Imidazole-containing inhibitors of ALK2 kinase

This application is a continuation of U.S. patent application Ser. No. 16/622,816, filed Dec. 13, 2019; which is a U.S. National Stage Application of International Patent Application No. PCT/US2018/037503, filed Jun. 14, 2018; which claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 62/520,150, filed Jun. 15, 2017.

A single mutation (R206H) within the kinase domain of one (ACVR1/ALK2) of the four human bone morphogenetic protein (BMP) receptors has been linked to a catastrophic disorder of secondary (heterotopic) bone formation. As a result of the mutation, all children presenting with features of classic Fibrodysplasia Ossificans Progressiva (FOP) eventually become encased in, and their movement blocked by, a second heterotopic skeleton. The disorder has long been associated with dysregulation of BMP signaling in soft tissues (skeletal muscle, tendon, ligament, fascia) that were transformed into ribbons, sheets and plates of heterotopic bone via an endochondral process. In addition to the common R206H mutation linked to the classic form of FOP, other dysregulating mutations have been identified in ACVR1/ALK2 that lead to atypical and variant forms of FOP. Further, compounds effective in regulating BMP signaling based on their ability to inhibit ALK2 have been shown also to inhibit kinases from multiple signaling pathways.

Thus, there remains a need for additional compounds that inhibit the ALK2 kinase which will be suitable for various important therapeutic applications.

In certain aspects, the invention provides a compound of formula (I) or formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a fused optionally 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 represents 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 represents H, halo, —OR 2 , —NR 2 R 3 , —C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl, or heteroaryl, wherein aryl or heteroaryl is optionally substituted by one or more occurrences of R 2a ;

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 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ;

R 2a , independently for each occurrence, represents halo, hydroxyl, —C(O)H, oxo, —NH 2 , —C(O)NH 2 , —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 any two germinal or vicinal occurrences of R 2a , taken together, may form a spiro or fused cycloalkyl ring;

R 5 , independently for each occurrence, represents optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; and R x and R y each independently represent H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

In further aspects, the invention provides a compound of formula (III) or formula (IV):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a fused optionally 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, 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 represents 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 represents H, halo, —OR 2 , —NR 2 R 3 , —C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl, or heteroaryl, wherein aryl or heteroaryl is optionally substituted by one or more occurrences of R 2a ;

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 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ;

R 2a , independently for each occurrence, represents halo, hydroxyl, —C(O)H, oxo, —NH 2 , —C(O)NH 2 , —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 any two germinal or vicinal occurrences of R 2a , taken together, may form a spiro or fused cycloalkyl ring;

R 5 , independently for each occurrence, represents optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; and

R x and R y each independently represent H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

In still further aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

In certain aspects, the invention provides a pharmaceutical composition, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

In certain aspects, the invention provides methods of inhibiting ALK2 kinase, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

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

In further aspects, the invention provides methods of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cancer is a glioma.

Provided herein are compounds of formulae (I), (II), (III), and (IV), and pharmaceutically acceptable salts thereof, that are useful for inhibiting ALK2 kinase, and useful in the treatment or prevention of a disease or condition that would benefit from inhibition of ALK2 kinase. 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.

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.

The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.

The term “alkyl” as used herein 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., C 1 -C 30 for straight chain, C 3 -C 30 for branched chain), and alternatively, about 20 or fewer, or 10 or fewer. In certain embodiments, the term “alkyl” refers to a C 1 -C 10 alkyl group. In certain embodiments, the term “alkyl” refers to a C 1 -C 6 alkyl group, for example a C 1 -C 6 straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C 3 -C 12 branched-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C 3 -C 8 branched-chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C 3 -C 7 )cycloalkyl, which represents 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 contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form —(CH 2 ) w —, 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. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are 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.

The term “(cycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of (cycloalkyl)alkyl is cyclohexylmethyl group.

The term “heterocycloalkyl” as used herein refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepines, 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-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. A heterocycloalkyl group is optionally substituted by one or more substituents as described below.

The term “(heterocycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

The term “alkenyl” as used herein means a straight or branched chain hydrocarbon radical containing from 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(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

The term “alkynyl” as used herein means a straight or branched chain hydrocarbon radical containing from 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.

The term “alkylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment an 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, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. That is, in one embodiment, a “substituted alkyl” is an “alkylene”.

The term “amino” is a term of art and as used herein refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

wherein R a , R b , and R c each independently represent a hydrogen, an alkyl, an alkenyl, —(CH 2 ) x —R d , or R a and R b , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R d represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R a or R b may be a carbonyl, e.g., R a , R b , and the nitrogen together do not form an imide. In other embodiments, R a and R b (and optionally R c ) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH 2 ) x —R d . In certain embodiments, the term “amino” refers to —NH 2 .

In certain embodiments, the term “alkylamino” refers to —NH(alkyl).

In certain embodiments, the term “dialkylamino” refers to —N(alkyl) 2 .

The term “amido”, as used herein, means —NHC(═O)—, wherein the amido group is bound to the parent molecular moiety through the nitrogen. Examples of amido include alkylamido such as CH 3 C(═O)N(H)— and CH 3 CH 2 C(═O)N(H)—.

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, e.g., alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

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

The term “aminoacyl” is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.

The term “aminothionyl” as used herein refers to an analog of an aminoacyl in which the O of RC(O)— has been replaced by sulfur, hence is of the form RC(S)—.

The term “phosphoryl” is a term of art and as used herein may in general be represented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl; for example, —P(O)(OMe)- or —P(O)(OH) 2 . When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:

wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N; for example, —O—P(O)(OH)OMe or —NH—P(O)(OH) 2 . When Q50 is S, the phosphoryl moiety is a “phosphorothioate.”

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)NMe 2 .

The term “azide” or “azido”, as used herein, means an —N 3 group.

The term “carbonyl” as used herein refers to —C(═O)—.

The term “thiocarbonyl” as used herein refers to —C(═S)—.

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.

The term “alkylthio” as used herein refers to alkyl-S—. The term “(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthio group.

The term “carboxy”, as used herein, means a —CO 2 H group.

The term “aryl” is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains from 6-10 carbon ring atoms (i.e., (C 6 -C 10 )aryl). The aromatic ring may be substituted at one or more ring positions with one or more 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, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. In certain embodiments, the term “aryl” refers to a phenyl group.

The term “arylene” means a diradical obtained by removing two hydrogen atoms of an aryl group, as defined above. In certain embodiments an 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, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, or the like. That is, in certain embodiments, a “substituted aryl” is an “arylene”.

The term “heteroaryl” is a term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. 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. The “heteroaryl” may be substituted at one or more ring positions with one or more 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, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.

The term “heteroarylene” means a diradical obtained by removing two hydrogen atoms of a heteroaryl group, as defined above. In certain embodiments an 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, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, or the like. That is, in certain embodiments, a “substituted heteroaryl” is an “heteroarylene”.

The term “aralkyl” or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group.

The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and as used herein refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkyl group.

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.

The term “alkoxyalkyl” refers to an alkyl group substituted by an alkoxy group.

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.

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.

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.

The term “alkylcarbonyloxy” and “arylcarbonyloxy”, as used herein, means 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.

The term “alkenoxy” or “alkenoxyl” means 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-propen-1-oxyl (i.e., CH 2 ═CH—CH 2 —O—) and vinyloxy (i.e., CH 2 ═CH—O—).

The term “aryloxy” as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

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

The term “cyano” is a term of art and as used herein refers to —CN.

The term “halo” is a term of art and as used herein refers to —F, —Cl, —Br, or —I.

The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms.

The term “hydroxy” is a term of art and as used herein refers to —OH.

The term “hydroxyalkyl”, as used herein, means at least one hydroxy group, as defined herein, is 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.

