7.09-6.99(m,1H),6.93-6.70(m,1H),6.46-6.26(m ,1H),5.43-5.21(m,1H),3.89-3.70(m,1H),3.42(s,1H),3.37-3.21(m,1H),2.47-2.29(m,1H) ,2.12-1.68(m,3H),1.09-0.87(m,3H),0.88-0.71(m,1H);MS(ES+):387.5(M+1),409.5(M+Na).

[0242] Scheme 28 [ka] Preparation of (S)-(1-(4-((1-cyclohexyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (28c)

[0243] Step 1: Preparation of 2-chloro-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (28b) Compound 28b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (376 mg, 2.0 mmol) in 2-propanol (10 mL) using DIPEA (1.05 mL, 6.0 mmol) and 1-cyclohexyl-1H-imidazol-4-amine hydrochloride 28a (572 mg, 2.4 mmol) according to the procedure described in Scheme 1. This afforded 2-chloro-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 28b (381 mg, 60% yield) as a pale off-white solid; 1 H NMR(300MHz,DMSO-d6)δ11.68(s,1H),8.76(s,1H),7.86(dd,J=2.6,1.5Hz,1H),7. 78(d,J=1.7Hz,1H),7.36(s,1H),6.79(dd,J=4.5,2.6Hz,1H),4.28(ddd,J=11.7,7 .9,3.8Hz,1H),2.10(d,J=11.9Hz,2H),1.85(d,J=13.3Hz,2H),1.72(dt,J=14.9,1 1.6Hz,3H),1.40(q,J=12.7Hz,2H),1.24(t,J=12.5Hz,1H);MS(ES+):317.3(M+1).

[0244] Step 2: Preparation of (S)-(1-(4-((1-cyclohexyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (28c) Compound 28c was prepared from 2-chloro-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (28b) (100 mg, 0.32 mmol), (S)-pyrrolidin-2-ylmethanol (160 mg, 1.56 mmol), and DIPEA (0.17 mL, 0.95 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-cyclohexyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (28c) (25 mg, 21% yield) as a pale off-white solid; 1 H NMR (300MHz, DMSO-d6) δ10.31 (s, 1H, D2O exchangeable), 7.66-7.51 (m, 2H), 7.43-7.28 (m, 1H), 7.18 -7.01(m,1H),6.45-6.22(m,1H),4.93-4.76(m,1H,D2O exchangeable),4.20-4.07(m,1H),4.07-3.92 (m,1H),3.83-3.65(m,1H),3.54-3.20(m,3H),2.13-1.84(m,6H),1.89-1.70(m,4H),1.72- 1.54(m,1H),1.47-1.12(m,3H);MS(ES+):382.5(M+1),404.5(M+Na);MS(ES-):380.4(M-1).

[0245] Scheme 29 [ka] Preparation of N-(1-cyclohexyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (29a) Compound 29a was prepared from 2-chloro-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (28b) (100 mg, 0.32 mmol), 2-(pyrrolidin-2-yl)pyridine (140 mg, 0.95 mmol), and DIPEA (0.17 mL, 0.95 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-cyclohexyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (29a) (47 mg, 35% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.25(s,1H,D2O exchangeable),8.64-8.52(m,1H),7.67(td,J=7.7,1.8Hz,1H),7.49(d,J=1.5Hz,1H),7 .38(s,1H),7.26-7.21(m,1H),7.19(d,J=7.9Hz,1H),7.08(dd,J=4.4,1.7Hz,1H),6.91-6.83(m,1H),6.36(dd,J=4.4,2. 5Hz,1H),5.33(d,J=8.1Hz,1H),3.87-3.70(m,2H),3.66-3.50(m,1H),2.42-2.28(m,1H),2.15-2.03(m,1H),2.03-1.78( m,6H),1.81-1.64(m,2H),1.67-1.51(m,1H),1.51-1.37(m,2H),1.37-1.15(m,1H).MS(ES+):429.6(M+1),451.6(M+Na).

[0246] Scheme 30 [ka] Preparation of N-(1-cyclopropyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (30a) Compound 30a was prepared from 2-chloro-N-(1-cyclopropyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (26b) (100 mg, 0.36 mmol), 2-phenylpyrrolidine (161 mg, 1.09 mmol), and DIPEA (0.19 mL, 1.09 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-cyclopropyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (30a) (74 mg, 53% yield) as a pale off-white solid; 1 H NMR(300MHz,DMSO-d6)δ10.36(s,1H,D2O exchangeable),7.89(s,1H),7.50-7.39(m,1H),7 .36-7.27(m,2H),7.26(d,J=7.5Hz,2H),7.23-7.16(m,1H),7.08-6.90(m,2H),6. 40(dd,J=4.4,2.4Hz,1H),5.33(d,J=7.9Hz,1H),4.00-3.29(m,3H),2.41-2.21(m ,1H),2.05-1.73(m,3H),1.11-0.76(m,4H).MS(ES+):386.5(M+1),408.5(M+Na).

[0247] Scheme 31 [ka] Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (31c)

[0248] Step 1: Preparation of 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (31b) Compound 31b was prepared from 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (500 mg, 2.44 mmol; CAS number 18740-39-1) in 2-propanol (10 mL) using DIPEA (1.70 mL, 9.75 mmol) and 1-phenyl-1H-imidazol-4-amine,HCl (8a) (716 mg, 3.66 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (31b) (640 mg, 80% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ11.06(s,1H,D2O exchangeable),8.26(d,J=1.7Hz,1H),8.04(d,J=5.6Hz,1H),7.94(d,J=1.6Hz,1H),7.71(d,J= 5.9Hz,1H),7.69-7.63(m,2H),7.62-7.54(m,2H),7.46-7.36(m,1H);MS(ES+):328.2(M+1),350.2(M+Na),(ES-):326.2(M-1).

[0249] Step 2: Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (31c) Compound 31c was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (31b) (100 mg, 0.31 mmol) and (S)-pyrrolidin-2-ylmethanol (93 mg, 0.92 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (31c) (95 mg, 79% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.16(s,1H,D2O exchangeable),8.22(s,1H),7.99(d,J=1.7 Hz,1H),7.89-7.59(m,2H),7.60-7.42(m,3H),7.35(t,J=7.3Hz,1H),7.03(d ,J=6.0Hz,1H),4.96(s,1H,D2O exchangeable),4.46-4.00(m,1H),3.95-3.36(m,4H), 2.17-1.82(m,4H);MS(ES+):393.5(M+1),415.5(M+Na),(ES-):391.4(M-1).

[0250] Scheme 32 [ka] Preparation of (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (32a) Compound 32a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)quinazolin-4-amine (24a) (100 mg, 0.31 mmol), (S)-pyrrolidin-2-ylmethanol (94 mg, 0.93 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (32a) (75 mg, 62% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.49-10.15(m,1H,D2O exchangeable),8.48(d,J=8.2Hz,1H),8.25 (s,1H),8.07(s,1H),7.93-7.63(m,3H),7.61-7.43(m,2H),7.43-7.24(m,2H),7.09 (t,J=7.5Hz,1H),5.16-4.88(m,1H,D2O exchangeable),4.49-4.14(m,1H),3.93-3.56(m,3H ),3.54-3.36(m,1H),2.19-1.79(m,4H);MS(ES+):387.4(M+1),(ES-):385.3(M-1).

[0251] Scheme 33 [ka] Preparation of N-(1-phenyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (33a) Compound 33a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (14a) (100 mg, 0.32 mmol), 2-(pyrrolidin-2-yl)pyridine hydrochloride (148 mg, 0.8 mmol), and DIPEA (0.22 mL, 1.28 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-phenyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (33a) (61 mg, 45% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.03(s,1H,D2O exchangeable),8.26(s,1H),8.17-7.90(m,2H),7 .80-7.45(m,5H),7.39(p,J=8.5,4.2Hz,1H),7.35-7.18(m,1H),7.11(d,J=7.7Hz, 2H),6.77(s,1H),5.39(s,1H),4.01-3.82(m,1H),3.79-3.54(m,1H),2.45-2.28( m,1H),2.11-1.88(m,2H),1.88-1.71(m,1H);MS(ES+):424.5(M+1),446.5(M+Na).

[0252] Scheme 34 [ka] Preparation of N-(1-methyl-1H-imidazol-4-yl)-2-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (34a) Compound 34a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (4b) (100 mg, 0.4 mmol) and 1-methylpiperazine (0.13 mL, 1.21 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded N-(1-methyl-1H-imidazol-4-yl)-2-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (34a) (37 mg, 30% yield) as an off-white solid after workup and purification by reverse-phase flash chromatography (silica gel C-18, 24 g, eluted with 0.1% TFA in acetonitrile and 0.1% TFA in water) followed by conversion to the free base using NaHCO. 1 H NMR(300MHz,DMSO-d6)δ10.32(s,1H,D2O exchangeable),7.49(d,J=1.4Hz,1H),7.37(t,J=2.1Hz,1H),7.30(d,J=1.6Hz,1H),7.11(s,1H),6.4 1(dd,J=4.5,2.5Hz,1H),3.69(s,3H),3.55(t,J=4.9Hz,4H),2.41(q,J=5.0Hz,4H),2.22(s,3H);MS(ES+):313.4(M+1),325.4(M+Na).

[0253] Scheme 35 [ka] Preparation of 2-(4-methylpiperazin-1-yl)-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (35a) Compound 35a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (8b) (100 mg, 0.32 mmol) and 1-methylpiperazine (0.11 mL, 0.97 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded 2-(4-methylpiperazin-1-yl)-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (35a) (16 mg, 13% yield) as a brown solid after workup and purification by reverse-phase flash chromatography (silica gel C-18, 24 g, eluted with 0.1% TFA in acetonitrile and 0.1% TFA in water) followed by conversion to the free base using NaHCO. 1 H NMR(300MHz,DMSO-d6)δ10.59(s,1H,D2O exchangeable),8.23(d,J=1.6Hz,1H),7.83(d ,J=1.6Hz,1H),7.63(dd,J=8.5,1.5Hz,2H),7.56(dd,J=8.7,7.1Hz,2H),7.45- 7.39(m,1H),7.39-7.34(m,1H),7.16(d,J=4.3Hz,1H),6.45(dd,J=4.4,2.5Hz, 1H),3.66-3.52(m,4H),2.50-2.36(m,4H),2.23(s,3H);MS(ES+):375.5(M+1).

[0254] Scheme 36 [ka] Preparation of (S)-(1-(4-((1-(2-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (36c)

[0255] Step 1: Preparation of 2-chloro-N-(1-(2-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (36b) Compound 36b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (260 mg, 1.38 mmol) in 2-propanol (20 mL) using DIPEA (0.73 mL, 4.15 mmol) and 1-(2-fluorophenyl)-1H-imidazol-4-amine hydrochloride 36a (450 mg, 1.8 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(2-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 36b (125 mg, 28% yield) as a pale solid. 1 H NMR(300MHz,DMSO-d6)δ11.40(s,1H,D2O exchangeable),8.08(t,J=1.5Hz,1H),7.83(t,J=1.9Hz,1H),7.77(dd ,J=2.6,1.5Hz,2H),7.73(td,J=7.9,1.6Hz,1H),7.59-7.46(m,2H),7.40(ddd,J=9.1,6.0,2.0Hz,2H); 19 F NMR (282MHz, DMSO-d6) δ-125.09; MS(ES+): 329.3(M+1); MS(ES-): 363.4(M+Cl).

[0256] Step 2: Preparation of (S)-(1-(4-((1-(2-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (36c) Compound 36c was prepared from 2-chloro-N-(1-(2-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (36b) (70 mg, 0.21 mmol), (S)-pyrrolidin-2-ylmethanol (108 mg, 1.07 mmol), and DIPEA (0.11 mL, 0.64 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(2-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (36c) (45 mg, 54% yield) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6)δ10.56(s,1H,D2O exchangeable),8.02(t,J=1.8Hz,1H),7.87(t,J=1.7H z,1H),7.76(td,J=7.9,1.7Hz,1H),7.55-7.41(m,2H),7.40-7.31(m,2H),7.15(dd,J= 4.5,1.7Hz,1H),6.39(dd,J=4.4,2.4Hz,1H),4.74(t,J=5.2Hz,1H,D2O exchangeable),4.20-4. 04(m,1H),3.72-3.62(m,1H),3.54-3.44(m,1H),3.46-3.26(m,2H),2.08-1.79(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-125.10; MS(ES+): 394.5(M+1); 416.5(M+Na); MS(ES-): 392.5(M-1), 428.5(M+Cl).

[0257] Scheme 37 [ka] Preparation of N-(1-cyclobutyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37c)

[0258] Step 1: Preparation of 2-chloro-N-(1-cyclobutyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37b) Compound 37b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (350 mg, 1.86 mmol) in 2-propanol (20 mL) using DIPEA (0.98 mL, 5.58 mmol) and 1-cyclobutyl-1H-imidazol-4-amine hydrochloride (37a) (420 mg, 2.42 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-cyclobutyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37b) (348 mg, 65% yield) as a yellowish solid; 1 H NMR(300MHz,DMSO-d6)δ11.16(s,1H,D2O exchangeable),7.83-7.62(m,2H),7.53(d,J=1.6Hz,1H),7.35(dd,J=4.5,1.6Hz,1H),6.68(dd,J=4 MS(ES+):289.3(M+1),311.3(M+Na);MS(ES-):287.3(M-1).

[0259] Step 2: Preparation of N-(1-cyclobutyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37c) Compound 37c was prepared from 2-chloro-N-(1-cyclobutyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37b) (70 mg, 0.24 mmol), 2-(pyrrolidin-2-yl)pyridine (108 mg, 0.73 mmol), and DIPEA (0.13 mL, 0.73 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-cyclobutyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37c) (65 mg, 67% yield) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6)δ10.27(s,1H,D2O exchangeable),8.59(d,J=4.8Hz,1H),7.67(t,J=7.7Hz,1H),7.56(s,1H) ),7.38(s,1H),7.29-7.12(m,2H),7.08(d,J=4.4Hz,1H),7.05-6.93(m,1H),6.42-6.30(m,1H),5.35(d, J=8.2Hz,1H),4.55(q,J=8.6Hz,1H),3.90-3.75(m,1H),3.71-3.54(m,1H),2.45-2.26(m,4H),2.26-2.0 9(m,1H),2.12-1.99(m,1H),2.02-1.88(m,1H),1.89-1.69(m,3H).MS(ES+):401.5(M+1);423.5(M+Na).

[0260] Scheme 38 [ka] Preparation of (S)-(1-(4-((1-(quinolin-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (38c)

[0261] Step 1: Preparation of 2-chloro-N-(1-(quinolin-3-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (38b) Compound 38b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (384 mg, 2.04 mmol) in 2-propanol (20 mL) using DIPEA (1.07 mL, 6.12 mmol) and 1-(quinolin-3-yl)-1H-imidazol-4-amine hydrochloride 38a (730 mg, 2.96 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(quinolin-3-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 38b (264 mg, 36% yield) as a pale off-white solid; 1 H NMR(300MHz,DMSO-d6)δ11.41(s,1H),9.30(d,J=2.7Hz,1H),8.68(d,J=2.6Hz,1H),8.47(d,J=1.6Hz,1H),8. 16-8.06(m,3H),7.88-7.76(m,2H),7.71(t,J=7.4Hz,1H),7.42(d,J=4.3Hz,1H),6.74(dd,J=4.5,2.6Hz,1H); 1 H NMR(300MHz,DMSO-d6 / D2O)δ9.24(d,J=2.5Hz,1H),8.63(d,J=2.6Hz,1H),8.41(s,1H),8.16-8.00(m,3H),7.80(t,J=7.7Hz,1H),7.75(d, MS(ES+): 362.3(M+1),384.3(M+Na);MS(ES-):360.2(M-1).

[0262] Step 2: Preparation of (S)-(1-(4-((1-(quinolin-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (38c) Compound 38c was prepared from 2-chloro-N-(1-(quinolin-3-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (38b) (100 mg, 0.28 mmol), (S)-pyrrolidin-2-ylmethanol (140 mg, 1.38 mmol), and DIPEA (0.15 mL, 0.83 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(quinolin-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (38c) (66 mg, 56% yield) as a yellow solid; 1 H NMR(300MHz,DMSO-d6)δ10.63(s,1H,D2O exchangeable),9.42(d,J=2.7Hz,1H),8.81(d,J=2.6Hz,1H),8.53(d,J=1.5Hz,1H),8. 15(d,J=1.6Hz,1H),8.12-8.00(m,2H),7.79(ddd,J=8.4,6.9,1.6Hz,1H),7.69(td,J=7.5,6.9,1.3Hz,1H),7.41(dd,J =2.4,1.7Hz,1H),7.18(dd,J=4.4,1.7Hz,1H),6.41(dd,J=4.5,2.4Hz,1H),5.28-5.16(m,1H,D2O exchangeable),4.37-4.18(m, 1H),3.93-3.79(m,1H),3.56-3.40(m,1H),3.45-3.20(m,2H),2.21-1.72(m,4H).MS(ES+):427.5(M+1);449.5(M+Na).

[0263] Scheme 39 [ka] Preparation of (S)-(1-(4-((1-(pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (39c)

[0264] Step 1: Preparation of 2-chloro-N-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (39b) Compound 39b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (500 mg, 2.66 mmol) in 2-propanol (20 mL) using DIPEA (1.39 mL, 7.98 mmol) and 1-(pyridin-3-yl)-1H-imidazol-4-amine 39a (511 mg, 3.19 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine 39b (728 mg, 88% yield) as a brownish solid; 1 H NMR(300MHz,DMSO-d6)δ11.38(s,1H,D2O exchangeable),8.96(d,J=2.7Hz,1H),8.61(dd,J= 4.7,1.4Hz,1H),8.35(d,J=1.6Hz,1H),8.13(ddd,J=8.3,2.8,1.4Hz,1H),7.97(d, J=1.6Hz,1H),7.78(dd,J=2.6,1.5Hz,1H),7.61(dd,J=8.3,4.7Hz,1H),7.47-7.35 (m,1H),6.73(dd,J=4.5,2.6Hz,1H);MS(ES+):312.3(M+1);MS(ES-):310.4(M-1).

[0265] Step 2: Preparation of (S)-(1-(4-((1-(pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (39c) Compound 39c was prepared from 2-chloro-N-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (39b) (100 mg, 0.32 mmol), (S)-pyrrolidin-2-ylmethanol (162 mg, 1.60 mmol), and DIPEA (0.17 mL, 0.96 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded (S)-(1-(4-((1-(pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (39c) (60 mg, 50% yield) as a brownish solid after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO3; 1 H NMR(300MHz,DMSO-d6)δ10.59(s,1H,D2O exchangeable),9.04(d,J=2.7Hz,1H),8.55(dd,J=4.7,1.3Hz,1H),8.35(d,J=1 .5Hz,1H),8.25-8.14(m,1H),8.01(d,J=1.6Hz,1H),7.54(dd,J=8.3,4.7Hz,1H),7.40(t,J=2.1Hz,1H),7.16(d d,J=4.4,1.7Hz,1H),6.40(dd,J=4.4,2.5Hz,1H),5.13-4.74(m,1H,D2O exchangeable),4.28-4.13(m,1H),3.77(dd,J=1 0.1,3.4Hz,1H),3.55-3.44(m,1H),3.46-3.25(m,2H),2.18-1.77(m,4H).MS(ES+):377.5(M+1);399.5(M+Na).

[0266] Scheme 40 [ka] Preparation of N-(1-phenyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (40a) Compound 40a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (14a) (100 mg, 0.32 mmol) and 2-phenylpyrrolidine (118 mg, 0.8 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, N-(1-phenyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (40a) (18 mg, 13% yield) was obtained as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ10.04(s,1H,D2O exchangeable),8.19-7.83(m,2H),7.66-7.50(m,2H),7.54-7.25(m,2H),7.26-7.14(m,3H),7.16-7 .00(m,4H),6.74(s,1H),5.41(s,1H),3.99-3.57(m,2H),2.40-2.24(m,1H),1.98-1.63(m,3H);MS(ES+)423.5(M+1),445.5(M+Na).

[0267] Scheme 41 [ka] Preparation of (S)-(1-(7-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (41c)

[0268] Step 1: Preparation of 2-chloro-7-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (41b) Compound 41b was prepared from 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (41a) (500 mg, 2.28 mmol, CAS number 35265-83-9) and DIPEA (1.59 mL, 9.13 mmol) in 2-propanol (10 mL) using 1-phenyl-1H-imidazol-4-amine,HCl (8a) (558 mg, 2.85 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-7-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (41b) (350 mg, 45% yield) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ10.72(s,1H,D2O exchangeable),8.27(d,J=1.6Hz,1H),7.95(d,J=1.6Hz,1H),7.89(s,1H),7.72-7.63(m,2H),7 .57(dd,J=8.6,7.1Hz,2H),7.46-7.36(m,1H),2.31(d,J=1.2Hz,3H);MS(ES+):342.3(M+1),364.3(M+Na),(ES-):340.3(M-1).

[0269] Step 2: Preparation of (S)-(1-(7-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (41c) Compound 41c was prepared from 2-chloro-7-methyl-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (41b) (100 mg, 0.29 mmol) and (S)-pyrrolidin-2-ylmethanol (89 mg, 0.88 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(7-methyl-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (41c) (82 mg, 69% yield) as an off-white solid; 1 H NMR(300MHz,DMSO-d6)δ10.08(s,1H,D2O exchangeable),8.20(d,J=1.5Hz,1H),7.99(d,J=1.6Hz, 1H),7.71(s,2H),7.57(d,J=1.3Hz,1H),7.51(t,J=7.7Hz,2H),7.35(t,J=7.4Hz,1H),5. 65-4.81(m,1H,D2O exchangeable),4.26(s,1H),3.86-3.52(m,2H),3.51-3.24(m,2H),2.22(d,J= 1.2Hz,3H),2.11-1.81(m,4H);MS(ES+):407.5(M+1),429.5(M+Na),(ES-):405.5(M-1).

[0270] Scheme 42 [ka] Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (42b)

[0271] Step 1: Preparation of 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)-6-methylthieno[3,2-d]pyrimidin-4-amine (42a) Compound 42a was prepared from 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (23a) (302 mg, 1.38 mmol) in 2-propanol (10 mL) using DIPEA (0.96 mL, 5.51 mmol), 1-(4-fluorophenyl)-1H-imidazol-4-amine hydrochloride (25a) (368 mg, 1.72 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)-6-methylthieno[3,2-d]pyrimidin-4-amine (42a) (100 mg, 21% yield) as a dark brown solid. 1 H NMR(300MHz,DMSO-d6)δ10.74(s,1H,D2O exchangeable),8.22(d,J=1.6Hz,1H),7.88(d,J=1. 6Hz,1H),7.76-7.67(m,2H),7.48-7.37(m,2H),7.13(d,J=1.3Hz,1H),2.60(s,3H); 19 F NMR (282MHz, DMSO-d6) δ-115.30; MS (ES+): 382.4 (M+Na), (ES-): 358.3 (M-1).

[0272] Step 2: Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (42b) Compound 42b was prepared from 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)-6-methylthieno[3,2-d]pyrimidin-4-amine (42a) (90 mg, 0.25 mmol) and (S)-pyrrolidin-2-ylmethanol (89 mg, 0.88 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (42b) (27 mg, 25% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6)δ9.95(s,1H,D2O exchangeable),8.14(d,J=1.6Hz,1H),7.92(d,J=1.7Hz,1H),7.86-7.62(m,2H),7.35(t,J=8.6Hz,2H),6.83 (d,J=1.3Hz,1H),5.06(s,1H,D2O exchangeable),4.37-4.01(m,1H),3.89-3.68(m,1H),3.68-3.44(m,3H),2.52(d,J=1.1Hz,3H),2.16-1.72(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-73.43; MS (ES+): 425.4 (M+1), 447.4 (M+Na), (ES-): 423.4 (M-1).