The term “silyl”, as used herein, includes hydrocarbyl derivatives of the silyl (H 3 Si—) group (i.e., (hydrocarbyl) 3 Si—), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).

The term “silyloxy”, as used herein, means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.

Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

The term “substituted” is also contemplated 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 may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

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

The phrase “protecting group”, as used herein, means temporary substituents which protect 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 and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.

For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Other chemistry terms herein are used according to conventional usage in the art, as exemplified by 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.

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

The terms “carrier” and “pharmaceutically acceptable carrier” as used herein 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 oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W. Martin, herein incorporated by reference in its entirety.

The term “treat” as used herein means prevent, halt or slow the progression of, or eliminate a disease or condition in a subject. In one embodiment “treat” means halt or slow the progression of, or eliminate a disease or condition in a subject. In one embodiment, “treat” means reduce at least one objective manifestation of a disease or condition in a subject.

The term “effective amount” as used herein refers to an amount that is sufficient to bring about a desired biological effect.

The term “therapeutically effective amount” as used herein refers to an amount that is sufficient to bring about a desired therapeutic effect.

The term “inhibit” as used herein means decrease by an objectively measurable amount or extent. In various embodiments “inhibit” means decrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to relevant control. In one embodiment “inhibit” means decrease 100 percent, i.e., halt or eliminate.

The term “subject” as used herein refers to a mammal. In various embodiments, a subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, a subject is a human.

Compounds

The present invention provides a compound of Formula (I) or (II):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a fused optionally 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 represents 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 represents H, halo, —OR 2 , —NR 2 R 3 , —C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl, or heteroaryl, wherein aryl or heteroaryl is optionally substituted by one or more occurrences of R 2a ;

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 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ;

R 2a , independently for each occurrence, represents halo, hydroxyl, —C(O)H, oxo, —NH 2 , —C(O)NH 2 , —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 any two germinal or vicinal occurrences of R 2a , taken together, may form a spiro or fused cycloalkyl ring;

R 5 , independently for each occurrence, represents optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; and

R x and R y each independently represent H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

In certain embodiments, the compound of the invention is represented by formula (Ia) or formula (IIa):

wherein:

valence permitting, Q, T, U, and V each independently represent CH, CH 2 , N, NH, O, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents 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 ;

m is an integer from 0-4, as permitted by valence.

In certain embodiments, the compound of the invention is represented by formula (Ib) or formula (IIb):

wherein Q represents CH or N; and V represents CH or N. In certain embodiments, Q is N and V is CH. In alternative embodiments, Q is CH and V is N.

In certain embodiments, the compound of the invention is represented by formula (Ic) or formula (IIc):

In certain embodiments, the compound of the invention is represented by formula (Id) or formula (IId):

wherein T represents CH 2 , NH, O, or SO 2 ; and U represents CH 2 , NH, O, or SO 2 . In certain embodiments, T is NH; and U is CH 2 . In other embodiments, T is CH 2 and U is NH.

In certain embodiments, the compound of the invention is represented by formula (Ie) or formula (IIe):

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

In certain embodiments, the compound of the invention is represented by formula (Ij) or (IIj):

wherein:

W is C or N;

valence permitting, X, Y, and Z each independently represent CH, CH 2 , CO, N, NH, O, S, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents 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 ;

n is an integer from 0-4, as permitted by valence.

In certain embodiments, R 4 , independently for each occurrence, represents halo, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 .

In certain embodiments, R 4 , independently for each occurrence, represents halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, or heteroarylalkyloxy.

In certain embodiments, one of X, Y, or Z is NR 4 .

In certain such embodiments, R 4 is selected from the group consisting of:

In certain embodiments, the compound of the invention is represented by formula (Ik) or (IIk):

wherein X, Y, and Z each independently represent CH, N, NH, O, S, or SO 2 .

In certain embodiments, the compound of the invention is represented by formula

Alternatively, in certain embodiments, the compound of the invention is represented by formula (Ik″) or (IIk″):

wherein at least one of X and Z is selected from the group consisting of O, N, NH, and S.

In certain embodiments of the 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.

In other embodiments of the compounds of formula (Ik″) and (IIk″), each of X and Z are selected from the group consisting of O, N, NH, and S. For example, one of X and Z may be N and the other of X and Z may be NH.

In certain embodiments, the compound of the invention is represented by formula (In) or (IIn):

wherein each of Y and Z are selected from the group consisting of O, N, NH, and S.

In certain such embodiments, Y is N and Z is NH.

In certain embodiments, the compound of the invention is represented by formula (Im) or (IIm):

wherein X, Y, and Z each independently represent CH 2 , CO, NH, O, S, or SO 2 .

In certain embodiments of the compounds of formula (Im) or (IIm), each of X, Y, and Z is CH 2 . In alternative embodiments, one of X, Y, and Z is N or O.

In any one of formulae (Ij), (IIj), (Ik), (IIk), (Ik′), (IIk′), (Ik″), (IIk″), (Im), and (IIm), in certain embodiments, n is 0 or 1.

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

In any of the foregoing embodiments, R a may be H.

In certain embodiments, R 1 is a nitrogen-containing heteroarylene, such as a 5-membered nitrogen-containing heteroarylene. In certain embodiments, R 1 is imidazolene.

In some embodiments, —R 1 -R 1a represents

In certain embodiments, R 1a is H.

Alternatively, R 1a may be optionally substituted phenyl. Specifically, R 1a may be phenyl, substituted by one or more occurrences of halo, hydroxyl, cyano, —C(O)NH 2 , hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, —C(O)alkyl, —C(O)O-alkyl, heterocycloalkyl, —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)heterocycloalkyl, —C(O)(prolinol), —C(O)NH((cycloalkyl)alkyl), or —C(O)NH(cycloalkyl). In certain embodiments, R 1a is phenyl, substituted by two or more occurrences of alkoxy. Preferably, R 1a is 3,4,5-trimethoxyphenyl.

In certain embodiments, R 1a is substituted phenyl, wherein two adjacent substituents on the phenyl, taken together with the intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring. For example, R 1a may be phenyl, wherein two adjacent substituents form a fused optionally substituted heterocyclic ring such as 1,4-dioxane or 1,3-dioxolane.

In certain embodiments, R 1a is optionally substituted heteroaryl, such as quinoline.

In certain embodiments, J is aryl, optionally substituted by one or more occurrences of R 2a .

In alternative embodiments, J is —NR 2 R 3 .

In certain such embodiments, R 2 and R 3 , taken together, form a heterocycloalkyl ring, for example, a pyrrolidine ring, optionally substituted by one or more occurrences of R 2a .

In certain such embodiments, R 2a , independently for each occurrence, may represent —C(O)NH 2 , —C(O)R 5 , hydroxyalkyl, heteroaryl, or aryl; preferably —C(O)NH 2 , or hydroxyalkyl.

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

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

In certain embodiments, the compound of the invention is selected from the group consisting of the compounds depicted in the following tables, or a pharmaceutically acceptable salt thereof:

In further aspects, the invention provides a compound represented by formula (III) or formula (IV):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a fused optionally 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, 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 represents 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 represents H, halo, —OR 2 , —NR 2 R 3 , —C(O)NR 2 R 3 , —C(O)O(alkyl), —C(O)OH, aryl, or heteroaryl, wherein aryl or heteroaryl is optionally substituted by one or more occurrences of R 2a ;

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 , taken together, form a heterocycloalkyl ring, optionally substituted by one or more occurrences of R 2a ;

R 2a , independently for each occurrence, represents halo, hydroxyl, —C(O)H, oxo, —NH 2 , —C(O)NH 2 , —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 any two germinal or vicinal occurrences of R 2a , taken together, may form a spiro or fused cycloalkyl ring;

R 5 , independently for each occurrence, represents optionally substituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl; and

R x and R y each independently represent H, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, or hydroxyalkyl.

In certain embodiments, the compound is represented by formula (IIIa) or formula (IVa):

wherein:

valence permitting, Q, T, U, and V each independently represent CH, CH 2 , N, NH, O, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents 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 ;

m is an integer from 0-4, as permitted by valence.

In certain embodiments, the compound is represented by formula (IIIb) or formula

wherein Q represents CH or N; and V represents CH or N. In certain embodiments, Q is N and V is CH. In alternative embodiments, Q is CH and V is N.

In certain embodiments, the compound is represented by formula (IIIc) or formula (IVc):

In certain embodiments, the compound is represented by formula (IIId) or formula

wherein T represents CH 2 , NH, O, or SO 2 ; and U represents CH 2 , NH, O, or SO 2 . In certain embodiments, T is NH; and U is CH 2 . In other embodiments, T is CH 2 and U is NH.

In certain embodiments, the compound is represented by formula (IIIe) or formula (IVe):

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

In certain embodiments, the compound is represented by formula (IIIj) or formula (IVj):

wherein:

W is C or N;

valence permitting, X, Y, and Z each independently represent CH, CH 2 , CO, N, NH, O, S, or SO 2 , wherein any hydrogen of a CH, CH 2 , or NH group is optionally replaced by an occurrence of R 4 ;

R 4 , independently for each occurrence, represents 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 ;

n is an integer from 0-4, as permitted by valence.

In certain embodiments, R 4 , independently for each occurrence, represents halo, or optionally substituted alkyl, alkenyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkenyl, (heterocycloalkyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, —CH 2 C(O)NH 2 , —C(O)R 5 , —C(O)OR 5 , or —S(O) 2 R 5 .

In certain embodiments, R 4 , independently for each occurrence, represents halocycloalkyl, hydroxycycloalkyl, aminocycloalkyl, aryloxy, heteroaryloxy, arylalkyloxy, or heteroarylalkyloxy.

In certain embodiments, one of X, Y, or Z is NR 4 .

In certain such embodiments, R 4 is selected from the group consisting of:

In certain embodiments, the compound is represented by formula (IIIk) or (IVk):

wherein X, Y, and Z each independently represent CH, N, NH, O, S, or SO 2 .

In further embodiments, the compound is represented by formula (IIIk′) or (IVk′):

In certain embodiments, the compound is represented by formula (IIIk″) or (IVk″):

wherein at least one of X and Z is selected from the group consisting of O, N, NH, and S.

In certain embodiments of the 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.

In further embodiments of the compounds of formula (IIIk″) and (IVk″), each of X and Z are 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.

In certain embodiments, the compound of the invention is represented by wherein the compound is represented by formula (IIIn) or (IVn):

wherein each of Y and Z are selected from the group consisting of O, N, NH, and S.

In certain embodiments, Y is N and Z is NH.

In certain embodiments, the compound of the invention is represented by formula (IIIm) or (IVm):

wherein X, Y, and Z each independently represent CH 2 , CO, NH, O, S, or SO 2 .

In certain embodiments of the compounds of formula (IIIm) or (IVm), each of X, Y, and Z is CH 2 . In alternative embodiments, one of X, Y, and Z is N or O.

In any one of formulae (IIIj), (IVj), (IIIk), (IVk), (IIIk′), (IVk′), (IIIk″), (IVk″), (IIIm), and (IVm), in certain embodiments, n is 0 or 1.

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

In any of the foregoing embodiments, R a may be H.

In certain embodiments, R 1 is a nitrogen-containing heteroarylene, such as a 5-membered nitrogen-containing heteroarylene. In certain embodiments, R 1 is imidazolene.

In some embodiments, —R 1 -R 1a represents.

In certain embodiments, R 1a is H.

Alternatively, R 1a may be optionally substituted phenyl. Specifically, R 1a may be phenyl, substituted by one or more occurrences of halo, hydroxyl, cyano, —C(O)NH 2 , hydroxlalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, —C(O)alkyl, —C(O)O-alkyl, heterocycloalkyl, —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)heterocycloalkyl, —C(O)(prolinol), —C(O)NH((cycloalkyl)alkyl), or —C(O)NH(cycloalkyl). In certain embodiments, R 1a is phenyl, substituted by two or more occurrences of alkoxy. Preferably, R 1a is 3,4,5-trimethoxyphenyl.

In certain embodiments, R 1a is substituted phenyl, wherein two adjacent substituents on the phenyl, taken together with the intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring. For example, R 1a may be phenyl, wherein two adjacent substituents form a fused optionally substituted heterocyclic ring such as 1,4-dioxane or 1,3-dioxolane.

In certain embodiments, R 1a is optionally substituted heteroaryl, such as quinoline.

In certain embodiments, J is aryl, optionally substituted by one or more occurrences of R 2a .

In alternative embodiments, J is —NR 2 R 3 .

In certain such embodiments, R 2 and R 3 , taken together, form a heterocycloalkyl ring, for example, a pyrrolidine ring, optionally substituted by one or more occurrences of R 2a .

In certain such embodiments, R 2a , independently for each occurrence, may represent —C(O)NH 2 , —C(O)R 5 , hydroxyalkyl, heteroaryl, or aryl; preferably —C(O)NH 2 , or hydroxyalkyl.

In certain embodiments, the compound of the invention is selected from the group consisting of the compounds depicted in the following table:

Pharmaceutical Compositions

The invention provides pharmaceutical compositions, each comprising one or more compounds of the invention, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a compound of the invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of a disease or condition that would be benefitted by inhibition of ALK2 kinase.

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.

Methods of Use

The present invention provides compounds, and pharmaceutically acceptable salts thereof, that are useful for treating or preventing a disease or condition whose treatment would benefit from ALK2 kinase inhibition.

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

In certain aspects, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

In certain aspects, the invention provides methods of treating fibrodysplasia ossificans progressive, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

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

In certain embodiments, the cancer comprises tumors of the central nervous system, breast cancer, prostate cancer, skin cancer (including basal cell carcinoma cell carcinoma, squamous cell carcinoma and melanoma), cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, glioma, pancreatic cancer, stomach cancer, liver cancer, colon cancer, renal cancer, bladder cancer, oesophageal cancer, cancer of the larynx, cancer of the parotid, cancer of the biliary tract, rectal cancer, endometrial cancer, adenocarcinomas, small cell carcinomas, neuroblastomas, mesotheliomas, adrenocortical carcinomas, epithelial carcinomas, desmoid tumors, desmoplastic small round cell tumors, endocrine tumors, Ewing sarcoma family tumors, germ cell tumors, hepatoblastomas, hepatocellular carcinomas, non-rhabdomyosarcoma, soft tissue sarcomas, osteosarcomas, peripheral primitive neuroectodermal tumors, retinoblastomas, rhabdomyosarcomas, and Wilms tumors.

In certain embodiments, the cancer is a glioma, such as diffuse intrinsic pontine glioma.

The compounds of the invention are useful in treating any disease or condition whose treatment would benefit from ALK2 kinase inhibition, meaning that in such disease or condition it would be desirable to reduce ALK2 kinase activity. For example, it may be desirable to reduce ALK2 kinase activity in the setting of inappropriate activation or hyperactivation of ALK2 kinase.

Formulations, Routes of Administration, and Dosing

The compounds of the invention, and pharmaceutically acceptable salts thereof, 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 chosen route of administration, e.g., orally or parenterally, by intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes. Additional routes of administration are also contemplated by the invention.

Thus, the present compounds or pharmaceutically acceptable salts thereof may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound (i.e., a compound of the invention or a pharmaceutically acceptable salt thereof) may 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 active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to 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.