[0273] Scheme 43 [ka] Preparation of (S)-(1-(4-((1-cyclobutyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (43a) Compound 43a was prepared from 2-chloro-N-(1-cyclobutyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37b) (100 mg, 0.35 mmol) and (S)-pyrrolidin-2-ylmethanol (175 mg, 1.73 mmol) and DIPEA (0.18 mL, 1.04 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography (24 g of silica gel, eluting with 0–40% CMA80 in chloroform), (S)-(1-(4-((1-cyclobutyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (43a) (67 mg, 55% yield) as a yellow solid; 1 H NMR (300MHz, DMSO-d6) δ10.33 (s, 1H, D2O exchangeable), 7.67-7.56 (m, 2H), 7.42-7.29 (m, 1H),7.09(dd,J=4.4,1.7Hz,1H),6.36(dd,J=4.4,2.4Hz,1H),4.97-4.76(m,1H,D2 (O exchangeable), 4.69 (p, J=8.5Hz, 1H), 4.29-4.05 (m, 1H), 3.84-3.67 (m, 1H), 3.55-3.42 (m ,1H),3.41-3.19(m,2H),2.52-2.28(m,4H),2.12-1.83(m,4H),1.83-1.62(m,2H); 19 F NMR (282MHz, DMSO) δ-73.48; MS(ES+): 354.5(M+1); 376.5(M+Na); MS(ES-): 352.4(M-1).

[0274] Scheme 44 [ka] Preparation of (S)-(1-(4-((1-(3-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (44c)

[0275] Step 1: Preparation of 2-chloro-N-(1-(3-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (44b) Compound 44b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (254 mg, 1.35 mmol) in 2-propanol (20 mL) using DIPEA (0.71 mL, 4.06 mmol) and 1-(3-fluorophenyl)-1H-imidazol-4-amine hydrochloride (44a) (440 mg, 1.76 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (44b) (343 mg, 77% yield) as a pale solid. 1 H NMR (300MHz, DMSO-d6) δ11.35 (s, 1H, D2O exchangeable), 8.33 (d, J=1.6Hz, 1H), 7.95 (d, J=1.6Hz,1H),7.78(dd,J=2.6,1.5Hz,1H),7.67(dt,J=10.1,2.1Hz,1H),7.63- 7.57(m,1H),7.55-7.49(m,1H),7.44-7.37(m,1H),7.30-7.20(m,1H),6.73(dd ,J=4.5,2.6Hz,1H);MS(ES+):329.3(M+1),351.3(M+Na);MS(ES-):327.3(M-1).

[0276] Step 2: Preparation of (S)-(1-(4-((1-(3-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (44c) Compound 44c was prepared from 2-chloro-N-(1-(3-fluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (44b) (100 mg, 0.3 mmol), (S)-pyrrolidin-2-ylmethanol (154 mg, 1.52 mmol), and DIPEA (0.16 mL, 0.91 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, followed by flash chromatography [silica gel (24 g), eluting with 0–40% CMA80 in chloroform], (S)-(1-(4-((1-(3-fluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (44c) (30 mg, 25% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.54(s,1H,D2O exchangeable),8.33(d,J=1.6Hz,1H),7.97(d,J=1.6Hz ,1H),7.81-7.70(m,1H),7.69-7.60(m,1H),7.58-7.46(m,1H),7.40(dd,J=2.4,1.7Hz,1 H),7.23-7.13(m,2H),6.39(dd,J=4.4,2.5Hz,1H),5.07-4.90(m,1H,D2O exchangeable),4.26-4 .12(m,1H),3.85-3.67(m,1H),3.56-3.43(m,1H),3.44-3.22(m,2H),2.22-1.75(m,4H); 19 F NMR (282MHz, DMSO) δ-110.92; MS(ES+): 394.5(M+1); 416.5(M+Na); MS(ES-): 392.4(M-1).

[0277] Scheme 45 [ka] Preparation of 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethanone (45d)

[0278] Step 1: Preparation of tert-butyl 4-(2-(2,6-difluoro-4-methoxyphenyl)acetyl)piperazine-1-carboxylate (45b) To a stirred suspension of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol), 2-(2,6-difluoro-4-methoxyphenyl)acetic acid (45a) (1.09 g, 5.37 mmol; CAS number 886498-98-2), EDC (1.24 g, 6.44 mmol) in acetonitrile (15 mL) and DMF (1 mL), TEA (2.25 mL, 16.11 mmol) and DMAP (33 mg, 0.27 mmol) were added and stirred at room temperature for 16 h. The reaction was concentrated to remove acetonitrile, diluted with ethyl acetate (100 mL), washed with 1N KHSO4 (2x20 mL), saturated sodium bicarbonate (2x20 mL), water (20 mL), brine (20 mL), dried and concentrated to give tert-butyl 4-(2-(2,6-difluoro-4-methoxyphenyl)acetyl)piperazine-1-carboxylate (45b) (1.00 g, 50% yield) as a colorless solid; 1 H NMR(300MHz,DMSO-d6)δ6.72(s,1H),6.69(d,J=1.4Hz,1H),3.77(s,3H),3.66(s,2H),3.57 (t,J=5.3Hz,2H),3.49-3.24(m,6H),1.41(s,9H);MS(ES+):393.5(+Na)(ES-):369.3(M-1).

[0279] Step 2: Preparation of 2-(2,6-difluoro-4-methoxyphenyl)-1-(piperazin-1-yl)ethanone 2,2,2-trifluoroacetate (45c) To a stirred solution of tert-butyl 4-(2-(2,6-difluoro-4-methoxyphenyl)acetyl)piperazine-1-carboxylate (45b) (0.95 g, 2.56 mmol) in dichloromethane (20 mL) was added TFA (1.98 mL, 25.6 mmol) at room temperature and stirred overnight at room temperature. The reaction was concentrated in vacuo to give 2-(2,6-difluoro-4-methoxyphenyl)-1-(piperazin-1-yl)ethanone 2,2,2-trifluoroacetate (45c) (800 mg, 81% yield) as an oil. 1 H NMR(300MHz,DMSO-d6)δ8.94(s,2H),6.88-6.43(m,2H),3.77(s,5H),3.72(s,2H),3.63(d,J=5.6Hz,2H),3.14(d,J=27.6Hz,4H); 19 F NMR(282MHz, DMSO-d6)δ-74.66,-112.12--120.42(m); MS(ES+)271.3(M+1),293.3(M+Na),541.6(2M+1),563.5(2M+Na).

[0280] Step 3: Preparation of 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethanone (45d) Compound 45d was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (31b) (100 mg, 0.31 mmol), 2-(2,6-difluoro-4-methoxyphenyl)-1-(piperazin-1-yl)ethanone 2,2,2-trifluoroacetate (45c) (371 mg, 0.97 mmol) and DIPEA (0.28 mL, 1.61 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethanone (45d) (43 mg, 24% yield) as an off-white solid; 1 H NMR (300MHz, DMSO-d6) δ10.30 (s, 1H, D2O exchangeable), 8.29 (d, J=1.7Hz, 1H), 7.87 (d ,J=1.7Hz,1H),7.81(d,J=6.0Hz,1H),7.70-7.64(m,2H),7.57(t,J=7.9Hz,2H ),7.43-7.34(m,1H),7.15(d,J=6.0Hz,1H),6.71(d,J=9.5Hz,2H),3.93-3.85 (m,2H),3.85-3.78(m,4H),3.77(s,3H),3.76-3.70(m,2H),3.65-3.56(m,2H); 19 F NMR (282MHz, DMSO-d6) δ-113.98; MS (ES+): 562.6 (M+1), 584.6 (M+Na).

[0281] Scheme 46 [ka] Preparation of (S)-N-(1-cyclohexyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (46a) Compound 46a was prepared from 2-chloro-N-(1-cyclohexyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (28b) (72 mg, 0.23 mmol), (S)-2-phenylpyrrolidine hydrochloride (50 mg, 0.27 mmol) and DIPEA (0.12 mL, 0.68 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-N-(1-cyclohexyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (46a) (13 mg, 13% yield) as a pale off-white solid; 1 H NMR (300MHz, DMSO-d6) δ10.42 (s, 1H, D2O exchangeable), 8.06 (s, 1H), 7.44 (s, 1H), 7.38-7. 13(m,6H),6.98(dd,J=4.5,1.6Hz,1H),6.42(dd,J=4.4,2.5Hz,1H),5.34(d,J=7.8 Hz,1H),3.99-3.81(m,1H),3.80-3.68(m,1H),3.66-3.49(m,1H),2.42-2.22(m,1H) ),2.05-1.64(m,9H),1.62-1.32(m,3H),1.32-1.14(m,1H);MS(ES+):428.6(M+1).

[0282] Scheme 47 [ka] Preparation of (S)-1-(3-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (47c)

[0283] Step 1: Preparation of 1-(3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (47b) Compound 47b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (185 mg, 1.0 mmol) in 2-propanol (20 mL) using DIPEA (0.52 mL, 2.96 mmol) and 1-(3-(4-amino-1H-imidazol-1-yl)phenyl)ethanone 47a (238 mg, 1.18 mmol) according to the procedure described in Scheme 1. This afforded 1-(3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone 47b (282 mg, 81% yield) as a pale off-white solid. 1 H NMR(300MHz,DMSO-d6)δ11.37(s,1H,D2O exchangeable),8.38(d,J=1.6Hz,1H),8.14(t,J=1.9Hz,1H),8.01-7.97(m,1H),7.97-7.89(m,2H),7.78(dd,J=2. 6,1.5Hz,1H),7.72(t,J=7.9Hz,1H),7.40(d,J=4.3Hz,1H),6.73(dd,J=4.5,2.6Hz,1H),2.68(s,3H);MS(ES+):353.3(M+1);MS(ES-):351.4(M-1).

[0284] Step 2: Preparation of (S)-1-(3-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (47c) Compound 47c was prepared from 1-(3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (47b) (100 mg, 0.28 mmol), (S)-pyrrolidin-2-ylmethanol (143 mg, 1.42 mmol), and DIPEA (0.15 mL, 0.85 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-1-(3-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (47c) (39 mg, 33% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.58(s,1H,D2O exchangeable),8.38(d,J=1.5Hz,1H),8.24-8.16(m,1H),8.07(d,J=1.6H z,1H),8.06-7.98(m,1H),7.98-7.84(m,1H),7.65(t,J=7.9Hz,1H),7.40(dd,J=2.4,1.6Hz,1H),7.15(dd, J=4.5,1.6Hz,1H),6.40(dd,J=4.4,2.5Hz,1H),4.87(t,J=5.0Hz,1H,D2O exchangeable),4.29-4.03(m,1H),3.84- 3.70(m,1H),3.63-3.46(m,1H),3.47-3.22(m,2H),2.68(s,3H),2.10-1.85(m,4H);MS(ES+):418.5(M+1).

[0285] Scheme 48 [ka] Preparation of (S)-4-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenol (48c)

[0286] Step 1: Preparation of 4-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenol (48b) Compound 48b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (410 mg, 2.18 mmol) in 2-propanol (20 mL) using DIPEA (1.14 mL, 6.54 mmol) and 4-(4-amino-1H-imidazol-1-yl)phenol (458 mg, 2.61 mmol) (48a) (238 mg, 1.18 mmol) according to the procedure described in Scheme 1. This gave 4-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenol (48b) (264 mg, 37% yield) as a slightly pink solid; 1 H NMR(300MHz,DMSO-d6)δ11.34(s,1H),9.78(s,1H),8.04(d,J=1.6Hz,1H),7.77(d,J=1.6Hz,1H),7.77-7.74(m,1H),7.47 -7.35(m,3H),6.94-6.86(m,2H),6.71(dd,J=4.5,2.6Hz,1H);MS(ES+):327.3(M+1);MS(ES-):325.2(M-1),361.2(M+Cl).

[0287] Step 2: Preparation of (S)-4-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenol (48c) Compound 48c was prepared from 4-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenol (48b) (100 mg, 0.31 mmol), (S)-pyrrolidin-2-ylmethanol (155 mg, 1.53 mmol), and DIPEA (0.16 mL, 0.92 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded (S)-4-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenol (48c) (60 mg, 50% yield) as a white solid after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO3; 1 H NMR (300MHz, DMSO-d6) δ10.46 (s, 1H, D2O exchangeable), 9.69 (s, 1H, D2O exchangeable), 8.02 (d, J=1.5Hz, 1H), 7.84 (d, J= 1.6Hz,1H),7.51(d,J=8.8Hz,2H),7.38(dd,J=2.4,1.6Hz,1H),7.14(dd,J=4.4,1.7Hz,1H),6.85(d,J=8 .8Hz,2H),6.38(dd,J=4.4,2.4Hz,1H),4.85(t,J=5.0Hz,1H,D2O exchangeable),4.26-4.06(m,1H),3.81-3.65(m ,1H),3.55-3.42(m,1H),3.45-3.23(m,2H),2.11-1.81(m,4H);MS(ES+):392.5(M+1);414.5(M+Na);Analysis:C 20 H 21 Calculated for N7O2: C, 61.37; H, 5.41; N, 25.05; Found: C, 60.88; H, 5.54; N, 24.96.

[0288] Scheme 49 [ka] Preparation of (S)-(1-(4-((1-(4-chlorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (49c)

[0289] Step 1: Preparation of 2-chloro-N-(1-(4-chlorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (49b) Compound 49b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (375 mg, 2.0 mmol) in 2-propanol (20 mL) using DIPEA (1.05 mL, 5.99 mmol) and 1-(4-chlorophenyl)-1H-imidazol-4-amine (49a) (464 mg, 2.396 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(4-chlorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (49b) (264 mg, 38% yield) as a pale off-white solid; 1 H NMR(300MHz,DMSO-d6)δ11.36(s,1H),8.29(d,J=1.6Hz,1H),7.91(d,J=1.7Hz,1H),7.78(dd,J=2.6, 1.5Hz,1H),7.74-7.68(m,2H),7.66-7.60(m,2H),7.40(d,J=4.5Hz,1H),6.72(dd,J=4.5,2.6Hz,1H); 1 H NMR(300MHz,DMSO-d6 / D2O)δ8.19(d,J=1.7Hz,1H),7.87(d,J=1.6Hz,1H),7.73(dd,J=2.6,1.5Hz,1H),7.70-7. 64(m,2H),7.62-7.56(m,2H),7.32(d,J=4.3Hz,1H),6.71(dd,J=4.5,2.6Hz,1H);MS(ES+):345.3,347.3(M+1).

[0290] Step 2: Preparation of (S)-(1-(4-((1-(4-chlorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (49c) Compound 49c was prepared from 2-chloro-N-(1-(4-chlorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (49b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (147 mg, 1.45 mmol), and DIPEA (0.15 mL, 0.87 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(4-chlorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (49c) (55 mg, 46% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.55(s,1H,D2O exchangeable),8.27(d,J=1.5Hz,1H),7.96(d,J=1.6Hz,1H ),7.86-7.77(m,2H),7.63-7.50(m,2H),7.39(dd,J=2.4,1.6Hz,1H),7.15(dd,J=4.5,1.7H z,1H),6.39(dd,J=4.4,2.5Hz,1H),5.03-4.80(m,1H,D2O exchangeable),4.31-4.07(m,1H),3.87-3 .67(m,1H),3.53-3.35(m,1H),3.42-3.23(m,2H),2.11-1.83(m,4H).MS(ES+):410.4(M+1).

[0291] Scheme 50 [ka] Preparation of (S)-(1-(4-((1-cyclopentyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (50c)

[0292] Step 1: Preparation of 2-chloro-N-(1-cyclopentyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50b) Compound 50b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (392 mg, 2.08 mmol) in 2-propanol (20 mL) using DIPEA (1.09 mL, 6.25 mmol) and 1-cyclopentyl-1H-imidazol-4-amine hydrochloride (50a) (469 mg, 2.499 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-cyclopentyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50b) (397 mg, 63% yield) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ11.17(s,1H,D2O exchangeable),7.72(dd,J=2.6,1.5Hz,1H),7.68(d,J=1.5Hz,1H),7.50(d,J=1.6Hz,1H),7.35(dd,J=4.5,1.5Hz,1H ),6.68(dd,J=4.5,2.6Hz,1H),4.69-4.50(m,1H),2.24-2.05(m,2H),1.92 -1.57(m,6H).MS(ES+):303.3(M+1),325.3(M+Na);MS(ES-):301.3(M-1).

[0293] Step 2: Preparation of (S)-(1-(4-((1-cyclopentyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (50c) Compound 50c was prepared from 2-chloro-N-(1-cyclopentyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50b) (100 mg, 0.33 mmol), (S)-pyrrolidin-2-ylmethanol (33 mg, 0.33 mmol), and DIPEA (0.17 mL, 0.99 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-cyclopentyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (50c) (80 mg, 66% yield); 1 H NMR(300MHz,DMSO-d6)δ10.32(s,1H,D2O exchangeable),7.59(d,J=1.5Hz,1H),7.54(d,J=1.6Hz,1H),7.35(d d,J=2.4,1.7Hz,1H),7.09(dd,J=4.6,1.7Hz,1H),6.35(dd,J=4.4,2.4Hz,1H),4.78(t,J=5.1Hz,1H,D 2O exchangeable), 4.52 (p, J=7.3Hz, 1H), 4.20-4.04 (m, 1H), 3.77-3.64 (m, 1H), 3.55-3.44 (m, 1H), 3.44-3.28 ( m,2H),2.22-1.97(m,2H),1.99-1.70(m,9H),1.73-1.52(m,1H).MS(ES+):368.5(M+1);370.5(M+Na).

[0294] Scheme 51 [ka] Preparation of 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-(4-((1-methyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperazin-1-yl)ethanone (51a) Compound 51a was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) (100 mg, 0.4 mmol), 2-(2,6-difluoro-4-methoxyphenyl)-1-(piperazin-1-yl)ethanone 2,2,2-trifluoroacetate (45c) (170 mg, 0.44 mmol) and DIPEA (0.21 mL, 1.21 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-(4-((1-methyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperazin-1-yl)ethanone (51a) (25 mg, 13% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.54(s,1H,D2O exchangeable),8.10(s,1H),7.54-7.40(m,2H),7.11-6.97(m,1H),6.72(d,J=9. 4Hz,2H),6.49(dd,J=4.5,2.4Hz,1H),3.79(s,3H),3.77(s,4H),3.71(s,3H),3.64(d,J=4.6Hz,2H),3.57(s,4H); 19 F NMR (282MHz, DMSO-d6) δ-114.02; MS (ES+): 483.5 (M+1), 505.5 (M+Na).

[0295] Scheme 52 [ka] Preparation of 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-(4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperazin-1-yl)ethanone (52a) Compound 52a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (8b) (100 mg, 0.32 mmol), 2-(2,6-difluoro-4-methoxyphenyl)-1-(piperazin-1-yl)ethanone 2,2,2-trifluoroacetate (45c) (247 mg, 0.64 mmol) and DIPEA (0.22 mL, 1.28 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, 2-(2,6-difluoro-4-methoxyphenyl)-1-(4-(4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperazin-1-yl)ethanone (52a) (25 mg, 14% yield) as a light brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.63(s,1H,D2O exchangeable),8.24(d,J=1.6Hz,1H),7.85(d,J=1.6Hz,1H),7.72-7.64(m,2H),7.57(dd,J=8.6,7.2Hz,2H),7.47(dd,J =2.5,1.7Hz,1H),7.43-7.34(m,1H),7.19(s,1H),6.72(d,J=9.5Hz,2H),6.4 7(dd,J=4.5,2.5Hz,1H),3.77(s,3H),3.76-3.65(m,6H),3.64-3.58(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-114.00 (d,J=9.4Hz); MS (ES+): 545.6 (M+1), 567.6 (M+Na), (ES-): 543.5 (M-1).

[0296] Scheme 53 [ka] Preparation of 1-(4-(4-((1-methyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)piperazin-1-yl)-2-phenylethanone (53b) Compound 53b was prepared from 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) (100 mg, 0.4 mmol), 2-phenyl-1-(piperazin-1-yl)ethanone 2,2,2-trifluoroacetate (53a) (256 mg, 0.80 mmol; prepared according to the procedure reported by Daniel E. et al. in International Patent Application WO 2003 / 022214 published March 20, 2003), and DIPEA (0.28 mL, 1.61 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, 1-(4-(4-(1-methyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)piperazin-1-yl)-2-phenylethanone (11 mg, 7% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.38(s,1H,D2O exchangeable),7.50(d,J=1.4Hz,1H),7.45-7.36(m,2H),7.36-7.29(m,2H),7.29-7.19(m,3H),7.18-7.09(m,1H),6 .42(dd,J=4.4,2.5Hz,1H),3.78(s,2H),3.70(s,3H),3.67-3.59(m,4H),3 .60-3.43(m,4H);MS(ES+):417.6(M+1),439.5(M+Na),(ES-):415.5(M-1).

[0297] Scheme 54 [ka] Preparation of tert-butyl 4-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)piperazine-1-carboxylate (54a) Compound 54a was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (16a) (100 mg, 0.31 mmol) and tert-butyl piperazine-1-carboxylate (170 mg, 0.92 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded tert-butyl 4-(4-(1-phenyl-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-2-yl)piperazine-1-carboxylate (54a) (92 mg, 63% yield) as an off-white solid after workup and purification by reverse-phase flash chromatography (silica gel C-18, 24 g, eluted with 0.1% TFA in acetonitrile and 0.1% TFA in water) followed by conversion to the free base using NaHCO. 1 H NMR(300MHz,DMSO-d6)δ10.10(s,1H),D2O exchangeable,8.22(d,J=1.5Hz,1H),7.97(d,J= 5.4Hz,1H),7.85(d,J=1.7Hz,1H),7.68(d,J=1.4Hz,1H),7.65(dd,J=1.9,0.9Hz, 1H),7.55(dd,J=8.7,7.1Hz,2H),7.43-7.35(m,1H),7.12(d,J=5.4Hz,1H),3.85- 3.71(m,4H),3.50-3.38(m,4H),1.43(s,9H);MS(ES+):478.6(M+1),500.5(M+Na).

[0298] Scheme 55 [ka] Preparation of (S)-(1-(4-((1-(4-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (55c)

[0299] Step 1: Preparation of 2-chloro-N-(1-(4-methoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (55b) Compound 55b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (423 mg, 2.25 mmol) in 2-propanol (20 mL) using DIPEA (1.18 mL, 6.75 mmol) and 1-(4-methoxyphenyl)-1H-imidazol-4-amine 55a (511 mg, 2.70 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(4-methoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 55b (635 mg, 83% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ11.33(s,1H),8.11(d,J=1.6Hz,1H),7.82(d,J=1.6Hz,1H),7.76(dd,J=2.6,1.5Hz,1H ),7.63-7.49(m,2H),7.40(dd,J=4.6,1.5Hz,1H),7.19-7.06(m,2H),6.71(dd,J=4.5,2.6Hz,1H),3.81(s,3H); 1 H NMR(300MHz,DMSO-d6-D2O)δ8.02(d,J=1.2Hz,1H),7.77(dd,J=1.6,0.8Hz,1H),7.74-7.67(m,1H),7.56-7.47(m,2H),7.30(d,J=4 .4Hz,1H),7.12-7.00(m,2H),6.70(dd,J=4.6,2.7Hz,1H),3.80(s,3H).MS(ES+):341.3(M+1),363.4(M+Na);MS(ES-):339.3(M-1).