The tablets, troches, pills, capsules, and the like may also contain the following diluents and carriers: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and 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. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound can be prepared in water or physiologically acceptable aqueous solution, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active compound which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, 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.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and the freeze drying techniques, which yield a powder of the active compound plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds or pharmaceutically acceptable salts thereof may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds or pharmaceutically acceptable salts thereof can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Examples of useful dermatological compositions which can be used to deliver the compounds of the invention, or pharmaceutically acceptable salts thereof, to the skin are known in the art; for example, see 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).

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

The amount of the compound, or pharmaceutically acceptable salt thereof, required for use in treatment 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 will be ultimately at the discretion of the attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg body weight of the recipient per day, e.g., from about 3 to about 90 mg/kg of body weight per day, from about 6 to about 75 mg per kilogram of body weight per day, from about of 10 to about 60 mg/kg of body weight per day, or from about 15 to about 50 mg/kg of body weight per day.

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

Compounds of the invention, or pharmaceutically acceptable salts thereof, can also be administered in combination with other therapeutic agents, for example, other agents that are useful for treating or preventing a disease or condition whose treatment would benefit from ALK2 kinase inhibition.

Other delivery systems can include time-release, delayed release, or sustained release delivery systems such as are well-known in the art. Such systems can avoid repeated administrations of the active compound, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. Use of a long-term sustained release implant may be desirable. Long-term release, as used herein, means that the delivery system or is implant constructed and arranged to deliver therapeutic levels of the active compound for at least 30 days, and preferably 60 days.

In certain embodiments, a compound of the invention, or pharmaceutically acceptable salt thereof, is formulated for intraocular administration, for example direct injection or insertion within or in association with an intraocular medical device.

The compounds of the invention, or pharmaceutically acceptable salts thereof, may be formulated for depositing into a medical device, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other device that can be deployed or permanently implanted within a body lumen. As a particular example, it would be desirable to have devices and methods which can deliver compounds of the invention, or pharmaceutically acceptable salts thereof, to the region of a body which has been treated by interventional technique.

In exemplary embodiments, a compound of the invention, or pharmaceutically acceptable salt thereof, may be deposited within a medical device, such as a stent, and delivered to the treatment site for treatment of a portion of the body.

Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral vessels. Stent designs include those of 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 metal and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents may also be used to deliver a drug at the site of contact with the vasculature, as disclosed 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 in International Patent Application Nos. WO 91/12779 (Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center), for example.

The term “deposited” means that the active compound is coated, adsorbed, placed, or otherwise incorporated into the device by methods known in the art. For example, the active compound may be embedded and released from within (“matrix type”) or surrounded by and released through (“reservoir type”) polymer materials that coat or span the medical device. In the latter example, the active compound may be entrapped within the polymer materials or coupled to the polymer materials using one or more the techniques for generating such materials known in the art. In other formulations, the active compound may be linked to the surface of the medical device without the need for a coating, for example by means of detachable bonds, and release with time or can be removed by active mechanical or chemical processes. In other formulations, the active compound may be in a permanently immobilized form that presents the active compound at the implantation site.

In certain embodiments, the active compound may be incorporated with polymer compositions during the formation of biocompatible coatings for medical devices, such as stents. The coatings produced from these components are typically homogeneous and are useful for coating a number of devices designed for implantation.

The polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability, but frequently a bioabsorbable polymer is suitable for this embodiment because, unlike a biostable polymer, it will typically not be present long after implantation to cause any adverse, chronic local response. Bioabsorbable polymers that could be used include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA/PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, 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), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, cross linked or amphipathic block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art. Also, biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used, and other polymers could also be used if they can be dissolved and cured or polymerized on the medical device such as 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 ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymer; polyhydroxy-propyl-methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysine substituted with palmitoyl residues; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; 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.

Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.

In certain embodiments of the invention, the compound of the invention, or pharmaceutically acceptable salt thereof, is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent-graft device.

Typically, polymers are applied to the surface of an implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be utilized for this purpose. Methods of spraying include traditional methods as well as microdeposition techniques with an inkjet type of dispenser. Additionally, a polymer can be deposited on an implantable device using photo-patterning to place the polymer on only specific portions of the device. This coating of the device provides a uniform layer around the device which allows for improved diffusion of various analytes through the device coating.

In certain embodiments of the invention, the compound of the invention, or pharmaceutically acceptable salt thereof, is formulated for release from the 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 time frame (e.g., months) using at least one of several well-known techniques involving polymer carriers or layers to control elution. Some of these techniques are described in U.S. Patent Application 2004/0243225A1, the entire disclosure of which is incorporated herein in its entirety.

Moreover, as described for example in U.S. Pat. No. 6,770,729, which is incorporated herein in its entirety, the reagents and reaction conditions of the polymer compositions can be manipulated so that the release of the active compound from the polymer coating can be controlled. For example, the diffusion coefficient of the one or more polymer coatings can be modulated to control the release of the active compound from the polymer coating. In a variation on this theme, the diffusion coefficient of the one or more polymer coatings can be controlled to modulate the ability of an analyte that is present in the environment in which the medical device is placed (e.g., an analyte that facilitates the breakdown or hydrolysis of some portion of the polymer) to access one or more components within the polymer composition (and for example, thereby modulate the release of the active compound from the polymer coating). Yet another embodiment of the invention includes a device having a plurality of polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the invention, the release of the active compound from the polymer coating can be modulated by the plurality of polymer coatings.

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

Kits

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 the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to treat or prevent a disease or condition that would benefit from ALK2 inhibition. In one embodiment, the mammal is a human.

It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof.

Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of 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 the exemplary compounds of the invention.

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” and the like in the context of a chemical name provided for a compound disclosed herein are understood to be synonymous and, therefore, may be and sometimes 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 a compound having the following structure:

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 following structure.

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 #956034-07-4) in 2-Propanol (20 mL) was added DIPEA (1.63 mL, 9.36 mmol), 1-methyl-1H-imidazol-4-amine hydrochloride (0.5 g, 3.74 mmol) and heated at reflux for 24 h. The reaction mixture was concentrated in vacuum to dryness and the residue obtained was triturated with water. The solid obtained was collected by filtration and dried in vacuum to afford 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (550 mg, 59% yield) as brown solid; H NMR (300 MHz, DMSO-d 6 ) δ 10.89 (s, 1H, D 2 O exchangeable), 8.35 (d, J=2.1 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.03 (d, J=2.1 Hz, 1H), 3.71 (s, 3H); MS (ES+): 250.3 (M+1), 272.3, 274.3 (M+Na), (ES−): 248.2 (M−1).

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 subjected to microwave irradiation at 150° C. for 2 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (2×20 mL), dried, filtered and concentrated in vacuum. The crude residue was purified by combiflash (silica gel, 12 g, eluting with chloroform/CMA-80) to afford (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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.90 (s, 1H, D 2 O exchangeable), 8.00 (d, J=2.1 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J=1.4 Hz, 1H), 6.71 (d, J=2.1 Hz, 1H), 4.94 (s, 1H, D 2 O 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%.

Preparation of (R)-(1-(4-((1-methyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (3a)

Reaction of 2-chloro-N-(1-methyl-1H-imidazol-4-yl)furo[3,2-d]pyrimidin-4-amine (1b) (100 mg, 0.40 mmol) with (R)-pyrrolidin-2-ylmethanol (122 mg, 1.20 mmol) in NMP (1 mL) according to the procedure as reported in Scheme 2 gave 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 color solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.91 (s, 1H, D 2 O exchangeable), 8.00 (d, J=2.2 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J=1.4 Hz, 1H), 6.71 (d, J=2.1 Hz, 1H), 4.93 (s, 1H, D 2 O 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).