[0300] Step 2: Preparation of (S)-(1-(4-((1-(4-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (55c) Compound 55c was prepared from 2-chloro-N-(1-(4-methoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (55b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (148 mg, 1.47 mmol), and DIPEA (0.15 mL, 0.87 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(4-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (55c) (83 mg, 70% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.49(s,1H,D2O exchangeable),8.11(d,J=1.5Hz,1H),7.88(d,J=1.6Hz,1H),7 .65(d,J=9.0Hz,2H),7.38(t,J=2.0Hz,1H),7.15(dd,J=4.5,1.7Hz,1H),7.04(d,J=9.0Hz,2H) ,6.39(dd,J=4.4,2.5Hz,1H),4.94-4.81(m,1H,D2O exchangeable),4.27-4.08(m,1H),3.80(s,3H),3.8 0-3.70(m,1H),3.56-3.43(m,1H),3.44-3.30(m,2H),2.13-1.79(m,4H);MS(ES+):406.5(M+1).

[0301] Scheme 56 [ka] Preparation of (S)-(1-(4-((1-(3-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (56c)

[0302] Step 1: Preparation of 2-chloro-N-(1-(3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (56b) Compound 56b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (373 mg, 1.99 mmol) in 2-propanol (20 mL) using DIPEA (1.04 mL, 5.96 mmol) and 1-(3-methoxyphenyl)-1H-imidazol-4-amine (56a) (451 mg, 2.38 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (56b) (556 mg, 82% yield) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6)δ11.34(s,1H),8.29(d,J=1.6Hz,1H),7.91(d,J=1.6Hz,1H),7.77(dd,J=2.6,1.5Hz,1H),7.47(t,J=8.1Hz, 1H),7.40(d,J=4.3Hz,1H),7.23(t,J=2.2Hz,1H),7.22-7.16(m,1H),7.03-6.93(m,1H),6.72(dd,J=4.5,2.6Hz,1H),3.85(s,3H); 1 H NMR(300MHz,DMSO-d6-D2O)δ8.22(d,J=1.6Hz,1H),7.88(d,J=1.6Hz,1H),7.74(dd,J=2.6,1.5Hz,1H),7.53-7.41(m,1H),7.34(d,J=4. 4Hz,1H),7.21-7.14(m,2H),7.03-6.93(m,1H),6.71(dd,J=4.5,2.6Hz,1H),3.82(s,3H);MS(ES+):341.4(M+1);MS(ES-):339.3(M-1).

[0303] Step 2: Preparation of (S)-(1-(4-((1-(3-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (56c) Compound 56c was prepared from 2-chloro-N-(1-(3-methoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (56b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (148 mg, 1.47 mmol), and DIPEA (0.15 mL, 0.87 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(3-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (56c) (58 mg, 49% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.53(s,1H,D2O exchangeable),8.27(d,J=1.5Hz,1H),7.97(d,J=1.6Hz,1H),7 .45-7.34(m,2H),7.35-7.23(m,2H),7.15(dd,J=4.4,1.7Hz,1H),6.97-6.86(m,1H),6.39(dd, J=4.5,2.4Hz,1H),5.02-4.68(m,1H,D2O exchangeable),4.30-4.11(m,1H),3.85(s,3H),3.74(dd,J=9. 9,3.5Hz,1H),3.61-3.46(m,1H),3.47-3.26(m,2H),2.17-1.77(m,4H);MS(ES+):406.5(M+1).

[0304] Scheme 57 [ka] Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (57c)

[0305] Step 1: Preparation of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (57b) Compound 57b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (226 mg, 1.2 mmol) in 2-propanol (20 mL) using DIPEA (0.63 mL, 3.61 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine 57a (300 mg, 1.02 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 57b (410 mg, 85% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ11.31(s,1H),8.21(d,J=1.6Hz,1H),7.89(d,J=1.6Hz,1H),7.77(dd,J=2.6,1 .6Hz,1H),7.39(d,J=4.4Hz,1H),6.93(s,2H),6.72(dd,J=4.4,2.6Hz,1H),3.87(s,6H),3.69(s,3H); 1 H NMR(300MHz,DMSO-d6-D2O)δ8.14(d,J=1.6Hz,1H),7.86(d,J=1.6Hz,1H),7.72(dd,J=2.6,1.6Hz,1H),7.35-7.28(m, 1H),6.88(s,2H),6.71(dd,J=4.5,2.6Hz,1H),3.84(s,6H),3.67(s,3H);MS(ES+):401.4(M+1);MS(ES-):399.3(M-1).

[0306] Step 2: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (57c) Compound 57c was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (57b) (100 mg, 0.25 mmol), (S)-pyrrolidin-2-ylmethanol (126 mg, 1.25 mmol), and DIPEA (0.13 mL, 0.74 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [silica gel C-18, 24 g, eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (57c) (18 mg, 16% yield) as a white solid; 1H NMR(300MHz,DMSO-d6)δ10.54(s,1H,D2O exchangeable),8.24(d,J=1.5Hz,1H),7.97(d,J=1.6Hz,1H),7.39(dd,J=2.4,1.6Hz,1H),7.14(d d,J=4.4,1.7Hz,1H),6.96(s,2H),6.39(dd,J=4.4,2.4Hz,1H),4.84(t,J=5.1Hz,1H,D2O exchangeable),4.29-4.15(m,1H),3.88(s,6H),3 .79-3.68 (m, 1H), 3.68 (s, 3H), 3.61-3.47 (m, 1H), 3.49-3.24 (m, 2H), 2.12-1.75 (m, 4H); MS (ES+): 466.5 (M+1), 488.5 (M+Na); The hydrochloride salt of compound 57c was obtained by purification of the crude reaction mixture from step 2 above by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluted with acetonitrile and 0.1% HCl in water], followed by lyophilization; 1 H NMR (300MHz, DMSO-d6): δ10.78(s,1H),8.59(s,1H),8.03(s,1H),7.44(s,1H),7.12(d,J=4.5Hz,1H),7.02(s,2H),6.43(dd,J=4.4 ,2.5Hz,1H),4.26-4.13(m,1H),3.88(s,6H),3.78-3.21(m,7H),2.08-1.80(m,4H).MS(ES+):466.3(M+1).MS(ES-):500.2(M+Cl).

[0307] Scheme 58 [ka] Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (58b)

[0308] Step 1: Preparation of 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (58a) Compound 58a was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (261 mg, 1.27 mmol) in 2-propanol (10 mL) using DIPEA (0.44 mL, 2.54 mmol) and 1-(4-fluorophenyl)-1H-imidazol-4-amine (25a) (225 mg, 1.27 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (58a) (268 mg, 61% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ10.96(s,1H,D2O exchangeable),8.29-8.18(m,2H),7.91(d,J=1.6Hz,1H),7.78-7.65(m,2H),7.48-7.35(m,3H); 19 F NMR (282MHz, DMSO-d6) δ-115.27; MS (ES+): 346.3 (M+1), 368.3 (M+Na); (ES-): 344.2 (M-1).

[0309] Step 2: Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (58b) Compound 58b was prepared from 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (58a) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (88 mg, 0.86 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-(1-(4-fluorophenyl)-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (58b) (69 mg, 58% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.14(s,1H,D2O exchangeable),8.15(d,J=1.5Hz,1H),8.01-7.88(m,2H),7.77(s,2H),7.36(t,J=8.4Hz,2H ),7.10(d,J=5.3Hz,1H),5.35-4.91(m,1H,D2O exchangeable),4.23(s,1H),3.92-3.69(m,1H),3.69-3.18(m,3H),2.15-1.73(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-116.11; MS (ES+): 411.4 (M+1), 433.4 (M+Na); (ES-): 409.4 (M-1).

[0310] Scheme 59 [ka] Preparation of 3-(4-((2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (59c)

[0311] Step 1: Preparation of 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (59b) Compound 59b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (145 mg, 0.77 mmol) in 2-propanol (10 mL) using DIPEA (0.4 mL, 2.31 mmol) and 3-(4-amino-1H-imidazol-1-yl)cyclobutanecarbonitrile 59a (125 mg, 0.77 mmol) according to the procedure described in Scheme 1. This gave 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile 59b (168 mg, 70% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ11.17(s,1H),7.86(d,J=1.5Hz,1H),7.73(dt,J=2.9,1.4Hz,1H),7.57(d,J=1.5Hz,1H),7.35(d,J=4.4Hz,1H),6.77-6.60(m ,1H),4.77(p,J=8.6Hz,1H),3.31-3.12(m,1H),2.96-2.81(m,2H),2.79-2 .63(m,2H); MS(ES+): 314.3(M+1); MS(ES-): 312.3(M-1); HPLC purity: 98.51%.

[0312] Step 2: Preparation of 3-(4-((2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (59c) Compound 59c was prepared from 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (59b) (60 mg, 0.19 mmol), 2-(pyrrolidin-2-yl)pyridine (85 mg, 0.57 mmol), and DIPEA (0.1 mL, 0.57 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, 3-(4-((2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (59c) (41 mg, 50% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.31(s,1H,D2O exchangeable),8.62(d,J=4.8Hz,1H),7.71(d,J=1.5Hz,1H),7.66(td,J =7.7,1.8Hz,1H),7.37(s,1H),7.25-7.19(m,1H),7.17(d,J=7.9Hz,1H),7.16-6.97(m,2H),6.36(dd,J=4 .4,2.5Hz,1H),5.32(d,J=8.2Hz,1H),4.68-4.40(m,1H),3.96-3.76(m,1H),3.76-3.50(m,1H),3.33-3. 21(m,1H),3.02-2.61(m,4H),2.44-2.26(m,1H),2.16-1.71(m,3H);MS(ES+):426.5(M+1),448.5(M+Na).

[0313] Scheme 60 [ka] Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (60b)

[0314] Step 1: Preparation of 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (60a) Compound 60a was prepared from 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (261 mg, 1.27 mmol) in 2-propanol (10 mL) using DIPEA (0.44 mL, 2.54 mmol), 1-(4-fluorophenyl)-1H-imidazol-4-amine (25a) (225 mg, 1.27 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (60a) (270 mg, 61% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ11.06(s,1H,D2O exchangeable),8.21(d,J=1.6Hz,1H),8.04( d,J=5.8Hz,1H),7.90(d,J=1.6Hz,1H),7.76-7.67(m,3H),7.48-7.37(m,2H); 19 F NMR (282MHz, DMSO-d6) δ-115.31; MS (ES+): 346.3 (M+1), 368.3 (M+Na); (ES-): 344.3 (M-1).

[0315] Step 2: Preparation of (S)-(1-(4-((1-(4-fluorophenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (60b) Compound 60b was prepared from 2-chloro-N-(1-(4-fluorophenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (60a) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (88 mg, 0.86 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-(1-(4-fluorophenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (60b) (25 mg, 22% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.17(s,1H,D2O exchangeable),8.17(s,1H),7.94(d,J=1.6Hz,1H),7.91-7.61(m,2H),7.47-7.21( m,3H),7.03(d,J=6.0Hz,1H),5.17-4.77(m,1H,D2O exchangeable),4.39-3.99(m,1H),3.89-3.19(m,4H),2.13-1.81(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-73.43; MS (ES+) 411.4 (M+1), 433.4 (M+Na).

[0316] Scheme 61 [ka] Preparation of 3,3-dimethyl-1-(4-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)piperazin-1-yl)butan-1-one (61b) Compound 61b was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (31b) (100 mg, 0.31 mmol), tert-3,3-dimethyl-1-(piperazin-1-yl)butan-1-one 2,2,2-trifluoroacetate (61a) (182 mg, 0.61 mmol; prepared according to the procedure described by Bisacchi, Gregory S. et al. in U.S. Pat. No. 6,335,324) and DIPEA (0.21 mL, 1.22 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, 3,3-dimethyl-1-(4-(4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)piperazin-1-yl)butan-1-one (61b) (95 mg, 66% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.26(s,1H,D2O exchangeable),8.25(d,J=1.6Hz,1H),7.86(d, J=1.6Hz,1H),7.81(d,J=6.0Hz,1H),7.70-7.63(m,2H),7.61-7.52(m,2H),7.45 -7.34(m,1H),7.13(d,J=6.0Hz,1H),3.87-3.74(m,4H),3.71-3.54(m,4H),2.3 0(s,2H),1.01(s,9H);MS(ES+):476.6(M+1),498.5(M+Na),(ES-):474.6(M-1).

[0317] Scheme 62 [ka] Preparation of 2-(ethyl(4-(1-phenyl-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-2-yl)amino)ethanol (62b) Compound 62b was prepared from 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (31b) (100 mg, 0.31 mmol) and 2-(ethylamino)ethanol (62a) (82 mg, 0.92 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, 2-(ethyl(4-(1-phenyl-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-2-yl)amino)ethanol (62b) (43 mg, 37% yield) as a light brown solid; 1 H NMR (300MHz, DMSO-d6) δ10.16 (s, 1H, D2O exchangeable), 8.23 ​​(d, J=1.5Hz, 1H), 7.92 (d, J=1.5Hz,1H),7.80(d,J=6.0Hz,1H),7.75-7.59(m,2H),7.53(t,J=7.7Hz,2H),7 .42-7.27(m,1H),7.02(d,J=6.0Hz,1H),4.82(s,1H,D2O exchangeable),3.82-3.54(m,6 H),1.31-1.06(m,3H);MS(ES+):381.4(M+1),403.4(M+Na),(ES-):379.4(M-1).

[0318] Scheme 63 [ka] Preparation of (S)-N-(1-cyclobutyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (63a) Compound 63a was prepared from 2-chloro-N-(1-cyclobutyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37b) (70 mg, 0.24 mmol), (S)-2-phenylpyrrolidine (54 mg, 0.36 mmol) and DIPEA (0.13 mL, 0.73 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-N-(1-cyclobutyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (63a) (65 mg, 67% yield) as a white solid; 1 H NMR (300MHz, DMSO-d6) δ10.32 (s, 1H, D2O exchangeable), 7.88-7.79 (m, 1H), 7.42-7.37 (m, 1H) ,7.36-7.23(m,4H),7.23-7.15(m,1H),7.09-6.97(m,2H),6.39(dd,J=4.4,2.5Hz,1H ),5.41-5.30(m,1H),4.66-4.43(m,1H),3.83-3.69(m,1H),3.67-3.51(m,1H),2.41- 2.08(m,6H),2.02-1.69(m,4H);MS(ES+):400.6(M+1),422.5(M+Na);HPLC purity:98.69%.

[0319] Scheme 64 [ka] Preparation of (S)-N-(1-cyclobutyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (64a) Compound 64a was prepared from 2-chloro-N-(1-cyclobutyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (37b) (60 mg, 0.21 mmol), (S)-2-(pyrrolidin-2-yl)pyridine dihydrochloride (55 mg, 0.25 mmol) and DIPEA (0.11 mL, 0.62 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-N-(1-cyclobutyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (64a) (10 mg, 12% yield) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6)δ10.26(s,1H,D2O exchangeable),8.67-8.48(m,1H),7.67(td,J=7.7,1.8Hz,1H),7.56(d,J=1.5Hz, 1H),7.38(s,1H),7.30-7.13(m,2H),7.08(dd,J=4.4,1.7Hz,1H),7.05-6.89(m,1H),6.36(dd,J=4.4,2.5Hz,1H),5 .35(d,J=8.1Hz,1H),4.65-4.36(m,1H),3.90-3.72(m,1H),3.68-3.49(m,1H),2.47-2.25(m,4H),2.26-2.11(m,1 HPLC purity: 96.63%.

[0320] Scheme 65 [ka] Preparation of (S)-(1-(4-((1-(1H-indol-6-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (65c)

[0321] Step 1: Preparation of N-(1-(1H-indol-6-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (65b) Compound 65b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (199 mg, 1.06 mmol) in 2-propanol (20 mL) using DIPEA (0.55 mL, 3.18 mmol) and 1-(1H-indol-6-yl)-1H-imidazol-4-amine 65a (231 mg, 1.17 mmol) according to the procedure described in Scheme 1. This gave N-(1-(1H-indol-6-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-amine 65b (271 mg, 73% yield) as a pale pink solid. 1 H NMR(300MHz,DMSO-d6)δ11.36(s,2H),8.18(d,J=1.6Hz,1H),7.90(d,J=1.6Hz,1H),7.77( dd,J=2.6,1.6Hz,1H),7.70(d,J=8.4Hz,1H),7.58(d,J=2.0Hz,1H),7.46(dd,J=3.1,2.4Hz ,1H),7.41(d,J=4.1Hz,1H),7.27(dd,J=8.4,2.0Hz,1H),6.72(dd,J=4.4,2.6Hz,1H),6.5 2(ddd,J=3.0,2.0,0.9Hz,1H);MS(ES+):350.4(M+1);MS(ES-):348.3(M-1),384.3(M+Cl).

[0322] Step 2: Preparation of (S)-(1-(4-((1-(1H-indol-6-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (65c) Compound 65c was prepared from N-(1-(1H-indol-6-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (65b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (145 mg, 1.43 mmol), and DIPEA (0.15 mL, 0.86 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(1H-indol-6-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (65c) (81 mg, 68% yield) as a white solid; 1 H NMR (300MHz, DMSO-d6) δ11.26 (s, 1H, D2O exchangeable), 10.50 (s, 1H, D2O exchangeable), 8.14 (s, 1H), 7.95 (d, J=1.6Hz, 1H),7.70-7.60(m,2H),7.46-7.41(m,1H),7.41-7.37(m,1H),7.33(dd,J=8.5,2.0Hz,1H),7.20-7.11(m ,1H),6.53-6.46(m,1H),6.40(dd,J=4.4,2.4Hz,1H),5.06-4.37(m,1H),4.30-4.09(m,1H),3.79-3.69( m,1H),3.58-3.48(m,1H),3.48-3.23(m,2H),2.15-1.71(m,4H);MS(ES+):415.5(M+1);HPLC purity:99.33%.

[0323] Scheme 66 [ka] Preparation of (S)-(1-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (66c)

[0324] Step 1: Preparation of 2-chloro-N-(1-(pyridin-2-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (66b) Compound 66b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (112 mg, 0.59 mmol) in 2-propanol (10 mL) using DIPEA (0.31 mL, 1.78 mmol) and 1-(pyridin-2-yl)-1H-imidazol-4-amine (66a) (95 mg, 0.59 mmol; prepared according to the procedure reported by Bleieher, Konrad et al. in International Patent Application WO 2011 / 089132 published July 28, 2011) according to the procedure described in Scheme 1. This gave, after purification by flash column chromatography [silica (24 g), eluting with 0–40% DMA80 in DCM], 2-chloro-N-(1-(pyridin-2-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (66b) (27 mg, 15% yield) as a solid; 1 H NMR(300MHz,DMSO-d6)δ11.37(s,1H),8.64-8.49(m,2H),8.25(d,J=1.5Hz,1H),8.11-7.97(m,1H),7.86(d,J=8.2Hz, 1H),7.80-7.75(m,1H),7.48-7.33(m,2H),6.72(dd,J=4.5,2.6Hz,1H);MS(ES+):312.3(M+1);MS(ES-):310.3(M-1).

[0325] Step 2: Preparation of (S)-(1-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (66c) Compound 66c was prepared from 2-chloro-N-(1-(pyridin-2-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (66b) (27 mg, 0.09 mmol), (S)-pyrrolidin-2-ylmethanol (44 mg, 0.43 mmol) and DIPEA (0.05 mL, 0.26 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (66c) (9 mg, 28% yield) as a white solid; 1 H NMR (300MHz, DMSO-d6) δ10.58 (s, 1H, D2O exchangeable), 8.51 (s, 1H), 8.48 (d, J=4.4Hz, 1H), 8.19 (s, 1H) ),7.98(t,J=7.7Hz,1H),7.90(d,J=8.2Hz,1H),7.47-7.31(m,2H),7.22-7.09(m,1H),6.46-6. 37(m,1H),5.02-4.81(m,1H,D2O exchangeable),4.26-4.11(m,1H),3.90-3.73(m,1H),3.63-3.46(m,1H ),3.47-3.15(m,2H),2.19-1.69(m,4H);MS(ES+):377.4(M+1),399.4(M+Na);HPLC purity: 97.04%.

[0326] Scheme 67 [ka] Preparation of (S)-(1-(4-((1-(1H-indol-5-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (67c)

[0327] Step 1: Preparation of N-(1-(1H-indol-5-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (67b) Compound 67b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (215 mg, 1.14 mmol) in 2-propanol (20 mL) using DIPEA (0.6 mL, 3.43 mmol) and 1-(1H-indol-5-yl)-1H-imidazol-4-amine 67a (249 mg, 1.26 mmol) according to the procedure described in Scheme 1. This gave N-(1-(1H-indol-5-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-amine 67b (314 mg, 79% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ11.36(s,1H),11.33(s,1H),8.16-8.05(m,1H),7.90-7. 84(m,1H),7.80-7.71(m,2H),7.61-7.52(m,1H),7.51-7.45(m,1H),7.46-7.37(m ,1H),7.37-7.25(m,1H),6.72(p,J=3.4,2.9Hz,1H),6.58-6.46(m,1H);MS(ES+): 350.4(M+1), 372.4(M+Na); MS(ES-): 348.3(M-1), 384.3(M+Cl); HPLC purity: 98.41%.

[0328] Step 2: Preparation of (S)-(1-(4-((1-(1H-indol-5-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (67c) Compound 67c was prepared from N-(1-(1H-indol-5-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (67b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (145 mg, 1.43 mmol), and DIPEA (0.15 mL, 0.86 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(1H-indol-5-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (67c) (80 mg, 68% yield) as a white solid; 1 H NMR (300MHz, DMSO-d6) δ11.30 (s, 1H, D2O exchangeable), 10.48 (s, 1H, D2O exchangeable), 8.09 (d, J=1.5Hz, 1H), 7.95 (d, J=1.6Hz, 1H),7.87(d,J=2.0Hz,1H),7.55-7.43(m,2H),7.44-7.32(m,2H),7.19-7.11(m,1H),6.53-6.47(m,1H),6.39(dd ,J=4.4,2.4Hz,1H),4.87(t,J=5.1Hz,1H,D2O exchangeable),4.28-4.06(m,1H),3.86-3.67(m,1H),3.57-3.45(m,1H),3. 47-3.25(m,2H),2.11-1.81(m,4H);MS(ES+):415.5(M+1);MS(ES-):413.5(M-1),449.4(M+Cl);HPLC purity: 99.37%.

[0329] Scheme 68 [ka] Preparation of (S)-3-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (68a)

[0330] Compound 68a was prepared from 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (59b) (50 mg, 0.16 mmol), (S)-pyrrolidin-2-ylmethanol (81 mg, 0.8 mmol) and DIPEA (0.08 mL, 0.48 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-3-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)cyclobutanecarbonitrile (68a) (36 mg, 60% yield) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6)δ10.38(s,1H,D2O exchangeable),7.72(d,J=1.5Hz,1H),7.65(d,J=1.6Hz,1H),7.36(d d,J=2.4,1.6Hz,1H),7.09(dd,J=4.5,1.7Hz,1H),6.36(dd,J=4.4,2.4Hz,1H),4.80(t,J=5.2Hz,1H, D2O exchangeable), 4.77-4.63(m,1H),4.23-4.04(m,1H),3.81-3.67(m,1H),3.57-3.45(m,1H),3.45-3.33(m ,2H),3.27-3.12(m,1H),2.98-2.62(m,4H),2.16-1.75(m,4H);MS(ES+):379.5(M+1);401.5(M+Na).