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)

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 PCT Int. Appl., WO 2008/005956, 10 Jan. 2008 (incorporated by reference). This gave 2-chloro-N-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4b) as a pale-off colored solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.15 (s, 1H), 7.75-7.67 (m, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.35 (dd, J=4.5, 1.5 Hz, 1H), 6.68 (dd, J=4.4, 2.6 Hz, 1H), 3.70 (s, 3H); MS (ES+): 249.3 (M+1), 271.3 (M+Na); MS (ES−): 247.2 (M−1).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA80 in CHCl 3 from 0 to 20%]] 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; 1 H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.67-8.56 (m, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.44-7.32 (m, 2H), 7.28-7.15 (m, 2H), 7.06 (dd, J=4.4, 1.7 Hz, 1H), 6.86-6.67 (m, 1H), 6.36 (dd, J=4.4, 2.5 Hz, 1H), 5.29 (d, J=8.3 Hz, 1H), 3.81 (t, J=9.0 Hz, 1H), 3.67-3.54 (m, 1H), 3.53 (s, 3H), 2.46-2.24 (m, 1H), 2.09-1.75 (m, 3H); MS (ES+): 361.5 (M+1); MS (ES−) 359.4 (M−1).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (12 g), eluting with CMA80 in CHCl 3 from 0 to 20%] 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; H NMR (300 MHz, DMSO-d 6 ) δ 9.83 (s, 1H, D 2 O exchangeable), 8.61 (s, 1H), 8.00 (s, 1H), 7.66 (td, J=7.6, 1.8 Hz, 1H), 7.38-7.27 (m, 1H), 7.26-7.18 (m, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.84-6.67 (m, 1H), 6.67-6.44 (m, 1H), 5.29 (d, J=8.2 Hz, 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).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA-80 in CHCl 3 from 0 to 40%] (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); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 7.47 (s, 2H), 7.35 (dd, J=2.4, 1.7 Hz, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 4.81 (t, J=5.0 Hz, 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).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA-80 in CHCl 3 from 0 to 40%] (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); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 7.47 (s, 2H), 7.35 (dd, J=2.5, 1.7 Hz, 1H), 7.08 (dd, J=4.5, 1.7 Hz, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 4.81 (t, J=5.0 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (240 mg, 1.28 mmol; CAS #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, Toshihiro et al in Bioorganic & Medicinal Chemistry, 17(14), 5015-5026; 2009 and Francini, Cinzia Maria et al; in Chem. Med. Chem, 10(12), 2027-2041). 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 (300 MHz, DMSO-d 6 ) δ 11.35 (s, 1H), 8.35-8.18 (m, 1H), 7.95-7.87 (m, 1H), 7.81-7.73 (m, 1H), 7.65 (d, J=7.9 Hz, 2H), 7.56 (t, J=7.7 Hz, 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).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA-80 in CHCl 3 from 0 to 40%] (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) TFA salt as a pale off-white solid (obtained by reverse phase column purification of final compound using 0.1% TFA in acetonitrile/water as a mobile phase); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.76 (d, J=7.8 Hz, 2H), 7.51 (t, J=7.7 Hz, 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 (282 MHz, DMSO-d 6 )) δ −74.29; MS (ES+): 376.5 (M+1); MS (ES−): 374.4 (M−1), 410.4 (M+Cl).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA-80 in CHCl 3 from 0 to 40%] 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 (300 MHz, DMSO-d 6 ) δ 10.55 (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), 7.20-7.10 (m, 1H), 6.42 (dd, J=4.4, 2.5 Hz, 1H), 5.47 (d, J=8.3 Hz, 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 (282 MHz, DMSO-d 6 ) δ −74.26; MS (ES+): 423.5 (M+1), 445.5 (M+Na); MS (ES−): 421.4 (M−1).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA-80 in CHCl 3 from 0 to 40%] 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 (300 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 7.41-7.25 (m, 6H), 7.24-7.15 (m, 1H), 7.05 (dd, J=4.4, 1.7 Hz, 1H), 6.78-6.66 (m, 1H), 6.35 (dd, J=4.4, 2.4 Hz, 1H), 5.32 (d, J=8.0 Hz, 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); MS (ES+): 360.5 (M+1), 382.5 (M+Na); MS (ES−): 358.4 (M−1), 394.5 (M+Cl); HPLC purity: 95.75%.

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), 3-(pyrrolidin-2-yl)pyridine (119 mg, 0.8 mmol) in NMP (1 mL) according to the procedure reported 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 0-100%] 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; H NMR (300 MHz, DMSO-d 6 ) δ 9.83 (s, 1H, D 2 O exchangeable), 8.54 (s, 1H), 8.41 (dd, J=4.8, 1.6 Hz, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.32 (dd, J=7.8, 4.7 Hz, 2H), 6.72 (s, 1H), 6.70-6.30 (m, 1H), 5.35 (d, J=7.9 Hz, 1H), 3.98-3.81 (m, 1H), 3.77-3.60 (m, 1H), 3.51 (s, 3H), 2.47-2.33 (m, 1H), 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).

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)

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 #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 reported in Scheme 1. This gave after workup and purification by flash column chromatography (silica gel, 24 g eluting with CMA-80 in chloroform) 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.21 (d, J=5.4 Hz, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.36 (d, J=5.4 Hz, 1H), 3.71 (s, 3H); MS (ES+): 266.3 (M+1), 288.3 (M+Na), (ES−): 264.2 (M−1).

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), 2-(pyrrolidin-2-yl)pyridine (167 mg, 1.13 mmol) in NMP (1 mL) according to the procedure reported in Scheme 2. This gave 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; H NMR (300 MHz, DMSO-d 6 ) δ 9.81 (s, 1H, D 2 O exchangeable), 8.62 (s, 1H), 8.02-7.80 (m, 1H), 7.66 (td, J=7.6, 1.8 Hz, 1H), 7.31 (s, 1H), 7.27-7.05 (m, 3H), 6.62 (s, 1H), 5.34 (d, J=8.2 Hz, 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).

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), 2-phenylpyrrolidine (147 mg, 1.0 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , N-(1-methyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (13a) (8 mg, 6% yield) as a colorless solid; H NMR (300 MHz, DMSO-d 6 ) δ 11.50 (s, 1H, D 2 O exchangeable), 8.33 (s, 1H), 7.68 (s, 1H), 7.36 (d, J=5.6 Hz, 4H), 7.32-7.20 (m, 1H), 6.97 (s, 1H), 6.58 (s, 1H), 5.47 (d, J=7.2 Hz, 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).

Preparation of (S)-(1-(44(1-phenyl-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (14b)

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 according to the procedure reported in Scheme 1 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). 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.88 (d, J=1.7 Hz, 1H), 7.70-7.63 (m, 2H), 7.63-7.50 (m, 2H), 7.45-7.35 (m, 1H), 7.06 (d, J=2.2 Hz, 1H); MS (ES+): 312.3 (M+1), 334.3 (M+Na), 310.3 (M−1).

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), (S)-pyrrolidin-2-ylmethanol (81 mg, 0.8 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , (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; 1H NMR (300 MHz, DMSO-d 6 ) δ 10.13 (s, 1H, D 2 O exchangeable), 8.18 (d, J=1.6 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.95 (d, J=1.7 Hz, 1H), 7.80-7.64 (m, 2H), 7.51 (t, J=7.7 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 6.74 (d, J=2.1 Hz, 1H), 5.00 (s, 1H, D 2 O 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).

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 reported 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 free base using NaHCO 3 , (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; H NMR (300 MHz, DMSO-d 6 ) δ 10.20 (s, 1H, D 2 O exchangeable), 7.40-7.34 (m, 2H), 7.34-7.26 (m, 4H), 7.25-7.15 (m, 1H), 7.05 (dd, J=4.3, 1.7 Hz, 1H), 6.73 (s, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 5.33 (d, J=8.0 Hz, 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).

Preparation of (S)-(1-(44(1-phenyl-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (16b)

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 according to the procedure reported in Scheme 1 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). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.97 (s, 1H, D 2 O exchangeable), 8.27 (s, 1H), 8.24 (d, J=5.4 Hz, 1H), 7.96 (d, J=1.7 Hz, 1H), 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).

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), (S)-pyrrolidin-2-ylmethanol (77 mg, 0.76 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.14 (s, 1H, D 2 O exchangeable), 8.20 (d, J=1.6 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.93 (d, J=5.4 Hz, 1H), 7.72 (s, 2H), 7.51 (t, J=7.8 Hz, 2H), 7.35 (t, J=7.4 Hz, 1H), 7.10 (d, J=5.4 Hz, 1H), 5.03 (s, 1H, D 2 O exchangeable), 4.24 (s, 1H), 3.87-3.70 (m, 1H), 3.70-3.45 (m, 1H), 3.43-3.36 (m, 2H), 2.12-1.78 (m, 4H); MS (ES+): 393.5 (M+1), 415.5 (M+Na), (ES−): 391.4 (M−1).

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 reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.10 (s, 1H, D 2 O 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=7.8 Hz, 2H), 7.48-7.30 (m, 3H), 7.33-7.19 (m, 3H), 7.22-7.07 (m, 1H), 7.04 (d, J=5.4 Hz, 1H), 5.32-5.16 (m, 1H), 1.50 (d, J=7.0 Hz, 3H); MS (ES+): 413.5 (M+1), (ES−): 411.5 (M−1); HPLC purity: 91.57%.

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 reported 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 free base using NaHCO 3 , (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 light yellow solid; 1H NMR (300 MHz, DMSO-d 6 ) δ 10.24 (s, 1H, D 2 O exchangeable), 8.66-8.56 (m, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.43-7.31 (m, 2H), 7.27-7.16 (m, 2H), 7.06 (dd, J=4.5, 1.7 Hz, 1H), 6.75 (bs, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 5.29 (d, J=8.2 Hz, 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).

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 reported 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 free base using NaHCO 3 , 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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.24 (s, 1H, D 2 O exchangeable), 8.66-8.56 (m, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.43-7.31 (m, 2H), 7.27-7.16 (m, 2H), 7.06 (dd, J=4.5, 1.7 Hz, 1H), 6.75 (bs, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 5.29 (d, J=8.2 Hz, 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).

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 reported 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 free base using NaHCO 3 , 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; H NMR (300 MHz, DMSO-d 6 ) δ 10.26 (s, 1H, D 2 O exchangeable), 8.55-8.42 (m, 2H), 7.37 (s, 2H), 7.34-7.30 (m, 2H), 7.07 (dd, J=4.4, 1.7 Hz, 1H), 6.74 (s, 1H), 6.36 (dd, J=4.5, 2.4 Hz, 1H), 5.30 (d, J=8.3 Hz, 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).

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

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. This gave 2-chloro-N-(1-methyl-1H-imidazol-4-yl)quinazolin-4-amine (21b) as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.97 (s, 1H, D 2 O exchangeable), 8.72 (dd, J=8.3, 1.3 Hz, 1H), 7.84 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.68 (dd, J=8.4, 1.2 Hz, 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).

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 reported 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 free base using NaHCO 3 , (S)-N4-(1-methyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)quinazoline-2,4-diamine (21c) (24 mg, 18% yield) as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.96 (s, 1H, D 2 O exchangeable), 8.36 (d, J=8.2 Hz, 1H), 7.96 (s, 1H), 7.55-7.39 (m, 4H), 7.37-7.3 (m, 5H), 7.08-6.93 (m, 1H), 5.29 (s, 1H), 3.69 (s, 3H), 1.50 (d, J=7.0 Hz, 3H); MS (ES+): 345.5 (M+1), 367.5 (M+Na), (ES−): 343.4 (M−1), 379.5 (M+Cl).

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)

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 according to the procedure reported in Scheme 1 from 2,4-dichloro-6-methylthieno[2,3-d]pyrimidine (22a) (500 mg, 2.28 mmol, CAS #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). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.88 (s, 1H, D 2 O exchangeable), 8.25 (d, J=1.7 Hz, 1H), 7.91 (d, J=1.7 Hz, 1H), 7.72 (s, 1H), 7.70-7.63 (m, 2H), 7.57 (dd, J=8.7, 7.1 Hz, 2H), 7.46-7.36 (m, 1H), 2.56 (d, J=1.2 Hz, 3H); MS (ES+): 364.3 (M+Na), (ES−): 340.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 9.98 (s, 1H, D 2 O exchangeable), 8.20 (s, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.84-7.60 (m, 2H), 7.57-7.42 (m, 3H), 7.40-7.29 (m, 1H), 4.94 (s, 1H, D 2 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.

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)

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 according to the procedure reported in Scheme 1 from 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (23a) (500 mg, 2.28 mmol, CAS #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). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.75 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.6 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.68 (dd, J=7.9, 1.6 Hz, 2H), 7.57 (dd, J=8.6, 7.1 Hz, 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).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 9.95 (s, 1H, D 2 O exchangeable), 8.19 (d, J=1.6 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.72 (s, 2H), 7.51 (t, J=7.7 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 6.83 (d, J=1.5 Hz, 1H), 5.37-4.71 (m, 1H, D 2 O 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).

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

Step-1: Preparation of 2-chloro-N-(1-phenyl-1H-imidazol-4-yl)quinazolin-4-amine (24a)

Compound 24a was prepared according to the procedure reported in Scheme 1 from 2,4-dichloroquinazoline (21a) (180 mg, 0.9 mmol; CAS #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). 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 (300 MHz, DMSO-d 6 ) δ 11.18 (s, 1H, D 2 O exchangeable), 8.77 (d, J=8.2 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.87 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.73 (dd, J=8.4, 1.2 Hz, 1H), 7.70-7.65 (m, 2H), 7.60 (tdd, J=8.5, 6.9, 1.5 Hz, 3H), 7.46-7.37 (m, 1H); MS (ES+): 322.4 (M+1), 344.4 (M+Na), (ES−): 320.3 (M−1).

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 reported 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 free base using NaHCO 3 , (S)-N4-(1-phenyl-1H-imidazol-4-yl)-N2-(1-phenylethyl)quinazoline-2,4-diamine (24b) (86 mg, 68% yield) as an off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.47-10.14 (m, 1H, D 2 O exchangeable), 8.66-8.36 (m, 2H), 8.22 (d, J=1.7 Hz, 1H), 7.82-7.63 (m, 1H), 7.59 (t, J=7.6 Hz, 2H), 7.51-7.28 (m, 9H), 7.26-7.15 (m, 2H), 5.35 (q, J=7.2 Hz, 1H), 1.57 (d, J=6.9 Hz, 3H); MS (ES+): 407.5 (M+1), (ES−): 405.6 (M−1).

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)

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 according to the procedure reported in Scheme 1 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, Toshihiro et al in Bioorganic & Medicinal Chemistry, 17(14), 5015-5026; 2009 and 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 (300 MHz, DMSO-d 6 ) δ 11.35 (s, 1H, D 2 O exchangeable), 8.21 (d, J=1.6 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.77 (dd, J=2.6, 1.5 Hz, 1H), 7.74-7.65 (m, 2H), 7.49-7.35 (m, 3H), 6.72 (dd, J=4.5, 2.6 Hz, 1H); 19 F NMR (282 MHz, DMSO) δ −114.97; MS (ES+): 329.3 (M+1); MS (ES−): 327.3 (M−1).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA-80 in CHCl 3 from 0 to 40%] (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 white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.53 (s, 1H, D 2 O exchangeable), 8.20 (d, J=1.6 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.86-7.74 (m, 2H), 7.39 (dd, J=2.4, 1.6 Hz, 1H), 7.38-7.29 (m, 2H), 7.15 (dd, J=4.5, 1.7 Hz, 1H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 4.91 (t, J=5.0 Hz, 1H, D 2 O 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 (282 MHz, DMSO-d 6 ) δ −115.67; MS (ES+): 394.5 (M+1), 416.5 (M+Na); MS (ES−): 392.5 (M−1).