[0331] Scheme 69 [ka] Preparation of N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (69a) Compound 69a was prepared from 2-chloro-N-(1-cyclopentyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50b) (50 mg, 0.17 mmol), 2-(pyrrolidin-2-yl)pyridine (73 mg, 0.5 mmol) and DIPEA (0.09 mL, 0.5 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (69a) (48 mg, 70% yield) as a pale yellow solid; 1 H NMR (300MHz, DMSO-d6) δ10.26 (s, 1H, D2O exchangeable), 8.61-8.50 (m, 1H), 7.67 (td, J=7.7, 1.8Hz, 1H), 7.51 (d ,J=1.5Hz,1H),7.37(s,1H),7.26-7.13(m,2H),7.13-7.05(m,1H),7.04-6.89(m,1H),6.36(dd,J=4.4, 2.4Hz,1H),5.31(d,J=8.1Hz,1H),4.43-4.23(m,1H),3.79(t,J=9.3Hz,1H),3.68-3.50(m,1H),2.41-2 .29(m,1H),2.18-1.87(m,5H),1.89-1.53(m,6H);MS(ES+):415.5(M+1),437.5(M+Na);HPLC purity:98.48%.

[0332] Scheme 70 [ka] Preparation of (S)-(1-(6-(hydroxymethyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (70f)

[0333] Step 1: Preparation of 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine (70a) To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (4 g, 19.51 mmol) in THF (100 mL) at 0 °C, sodium thiomethoxide (1.418 g, 19.51 mmol) was added and the mixture was allowed to warm to room temperature. The reaction mixture was quenched by adding 1 N HCl and poured into water (200 mL). The separated solid was collected by filtration and dried in vacuo to give 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine (70a) (3.76 g, 89% yield) as a brown solid. 1 H NMR (300MHz, DMSO-d6) δ7.96 (d, J = 6.0 Hz, 1H), 7.50 (d, J = 6.0 Hz, 1H), 2.68 (s, 3H).

[0334] Step 2: Preparation of 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (70b) To a solution of 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine (70a) (3.68 g, 17.0 mmol) in dry THF (100 mL) at −78° C. under nitrogen was added n-butyllithium (1.6 M solution in hexanes, 21.25 mL, 34.0 mmol) dropwise. The reaction was stirred at −78° C. for 1.5 h and slowly quenched by the dropwise addition of N,N-dimethylformamide (2.63 mL, 34.0 mmol). The reaction was stirred at −78° C. for 2 h and allowed to warm to room temperature overnight. The reaction mixture was cooled to 0° C., quenched with 1 N HCl, and extracted with ethyl acetate (2×100 mL). The organic phase was separated, washed with water (2×20 mL); brine (20 mL), dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with 0–100% ethyl acetate in hexane] to give 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (70b) (2.48 g, 60% yield) as a brown solid. 1 H NMR (300MHz, DMSO-d6) δ 10.13 (s, 1H), 8.55 (s, 1H), 2.73 (s, 3H); MS (ES+): 277.2 (M+Na).

[0335] Step 3: Preparation of 2,4-dichlorothieno[2,3-d]pyrimidine-6-carbaldehyde (70c) To a solution of 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (70b) (2 g, 8.17 mmol) in acetonitrile (50 mL) and dichloromethane (20 mL) at 0 °C, sulfuryl chloride (3.32 mL, 40.9 mmol) in dichloromethane (20 mL) was added over 30 minutes. The reaction mixture was stirred at 0 °C for 10 minutes and quenched with saturated sodium bicarbonate solution. The reaction mixture was concentrated in vacuo to remove the organic solvent, and the aqueous residue was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine, dried, filtered, and concentrated under reduced pressure to give 2,4-dichlorothieno[2,3-d]pyrimidine-6-carbaldehyde (70c) (1.9 g, 100% yield) as a dark brown solid. 1H NMR (300MHz, DMSO-d6) δ10.19(s,1H),8.62(s,1H).

[0336] Step 4: Preparation of (2,4-dichlorothieno[2,3-d]pyrimidin-6-yl)methanol (70d) To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine-6-carbaldehyde (70c) (1 g, 4.29 mmol) in THF (30 mL) and water (1 mL), sodium borohydride (162 mg, 4.29 mmol) was added at room temperature and stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and quenched with 1N HCl. The organic phase was separated, washed with brine, dried, and concentrated. The resulting residue was purified by flash column chromatography [silica gel (25 g), eluted with 0-100% ethyl acetate in hexane] to give (2,4-dichlorothieno[2,3-d]pyrimidin-6-yl)methanol (70d) (450 mg, 45% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ7.43 (t, J = 1.3 Hz, 1H), 6.07 (t, J = 5.7 Hz, 1H, DO exchangeable), 4.83 (dd, J = 5.8, 1.3 Hz, 2H).

[0337] Step 5: Preparation of (2-chloro-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-6-yl)methanol (70e) Compound 70e was prepared from (2,4-dichlorothieno[2,3-d]pyrimidin-6-yl)methanol (70d) (40 mg, 0.17 mmol) in 2-propanol (10 mL) using DIPEA (0.12 mL, 0.68 mmol) and 1-phenyl-1H-imidazol-4-amine hydrochloride (8a) (50 mg, 0.26 mmol) according to the procedure described in Scheme 1. This gave (2-chloro-4-(1-phenyl-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-6-yl)methanol (70e) (25 mg, 41% yield) as a bright pink solid; 1H NMR(300MHz,DMSO-d6)δ10.95(s,1H,D2O exchangeable),8.25(d,J=1.6Hz,1H),7.92(d,J=1.6Hz,1H),7.87(s,1H),7.66(dd,J=8.4,1.4Hz,2H),7. 57(t,J=7.9Hz,2H),7.46-7.35(m,1H),5.83(t,J=5.8Hz,1H,D2O exchangeable),4.72(d,J=5.6Hz,2H);MS(ES+):380.3(M+Na),(ES-):356.2(M-1).

[0338] Step 6: Preparation of (S)-(1-(6-(hydroxymethyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (70f) Compound 70f was prepared from (2-chloro-4-(1-phenyl-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-6-yl)methanol (70e) (24 mg, 0.07 mmol), (S)-pyrrolidin-2-ylmethanol (20 mg, 0.2 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(6-(hydroxymethyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (70f) (10 mg, 35% yield) as a brown solid; 1H NMR(300MHz,DMSO-d6)δ10.07(s,1H,D2O exchangeable),8.20(s,1H),7.97(d,J=1.7Hz,1H),7.8 5-7.67(m,2H),7.65(s,1H),7.58-7.42(m,2H),7.39-7.28(m,1H),5.50(t,J=5.7Hz,1H, D2O exchangeable), 5.05-4.82 (m, 1H, D2O exchangeable), 4.57 (d, J=5.7Hz, 2H), 4.42-3.99 (m, 1H), 3.97-3 .34(m,4H),2.16-1.76(m,4H);MS(ES+):423.4(M+1),(ES-):421.3(M-1),457.4(M+Cl).

[0339] Scheme 71 [ka] Preparation of (S)-(1-(4-((1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (71c)

[0340] Step 1: Preparation of N-(1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (71b) Compound 71b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine 4a (357 mg, 1.9 mmol) in 2-propanol (10 mL) using DIPEA (1.0 mL, 5.7 mmol) and 1-(1H-pyrazol-3-yl)-1H-imidazol-4-amine 71a (340 mg, 2.28 mmol) according to the procedure described in Scheme 1. This gave N-(1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-amine 71b (496 mg, 87% yield) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ12.92(s,1H),11.34(s,1H),8.35-8.13(m,1H),8.02-7.93(m,1H),7. 93-7.81(m,1H),7.81-7.66(m,1H),7.52-7.26(m,1H),6.83-6.68(m,1H),6.67-6.53(m,1H); 1 H NMR(300MHz,DMSO-d6 / D2O)δ8.14(d,J=1.6Hz,1H),7.92(d,J=1.5Hz,1H),7.82(d,J=2.4Hz,1H),7.72(dd,J=2.6,1.5Hz,1H),7.3 3-7.26(m,1H),6.71(dd,J=4.5,2.6Hz,1H),6.60(d,J=2.5Hz,1H);MS(ES+):301.3(M+1);MS(ES-):299.3(M-1);HPLC purity:98.56%.

[0341] Step 2: Preparation of (S)-(1-(4-((1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (71c) Compound 71c was prepared from N-(1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (71b) (90 mg, 0.3 mmol), (S)-pyrrolidin-2-ylmethanol (151 mg, 1.5 mmol), and DIPEA (0.16 mL, 0.9 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (71c) (86 mg, 79% yield) as a white solid; 1H NMR (300MHz, DMSO-d6) δ12.94 (s, 1H, D2O exchangeable), 10.54 (s, 1H, D2O exchangeable), 8.15 (d, J=1.5Hz, 1H), 7.97 (d, J=1 .5Hz,1H),7.86(dd,J=2.4,1.1Hz,1H),7.39(dd,J=2.4,1.7Hz,1H),7.13(dd,J=4.4,1.7Hz,1H),6.69(s,1 H),6.39(dd,J=4.4,2.4Hz,1H),4.86(t,J=5.6Hz,1H,D2O exchangeable),4.25-4.04(m,1H),3.88-3.71(m,1H),3.5 8-3.45(m,1H),3.45-3.24(m,2H),2.17-1.70(m,4H);MS(ES+):366.5(M+1),388.5(M+Na);HPLC purity:99.33%.

[0342] Scheme 72 [ka] Preparation of (S)-(1-(4-((1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (72c)

[0343] Step 1: Preparation of 2-chloro-N-(1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (72b) Compound 72b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (313 mg, 1.67 mmol) in 2-propanol (20 mL) using DIPEA (0.87 mL, 5.0 mmol) and 1-(3,5-dimethoxyphenyl)-1H-imidazol-4-amine (72a) (365 mg, 1.67 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (72b) (492 mg, 80% yield) as a solid.1 H NMR(300MHz,DMSO-d6)δ11.32(s,1H,D2O exchangeable),8.29(d,J=1.6Hz,1H),7.90(d,J=1.6Hz,1H),7.77(dd,J=2.6,1.6Hz,1H),7.39(d,J=4.4Hz,1H),6. 80(d,J=2.2Hz,2H),6.72(dd,J=4.5,2.6Hz,1H),6.54(t,J=2.2Hz,1H),3.83(s,6H);MS(ES+):371.4(M+1);MS(ES-):369.3(M-1);HPLC purity: 98.98%.

[0344] Step 2: Preparation of (S)-(1-(4-((1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (72c) Compound 72c was prepared from 2-chloro-N-(1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (72b) (100 mg, 0.27 mmol), (S)-pyrrolidin-2-ylmethanol (136 mg, 1.35 mmol), and DIPEA (0.14 mL, 0.81 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded (S)-(1-(4-((1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (72c) (73 mg, 62% yield) as a white solid after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO3; 1H NMR(300MHz,DMSO-d6)δ10.53(s,1H,D2O exchangeable),8.27(d,J=1.5Hz,1H),7.97(d,J=1.6Hz,1H),7.39(dd,J=2.4, 1.7Hz,1H),7.14(dd,J=4.5,1.7Hz,1H),6.86(d,J=2.2Hz,2H),6.47(t,J=2.2Hz,1H),6.39(dd,J=4.4,2.4Hz,1 H),4.82(t,J=5.1Hz,1H,D2O exchangeable),4.27-4.13(m,1H),3.82(s,6H),3.78-3.65(m,1H),3.62-3.48(m,1H),3.4 9-3.24(m,2H),2.10-1.79(m,4H);MS(ES+):436.5(M+1),458.4(M+Na);MS(ES-):434.4(M-1);HPLC purity: 98.94%.

[0345] Scheme 73 [ka] Preparation of (S)-(1-(4-((1-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (73c)

[0346] Step 1: Preparation of 2-chloro-N-(1-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (73b) Compound 73b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (313 mg, 1.67 mmol) in 2-propanol (10 mL) using DIPEA (0.87 mL, 5.0 mmol) and 1-(3,4-dimethoxyphenyl)-1H-imidazol-4-amine (73a) (365 mg, 1.67 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (73b) (513 mg, 83% yield) as a solid. 1 H NMR(300MHz,DMSO-d6)δ11.32(s,1H,D2O exchangeable),8.16(d,J=1.6Hz,1H),7.84(d,J=1.6Hz,1H),7.76(dd,J=2.6,1.5Hz,1H),7.49-7.34(m,1H),7.25(t, J=1.3Hz,1H),7.16-7.06(m,2H),6.72(dd,J=4.4,2.6Hz,1H),3.86(s,3H), 3.80(s,3H); MS(ES+): 371.5(M+1); MS(ES-): 369.3(M-1); HPLC purity: 99.51%.

[0347] Step 2: Preparation of (S)-(1-(4-((1-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (73c) Compound 73c was prepared from 2-chloro-N-(1-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (73b) (100 mg, 0.27 mmol), (S)-pyrrolidin-2-ylmethanol (136 mg, 1.35 mmol), and DIPEA (0.14 mL, 0.81 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (73c) (38 mg, 32% yield) as a pale off-white solid; 1 H NMR(300MHz,DMSO-d6)δ10.51(s,1H,D2O exchangeable),8.16(d,J=1.5Hz,1H),7.92(d,J=1.6Hz,1H),7.42-7. 35(m,1H),7.23(d,J=8.3Hz,2H),7.14(dd,J=4.4,1.7Hz,1H),7.04(d,J=8.3Hz,1H),6.39(dd,J=4.4,2 .4Hz,1H),4.85(t,J=5.1Hz,1H,D2O exchangeable),4.19(s,1H),3.87(s,3H),3.80(s,3H),3.80-3.67(m,1H), 3.60-3.47(m,1H),3.47-3.25(m,2H),2.09-1.80(m,4H);MS(ES+):436.5(M+1);MS(ES-):434.4(M-1).

[0348] Scheme 74 [ka] Preparation of N-(1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (74a) Compound 74a was prepared from N-(1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (71b) (90 mg, 0.3 mmol), 2-(pyrrolidin-2-yl)pyridine (133 mg, 0.9 mmol), and DIPEA (0.16 mL, 0.9 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (74a) (53 mg, 43% yield) as a yellowish solid; 1 H NMR (300MHz, DMSO-d6) δ12.93 (s, 1H, D2O exchangeable), 10.43 (s, 1H, D2O exchangeable), 8.40 (d, J=4.8Hz, 1H), 8.03 (s ,1H),7.93(t,J=2.0Hz,1H),7.73-7.46(m,2H),7.37(s,1H),7.20(d,J=7.9Hz,1H),7.17-7.03(m,2H), 6.69(t,J=2.2Hz,1H),6.38(dd,J=4.4,2.4Hz,1H),5.34(d,J=8.1Hz,1H),3.98-3.78(m,1H),3.78-3. 50(m,1H),2.44-2.27(m,1H),2.11-1.71(m,3H);MS(ES+):413.5(M+1),435.5(M+Na);HPLC purity:98.54%.

[0349] Scheme 75 [ka] Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (75b)

[0350] Step 1: Preparation of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (75a) Compound 75a was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (304 mg, 1.48 mmol) in 2-propanol (10 mL) using DIPEA (0.52 mL, 2.97 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (370 mg, 1.48 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (75a) (403 mg, 65% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ10.86(s,1H,D2O exchangeable),8.24(d,J=6.0Hz,2H),7.95(s,1H),7.39(d,J= 5.4Hz,1H),6.96(s,2H),3.87(s,6H),3.69(s,3H);MS(ES+):440.3(M+Na),(ES-):416.3(M-1).

[0351] Step 2: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (75b) Compound 75b was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (75a) (100 mg, 0.24 mmol), (S)-pyrrolidin-2-ylmethanol (73 mg, 0.72 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (75b) (93 mg, 81% yield) as a brown solid; 1 H NMR (300MHz, DMSO-d6) δ10.19 (s, 1H, D2O exchangeable), 8.22 (d, J=1.5Hz, 1H), 8.09-7.98 (m, 1H) ,7.93(d,J=5.4Hz,1H),7.10(d,J=5.3Hz,1H),6.95(s,2H),5.29-4.79(m,1H,D2O exchangeable), 4.53-4.04(m,1H),3.88(s,6H),3.81-3.55(m,5H),3.46-3.24(m,2H),2.10-1.69(m,4H) ;MS(ES+):483.5(M+1),505.5(M+Na),965.8(2M+1),987.8(2M+Na),(ES-):481.5(M-1).

[0352] Scheme 76 [ka] Preparation of (S)-(1-(4-((1-(quinolin-5-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (76c)

[0353] Step 1: Preparation of 2-chloro-N-(1-(quinolin-5-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (76b) Compound 76b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.65 mmol) in DCM (20 mL) using DIPEA (1.03 g, 7.97 mmol) and 1-(quinolin-5-yl)-1H-imidazol-4-amine (76a) (0.67 g, 3.19 mmol) according to the procedure described in Scheme 1. This afforded, after workup and purification by flash column chromatography (silica gel, eluting with 0–80% ethyl acetate in hexanes), 2-chloro-N-(1-(quinolin-5-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (76b) (300 mg, 31% yield) as an off-white solid; 1 H NMR(300MHz,DMSO-d6):δ11.45(s,1H),9.04-9.03(s,1H),8.23-8.20(d,1H),8.11-7.96(d,2H),7.93-7.91 (t,1H),7.84-7.82(m,3H),7.77-7.76(m,1H),7.45-7.44(s,1H),6.75-6.74(s,1H);MS(ES+):362.0(M+1).

[0354] Step 2: Preparation of (S)-(1-(4-((1-(quinolin-5-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (76c) A stirred solution of 2-chloro-N-(1-(quinolin-5-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (76b) (300 mg, 0.83 mmol) and (S)-pyrrolidin-2-ylmethanol (838 mg, 8.29 mmol) in NMP (10 mL) was heated at 150° C. for 16 h. The reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine solution (100 mL), dried, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (silica gel, eluting with 0–10% ethyl acetate in methanol) to give (S)-(1-(4-((1-(quinolin-5-yl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (76c) (110 mg, 31%) as an off-white solid; 1 H NMR(300MHz,DMSO-d6)δ10.63(s,1H,D2O exchangeable),9.03(dd,J=4.1,1.6Hz,1H),8.30-8.10(m,2H),8.02(d,J =1.4Hz,1H),7.96-7.86(m,2H),7.80(dd,J=7.4,1.2Hz,1H),7.66(dd,J=8.6,4.2Hz,1H),7.40(t,J=2.0Hz ,1H),7.18(dd,J=4.5,1.7Hz,1H),6.41(dd,J=4.4,2.4Hz,1H),4.51(t,J=5.3Hz,1H,D2O exchangeable),4.10-3.9 6(m,1H),3.63-3.49(m,1H),3.47-3.20(m,3H),1.98-1.68(m,4H);MS(ES+)449.5(M+Na);HPLC purity: 94.15%.

[0355] Scheme 77 [ka] Preparation of (S)-(1-(7-(4-methoxyphenyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (77d)

[0356] Step 1: Preparation of 7-bromo-2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (77b) Compound 77b was prepared from 7-bromo-2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (77a) (50 mg, 0.19 mmol; CAS number 1008112-03-5) in 2-propanol (6 mL) using DIPEA (0.67 mL, 3.83 mmol) and 1-phenyl-1H-imidazol-4-amine, HCl (8a) (250 mg, 1.28 mmol) according to the procedure described in Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel, 40 g, eluting with a 9:1 mixture of ethyl acetate and methanol in hexane (0–100%)], 7-bromo-2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (77b) (22 mg, 30% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ11.50(s,1H,D2O exchangeable),8.27(d,J=1.6Hz,1H),7.92(d,J=1.6Hz,1H),7.71-7.63(m,2H),7.57(dd,J=8.8,7.1 Hz,2H),7.52(d,J=4.7Hz,1H),7.46-7.37(m,1H),6.91(d,J=4.7Hz,1H).MS(ES+):389.2,391.3(M+2);MS(ES-):387.2,389.1(M+2).

[0357] Step 2: Preparation of (S)-(1-(7-bromo-4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (77c) Compound 77c was prepared from 7-bromo-2-chloro-N-(1-phenyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (77b) (50 mg, 0.13 mmol), (S)-pyrrolidin-2-ylmethanol (0.04 mL, 0.39 mmol), and DIPEA (0.07 mL, 0.39 mmol) in NMP (0.5 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by flash chromatography [silica (4 g), eluting with 0–20% DMA80 in CHCl], (S)-(1-(7-bromo-4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (77c), which was used directly in the next step without further purification.

[0358] Step 3: Preparation of (S)-(1-(7-(4-methoxyphenyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (77d) A slurry of (S)-(1-(7-bromo-4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (77c) (20 mg, 0.04 mmol), 4-methoxyphenylboronic acid (33 mg, 0.22 mmol), Pd(dppf)Cl (7 mg, 8.80 μmol), sodium carbonate (12 mg, 0.11 mmol) in dioxane (3 mL) and water (1 mL) under a positive flow of nitrogen in a sealed reactor was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and filtered through a pad of Celite. The reaction mixture was purified by reverse-phase flash column chromatography (silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water. The appropriate product-containing fractions were combined and concentrated to remove acetonitrile. The aqueous solution was basified with saturated sodium bicarbonate, and the resulting solid was collected by filtration and dried under vacuum to give (S)-(1-(7-(4-methoxyphenyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (77d) (6 mg, 28% yield) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): δ10.53 (s, 1H, D2O exchangeable), 8.29 (d, J=1.5Hz, 1H), 8.22-8.13 (m, 2H), 8. 01(d,J=1.7Hz,1H),7.76(d,J=7.9Hz,2H),7.51(t,J=7.8Hz,2H),7.36(t,J=7.3Hz,1H),7.29( d,J=4.6Hz,1H),7.04-6.96(m,2H),6.81(d,J=4.6Hz,1H),4.23(s,1H),3.82(s,1H),3.79(s, 3H),3.64-3.52(m,1H),3.44(q,J=10.0,9.2Hz,2H),2.16-1.82(m,4H);MS(ES+):482.6(M+1).

[0359] Scheme 78 [ka] Preparation of (S)-(1-(6-(hydroxymethyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (78f)

[0360] Step 1: Preparation of 2-chloro-4-(methylthio)thieno[3,2-d]pyrimidine (78a) Compound 78a was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (2 g, 9.75 mmol) and sodium thiomethoxide (0.75 g, 10.24 mmol) according to the procedure described in Step 1 of Scheme 70. This gave, after workup, 2-chloro-4-(methylthio)thieno[3,2-d]pyrimidine (78a) (1.85 g, 88% yield) as a brown solid; 1 H NMR (300MHz, DMSO-d6) δ8.47(d,J=5.4Hz,1H),7.60(d,J=5.4Hz,1H),2.75(s,3H).

[0361] Step 2: Preparation of 2-chloro-4-(methylthio)thieno[3,2-d]pyrimidine-6-carbaldehyde (78b) Compound 78b was prepared from 2-chloro-4-(methylthio)thieno[3,2-d]pyrimidine (78a) (1 g, 4.61 mmol) according to the procedure described in Step 2 of Scheme 70. This gave, after workup, 2-chloro-4-(methylthio)thieno[3,2-d]pyrimidine-6-carbaldehyde (78b) (1.05 g, 93% yield) as a red solid; 1 H NMR (300MHz, DMSO-d6) δ10.25(s,1H), 8.50(s,1H), 2.77(s,3H).