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.19 (s, 1H, D 2 O exchangeable), 7.73 (dd, J=2.6, 1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.35 (dd, J=4.5, 1.6 Hz, 1H), 6.68 (dd, J=4.5, 2.6 Hz, 1H), 3.62-3.46 (m, 1H), 1.14-0.89 (m, 4H); MS (ES−): 273.3 (M−1).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (24 g), eluting with CMA-80 in CHCl 3 from 0 to 40%] (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 (300 MHz, DMSO-d 6 ) δ 10.31 (s, 1H, D 2 O exchangeable), 7.60 (d, J=1.4 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.35 (dd, J=2.4, 1.6 Hz, 1H), 7.09 (dd, J=4.5, 1.7 Hz, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 4.77 (t, J=5.1 Hz, 1H, D 2 O 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).

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 reported 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 free base using NaHCO 3 , 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; 1H NMR (300 MHz, DMSO-d 6 ) δ 10.19 (s, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 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). This gave 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 colored solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.68 (s, 1H), 8.76 (s, 1H), 7.86 (dd, J=2.6, 1.5 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.36 (s, 1H), 6.79 (dd, J=4.5, 2.6 Hz, 1H), 4.28 (ddd, J=11.7, 7.9, 3.8 Hz, 1H), 2.10 (d, J=11.9 Hz, 2H), 1.85 (d, J=13.3 Hz, 2H), 1.72 (dt, J=14.9, 11.6 Hz, 3H), 1.40 (q, J=12.7 Hz, 2H), 1.24 (t, J=12.5 Hz, 1H); MS (ES+): 317.3 (M+1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.31 (s, 1H, D 2 O 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, D 2 O 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).

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 reported 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 free base using NaHCO 3 , 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% oyield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.25 (s, 1H, D 2 O exchangeable), 8.64-8.52 (m, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.38 (s, 1H), 7.26-7.21 (m, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.08 (dd, J=4.4, 1.7 Hz, 1H), 6.91-6.83 (m, 1H), 6.36 (dd, J=4.4, 2.5 Hz, 1H), 5.33 (d, J=8.1 Hz, 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).

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.36 (s, 1H, D 2 O exchangeable), 7.89 (s, 1H), 7.50-7.39 (m, 1H), 7.36-7.27 (m, 2H), 7.26 (d, J=7.5 Hz, 2H), 7.23-7.16 (m, 1H), 7.08-6.90 (m, 2H), 6.40 (dd, J=4.4, 2.4 Hz, 1H), 5.33 (d, J=7.9 Hz, 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).

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

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 according to the procedure reported in Scheme 1 from 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (500 mg, 2.44 mmol; CAS #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). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.06 (s, 1H, D 2 O exchangeable), 8.26 (d, J=1.7 Hz, 1H), 8.04 (d, J=5.6 Hz, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.71 (d, J=5.9 Hz, 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).

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), (S)-pyrrolidin-2-ylmethanol (93 mg, 0.92 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.16 (s, 1H, D 2 O 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=7.3 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H), 4.96 (s, 1H, D 2 O 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).

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 reported 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 free base using NaHCO 3 , (S)-(1-(4-((1-phenyl-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (32a) (75 mg, 62% yield) as light brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.49-10.15 (m, 1H, D 2 O exchangeable), 8.48 (d, J=8.2 Hz, 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=7.5 Hz, 1H), 5.16-4.88 (m, 1H, D 2 O 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).

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.03 (s, 1H, D 2 O exchangeable), 8.26 (s, 1H), 8.17-7.90 (m, 2H), 7.80-7.45 (m, 5H), 7.39 (p, J=8.5, 4.2 Hz, 1H), 7.35-7.18 (m, 1H), 7.11 (d, J=7.7 Hz, 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).

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), 1-methylpiperazine (0.13 mL, 1.21 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.32 (s, 1H, D 2 O exchangeable), 7.49 (d, J=1.4 Hz, 1H), 7.37 (t, J=2.1 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.11 (s, 1H), 6.41 (dd, J=4.5, 2.5 Hz, 1H), 3.69 (s, 3H), 3.55 (t, J=4.9 Hz, 4H), 2.41 (q, J=5.0 Hz, 4H), 2.22 (s, 3H); MS (ES+): 313.4 (M+1), 325.4 (M+Na).

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), 1-methylpiperazine (0.11 mL, 0.97 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.59 (s, 1H, D 2 O exchangeable), 8.23 (d, J=1.6 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.63 (dd, J=8.5, 1.5 Hz, 2H), 7.56 (dd, J=8.7, 7.1 Hz, 2H), 7.45-7.39 (m, 1H), 7.39-7.34 (m, 1H), 7.16 (d, J=4.3 Hz, 1H), 6.45 (dd, J=4.4, 2.5 Hz, 1H), 3.66-3.52 (m, 4H), 2.50-2.36 (m, 4H), 2.23 (s, 3H); MS (ES+): 375.5 (M+1).

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)

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 according to the procedure reported in Scheme 1 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). 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-off colored solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.40 (s, 1H, D 2 O exchangeable), 8.08 (t, J=1.5 Hz, 1H), 7.83 (t, J=1.9 Hz, 1H), 7.77 (dd, J=2.6, 1.5 Hz, 2H), 7.73 (td, J=7.9, 1.6 Hz, 1H), 7.59-7.46 (m, 2H), 7.40 (ddd, J=9.1, 6.0, 2.0 Hz, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −125.09; MS (ES+): 329.3 (M+1); MS (ES−): 363.4 (M+Cl).

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 reported 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 free base using NaHCO 3 , (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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.56 (s, 1H, D 2 O exchangeable), 8.02 (t, J=1.8 Hz, 1H), 7.87 (t, J=1.7 Hz, 1H), 7.76 (td, J=7.9, 1.7 Hz, 1H), 7.55-7.41 (m, 2H), 7.40-7.31 (m, 2H), 7.15 (dd, J=4.5, 1.7 Hz, 1H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 4.74 (t, J=5.2 Hz, 1H, D 2 O 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 (282 MHz, DMSO-d 6 ) δ −125.10; MS (ES+): 394.5 (M+1); 416.5 (M+Na); MS (ES−): 392.5 (M−1), 428.5 (M+Cl).

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.16 (s, 1H, D 2 O exchangeable), 7.83-7.62 (m, 2H), 7.53 (d, J=1.6 Hz, 1H), 7.35 (dd, J=4.5, 1.6 Hz, 1H), 6.68 (dd, J=4.4, 2.6 Hz, 1H), 4.88-4.61 (m, 1H), 2.55-2.19 (m, 4H), 1.96-1.64 (m, 2H); MS (ES+): 289.3 (M+1), 311.3 (M+Na); MS (ES−): 287.3 (M-1).

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 reported 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 free base using NaHCO 3 , 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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.27 (s, 1H, D 2 O exchangeable), 8.59 (d, J=4.8 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.29-7.12 (m, 2H), 7.08 (d, J=4.4 Hz, 1H), 7.05-6.93 (m, 1H), 6.42-6.30 (m, 1H), 5.35 (d, J=8.2 Hz, 1H), 4.55 (q, J=8.6 Hz, 1H), 3.90-3.75 (m, 1H), 3.71-3.54 (m, 1H), 2.45-2.26 (m, 4H), 2.26-2.09 (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).