[0362] Step 3: Preparation of 2,4-dichlorothieno[3,2-d]pyrimidine-6-carbaldehyde (78c) Compound 78c was prepared from 2-chloro-4-(methylthio)thieno[3,2-d]pyrimidine-6-carbaldehyde (78b) (200 mg, 0.82 mmol) according to the procedure described in Step 3 of Scheme 70. This gave, after workup, 2,4-dichlorothieno[3,2-d]pyrimidine-6-carbaldehyde (78c) (75 mg, 39% yield) as a white solid; 1 H NMR (300MHz, DMSO-d6) δ10.29(s,1H),8.63(s,1H).

[0363] Step 4: Preparation of (2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)methanol (78d) Compound 78d was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine-6-carbaldehyde (78c) (70 mg, 0.3 mmol) according to the procedure described in Step 4 of Scheme 70, which gave, after workup, (2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)methanol (78d) (95 mg) as a light orange solid; 1 H NMR (300MHz, DMSO-d6) δ7.43 (t, J = 1.3 Hz, 1H), 6.07 (t, J = 5.7 Hz, 1H, DO exchangeable), 4.83 (dd, J = 5.8, 1.3 Hz, 2H).

[0364] Step 5: Preparation of (2-chloro-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-6-yl)methanol (78e) Compound 78e was prepared from (2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)methanol (78d) (90 mg, 0.38 mmol) in 2-propanol (10 mL) using DIPEA (0.1 mL, 0.57 mmol) and 1-phenyl-1H-imidazol-4-amine hydrochloride (8a) (91 mg, 0.57 mmol) according to the procedure described in Scheme 1. This gave (2-chloro-4-(1-phenyl-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-6-yl)methanol (78e) (45 mg, 33% yield) as a dark brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.99-10.67(m,1H,D2O exchangeable),8.27(s,1H),7.94(d,J=1.7Hz,1H),7.68(d,J=7.9Hz,2H),7.57(t,J=7.8Hz ,2H),7.41(t,J=7.3Hz,1H),7.21(s,1H),5.92(s,1H,D2O exchangeable),4.78(d,J=5.4Hz,2H);MS(ES+):358.3(M+1),(ES-):356.3(M-1).

[0365] Step 6: Preparation of (S)-(1-(6-(hydroxymethyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (78f) Compound 78f was prepared from (2-chloro-4-(1-phenyl-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-6-yl)methanol (78e) (39 mg, 0.11 mmol), (S)-pyrrolidin-2-ylmethanol (33 mg, 0.33 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(6-(hydroxymethyl)-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (78f) (12 mg, 26% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.00(s,1H,D2O exchangeable),8.20(d,J=1.7Hz,1H),7.97(d,J=1.7Hz,1H),7.81-7.5 9(m,2H),7.51(t,J=7.7Hz,2H),7.34(t,J=7.4Hz,1H),6.93(d,J=1.1Hz,1H),5.72(t,J=5.8Hz,1H,D2O exchangeable), 5.04 (s, 1H, D2O exchangeable), 4.70 (dd, J=5.8, 1.2Hz, 2H), 4.22 (s, 1H), 3.88-3.69 (m, 1H), 3.69-3.49 ( m,2H),3.44-3.24(m,1H),2.12-1.81(m,4H);MS(ES+):423.4(M+1);(ES-):421(M-1);HPLC purity: 95.50%.

[0366] Scheme 79 [ka] Preparation of (S)-(1-(7-(pent-1-en-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (79d)

[0367] Step 1: Preparation of 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (79b) Compound 79b was prepared from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (79a) (400 mg, 1.85 mmol) in 2-propanol (20 mL) using DIPEA (0.97 mL, 5.55 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (635 mg, 2.22 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (79b) (564 mg, 71% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ11.81(s,1H),10.21(s,1H),9.46(s,0H),8.25(d,J=1.5Hz,1H),7.93(d,J=1.6Hz,1H),7.50(d,J =4.9Hz,1H),7.35(d,J=4.8Hz,1H),6.94(s,2H),3.88(s,6H),3.69(s,3H).MS(ES+):429.5(M+1);MS(ES-):427.3(M-1).

[0368] Step 2: Preparation of 1-(2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)pentan-1-ol (79c) To a solution of 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (79b) (100 mg, 0.23 mmol) in THF (10 mL) at −78° C., n-BuLi (1.6 M, 0.32 mL, 0.51 mmol) was added and stirred at −78° C. for 4 h. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine, dried, filtered, concentrated under vacuum, and purified by flash column chromatography (silica gel 12 g, eluted with 0–20% MeOH in DCM) to give 1-(2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)pentan-1-ol (79c) (65 mg, 57% yield) as a yellow solid; 1 H NMR(300MHz,Chloroform-d)δ10.51(s,1H),7.94(d,J=1.6Hz,1H),7.65(d,J=1.6Hz,1H),6.84(d,J=4.5Hz,1H),6.65(s,2H),6.58(d,J=4.4Hz,1H),5.16( dd,J=7.5,6.1Hz,1H),3.92(s,6H),3.88(s,3H),2.14-1.79(m,2H),1.65-1.2 1(m,4H),0.91(t,J=7.0Hz,3H);MS(ES+):487.5(M+1);MS(ES-):485.5(M-1).

[0369] Step 3: Preparation of (S)-(1-(7-(pent-1-en-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (79d) Compound 79d was prepared from 1-(2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)pentan-1-ol (79c) (65 mg, 0.13 mmol), (S)-pyrrolidin-2-ylmethanol (68 mg, 0.67 mmol), DIPEA (0.07 mL, 0.4 mmol) in NMP (2.5 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(7-(pent-1-en-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (79d) (11 mg, 15% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.47(s,1H,D2O exchangeable),8.24(d,J=1.6Hz,1H),7.97(d,J=1.6Hz,1H),7.14(d,J=4.6Hz,1H),6.95( s,2H),6.70(d,J=16.1Hz,1H),6.55(d,J=4.6Hz,1H),6.52-6.40(m,1H),4.84(t,J=5.1Hz,1H,D2O exchangeable),4.30-4.17(m,1H) ,3.88(s,6H),3.81-3.68(m,1H),3.68(s,3H),3.66-3.53(m,1H),3.54-3.35(m,2H),2.19(q,J=7.1Hz,2H),2.10-1.81(m, 4H),1.56-1.39(m,2H),0.93(t,J=7.2Hz,3H);MS(ES+):534.6(M+1);MS(ES-):532.7(M-1),568.6(M+Cl);HPLC purity: 94.02%.

[0370] Scheme 80 [ka] Preparation of (S)-tert-butyl 4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-phenyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (80a) Compound 80a was prepared from (S)-(1-(7-bromo-4-(1-phenyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (77c) (30 mg, 0.07 mmol), 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-ylboronic acid (30.0 mg, 0.13 mmol), Pd(dppf)Cl (9.69 mg, 0.01 mmol), sodium carbonate (17.50 mg, 0.17 mmol) in dioxane (3 mL) and water (1 mL) according to the procedure described in Step 3 of Scheme 77. This gave, after purification by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], (S)-tert-butyl 4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-phenyl-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (80a) (7 mg, 19% yield) as a brown solid; 1 H NMR (300MHz, DMSO-d6): δ10.52 (s, 1H, D2O exchangeable), 8.27 (d, J=1.6Hz, 1H), 7.98 (d, J=1 .6Hz,1H),7.75(d,J=7.9Hz,2H),7.51(t,J=7.8Hz,2H),7.35(t,J=7.3Hz,1H),7.21 (d,J=4.9Hz,1H),6.50(d,J=4.7Hz,1H),4.19(s,3H),4.06(s,3H),3.78(d,J=9.8Hz ,1H),3.54(s,3H),3.38(s,1H),2.59-2.53(m,1H),2.10-1.91(m,4H),1.43(s,9H). 19F NMR (282MHz, DMSO-d6) δ-73.99; MS (ES+): 557.6 (M+1); 579.6 (M+Na).

[0371] Scheme 81 [ka] Preparation of N-(1'-methyl-1'H-[1,4'-biimidazol]-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (81c)

[0372] Step 1: Preparation of 2-chloro-N-(1'-methyl-1'H-[1,4'-biimidazol]-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (81b) Compound 81b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (187 mg, 0.99 mmol) in 2-propanol (10 mL) using DIPEA (0.52 mL, 2.98 mmol) and 1'-methyl-1'H-1,4'-biimidazol-4-amine (81a) (162 mg, 0.99 mmol) according to the procedure described in Scheme 1. This afforded 2-chloro-N-(1'-methyl-1'H-[1,4'-biimidazol]-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (81b) (205 mg, 66% yield) as a pale off-white solid; 1 H NMR (300MHz, DMSO-d6) δ11.31 (s, 1H, D2O exchangeable), 8.03 (d, J=1.5Hz, 1H), 7.84 (d ,J=1.5Hz,1H),7.76(dd,J=2.6,1.5Hz,1H),7.65(d,J=1.4Hz,1H),7.49(d,J=1 .5Hz,1H),7.39(dd,J=4.5,1.6Hz,1H),6.71(dd,J=4.4,2.6Hz,1H),3.71(s,3H) );MS(ES+):315.3(M+1),337.3(M+Na);MS(ES-):313.3(M-1);HPLC purity: 99.21%.

[0373] Step 2: Preparation of N-(1'-methyl-1'H-[1,4'-biimidazol]-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (81c) Compound 81c was prepared from 2-chloro-N-(1′-methyl-1′H-[1,4′-biimidazol]-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (81b) (70 mg, 0.22 mmol), 2-(pyrrolidin-2-yl)pyridine (99 mg, 0.67 mmol) and DIPEA (0.12 mL, 0.67 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, N-(1'-methyl-1'H-[1,4'-biimidazol]-4-yl)-2-(2-(pyridin-2-yl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (81c) (55 mg, 58% yield) as an off-white solid; 1 H NMR(300MHz,DMSO-d6)δ10.40(s,1H,D2O exchangeable),8.44(d,J=4.8Hz,1H),7.89(d,J=1.5Hz,1H),7.65(s,1H) ,7.64-7.55(m,1H),7.44(d,J=1.5Hz,1H),7.42-7.33(m,2H),7.20(d,J=7.9Hz,1H),7.21-7.10(m,1H),7. 12-7.08(m,1H),6.38(dd,J=4.5,2.4Hz,1H),5.34(d,J=8.1Hz,1H),3.92-3.80(m,1H),3.79(s,3H),3.74 -3.57(m,1H),2.53-2.25(m,1H),2.11-1.74(m,3H);MS(ES+):427.5(M+1),449.5(M+Na);HPLC purity:98.90%.

[0374] Scheme 82 [ka] Preparation of (S)-(1-(4-((1'-methyl-1'H-[1,4'-biimidazol]-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (82a) Compound 82a was prepared from 2-chloro-N-(1′-methyl-1′H-[1,4′-biimidazol]-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (81b) (70 mg, 0.22 mmol), (S)-pyrrolidin-2-ylmethanol (112 mg, 1.11 mmol), and DIPEA (0.12 mL, 0.67 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1'-methyl-1'H-[1,4'-biimidazol]-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (82a) (65 mg, 77% yield) as an off-white solid; 1 H NMR(300MHz,DMSO-d6)δ10.52(s,1H),8.01(d,J=1.5Hz,1H),7.89(d,J=1.6Hz,1H),7.71-7.58 (m,1H),7.54(d,J=1.5Hz,1H),7.39(dd,J=2.4,1.6Hz,1H),7.12(dd,J=4.4,1.7Hz,1H),6.39(d d,J=4.4,2.5Hz,1H),5.26-4.98(m,1H),4.31-4.00(m,1H),3.95-3.76(m,1H),3.73-3.65(m,3 HPLC purity: 99.92%.

[0375] Scheme 83 [ka] Preparation of ((S)-1-(4-((1-(3-fluoro-5-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (83c)

[0376] Step 1: Preparation of 2-chloro-N-(1-(3,5-difluorophenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (83b) Compound 83b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (365 mg, 1.94 mmol) in 2-propanol (10 mL) using DIPEA (1.02 mL, 5.83 mmol) and 1-(3,5-difluorophenyl)-1H-imidazol-4-amine (83a) (379 mg, 1.94 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3,5-difluorophenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine-4-amine (83b) (521 mg, 77% yield) as a solid. 1 H NMR(300MHz,DMSO-d6)δ11.33(s,1H,D2O exchangeable),8.38(d,J=1.6Hz,1H),7.97(d,J=1.6Hz,1H),7.79(dd,J=2.6 ,1.5Hz,1H),7.65-7.53(m,2H),7.45-7.36(m,1H),7.31(tt,J=9.3,2.2Hz,1H),6.73(dd,J=4.5,2.6Hz,1H); 19 F NMR (282MHz, DMSO-d6) δ-107.50; MS(ES+): 347.3(M+1); MS(ES-): 345.2(M-1); HPLC purity: 98.86%.

[0377] Step 2: Preparation of ((S)-1-(4-((1-(3-fluoro-5-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (83c) Compound 83c was prepared from 2-chloro-N-(1-(3,5-difluorophenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (83b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (146 mg, 1.44 mmol), and DIPEA (0.15 mL, 0.87 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, ((S)-1-(4-((1-(3-fluoro-5-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (83c) (66 mg, 47% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.55(s,1H,D2O exchangeable),8.24(d,J=1.5Hz,1H),7.95(d,J=1.6Hz,1H),7.3 9(dd,J=2.5,1.7Hz,1H),7.14(dd,J=4.5,1.7Hz,1H),6.90-6.77(m,1H),6.60(s,1H),6.46-6.33 (m,2H),4.83(t,J=6.1Hz,2H,D2O exchangeable),4.27-4.08(m,1H),3.83-3.75(m,1H),3.74-3.64(m,1H) ,3.61-3.55(m,1H),3.53-3.29(m,4H),3.27-3.21(m,1H),3.18-3.05(m,1H),2.22-1.72(m,8H); 19F NMR(282MHz,DMSO-d6)δ-110.98-111.15(m);19FCPDNMR(282MHz,DMSO-d6)δ-111.06;MS(ES+):493.5(M+1);MS(ES-):491.4(M-1),527.6(M+Cl);HPLC purity: 96.03%.

[0378] Scheme 84 [ka] Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (84b)

[0379] Step 1: Preparation of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (84a) Compound 84a was prepared from 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (0.4 g, 1.95 mmol) in 2-propanol (10 mL) using DIPEA (1.36 mL, 7.8 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (669 mg, 2.34 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (84a) (275 mg, 34% yield) as a buff-colored solid; 1 H NMR(300MHz,DMSO-d6)δ11.01(s,1H,D2O exchangeable),8.21(d,J=1.6Hz,1H),8.02(s,1H),7.91(d,J=1.6Hz,1H), 7.71(d,J=5.9Hz,1H),6.93(s,2H),3.87(s,6H),3.69(s,3H);MS(ES+):440.3(M+Na),(ES-):416.2(M-1).

[0380] Step 2: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (84b) Compound 84b was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (84a) (100 mg, 0.24 mmol), (S)-pyrrolidin-2-ylmethanol (73 mg, 0.72 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (84b) (65 mg, 56% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6)δ10.17(s,1H,D2O exchangeable),8.23(d,J=1.7Hz,1H),8.08-7.94(m,1H),7.79(d,J=6.0Hz, 1H),7.02(d,J=6.0Hz,1H),6.95(s,2H),4.90(s,1H,D2O exchangeable),4.47-4.24(m,1H),3.88(s,6H),3.82-3.51(m , 5H), 3.46-3.23 (m, 2H), 2.13-1.79 (m, 4H); MS (ES+): 483.4 (M+1), 505.4 (M+Na), (ES-): 481.4 (M-1); The hydrochloride salt of compound 84b was prepared by purification of the crude reaction mixture from step 2 above by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluted with acetonitrile and 0.1% aqueous HCl]; 1H NMR(300MHz,DMSO-d6):δ11.36(s,1H),8.45(s,1H),8.20-7.84(m,2H),7.37(d,J=5.8Hz,1H),6.99(s,2H),4.68-4.19(m, 1H),4.14-3.07(m,13H),2.20-1.76(m,4H).MS(ES+):483.2(M+1),505.3(M+Na);MS(ES-):517.2(M+Cl);HPLC purity;95.11%.

[0381] Scheme 85 [ka] Preparation of (S)-(1-(7-bromo-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (85b)

[0382] Step 1: Preparation of 7-bromo-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (85a) Compound 85a was prepared from 7-bromo-2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (77a) (500 mg, 1.87 mmol) in 2-propanol (20 mL) using DIPEA (0.98 mL, 5.62 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.71 g, 2.47 mmol) according to the procedure described in Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel, 40 g, eluting with DCM and methanol (0–30%)], 7-bromo-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (85a) (480 mg, 53% yield) as a brown solid; 1H NMR(300MHz,DMSO-d6)δ11.46(s,1H,D2O exchangeable),8.22(d,J=1.6Hz,1H),7.90(d,J=1.6Hz,1H),7.51(d,J=4.7Hz,1H) ,6.93(s,2H),6.90(d,J=4.6Hz,1H),3.87(s,6H),3.69(s,3H).MS(ES+):481.3(M+2);MS(ES-):479.2,481.2(M+2).

[0383] Step 2: Preparation of (S)-(1-(7-bromo-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (85b) Compound 85b was prepared from 7-bromo-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (85a) (50 mg, 0.1 mmol), (S)-pyrrolidin-2-ylmethanol (0.03 mL, 0.31 mmol), and DIPEA (0.06 mL, 0.31 mmol) in NMP (3 mL) according to the procedure described in Scheme 2. After work-up and purification by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by lyophilization, (S)-(1-(7-bromo-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (85b) (16 mg, 28% yield) was obtained as a white solid; 1 H NMR(300MHz,DMSO-d6):δ10.68(s,1H,D2O exchangeable),8.26(d,J=1.5Hz,1H),7.98(d,J=1.6Hz,1H),7.28(d,J=4.6Hz,1H ),6.96(s,2H),6.55(d,J=4.6Hz,1H),4.24(s,1H),3.88(s,6H),3.68(s,3H),3.40-3.34(m,2H),2.07-1.83(m,4H).19 F NMR (282MHz, DMSO-d6) δ - 74.03; MS (ES+): 544.4, 546.4 (M + 2); MS (ES -): 542.4, 544.3 (M + 2).

[0384] Scheme 86 [ka] Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (86b)

[0385] Step 1: Preparation of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (86a) Compound 86a was prepared from 2,4-dichloroquinazoline 21a (0.4 g, 2.01 mmol) in 2-propanol (10 mL) using DIPEA (1.4 mL, 8.04 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride 57a (0.69 g, 2.41 mmol) according to the procedure described in Scheme 1. This gave 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine 86a (1.26 mmol, 63% yield) as a pale pink solid; 1 H NMR(300MHz,DMSO-d6)δ11.12(s,1H,D2O exchangeable),8.75(d,J=8.3Hz,1H),8.24(s,1H),8.01(d,J=1.7Hz,1H),7.87(t,J=7.6Hz,1H),7.72( d,J=8.2Hz,1H),7.61(t,J=7.7Hz,1H),6.95(s,2H),3.88(s,6H),3.70(s,3H);MS(ES+):412.4(M+1),434.3(M+Na),(ES-):410.3(M-1).

[0386] Step 2: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (86b) Compound 86b was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (86a) (100 mg, 0.24 mmol), (S)-pyrrolidin-2-ylmethanol (74 mg, 0.73 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after workup and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO, (S)-(1-(4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (86b) (55 mg, 48% yield) as a cream-colored solid; 1 H NMR(300MHz,DMSO-d6)δ10.59-10.09(m,1H,D2O exchangeable),8.47(d,J=8.1Hz,1H),8.27(s, 1H),8.20-7.94(m,1H),7.54(t,J=7.7Hz,1H),7.31(d,J=8.4Hz,1H),7.08(t,J=7.6Hz, 1H), 6.98(s, 2H), 5.09-4.67(m, 1H, D2O exchangeable), 4.56-4.14(m, 2H), 3.89(s, 6H), 3.69(s ,5H),3.57-3.17(m,1H),2.18-1.79(m,4H);MS(ES+):477.5(M+1),(ES-):475.5(M-1).

[0387] Scheme 87 [ka] Preparation of (S)-(1-(7-bromo-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (87c)

[0388] Step 1: Preparation of 7-bromo-2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (87b) Compound 87b was prepared from 7-bromo-2,4-dichlorothieno[3,2-d]pyrimidine (87a) (0.2 g, 0.70 mmol; CAS No. 41102-25-4) in 2-propanol (6 mL) using DIPEA (0.67 mL, 3.83 mmol) and 1-phenyl-1H-imidazol-4-amine,HCl (8a) (182 mg, 0.93 mmol) according to the procedure described in Scheme 1. This afforded 7-bromo-2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (87b) (122 mg, 43% yield) as a brown solid after workup and purification by flash column chromatography [silica gel 12 g, eluted with a 9:1 mixture of ethyl acetate and methanol in hexane (0–100%)]. 1 H NMR(300MHz,DMSO-d6)δ11.34(s,1H,D2O exchangeable),8.44(s,1H),8.29(s,1H),7.96(s,1H), 7.73-7.64(m,2H),7.62-7.52(m,2H),7.46-7.36(m,1H).MS(ES-):404.1,406.1(M-2).

[0389] Step 2: Preparation of (S)-(1-(7-bromo-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (87c) Compound 87c was prepared from 7-bromo-2-chloro-N-(1-phenyl-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (87b) (50 mg, 0.12 mmol), (S)-pyrrolidin-2-ylmethanol (0.04 mL, 0.39 mmol), and DIPEA (0.06 mL, 0.37 mmol) in NMP (0.5 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by lyophilization, (S)-(1-(7-bromo-4-((1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (87c) (22 mg, 38% yield) as a pale yellow solid; 1 H NMR (300MHz, methanol-d4) δ8.78-8.54(m,1H),8.28(s,1H),8.21-8.01(m,1H),7.74-7.54(m,4H),7.54-7.43(m,1H), 4.38-4.15(m,1H),4.14-3.93(m,2H),3.93-3.65(m,2H),2.44-2.21(m,1H),2.21-1.99(m,2H),1.99-1.79(m,1H); 19 F NMR (282 MHz, methanol-d₄) δ −77.25; MS (ES+): 471.3, 473.3 (M+2). HPLC purity: 97.84%.

[0390] Scheme 88 [ka] Preparation of 2-(4-methoxyphenyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (88a) Compound 88a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (57b) (200 mg, 0.5 mmol), 4-methoxyphenylboronic acid (114 mg, 0.75 mmol), PdCl(dppf) (73 mg, 0.100 mmol) in anhydrous 1,4-dioxane (15 mL) and water (1 mL) using potassium carbonate (207 mg, 1.5 mmol) according to the procedure described in Step 3 of Scheme 77. This gave, after workup, 2-(4-methoxyphenyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (88a) (52 mg, 22% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.89(s,1H,D2O exchangeable),8.33-8.29(m,1H),8.28(s,1H),8.24(s,1H),8.20-8.15(m,1H),7.78(s,1H),7.34(s,1H),7.08- 6.97(m,4H),6.73-6.67(m,1H),3.93(s,6H),3.82(s,3H),3.71(s,3H);M S(ES+):473.5(M+1),495.4(M+Na),MS(ES-):471.4(M-1),507.4(M+Cl).

[0391] Scheme 89 [ka] Preparation of (S)-(1-(7-(4-methoxyphenyl)-4-(1-phenyl-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (89a) Compound 89a was prepared from (S)-(1-(7-bromo-4-(1-phenyl-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (87c) (50 mg, 0.11 mmol), 4-methoxyphenylboronic acid (81 mg, 0.53 mmol), Pd(dppf)Cl (4 mg, 5.30 μmol) in anhydrous 1,4-dioxane (3 mL) and water (1 mL) using sodium carbonate (28 mg, 0.27 mmol) according to the procedure described in Step 3 of Scheme 77. This gave, after workup, purification by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], and lyophilization, (S)-(1-(7-(4-methoxyphenyl)-4-(1-phenyl-1H-imidazol-4-ylamino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (89a) (20 mg, 38% yield) as a yellow solid; 1 H NMR (300MHz, methanol-d4): δ8.20(s,1H),8.03(d,J=12.4Hz,2H),7.61(dd,J=11.6,7.7Hz,4H),7.53-7.42(m,3H),7.13-7.03(m,2H),4.18(s,1H) ),4.12-3.96(m,1H),3.86(s,3H),3.78(dd,J=10.4,2.4Hz,1H),3.73- 3.63(m,1H),3.60(s,1H),2.34-2.17(m,1H),2.05(s,2H),1.87(s,1H). 19 F NMR (282 MHz, methanol-d4) δ -77.28; MS (ES+): 499.5 (M+1), 521.5 (M+Na); MS (ES-): 497.5 (M-1).

[0392] Scheme 90 [ka] Preparation of (S)-(1-(7-(4-methoxyphenyl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (90a) Compound 90a was prepared from (S)-(1-(7-bromo-4-(1-(3,4,5)-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (85b) (70 mg, 0.13 mmol), 4-methoxyphenylboronic acid (98 mg, 0.64 mmol), Pd(dppf)Cl (5 mg, 6.43 μmol) in anhydrous 1,4-dioxane (3 mL) and water (1 mL) using sodium carbonate (34 mg, 0.32 mmol) according to the procedure described in Step 3 of Scheme 77. This gave, after workup, purification by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], and lyophilization, (S)-(1-(7-(4-methoxyphenyl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (90a) (31 mg, 42% yield) as a yellow solid; 1 H NMR(300MHz,DMSO-d6):δ10.57(s,1H,D2O exchangeable),8.33(s,1H),8.17(d,J=8.7Hz,2H),8.01(s,1H),7.27(s,1H),7.06-6.92(m,4H),6.81(s,1H) ,4.57(s,1H),4.36-4.16(m,1H),4.04(s,1H),3.92-3.87(m,6H),3.83 -3.75(m,3H),3.73-3.64(m,3H),3.57-3.31(m,2H),2.12-1.85(m,4H). 19 F NMR (282MHz, DMSO-d6) δ-74.45; MS (ES+): 572.6, 594.6 (M+Na), 610.4 (M+K).

[0393] Scheme 91 [ka] Preparation of (S)-1-(4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidine-2-carboxamide (91a) Compound 91a was prepared from a stirred suspension of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (57b) (0.2 g, 0.5 mmol), (S)-pyrrolidine-2-carboxamide (0.17 g, 1.5 mmol) and DIPEA (0.26 mL, 1.5 mmol) in NMP (2 mL) according to the procedure described in Scheme 2. After workup and purification by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluted with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by lyophilization, (S)-1-(4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidine-2-carboxamide (91a) (50 mg, 19% yield) was obtained as a white solid; 1 H NMR (300MHz, DMSO-d6): δ10.50 (s, 1H, D2O exchangeable), 8.22 (d, J=5.6Hz, 1H), 7.92 (d, J=5.4H z,1H),7.42(d,J=5.4Hz,1H),7.23(s,1H,D2O exchangeable),7.17(s,1H),7.12-7.05(m,2H),7. 02(s,1H,D2O replaceable),6.41(d,J=5.6Hz,1H),4.41(s,1H),3.93(t,J=4.2Hz,6H),3.68(t, J=4.2Hz,3H),3.35(s,1H),2.19(s,1H),1.95(d,J=13.6Hz,4H);MS(ES+):479.5(M+1).

[0394] Scheme 92 [ka] Preparation of (S)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidine-6-carboxylate isobutyl ester (92d)

[0395] Step 1: Preparation of isobutyl 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylate (92a) Compound 92a was prepared from 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine (70a) (0.5 g, 2.31 mmol) in THF (20 mL) using n-butyllithium (1.6 M solution in hexanes, 3.03 mL, 4.85 mmol) and quenched with isobutyl chloroformate (0.6 mL, 4.61 mmol) according to the procedure described in Step 2 of Scheme 70. This afforded isobutyl 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylate (92a) (403 mg, 55% yield) as a brown solid after workup and purification by flash column chromatography [silica gel, (25 g), eluted with 0–100% ethyl acetate in hexanes]. 1 H NMR(300MHz,DMSO-d6)δ8.09(s,1H),4.14(d,J=6.6Hz,2H),2.70(s,3H),2.04(hept,J=6.6Hz,1H),0.97(d,J=6.7Hz,6H);MS(ES+):339.2(M+Na).

[0396] Step 2: Preparation of isobutyl 2,4-dichlorothieno[2,3-d]pyrimidine-6-carboxylate (92b). Compound 92b was prepared from isobutyl 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylate (92a) (375 mg, 1.18 mmol) in acetonitrile (30 mL) and DCM (5 mL) using sulfuryl chloride (0.48 mL, 5.92 mmol) according to the procedure described in Step 3 of Scheme 70. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with 0–100% ethyl acetate in hexanes], isobutyl 2,4-dichlorothieno[2,3-d]pyrimidine-6-carboxylate (92b) (174 mg, 48% yield) as a syrup; 1 H NMR (300MHz, DMSO-d6) δ8.21(s,1H),4.17(d,J=6.6Hz,2H),2.06(dt,J=13.4,6.7Hz,1H),0.99(d,J=6.8Hz,6H).

[0397] Step 3: Preparation of isobutyl 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidine-6-carboxylate (92c) Compound 92c was prepared from isobutyl 2,4-dichlorothieno[2,3-d]pyrimidine-6-carboxylate (92b) (160 mg, 0.52 mmol) in 2-propanol (5 mL) using DIPEA (0.27 mL, 1.57 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.22 g, 0.78 mmol) according to the procedure described in Scheme 1. This gave isobutyl 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidine-6-carboxylate (92c) (160 mg, 59% yield) as a brown solid. 1H NMR(300MHz,DMSO-d6)δ11.43(s,1H,D2O exchangeable),8.87(s,1H),8.22(d,J=1.6Hz,1H),7.91(d,J=1.6Hz,1H),6.94(s,2H),4.12(d ,J=6.5Hz,2H),3.88(s,6H),3.70(s,3H),2.09-1.96(m,1H),1.01(d,J=6.7Hz,6H);MS(ES+):540.5(M+Na),(ES-):516.5(M-1).

[0398] Step 4: Preparation of (S)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidine-6-carboxylate (92d) Compound 92d was prepared from isobutyl 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidine-6-carboxylate (92c) (80 mg, 0.15 mmol), (S)-pyrrolidin-2-ylmethanol (46.9 mg, 0.46 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. The reaction mixture was poured into water, and the solid separated by filtration was collected and subsequently dried in vacuo to give isobutyl (S)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidine-6-carboxylate (92d) (65 mg, 72% yield) as a brown solid. 1 H NMR(300MHz,DMSO-d6)δ10.32(s,1H,D2O exchangeable),8.63(s,1H),8.12(d,J=1.7Hz,1H),7.95(s,1H),6.92(s,1H),4.61(s,1H),4.31(s,1H),4. 08-3.99(m,2H),3.87(s,6H),3.84-3.58(m,5H),3.52-3.36(m,2H),2.13-1.76(m,5H),1.00(dd,J=6.6,1.6Hz,6H);MS(ES+):583.6(M+1).

[0399] Scheme 93 [ka] Preparation of (S)-4-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (93c)

[0400] Step 1: Preparation of 4-(4-(2-chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (93b) Compound 93b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (180 mg, 0.97 mmol) in 2-propanol (20 mL) using DIPEA (0.51 mL, 2.92 mmol) and 4-(4-amino-1H-imidazol-1-yl)benzamide hydrochloride (93a) (0.26 g, 1.29 mmol) according to the procedure described in Scheme 1. This afforded, after workup and purification by flash column chromatography [silica gel, (40 g), eluted with DCM and methanol (0–30%)], 4-(4-(2-chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (93b) (0.26 g, 76% yield) as a brown solid; 1 H NMR (300MHz, DMSO-d6): δ11.37 (s, 1H, D2O exchangeable), 8.38 (d, J=1.7Hz, 1H), 8.09 (s, 1H, D2O exchangeable), 8.08-8.01 (m, 2H), 7.98 (d, J=1.7Hz, 1H), 7.7 8(d,J=2.3Hz,2H),7.75(s,1H),7.50(s,1H,D2O exchangeable),7.40(d,J=4.4Hz,1H),6.73(dd,J=4.5,2.6Hz,1H).MS(ES+):354.4;MS(ES-):352.3.

[0401] Step 2: Preparation of (S)-4-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (93c) Compound 93c was prepared from 4-(4-(2-chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (93b) (160 mg, 0.45 mmol), (S)-pyrrolidin-2-ylmethanol (0.13 mL, 1.34 mmol), and DIPEA (0.23 mL, 1.34 mmol) in NMP (1.5 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-4-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (93c) (102 mg, 55% yield) as a brown solid; 1 H NMR (300MHz, DMSO-d6): δ10.57 (s, 1H, D2O exchangeable), 8.37 (d, J=1.5Hz, 1H), 8.08 (s, 1H, D2O exchangeable), 8 .05-8.01(m,2H),7.99(s,1H),7.86(d,J=8.4Hz,2H),7.44(s,1H,D2O exchangeable),7.40(t,J=2.0Hz,1H ),7.16(dd,J=4.4,1.7Hz,1H),6.40(dd,J=4.5,2.4Hz,1H),4.99(s,1H,D2O exchangeable),4.21(s,2H),3 .89-3.70(m,1H),3.50(s,2H),2.17-1.75(m,4H);MS(ES+):419.4(M+1);MS(ES-):453.4(M+Cl).

[0402] Scheme 94 [ka] Preparation of (S)-3-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (94c)

[0403] Step 1: Preparation of 3-(4-(2-chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (94b) Compound 94b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (240 mg, 1.29 mmol) in 2-propanol (20 mL) using DIPEA (0.68 mL, 3.87 mmol) and 3-(4-amino-1H-imidazol-1-yl)benzamide hydrochloride (94a) (0.4 g, 1.68 mmol) according to the procedure described in Scheme 1. This gave, after workup and purification by flash column chromatography [silica gel, (40 g), eluted with DCM and methanol (0–30%)], 3-(4-(2-chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (94b) (0.27 g, 60% yield) as a brown solid; 1 H NMR (300MHz, DMSO-d6): δ11.36 (s, 1H, D2O exchangeable), 8.31 (d, J=1.6Hz, 1H), 8.18 (s, 1H), 8.11(t,J=1.9Hz,1H),7.96(d,J=1.6Hz,1H),7.89(dt,J=7.6,1.3Hz,1H),7.86-7.80 (m,1H),7.78(dd,J=2.6,1.5Hz,1H),7.65(t,J=7.9Hz,1H),7.60(s,1H),7.41(d,J=4 .4Hz,1H),6.73(dd,J=4.5,2.6Hz,1H).MS(ES+):354.3(M+1);MS(ES-):352.3(M-1).

[0404] Step 2: Preparation of (S)-3-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (94c) Compound 94c was prepared from 3-(4-(2-chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (94b) (150 mg, 0.42 mmol), (S)-pyrrolidin-2-ylmethanol (0.13 mL, 1.34 mmol), and DIPEA (0.22 mL, 1.27 mmol) in NMP (1.5 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water], followed by conversion to the free base using NaHCO3, (S)-3-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)benzamide (94c) (0.12 g, 69% yield) as a brown solid; 1 H NMR (300MHz, DMSO-d6): δ10.57 (s, 1H, D2O exchangeable), 8.30 (d, J=1.5Hz, 1H), 8.15-8.08 (m, 2H), 8.04 (d,J=1.6Hz,1H),7.92(dd,J=8.0,2.1Hz,1H),7.83(d,J=7.7Hz,1H),7.69-7.53(m,2H),7.39(t, J=2.0Hz,1H),7.14(dd,J=4.4,1.6Hz,1H),6.40(dd,J=4.5,2.4Hz,1H),4.97(s,1H,D2O exchangeable),4. 21(s,1H),3.78(dd,J=10.0,3.5Hz,1H),3.51(d,J=18.1Hz,2H),3.35(s,1H),2.11-1.82(m,4H). 19 F NMR (282MHz, DMSO-d6) δ-73.49; MS(ES+): 419.5(M+1); MS(ES-): 453.4(M+Cl).

[0405] Scheme 95 [ka] Preparation of (S)-1-(4-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)phenyl)ethanone (95c)

[0406] Step 1: Preparation of 1-(4-(4-(2-(chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)phenyl)ethanone (95b) Compound 95b was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (240 mg, 1.3 mmol) in 2-propanol (20 mL) using DIPEA (0.51 mL, 2.92 mmol) and 1-(4-(4-amino-1H-imidazol-1-yl)phenyl)ethanone hydrochloride (95a) (0.4 g, 1.68 mmol) according to the procedure described in Scheme 1. This gave, after work-up and purification by flash column chromatography [silica gel, (40 g), eluted with DCM and methanol (0–30%)], 1-(4-(4-(2-chloropyrrolo[1,2-f])[1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)phenyl)ethanone (95b) (0.26 g, 57% yield) as a brown solid; 1 H NMR(300MHz,DMSO-d6):δ11.40(s,1H,D2O exchangeable),8.45(d,J=1.6Hz,1H),8.18-8.09(m,2H),8.01(d,J=1.6Hz,1H),7.86-7.80(m, 2H),7.79(dd,J=2.6,1.5Hz,1H),7.41(d,J=4.4Hz,1H),6.73(dd,J=4.5,2.6Hz,1H),2.62(s,3H).MS(ES-):351.3,353.3(M-1).

[0407] Step 2: Preparation of (S)-1-(4-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)phenyl)ethanone (95c) Compound 95c was prepared from 1-(4-(4-(2-(chloropyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)phenyl)ethanone (95b) (150 mg, 0.43 mmol), (S)-pyrrolidin-2-ylmethanol (0.13 mL, 1.34 mmol), and DIPEA (0.22 mL, 1.28 mmol) in NMP (1.5 mL) according to the procedure described in Scheme 2. This allowed for workup and reverse phase filtration. After purification by rush chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO3, (S)-1-(4-(4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)-1H-imidazol-1-yl)phenyl)ethanone (95c) (30 mg, 14% yield) was obtained as a brown solid; 1 H NMR (300MHz, DMSO-d6): δ10.79 (s, 1H, D2O exchangeable), 8.64 (s, 1H), 8.13-8.05 (m, 3H), 7.95 (d ,J=8.5Hz,2H),7.44(t,J=2.0Hz,1H),7.16(dd,J=4.5,1.6Hz,1H),6.43(dd,J=4.4,2.4H z,1H),4.19(s,1H),3.76(dd,J=10.0,3.6Hz,1H),3.58-3.42(m,1H),3.36(dd,J=11.7,7 .1Hz,2H),2.62(s,3H),2.11-1.83(m,4H).MS(ES+):418.5(M+1);MS(ES-):452.5(M+Cl).

[0408] Scheme 96 [ka] Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (96b)

[0409] Step 1: Preparation of (S)-(1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (96a) To a solution of 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.7 mmol) in 2-propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol), and heated at 90° C. for 1 hour. The reaction was cooled to room temperature, and the resulting solid was collected by filtration to give (S)-(1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6): δ7.70(dd,J=2.6,1.4Hz,1H),6.97(dd,J=4.7,1.6Hz,1H),6.80-6.57(m,1H),5.15(t,J=5.7Hz,1H,D2O exchangeable),4.87(t,J=5.7H) z,1H),4.44(d,J=17.8Hz,1H),4.05-3.82(m,1H),3.72-3.39(m,2H),2.22 -1.84(m,4H).MS(ES+):253.3,255.3(M+2);MS(ES-):287.2,289.2(M+Cl).

[0410] Step 2: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (96b) A slurry of (S)-(1-(2-chloropyrrolo[1,2-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (96a) (0.1 g, 0.4 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.11 g, 0.4 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (30 mg, 0.04 mmol), sodium tert-butoxide (80 mg, 0.79 mmol), and Pd(dba) (40 mg, 0.04 mmol) in anhydrous dioxane (4 mL) was heated at 90° C. for 18 h under a positive flow of nitrogen in a sealed reactor. The reaction mixture was diluted with EtOAc (100 mL), and the organic phase was separated. The organic phase was washed with water (3xs), brine, dried, filtered, and concentrated to dryness in vacuo. The residue was purified by reverse-phase flash column chromatography (silica gel C-18, 24 g), eluted with acetonitrile and 0.1% aqueous HCl, and lyophilized to give (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (96b) (21 mg, 11% yield) hydrochloride as a yellow solid. 1 H NMR (300MHz, DMSO-d6): δ9.72 (s, 1H, D2O exchangeable), 9.63 (s, 1H, D2O exchangeable), 9.38 (s, 1H), 7. 92(s,1H),7.66(s,1H),7.15(s,2H),6.90(d,J=4.5Hz,1H),6.56(s,1H),4.54(s,1H),4 .07-3.93(m,1H),3.89(s,6H),3.77(s,1H),3.71(s,3H),3.68-3.62(m,1H),3.60-3.47 (m,1H),2.23-1.88(m,4H).MS(ES+):466.5(M+1),688.5(M+Na);MS(ES-):464.6(M-1).

[0411] Scheme 97 [ka] Preparation of (S)-(1-(6-(morpholinomethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (97d)

[0412] Step 1: Preparation of (2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-6-yl)methanol (97a) Compound 97a was prepared from (2,4-dichlorothieno[2,3-d]pyrimidin-6-yl)methanol (70d) (1.2 g, 5.1 mmol) in 2-propanol (15 mL) using DIPEA (2.67 mL, 15.31 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (1.89 g, 6.64 mmol) according to the procedure described in Scheme 1. This gave (2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-6-yl)methanol (97a) (1.48 g, 65% yield) as a light brown solid. 1 H NMR(300MHz,DMSO-d6)δ10.90(s,1H,D2O exchangeable),8.19(d,J=1.6Hz,1H),7.89(d,J=1.6Hz,1H),7.84(s,1H),6.93(s,2H),5.82(t,J=5 .8Hz,1H,D2O exchangeable), 4.72(dd,J=5.8,1.2Hz,2H),3.87(s,6H),3.69(s,3H);MS(ES+):448.3(M+1),470.3(M+Na),(ES-):446.3(M-1).

[0413] Step 2: Preparation of 2-chloro-6-(chloromethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97b) To a stirred suspension of (2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-6-yl)methanol (97a) (0.5 g, 1.12 mmol) in DCM (50 mL) at 0 °C, N,N-dimethylformamide (5 mL) and thionyl chloride (0.2 mL, 2.79 mmol) were added. The reaction mixture was warmed to room temperature overnight, concentrated to dryness in vacuo, triturated with hexanes, and filtered to give 2-chloro-6-(chloromethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97b) (520 mg, 100% yield) as a solid, which was used directly in the next step. 1 H NMR(300MHz,DMSO-d6 / D2O)δ11.26(s,1H,D2O exchangeable),8.07(s,1H),8.00(s,1H),7.96(s,1H),7.01(s, 2H),5.17(s,2H),3.88(s,6H),3.70(s,3H);MS(ES+):466.4,468.4(M+1),(ES-):464.3,466.4(M-1).

[0414] Step 3: Preparation of 2-chloro-6-(morpholinomethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97c) To a solution of 2-chloro-6-(chloromethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97b) (100 mg, 0.21 mmol) in THF (3 mL) was added morpholine (0.04 mL, 0.43 mmol), DIPEA (0.15 mL, 0.86 mmol) and heated at 50° C. overnight. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to give 2-chloro-6-(morpholinomethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97c); 1H NMR(300MHz,DMSO-d6)δ10.89(s,1H),8.19(d,J=1.6Hz,1H),7.88(d,J=1.6Hz,1H),6.93(s,2H), 3.87(s,6H),3.75(s,2H),3.60(m,6H),2.47(m,6H);MS(ES+):539.4(M+Na),(ES-):515.4(M-1).

[0415] Step 4: Preparation of (S)-(1-(6-(morpholinomethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (97d) Compound 97d was prepared from 2-chloro-6-(morpholinomethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97c) (50 mg, 0.09 mmol), (S)-pyrrolidin-2-ylmethanol (0.03 mL, 0.26 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with acetonitrile and 0.1% aqueous HCl] followed by lyophilization, the HCl salt of (S)-(1-(6-(morpholinomethyl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (97d) (21 mg, 42% yield) as a yellow solid; 1H NMR (300MHz, DMSO-d6): δ11.70 (s, 1H, D2O exchangeable), 11.49 (s, 1H, D2O exchangeable), 8.52 (s, 1H), 8.11(s,1H),8.07(s,1H),8.02(s,1H,D2O exchangeable),7.01(s,2H),4.60(s,2H),4.50(s,1H) ),4.34(s,1H),3.96(s,1H),3.88(s,6H),3.81(s,2H),3.68(s,3H),3.60-3.41(m,4H) ,3.40-3.07(m,4H),2.15-1.86(m,4H).MS(ES+):582.6(M+1);MS(ES-):616.6(M+Cl).

[0416] Scheme 98 [ka] Preparation of (S)-tert-butyl 4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (98a) Compound 98a was prepared from (S)-(1-(7-bromo-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (85b) (150 mg, 0.28 mmol), 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-ylboronic acid (188 mg, 0.83 mmol), Pd(dppf)Cl (10 mg, 0.01 mmol), sodium carbonate (73 mg, 0.69 mmol) in dioxane (3 mL) and water (1 mL) according to the procedure described in Step 3 of Scheme 77. This afforded (S)-tert-butyl 4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (98a) (70 mg, 38% yield) as a white solid after purification by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by conversion to the free base using NaHCO3; 1 H NMR(300MHz,DMSO-d6):δ10.53(s,1H,D2O exchangeable),8.24(d,J=1.5Hz,1H),7.98(d,J=1.6Hz,1 H),7.20(d,J=4.6Hz,2H),6.96(s,2H),6.50(d,J=4.6Hz,1H),4.85(s,1H,D2O exchangeable),4.21(s ,2H),4.06(s,2H),3.88(s,6H),3.79-3.71(m,1H),3.68(s,3H),3.54(s,2H),3.42(d,J=6. 9Hz,1H),3.28(s,1H),2.54(s,2H),2.09-1.86(m,4H),1.43(s,9H).MS(ES+):669.7(M+Na).

[0417] Scheme 99 [ka] Preparation of 1-(2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (99b)

[0418] Step 1: Preparation of 1-(2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (99a) Compound 99a was prepared from 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (79b) (200 mg, 0.47 mmol) in THF (10 mL) using MeLi (3 M in THF, 0.33 mL, 1.03 mmol) according to the procedure described in Step 2 of Scheme 79. This gave, after workup and purification by flash column chromatography (silica gel 12 g, eluting with 0–10% MeOH in DCM), 1-(2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (99a) (103 mg, 50% yield) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6)δ11.21(s,1H),8.20(d,J=1.6Hz,1H),7.88(d,J=1.6Hz,1H),7.36(d,J=4.5Hz,1H),6.93(s,2H),6.68(d,J=4.5Hz) ,1H),5.31(d,J=5.0Hz,1H),5.16(p,J=6.4Hz,1H),3.87(s,6H),3.69(s,3H),1.45(d,J=6.5Hz,3H);MS(ES+):445.5(M+1),467.4(M+Na).

[0419] Step 2: Preparation of 1-(2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (99b) Compound 99b was prepared from 1-(2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (99a) (35 mg, 0.08 mmol), (S)-pyrrolidin-2-ylmethanol (80 mg, 0.79 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by lyophilization, the TFA salt of 1-(2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (99b) (25 mg, 51% yield) as a yellow solid; 1 H NMR (300MHz, DMSO-d6) δ10.79 (s, 1H, D2O exchangeable), 9.32 (s, 1H, D2O exchangeable), 9.20 (s, 1H, D2O exchangeable) ,8.37-8.15(m,1H),8.07-7.90(m,1H),7.25(dd,J=10.5,4.6Hz,1H),6.96(s,2H),6.77(dd, J=16.6,4.6Hz,1H),5.45-5.21(m,1H),4.37-4.14(m,1H),3.88(s,6H),3.68(s,3H),3.67-3 .49(m,2H),3.47-3.18(m,3H),2.17-1.76(m,4H),1.76-1.65(m,3H);MS(ES+):492.5(M-OH); 19 F NMR(282MHz,DMSO-d6)δ-74.28;HPLC purity:92.61%;Elemental analysis:C 25 H 31Calculated for N7O5·2CF3COOH·3H2O: C, 42.29; H, 4.77; N, 11.90; found: C, 42.02; H, 4.79; N, 12.08.

[0420] Scheme 100 [ka] Preparation of (S)-(1-(6-bromo-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (100e)

[0421] Step 1: Preparation of 2-chlorothieno[2,3-d]pyrimidin-4-ol (100a) Compound 100a was prepared from 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (4 g, 19.51 mmol) using the procedure reported by Deng, Jifeng et al. in European Journal of Medicinal Chemistry, 46(1), 71-76; 2010. This gave 2-chlorothieno[2,3-d]pyrimidin-4-ol (100a) (2.45 g, 13.13 mmol, 67.3% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ13.54 (s, 1H, D2O exchangeable), 7.61 (d, J = 5.8 Hz, 1H), 7.39 (d, J = 5.8 Hz, 1H); MS (ES-): 185.1 (M-1).

[0422] Step 2: Preparation of 6-bromo-2-chlorothieno[2,3-d]pyrimidin-4-ol (100b). To a solution of 2-chlorothieno[2,3-d]pyrimidin-4-ol (100a) (2.43 g, 13.02 mmol) in acetic acid (30 mL), bromine (2.01 mL, 39.1 mmol) was added and stirred at room temperature for 10 hours. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give 6-bromo-2-chlorothieno[2,3-d]pyrimidin-4-ol (100b) (2.85 g, 82% yield) as a tan solid. 1 H NMR (300MHz, DMSO-d6) δ7.94(s, 1H).

[0423] Step 3: Preparation of 6-bromo-2,4-dichlorothieno[2,3-d]pyrimidine (100c) A mixture of 6-bromo-2-chlorothieno[2,3-d]pyrimidin-4-ol (100b) (2.84 g, 10.70 mmol) and phosphorus oxychloride (9.97 mL, 107 mmol) was heated to reflux for 30 h. The mixture was concentrated to remove excess phosphorus oxychloride, diluted with ice-cold water, and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with water (20 mL), brine (30 mL), dried, filtered, and concentrated in vacuo to give 6-bromo-2,4-dichlorothieno[2,3-d]pyrimidine (100c) (1.4 g, 46% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ7.94(s, 1H).

[0424] Step 4: Preparation of 6-bromo-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (100d) Compound 100d was prepared from 6-bromo-2,4-dichlorothieno[2,3-d]pyrimidine (100c) (0.5 g, 1.76 mmol) in 2-propanol (10 mL) using DIPEA (0.92 mL, 5.28 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (654 mg, 2.29 mmol) according to the procedure described in Scheme 1. This gave 6-bromo-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (100d) (718 mg, 82% yield) as a pale purple solid. 1 H NMR(300MHz,DMSO-d6)δ11.04(s,1H,D2O exchangeable),8.21(d,J=1.6Hz,2H),7.88(d,J= 1.6Hz,1H),6.93(s,2H),3.87(s,6H),3.70(s,3H);MS(ES-):494.2,496.3(M-1).

[0425] Step 5: Preparation of (S)-(1-(6-bromo-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (100e) Compound 100e was prepared from 6-bromo-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (100d) (300 mg, 0.6 mmol), (S)-pyrrolidin-2-ylmethanol (18 mg, 1.81 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded (S)-(1-(6-bromo-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (100e) (35 mg, 10% yield) as a white solid after workup by pouring into water, collecting the separated solid by filtration, and then drying under vacuum; 1H NMR(300MHz,DMSO-d6):11.08(s,1H,D2O exchangeable),8.57(s,1H),8.04(d,J=15.7Hz,2H),7.01(s,2H),4.42(s,1H),4.20(s,1H),3.94(s,1H), 3.88(s,6H),3.81(s,1H),3.68(s,3H),3.44(d,J=9.3Hz,1H),2.12-1.85(m,4H).MS(ES+):561.3,564.3(M+1),(ES-)595.3597.4(M+Cl).

[0426] Scheme 101 [ka] Preparation of (S)-(1-(7-(hydroxymethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (101c)

[0427] Step 1: Preparation of (2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)methanol (101a) Compound 101a was prepared from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79a) (100 mg, 0.46 mmol) according to the procedure described in Step 4 of Scheme 70. After workup, this afforded (2,4-dichloropyrrolo[1,2-f][1,2,4]triazin-7-yl)methanol (101a) (100 mg, 99% yield) as an oil, which was used in the next reaction without further purification. MS (ES+): 218.1 (M+1).

[0428] Step 2: Preparation of (2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methanol (101b) Compound 101b was prepared from (2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)methanol 101a (100 mg, 0.46 mmol) in 2-propanol (10 mL) using DIPEA (0.24 mL, 1.38 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride 57a (157 mg, 0.55 mmol) according to the procedure described in Scheme 1. This afforded (2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)methanol 101b (85 mg, 43% yield) as a pale off-white solid. 1 H NMR(300MHz,DMSO-d6)δ11.24(s,1H,D2O exchangeable),8.20(d,J=1.6Hz,1H),7.89( d,J=1.6Hz,1H),7.37(d,J=4.3Hz,1H),6.93(s,2H),6.69(d,J=4.4Hz,1H),5 .24(t,J=5.6Hz,1H,D2O replaceable),4.70(d,J=5.5Hz,2H),3.87(s,6H),3.69(s,3 H);MS(ES+):431.4(M+1),453.4(M+Na);MS(ES-):429.3(M-1);HPLC:98.24%.

[0429] Step 3: Preparation of (S)-(1-(7-(hydroxymethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (101c) A slurry of (2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)methanol (101b) (97 mg, 0.23 mmol), (S)-pyrrolidin-2-ylmethanol (171 mg, 1.69 mmol), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (di-t-Bu-XPhos, 14 mg, 0.034 mmol), Pd(dba) (14 mg, 0.016 mmol), and sodium tert-butoxide (162 mg, 1.69 mmol) in PhMe (5 mL) was degassed and placed in a sealed reactor. The reaction was heated at 100 °C for 48 h, cooled to room temperature, quenched with saturated aqueous NH4Cl, and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with water, brine, dried, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (12 g silica gel, eluted with 0-40% MeOH in DCM) to afford (S)-(1-(7-(hydroxymethyl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (101c) (12 mg, 11% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.47(s,1H,D2O exchangeable),8.24(d,J=1.5Hz,1H),7.97(s,1H), 7.10(d,J=4.4Hz,1H),6.96(s,2H),6.37(d,J=4.4Hz,1H),4.67(s,2H),4.32-4.09(m ,1H),3.88(s,6H),3.79-3.70(m,1H),3.68(s,3H),3.67-3.52(m,1H),3.53-3.20(m ,2H),2.14-1.75(m,4H);MS(ES+):496.5(M+1),518.5(M+Na);MS(ES-):494.4(M-1).

[0430] Scheme 102 [ka]

[0431] Preparation of (S)-1-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (102b)

[0432] Step 1: Preparation of 1-((2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (102a) Compound 102a was prepared from 2-chloro-6-(chloromethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97b) (100 mg, 0.21 mmol), DIPEA (0.15 mL, 0.86 mmol) and piperidin-4-ol (43 mg, 0.43 mmol) in THF (3 mL) according to the procedure described in Step 3 of Scheme 97. This gave 1-((2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (102a) (32 mg, 28% yield); MS (ES+): 531.5, 533.5 (M+1), (ES−): 529.4, 531.4 (M−1).

[0433] Step 2: Preparation of (S)-1-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (102b) Compound 102b was prepared from 1-((2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-6-yl(methyl)piperidin-4-ol (102a) (0.03 g, 0.06 mmol), (S)-pyrrolidin-2-ylmethanol (0.02 mL, 0.18 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This allowed for workup and reverse-phase flash chromatography. After purification by chromatography [(silica gel C-18, 24 g), eluting with acetonitrile and 0.1% aqueous HCl] followed by lyophilization, the HCl salt of (S)-1-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (102b) (13 mg, 36% yield) was obtained as a solid. 1 H NMR (300MHz, DMSO-d6): δ11.40(s,1H),10.97(s,1H),8.49(s,1H),8.19-7.88(m,2H),7.00(s,2H),4.65-4.41(m,2H),4.40-3.91(m,6) H),3.88(s,6H),3.68(s,3H),3.64-2.87(m,4H),2.15-1.86(m,7H),1.85-1.60(m,1H).MS(ES+):596.6(M+1);MS(ES-):630.6(M+Cl).

[0434] Scheme 103 [ka] Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (103b)

[0435] Step 1: Preparation of (2-chloro-furo[3,2-d]pyrimidin-4-yl)-[1-(3,4,5-trimethoxy-phenyl)-1H-imidazol-4-yl]-amine (103a) Compound 103a was prepared from 2,4-dichloro-furo[3,2-d]pyrimidine (1a) (1.0 g, 5.29 mmol) in IPA (30 mL) using DIPEA (2.06 mL, 15.87 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamine hydrochloride (57a) (1.81 g, 6.34 mmol) according to the procedure described in Scheme 1. After workup, this afforded (2-chloro-furo[3,2-d]pyrimidin-4-yl)-[1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl]-amine (103a) (1.0 g, 47%) as an off-white solid; MS(ES+): 402.0 (M+1); MS(ES-): 400.0 (M+1).

[0436] Step 2: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (103b) Compound 103b was prepared from (2-chloro-furo[3,2-d]pyrimidin-4-yl)-[1-(3,4,5-trimethoxy-phenyl)-1H-imidazol-4-yl]-amine (103a) (300 mg, 0.75 mmol) and (S)-pyrrolidin-2-ylmethanol (0.76 g, 7.5 mmol) in NMP (20 mL) according to the procedure described in Step 2 of Scheme 76. This afforded the free base of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (103b) (100 mg, 29%) as a white solid after workup and purification by flash chromatography (silica gel, eluting with 0–10% methanol in ethyl acetate). The free base was repurified by reverse-phase flash column chromatography [(silica gel C-18 column, 24 g), eluted with acetonitrile and 0.1% aqueous HCl (0–50%)] and then lyophilized to give the HCl salt of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (103b) (25 mg) as a pale yellow solid; 1 H NMR(300MHz,DMSO-d6):δ13.40(s,1H),11.91(s,1H),8.54(s,1H),8.35(s ,1H),8.04(s,1H),7.01(d,J=10.6Hz,3H),4.44(s,1H),3.87(d,J=3.8Hz,6 H),3.75(s,1H),3.68(d,J=3.7Hz,3H),3.58-3.34(m,3H),2.02(s,4H).MS(ES+):467.5(M+1),489.5(M+Na);MS(ES-):501.5(M+Cl);HPLC purity: 98.60%.

[0437] Scheme 104 [ka] Preparation of (S)-(1-(6-((4-methylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (104b)

[0438] Step 1: Preparation of 2-chloro-6-((4-methylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (104a) Compound 104a was prepared from 2-chloro-6-(chloromethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97b) (100 mg, 0.21 mmol), DIPEA (0.15 mL, 0.86 mmol) and 1-methylpiperazine (0.048 mL, 0.43 mmol) in THF (3 mL) according to the procedure described in Step 3 of Scheme 97. This gave 2-chloro-6-((4-methylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (104a) (32 mg, 28% yield); MS (ES+): 530.5, 532.5 (M+1), (ES-): 528.4 (M-1), 564.4, 566.4 (M+Cl).

[0439] Step 2: Preparation of (S)-(1-(6-((4-methylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (104b) Compound 104b was prepared from 2-chloro-6-((4-methylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (104a) (0.05 g, 0.09 mmol), (S)-pyrrolidin-2-ylmethanol (0.03 mL, 0.26 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after workup and purification by reverse-phase flash chromatography ([silica gel C-18, 24 g], eluting with acetonitrile and 0.1% aqueous HCl] followed by lyophilization, the HCl salt of (S)-(1-(6-((4-methylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (104b) (10 mg, 24% yield) as a tan solid; 1 H NMR (300MHz, DMSO-d6): δ11.14(s,1H),8.43(s,1H),8.07-7.85(m,2H),6.98(d,J=4.6Hz,2H),4.48(s,1H),4.27(s,2H),3.94(s,1H),3.88( s,6H),3.86(s,2H),3.81(s,1H),3.68(s,3H),3.61-3.40(m,4H),3.40-3.12(m,4H),2.79(s,3H),2.11-1.85(m,4H).MS(ES+):595.6(M+1).

[0440] Scheme 105 [ka] Preparation of (S)-(1-(7-(piperidin-1-ylmethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (105b)

[0441] Step 1: Preparation of 2-chloro-7-(piperidin-1-ylmethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (105a) To a solution of 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (100 mg, 0.23 mmol) in dichloroethane (5 mL) was added piperidine (0.025 mL, 0.26 mmol) and acetic acid (0.03 mL). To this suspension was added NaBH(OAc) (64 mg, 0.3 mmol), and the reaction was stirred for 8 h. An additional amount of NaBH(OAc) (64 mg, 0.3 mmol) was added and the reaction was stirred for 8 h. The reaction was quenched with 1 N NaOH (2 mL), the organic phase was separated, and the aqueous phase was extracted with CHCl (3×10 mL). The combined organic phases were dried, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g silica gel, eluted with 0% to 10% MeOH in DCM) to give 2-chloro-7-(piperidin-1-ylmethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (105a) (43 mg, 37% yield) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 10.56 (s, 1H), 7.95 (s, 1H), 7.66 (s, 1H), 7.07-6.81 (m, 1H), 6.84-6.40 (m, 3H), 4.10-3.73 (m, 11H), 2.61-2.41 (m, 4H), 1.67-1.49 (m, 4H), 1.48-1.33 (m, 2H); MS (ES+): 498.5 (M+1); MS (ES-): 496.5 (M-1).

[0442] Step 2: Preparation of (S)-(1-(7-(piperidin-1-ylmethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (105b) Compound 105b was prepared from 2-chloro-7-(piperidin-1-ylmethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (105a) (43 mg, 0.09 mmol), (S)-pyrrolidin-2-ylmethanol (87 mg, 0.86 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by flash chromatography (4 g silica gel, eluting with 0% to 10% MeOH in DCM), (S)-(1-(7-(piperidin-1-ylmethyl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (105b) (6 mg, 13% yield) as a white solid; 1 H NMR (300 MHz, methanol-d4) δ 7.98 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 6.88-6.83 (m, 3H), 6.45 (d, J = 4.5 Hz, 1H), 4.33-4.16 (m, 1H), 3.91 (s, 6H), 3.87 (s, 2H), 3.88-3.78 (m , 1H), 3.79 (s, 3H), 3.75-3.50 (m, 2H), 3.40-3.25 (m, 1H), 2.64-2.45 (m, 4H), 2.14-1.86 (m, 4H), 1.72-1.53 ​​(m, 4H), 1.49-1.36 (m, 2H); MS (ES+): 563.6 (M+1), 585.6 (M+Na). The hydrochloride salt of compound 105b was obtained as a yellow solid by purifying the crude reaction mixture from Step 2 above by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with acetonitrile and 0.1% aqueous HCl] followed by lyophilization. 1H NMR(300MHz,DMSO-d6):δ10.90(s,1H),10.36(s,1H),8.46(s,1H),8.01(s,1H) ),7.23(d,J=4.6Hz,1H),6.99(s,2H),6.72(d,J=4.5Hz,1H),4.49(s,2H),4.2 9-4.14(m,1H),3.88(s,6H),3.84-3.26(m,9H),2.86(d,J=11.4Hz,2H),2.13- 1.16(m,10H).MS(ES+):563.3(M+1);MS(ES-):597.4(M+Cl).HPLC purity:95.10%.

[0443] Scheme 106 [ka] Preparation of (S)-(1-(7-((4-cyclopropylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (106b)

[0444] Step 1: Preparation of 2-chloro-7-((4-cyclopropylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (106a) Compound 106a was prepared from 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (100 mg, 0.23 mmol) in dichloroethane (3 mL) using 1-cyclopropylpiperazine (44 mg, 0.35 mmol), acetic acid (0.03 mL), and NaBH(OAc) (74 mg, 0.35 mmol) according to the procedure described for reductive amination in Step 1 of Scheme 105. This gave, after workup and purification by flash column chromatography (12 g silica gel, eluting with 0% to 10% DMA80 in DCM), 2-chloro-7-((4-cyclopropylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (106a) (46 mg, 37% yield) as a solid; 1 H NMR (300 MHz, chloroform-d) δ 10.64 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 6.91 (d, J = 4.5 Hz, 1H), 6.66 (s, 2H), 6.61 (d, J = 4.5 Hz, 1H), 4.18-3.61 (m, 11H), 3.36-2.11 (m, 8H), 1.68-1.47 (m, 1H), 0.62-0.15 (m, 4H); MS (ES+): 539.5 (M+1), 561.5 (M+Na); MS (ES-): 537.5 (M-1).

[0445] Step 2: Preparation of (S)-(1-(7-((4-cyclopropylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (106b) Compound 106b was prepared from 2-chloro-7-((4-cyclopropylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (106a) (46 mg, 0.09 mmol), (S)-pyrrolidin-2-ylmethanol (86 mg, 0.85 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] followed by lyophilization, (S)-(1-(7-((4-cyclopropylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (106b) (14 mg, 27% yield) as a solid; 1 H NMR(300MHz,DMSO-d6)δ10.47(s,1H,D2O exchangeable),8.24(d,J=1.5Hz,1H),7.97(d,J=1.6Hz,1H),7.13(d,J=4.4Hz,1H),6.95(s,2H),6.33(d, J=4.5Hz,1H),4.89-4.79(m,1H,D2O exchangeable),4.26-4.08(m,1H),3.87(s,6H),3.85-3.66(m,3H),3.68(s,3H),3.64-3.54(m,1H),3.52-3.38( m, 2H), 2.67-2.25 (m, 8H), 2.11-1.81 (m, 4H), 1.65-1.49 (m, 1H), 0.37 (s, 2H), 0.28-0.18 (m, 2H); MS (ES+): 604.7 (M+1), 626.6 (M+Na); The hydrochloride salt of compound 106b was obtained as a yellow solid by purifying the crude reaction mixture from step 2 above by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with acetonitrile and 0.1% aqueous HCl] followed by lyophilization; 1H NMR(300MHz,DMSO-d6):δ10.49(s,1H),8.23(s,1H),7.97(s,1H),7.13(d,J=4.4Hz, 1H),6.95(s,2H),6.34(d,J=4.2Hz,1H),4.83(s,1H),4.19(s,1H),3.87(s,6H),3.79 (s,2H),3.68(s,3H),3.58(s,1H),3.52-3.42(m,2H),3.42-3.20(m,9H),2.11-1.71( m,4H),1.67-1.40(m,1H),0.44-0.13(m,4H).MS(ES-):602.6(M-1).HPLC purity:93.61%.

[0446] Scheme 107 [ka] Preparation of (S)-(1-(7-(1,2,3,6-tetrahydropyridin-4-yl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (107a) To a solution of (S)-tert-butyl 4-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (98a) (0.06 g, 0.05 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (0.04 mL, 0.54 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL), washed with water (3 times), brine, dried, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash column chromatography [(silica gel C-18, 24 g), eluted with acetonitrile and 0.1% aqueous HCl] and lyophilized to give (S)-(1-(7-(1,2,3,6-tetrahydropyridin-4-yl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (107a) (8 mg, 27% yield) as the HCl salt; 1 H NMR(300MHz,DMSO-d6)δ10.68(s,1H),9.16(s,2H),8.37(s,1H),8.01(s,1H),7.29(s,1H),7.22(d,J=4.6Hz,1H),6.98(s,2H), 6.58(d,J=4.7Hz,1H),4.20(s,1H),4.00-3.25(m,17H),2.83-2.68(m,2H),2.11-1.83(m,4H);MS(ES+):547.6.HPLC purity:96.94%.

[0447] Scheme 108 [ka] Preparation of (S)-(1-(6-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (108b)

[0448] Step 1: Preparation of 2-chloro-6-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (108a) Compound 108a was prepared from 2-chloro-6-(chloromethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97b) (100 mg, 0.21 mmol), DIPEA (0.15 mL, 0.86 mmol) and 1-(pyridin-2-yl)piperazine (0.065 mL, 0.43 mmol) in THF (3 mL) according to the procedure described in Step 3 of Scheme 97. This gave 2-chloro-6-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (108a) (60 mg, 47%) as a solid; MS (ES+): 593.5 (M+1), (ES−): 591.4 (M−1), 627.5, 629.5 (M+Cl).

[0449] Step 2: Preparation of (S)-(1-(6-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (108b) Compound 108b was prepared from 2-chloro-6-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (108a) (0.06 g, 0.1 mmol), (S)-pyrrolidin-2-ylmethanol (0.03 mL, 0.3 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This afforded, after work-up and purification by reverse-phase flash chromatography [(silica gel 18, 24 g), eluting with acetonitrile and 0.1% aqueous HCl] followed by lyophilization, the HCl salt of (S)-(1-(6-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (108b) (10 mg, 15% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ12.16(s,1H),11.60(s,1H),8.58(s,1H),8.19-7.93(m,5H),7.37(d,J=8.9Hz,1H),7.00(d,J=8.5Hz,2H), 4.74-4.30(m,4H),3.88(s,6H),3.81-3.19(m,13H),2.16-1.89(m,4H);.MS(ES+):658.5;MS(ES-):692.5(M+Cl).HPLC purity:97.78%.

[0450] Scheme 109 [ka] Preparation of 3-(6-(hydroxymethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)benzaldehyde (109a) Compound 109a was prepared from (2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-6-yl)methanol (97a) (0.2 g, 0.44 mmol) using 3-formylphenylboronic acid (0.1 g, 0.67 mmol), PdCl(dppf) (65 mg, 0.09 mmol), potassium carbonate (185 mg, 1.34 mmol) in 1,4-dioxane (10 mL) and water (1 mL) according to the procedure described in Step 3 of Scheme 77. This gave, after work-up and purification by flash column chromatography [(silica gel, 12 g), eluting with DMA80 in dichloromethane], 3-(6-(hydroxymethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)benzaldehyde (109a) (134 mg, 58% yield) as a yellow solid; 1 H NMR(300MHz,DMSO-d6)δ10.63(s,1H,D2O exchangeable),10.14(s,1H),8.95(d,J=1.9Hz,1H),8 .76(d,J=7.8Hz,1H),8.28(d,J=1.6Hz,1H),8.18(d,J=1.6Hz,1H),8.03(d,J=7.6Hz,1 H),7.94(s,1H),7.73(t,J=7.7Hz,1H),7.03(s,2H),5.84(s,1H,D2O exchangeable),4.76(s,2H) ),3.90(s,6H),3.71(s,3H);MS(ES+):518.5(M+1),540.3(M+Na),(ES-):516.5(M-1).

[0451] Scheme 110 [ka] Preparation of 3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzaldehyde (110a) Compound 110a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (57b) (0.2 g, 0.5 mmol) using 3-formylphenylboronic acid (112 mg, 0.75 mmol), PdCl(dppf) (73 mg, 0.1 mmol), potassium carbonate (207 mg, 1.5 mmol) in 1,4-dioxane (10 mL) and water (1 mL) according to the procedure described in Step 3 of Scheme 77. This gave, after workup and purification by flash column chromatography [(silica gel, 12 g), eluting with DMA80 in dichloromethane], 3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzaldehyde (110a) (45 mg, 19% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ11.02(s,1H,D2O exchangeable),10.13(s,1H),8.82(t,J=1.7Hz,1H),8.64(d t,J=7.8,1.5Hz,1H),8.30(d,J=1.6Hz,1H),8.18(d,J=1.7Hz,1H),8.04(dt,J=7.7,1.4Hz,1 H),7.88(dd,J=2.6,1.6Hz,1H),7.73(t,J=7.7Hz,1H),7.51-7.25(m,1H),7.03(s,2H),6.77 (dd,J=4.4,2.6Hz,1H),3.90(s,6H),3.71(s,3H);MS(ES+):471.4(M+1),(ES-):469.4(M-1).

[0452] Scheme 111 [ka] Preparation of (S)-(1-(7-(morpholinomethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (111b)

[0453] Step 1: Preparation of 2-chloro-7-(morpholinomethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (111a) Compound 111a was prepared from 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (200 mg, 0.47 mmol) in dichloroethane (3 mL) using 1-morpholine (0.045 mL, 0.51 mmol), acetic acid (0.05 mL), and NaBH(OAc) (129 mg, 0.61 mmol) according to the procedure described for reductive amination in Step 1 of Scheme 105. This gave, after workup and purification by flash column chromatography (silica gel 12 g, eluting with 0% to 10% MeOH in DCM), 2-chloro-7-(morpholinomethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (111a) (131 mg, 56% yield) as a slightly pink solid; 1 H NMR(300MHz,DMSO-d6)δ11.24(s,1H,D2O exchangeable),8.20(d,J=1.6Hz,1H),7.88(d,J=1.6Hz,1H),7.40(d,J=4.4Hz,1H),6.93(s,2H),6.67(d,J=4.5 Hz,1H),3.87(s,6H),3.78(s,2H),3.69(s,3H),3.56(t,J=4.6Hz,4H),2.47-2.37(m,4H);MS(ES+):500.4(M+1),522.4(M+Na);HPLC purity: 95.21%.

[0454] Step 2: Preparation of (S)-(1-(7-(morpholinomethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (111b) Compound 111b was prepared from 2-chloro-7-(morpholinomethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (111a) (106 mg, 0.21 mmol), (S)-pyrrolidin-2-ylmethanol (161 mg, 1.59 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (di-t-Bu-XPhos) (14 mg, 0.032 mmol), Pd(dba) (14 mg, 0.015 mmol), and sodium tert-butoxide (153 mg, 1.59 mmol) in toluene (5 mL) according to the procedure described in Step 3 of Scheme 101. This gave, after workup and purification by flash chromatography (24 g silica gel, eluting with 0% to 10% MeOH in DCM), (S)-(1-(7-(mophorinomethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (111b) (75 mg, 63% yield) as a solid; 1 H NMR(300MHz,DMSO-d6)δ10.48(s,1H,D2O exchangeable),8.24(s,1H),7.98(s,1H),7.14(d,J=4.4Hz, 1H),6.95(s,2H),6.35(d,J=4.4Hz,1H),4.83(t,J=5.2Hz,1H,D2O exchangeable),4.31-4.07(m,1H), 3.87 (s, 6H), 3.85-3.63 (m, 5H), 3.65-3.43 (m, 4H), 3.42-3.23 (m, 4H), 2.46-2.29 (m, 4H), 2.13-1.74 (m, 4H); MS (ES+): 565.6 (M+1), 587.4 (M+Na); MS (ES-): 563.6 (M-1); HPLC purity: 84.98%. The hydrochloride salt of compound 111b was obtained by purifying the crude reaction mixture from Step 2 above by reverse-phase flash chromatography (silica gel C-18, 24 g), eluting with acetonitrile and 0.1% aqueous HCl, followed by lyophilization. 1H NMR (300MHz, DMSO-d6): δ11.51(s,1H),11.15(s,1H),8.77(s,1H),8.09(s,1H),7.25(d,J=4.5 Hz,1H),7.04(s,2H),6.78(d,J=4.4Hz,1H),4.58(s,2H),4.20(s,1H),3.99-3.90(m,1H),3.88 (s,6H),3.85-3.71(m,2H),3.69(s,3H),3.47(s,1H),3.37-3.21(m,4H),3.19-2.96(m,4H),2. 09-1.78(m,4H).MS(ES+):565.4(M+1),587.3(M+Na).MS(ES-):599.5(M+Cl).HPLC purity: 94.30%.

[0455] Scheme 112 [ka] Preparation of (S)-(1-(7-((4-methylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (112b)

[0456] Step 1: Preparation of 2-chloro-7-((4-methylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (112a) Compound 112a was prepared from 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (200 mg, 0.47 mmol) in dichloroethane (10 mL) using 1-methylpiperazine (0.078 mL, 0.7 mmol), acetic acid (0.05 mL), and NaBH(OAc) (148 mg, 0.7 mmol) according to the procedure described for reductive amination in Step 1 of Scheme 105. The combined organic phases were dried, filtered, and concentrated in vacuo. This gave, after workup and purification by flash column chromatography (silica gel 12 g, eluting with 0–50% DMA80 in DCM), 2-chloro-7-((4-methylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (112a) (122 mg, 51.0% yield) as a solid; 1 H NMR(300MHz,chloroform-d)δ10.13(s,1H),7.94(d,J=1.5Hz,1H),7.65(d,J=1.6Hz,1H),6.87(d,J=4.5Hz,1H),6.66(s,2H), 6.63(d,J=4.5Hz,1H),4.25-3.56(m,11H),2.86-2.37(m,8H),2.29(s,3H);MS(ES+):513.5(M+1);MS(ES-):511.5(M-1).

[0457] Step 2: Preparation of (S)-(1-(7-((4-methylpiperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (112b) Compound 112b was prepared from 2-chloro-7-((4-methylpiperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (112a) (106 mg, 0.21 mmol), (S)-pyrrolidin-2-ylmethanol (157 mg, 1.55 mmol), (di-t-Bu-XPhos) (13 mg, 0.031 mmol), Pd(dba) (13 mg, 0.015 mmol), and sodium tert-butoxide (149 mg, 1.55 mmol) in toluene (5 mL) according to the procedure described in Step 3 of Scheme 101. This afforded, after workup and purification by flash chromatography (12 g silica gel, eluting with 0–40% MeOH in DCM), (S)-(1-(7-((4-methylpiperazin-1-yl)methyl)-4)-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (112b) (31 mg, 26.0% yield) as a white solid; 1 H NMR(300MHz,DMSO-d6)δ10.47(s,1H,D2O exchangeable),8.24(d,J=1.5Hz,1H),7.97(d,J=1.6Hz,1H),7.13(d ,J=4.4Hz,1H),6.95(s,2H),6.33(d,J=4.4Hz,1H),4.83(t,J=5.2Hz,1H,D2O exchangeable),4.28-4.06(m,1H) ,3.87(s,6H),3.82-3.69(m,1H),3.76(s,2H),3.68(s,3H),3.65-3.54(m,1H),3.54-3.37(m,2H),2.5 5-2.18(m,8H),2.15(s,3H),2.11-1.79(m,4H);MS(ES+):578.6(M+1),600.6(M+Na);HPLC purity:88.41%.

[0458] Scheme 113 [ka] Preparation of (S)-(1-(6-(piperidin-1-ylmethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (113b)

[0459] Step 1: Preparation of 2-chloro-6-(piperidin-1-ylmethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (113a) Compound 113a was prepared from 2-chloro-6-(chloromethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97b) (150 mg, 0.32 mmol), DIPEA (0.23 mL, 1.29 mmol) and piperidine (0.04 mL, 0.64 mmol) in THF (3 mL) according to the procedure described in Step 3 of Scheme 97. This gave 2-chloro-6-(piperidin-1-ylmethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (113a) (100 mg, 60%) as a solid, which was used in the next step without further purification; MS(ES-): 514.4 (M-1).

[0460] Step 2: Preparation of (S)-(1-(6-(piperidin-1-ylmethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (113b) Compound 113b was prepared from 2-chloro-6-(piperidin-1-ylmethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (113a) (0.1 g, 0.19 mmol), (S)-pyrrolidin-2-ylmethanol (0.1 mL, 0.97 mmol) in NMP (1 mL) according to the procedure described in Scheme 2. This gave, after work-up and purification by flash chromatography [silica (4 g), eluting with 0–30% DMA80 in CHCl], (S)-(1-(6-(piperidin-1-ylmethyl)-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (113b) (15 mg, 13% yield) as a white solid; 1 H NMR (300MHz, chloroform-d) δ7.88(d,J=1.6Hz,1H),7.75(s,1H),7.62(d,J=1.6Hz,1H),6.93(s,1H),6.67(s ,2H),4.42(s,1H),3.92(s,6H),3.89(s,3H),3.83-3.69(m,2H),3.65(s,2H),2.55-2.37(m,4H),2.22-1. 51 (m, 9H), 1.52-1.35 (m, 3H). MS (ES+): 580.6 (M+1); MS (ES-): 578.6 (M-1); The hydrochloride salt of compound 113b was obtained by purifying the crude reaction mixture from step 2 above by reverse-phase flash chromatography [(silica gel C-18, 24 g), eluting with acetonitrile and 0.1% HCl in water], followed by lyophilization; 1H NMR(300MHz,DMSO-d6)δ11.36(s,1H),10.85(s,1H),8.49(s,1H),8.07(s,2H) ),7.00(s,2H),4.51(s,2H),4.39-4.06(m,1H),3.88(s,6H),3.79-3.62(m,4H ),3.58-3.28(m,3H),3.06-2.78(m,4H),2.19-1.88(m,4H),1.88-1.56(m,4H) ,1.51-1.19(m,2H);MS(ES+):580.4;MS(ES-):614.5(M+Cl).HPLC purity:98.49%.

[0461] Scheme 114 [ka] Preparation of (S)-(1-(7-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (114b)

[0462] Step 1: Preparation of 2-chloro-7-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (114a) Compound 114a was prepared from 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (200 mg, 0.47 mmol) in dichloroethane (8 mL) using 1-(2-methoxyethyl)piperazine (101 mg, 0.7 mmol), acetic acid (0.05 mL), and NaBH(OAc) (148 mg, 0.7 mmol) according to the procedure described for reductive amination in Step 1 of Scheme 105. This gave, after workup and purification by flash column chromatography (12 g silica gel, eluting with 0–50% DMA80 in DCM), 2-chloro-7-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (114a) (72 mg, 28% yield) as a yellow solid; MS (ES+): 557.5, 579.5 (M+1); MS (ES−): 555.5 (M−1).

[0463] Step 2: Preparation of (S)-(1-(7-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (114b) Compound 114b was prepared from 2-chloro-7-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (114a) (72 mg, 0.13 mmol), (S)-pyrrolidin-2-ylmethanol (98 mg, 0.97 mmol), (di-t-Bu-XPhos) (8 mg, 0.019 mmol), Pd(dba) (8 mg, 0.009 mmol), and sodium tert-butoxide (93 mg, 0.97 mmol) in PhMe (5 mL) according to the procedure described in Step 3 of Scheme 101. This gave, after workup and purification by flash chromatography (12 g silica gel, eluting with 0–50% MeOH in DCM), (S)-(1-(7-((4-(2-methoxyethyl)piperazin-1-yl)methyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (114b) (16 mg, 20% yield) as a solid; 1 H NMR (300MHz, DMSO-d6) δ10.50 (s, 1H, D2O exchangeable), 8.24 (d, J=1.6Hz, 1H), 7.97 (s, 1H), 7.14 (d, J=4.4Hz,1H),6.95(s,2H),6.35(s,1H),4.96-4.75(m,1H,D2O exchangeable),4.30-4.06(m,1H),3.5 4-3.25(m,4H),3.87(s,6H),3.84-3.68(m,1H),3.68(s,3H),3.67-3.52(m,1H),3.31-3.14( m,3H),2.76-2.24(m,10H),2.10-1.79(m,4H);MS(ES+):622.7(M+1);MS(ES-):656.7(M+Cl).

[0464] Scheme 115 [ka] Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidin-2-yl)methanol (115b)

[0465] Step 1: Preparation of (S)-(1-(2-chloroquinazolin-4-yl)pyrrolidin-2-yl)methanol (115a) To a solution of 2,4-dichloroquinazoline (21a) (2.0 g, 10.04 mmol) in DCM (30 mL) was added (S)-pyrrolidin-2-ylmethanol (2.0 mL, 19.77 mmol) and DIPEA (3.5 mL, 27.15 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic phases were dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0-40% ethyl acetate in hexanes) to give (S)-(1-(2-chloroquinazolin-4-yl)pyrrolidin-2-yl)methanol (115a) (1.4 g, 54% yield) as an off-white solid. 1 H NMR(300MHz,DMSO-d6):δ8.33-8.22(m,1H),7.78(ddd,J=8.2,6.9,1.2Hz,1H),7 .62(dd,J=8.4,1.3Hz,1H),7.47(ddd,J=8.4,6.9,1.4Hz,1H),4.85(t,J=5.8Hz,1 H),4.57(t,J=5.7Hz,1H),4.11-3.87(m,2H),3.64(t,J=5.2Hz,2H),2.16-1.78( m,4H).MS(ES-):264.3(M+1),286.3(M+Na);MS(ES-):262.3(M-1),298.3(M+Cl).

[0466] Step 2: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidin-2-yl)methanol (115b) Compound 115b was prepared from (S)-(1-(2-chloroquinazolin-4-yl)pyrrolidin-2-yl)methanol (115a) (250 mg, 0.95 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.41 g, 1.42 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 0.07 g, 0.11 mmol), Pd(dba) (0.09 g, 0.1 mmol), and sodium tert-butoxide (0.18 g, 1.9 mmol) in PhMe (4 mL) according to the procedure described in Step 2 of Scheme 96. This gave, after workup and purification by flash column chromatography [silica (4 g), eluting with 0–30% DMA80 in CHCl], (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidin-2-yl)methanol (115b) (169 mg, 37% yield) as a yellow solid; 1 H NMR(300MHz,DMSO-d6)δ9...

Claims

1. A compound represented by formula (I) or (II), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, A is one or more fused R ４ an aromatic ring, a heteroaromatic ring, a partially unsaturated cycloalkyl ring or a partially unsaturated heterocycloalkyl ring, which may be substituted by occurrences of W is C or N; R ａ represents H or alkyl; -R １ -R １ａ teeth, 【Chemistry 2】 represents R １ａ is an unsubstituted phenyl, or an optionally substituted —C(O)alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)O(alkyl), —C(O)(heterocyclyl), —C(O)NR ｘ R ｙ , cycloalkyl, heterocycloalkyl, or heteroaryl; J is -OR ２ , -NR ２ R ３ , —C(O)O(alkyl), or —C(O)OH; R ２ represents optionally substituted alkyl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl; R ３ represents H or alkyl; Or R ２ and R ３ Together, they form one or more R ２ａ occurrences of form an optionally substituted heterocycloalkyl ring, R ２ａ is independently at each occurrence halo, hydroxyl, -C(O)H, oxo, -NH ２ , -C(O)NH ２ , -C(O)R ５ , -C(O)OR ５ or optionally substituted alkyl, alkoxyl, hydroxyalkyl, heteroaryl, aryl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, or -N(alkyl) ２ represents Or, R ２ａ any two geminal or vicinal occurrences of may be taken together to form a spiro or fused cycloalkyl ring; R ４ is independently at each occurrence halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, -CH ２ C(O)NH ２ , -C(O)R ５ , -C(O)OR ５ or -S(O) ２ R ５ represents R ５ represents independently at each occurrence an optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; R ｘ and R ｙ each independently represents H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

2. Formula (Ia) or Formula (IIa): 【Chemistry 3】 [In the formula, As valences permit, Q, T, U and V are each independently CH, CH ２ , N, NH, O, or SO ２ where CH, CH ２ or the hydrogen of the NH group is R ４ can be replaced by the appearance of R ４ is independently at each occurrence halo, cyano, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, -CH ２ C(O)NH ２ , -C(O)R ５ , -C(O)OR ５ or -S(O) ２ R ５ represents m is an integer from 0 to 4, as valences permit.

2. The compound of claim 1 , represented by:

3. Formula (Ib) or (IIb): 【Chemistry 4】 [In the formula, Q represents CH or N, and V represents CH or N] The compound of claim 2, represented by:

4. Formula (Ic) or (IIc): 【Chemistry 5】 The compound of claim 2, represented by:

5. Formula (Id) or (IId): 【Chemistry 6】 [Wherein T is CH ２ , NH, O or SO ２ and U is CH ２ , NH, O or SO ２ Represents The compound of claim 2, represented by:

6. Formula (Ie) or (IIe): 【Chemistry 7】 The compound of claim 2, represented by:

7. 4. The compound of claim 3, represented by formula (Ib) or (IIb), wherein Q is N and V is CH, or Q is CH and V is N.

8. Represented by formula (Id) or (IId), wherein T is NH and U is CH ２ or T is CH ２ and U is NH.

9. Formula (Ij) or Formula (IIj): 【Chemistry 8】 [In the formula, W is C or N; As valences permit, X, Y and Z are each independently CH, CH ２ , CO, N, NH, O, S, or SO ２ where CH, CH ２ or the hydrogen of the NH group is R ４ can be replaced by the appearance of R ４ is independently at each occurrence cyano, halo, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, -CH ２ C(O)NH ２ , -C(O)R ５ , -C(O)OR ５ or -S(O) ２ R ５ represents n is an integer from 0 to 4, as valences permit.

2. The compound of claim 1 , represented by:

10. Formula (Ik) or (IIk): 【Chemistry 9】 [In the formula, X, Y and Z are each independently CH, N, NH, O, S, or SO ２ Represents 10. The compound of claim 9 , represented by:

11. Formula (Ik') or (IIk'): 【Chemistry 10】 11. The compound of claim 10, represented by:

12. Formula (Ik″) or (IIk″): 【Chemistry 11】 wherein at least one of X and Z is selected from the group consisting of O, N, NH, and S.

11. The compound of claim 10, represented by:

13. (a) one of X and Z is selected from the group consisting of O, NH, and S, and the other of X and Z is CH; (b) X is selected from the group consisting of O, NH, and S; (c) Z is selected from the group consisting of O, NH, and S; (d) each of X and Z is selected from the group consisting of O, N, NH, and S; or (e) one of X and Z is N, and the other of X and Z is NH; 13. The compound of claim 12.

14. Formula (In) or (IIn): 【Chemistry 12】 wherein each of Y and Z is selected from the group consisting of O, N, NH, and S.

11. The compound of claim 10, represented by:

15. 15. The compound of claim 14, wherein Y is N and Z is NH.

16. Formula (Im) or (IIm): 【Chemistry 13】 [In the formula, X, Y and Z each independently represent CH ２ , CO, NH, O, S, or SO ２ Represents 10. The compound of claim 9 , represented by:

17. (a) each of X, Y and Z is CH ２ is; or (b) one of X, Y and Z is NH or O; 17. The compound of claim 16.

18. R ４ The compound of any one of claims 1 to 17, wherein, if present, is selected from the group consisting of optionally substituted alkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, and (heterocycloalkyl)alkyl.

19. R ａ The compound according to any one of claims 1 to 18, wherein

20. -R １ -R １ａ teeth, 【Chemistry 14】 The compound according to any one of claims 1 to 19, which represents

21. R １ａ is an unsubstituted phenyl, or an optionally substituted —C(O)alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)O(alkyl), —C(O)(heterocyclyl), —C(O)NR ｘ R ｙ 21. The compound according to any one of claims 1 to 20, wherein R represents a heterocycloalkyl or heteroaryl.

22. R １ａ The compound of any one of claims 1 to 21, wherein is unsubstituted phenyl.

23. R １ａ The compound of any one of claims 1 to 21, wherein is optionally substituted heteroaryl.

24. The compound of claim 23, wherein R 1a is quinoline.

25. J is -NR ２ R ３ The compound according to any one of claims 1 to 24,

26. R ２ and R ３ Together, they form one or more R ２ａ 26. The compound of claim 25, wherein the occurrences of form an optionally substituted heterocycloalkyl ring.

27. R ２ and R ３ Together, they form one or more R ２ａ 27. The compound of claim 26, wherein the occurrences of form an optionally substituted pyrrolidine ring.

28. R ２ａ is independently at each occurrence -C(O)NH ２ , -C(O)R ５ 28. A compound according to claim 26 or 27, wherein R represents hydroxyalkyl, heteroaryl or aryl.

29. R ２ａ -C(O)NH ２ The compound according to any one of claims 26 to 28,

30. R ２ａ The compound of any one of claims 26 to 28, wherein is hydroxyalkyl.

31. 2. The compound according to claim 1, selected from the compounds in the following table: 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】

32. 2. The compound of claim 1, wherein the optional substituents are selected from halogen, haloalkyl, hydroxyl, carbonyl, carboxy, alkoxycarbonyl, formyl, acyl, thiocarbonyl, thioester, thioacetate, thioformate, alkoxy, alkenyloxy, alkynyloxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, alkylamino, dialkylamino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, silyl, silyloxy, heterocycloalkyl, cycloalkyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl.

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

34. A pharmaceutical composition for inhibiting ALK2 kinase, comprising an effective amount of a compound according to any one of claims 1 to 32 or a pharma- ceutically acceptable salt thereof.

35. A pharmaceutical composition for treating fibrodysplasia ossificans progressiva, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 32 or a pharma- ceutically acceptable salt thereof.

36. A pharmaceutical composition for treating glioma, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 32 or a pharma- ceutically acceptable salt thereof.

37. 37. The pharmaceutical composition of claim 36, wherein the glioma is diffuse intrinsic pontine glioma.

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