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)

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 according to the procedure reported in Scheme 1 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 11-(quinolin-3-yl)-1H-imidazol-4-amine hydrochloride (38a) (730 mg, 2.96 mmol). 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 colored solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.41 (s, 1H), 9.30 (d, J=2.7 Hz, 1H), 8.68 (d, J=2.6 Hz, 1H), 8.47 (d, J=1.6 Hz, 1H), 8.16-8.06 (m, 3H), 7.88-7.76 (m, 2H), 7.71 (t, J=7.4 Hz, 1H), 7.42 (d, J=4.3 Hz, 1H), 6.74 (dd, J=4.5, 2.6 Hz, 1H); 1 H NMR (300 MHz, DMSO-d 6 /D 2 O) δ 9.24 (d, J=2.5 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.41 (s, 1H), 8.16-8.00 (m, 3H), 7.80 (t, J=7.7 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.36 (s, 1H), 6.72 (dd, J=4.4, 2.5 Hz, 1H); MS (ES+): 362.3 (M+1), 384.3 (M+Na); MS (ES−): 360.2 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.63 (s, 1H, D 2 O exchangeable), 9.42 (d, J=2.7 Hz, 1H), 8.81 (d, J=2.6 Hz, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.12-8.00 (m, 2H), 7.79 (ddd, J=8.4, 6.9, 1.6 Hz, 1H), 7.69 (td, J=7.5, 6.9, 1.3 Hz, 1H), 7.41 (dd, J=2.4, 1.7 Hz, 1H), 7.18 (dd, J=4.4, 1.7 Hz, 1H), 6.41 (dd, J=4.5, 2.4 Hz, 1H), 5.28-5.16 (m, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 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). This gave 2-chloro-N-(1-(pyridin-3-yl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (39b) (728 mg, 88% yield) as a brownish solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.38 (s, 1H, D 2 O exchangeable), 8.96 (d, J=2.7 Hz, 1H), 8.61 (dd, J=4.7, 1.4 Hz, 1H), 8.35 (d, J=1.6 Hz, 1H), 8.13 (ddd, J=8.3, 2.8, 1.4 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.78 (dd, J=2.6, 1.5 Hz, 1H), 7.61 (dd, J=8.3, 4.7 Hz, 1H), 7.47-7.35 (m, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H); MS (ES+): 312.3 (M+1); MS (ES−): 310.4 (M−1).

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 reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.59 (s, 1H, D 2 O exchangeable), 9.04 (d, J=2.7 Hz, 1H), 8.55 (dd, J=4.7, 1.3 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H), 8.25-8.14 (m, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.54 (dd, J=8.3, 4.7 Hz, 1H), 7.40 (t, J=2.1 Hz, 1H), 7.16 (dd, J=4.4, 1.7 Hz, 1H), 6.40 (dd, J=4.4, 2.5 Hz, 1H), 5.13-4.74 (m, 1H, D 2 O exchangeable), 4.28-4.13 (m, 1H), 3.77 (dd, J=10.1, 3.4 Hz, 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).

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), 2-phenylpyrrolidine (118 mg, 0.8 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , N-(1-phenyl-1H-imidazol-4-yl)-2-(2-phenylpyrrolidin-1-yl)furo[3,2-d]pyrimidin-4-amine (40a) (18 mg, 13% yield) as a light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.04 (s, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 from 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (41a) (500 mg, 2.28 mmol; CAS #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). 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 (300 MHz, DMSO-d 6 ) δ 10.72 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.6 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.89 (s, 1H), 7.72-7.63 (m, 2H), 7.57 (dd, J=8.6, 7.1 Hz, 2H), 7.46-7.36 (m, 1H), 2.31 (d, J=1.2 Hz, 3H); MS (ES+): 342.3 (M+1), 364.3 (M+Na), (ES−): 340.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.08 (s, 1H, D 2 O exchangeable), 8.20 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.71 (s, 2H), 7.57 (d, J=1.3 Hz, 1H), 7.51 (t, J=7.7 Hz, 2H), 7.35 (t, J=7.4 Hz, 1H), 5.65-4.81 (m, 1H, D 2 O exchangeable), 4.26 (s, 1H), 3.86-3.52 (m, 2H), 3.51-3.24 (m, 2H), 2.22 (d, J=1.2 Hz, 3H), 2.11-1.81 (m, 4H); MS (ES+): 407.5 (M+1), 429.5 (M+Na), (ES−): 405.5 (M−1).

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 10.74 (s, 1H, D 2 O exchangeable), 8.22 (d, J=1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.76-7.67 (m, 2H), 7.48-7.37 (m, 2H), 7.13 (d, J=1.3 Hz, 1H), 2.60 (s, 3H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −115.30; MS (ES+): 382.4 (M+Na), (ES−): 358.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 9.95 (s, 1H, D 2 O exchangeable), 8.14 (d, J=1.6 Hz, 1H), 7.92 (d, J=1.7 Hz, 1H), 7.86-7.62 (m, 2H), 7.35 (t, J=8.6 Hz, 2H), 6.83 (d, J=1.3 Hz, 1H), 5.06 (s, 1H, D 2 O exchangeable), 4.37-4.01 (m, 1H), 3.89-3.68 (m, 1H), 3.68-3.44 (m, 3H), 2.52 (d, J=1.1 Hz, 3H), 2.16-1.72 (m, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −73.43; MS (ES+): 425.4 (M+1), 447.4 (M+Na), (ES−): 423.4 (M−1).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography (silica gel 24 g, eluting with CMA-80 in Chloroform 0-40%) (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 (300 MHz, DMSO-d 6 ) δ 10.33 (s, 1H, D 2 O exchangeable), 7.67-7.56 (m, 2H), 7.42-7.29 (m, 1H), 7.09 (dd, J=4.4, 1.7 Hz, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 4.97-4.76 (m, 1H, D 2 O exchangeable), 4.69 (p, J=8.5 Hz, 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 (282 MHz, DMSO) δ −73.48; MS (ES+): 354.5 (M+1); 376.5 (M+Na); MS (ES−): 352.4 (M−1).

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)

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 according to the procedure reported in Scheme 1 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). 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-off colored solid; 1 H NMR (300 MHz, DMSO-d6) δ 11.35 (s, 1H, D 2 O exchangeable), 8.33 (d, J=1.6 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.78 (dd, J=2.6, 1.5 Hz, 1H), 7.67 (dt, J=10.1, 2.1 Hz, 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, 2.6 Hz, 1H); MS (ES+): 329.3 (M+1), 351.3 (M+Na); MS (ES−): 327.3 (M−1).

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 reported 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 free base using NaHCO 3 followed by flash chromatography [silica gel (24 g), eluting with CMA-80 in chloroform, 0 to 40%], (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 (300 MHz, DMSO-d 6 ) δ 10.54 (s, 1H, D 2 O exchangeable), 8.33 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.6 Hz, 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, 1.7 Hz, 1H), 7.23-7.13 (m, 2H), 6.39 (dd, J=4.4, 2.5 Hz, 1H), 5.07-4.90 (m, 1H, D 2 O 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 (282 MHz, DMSO) δ −110.92; MS (ES+): 394.5 (M+1); 416.5 (M+Na); MS (ES−): 392.4 (M−1).

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)

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 #886498-98-2), EDC (1.24 g, 6.44 mmol), in acetonitrile (15 mL) and DMF (1 mL) was added TEA (2.25 mL, 16.11 mmol) and DMAP (33 mg, 0.27 mmol) and stirred at room temperature for 16 h. The reaction was concentrated to remove acetonitrile and diluted with ethyl acetate (100 mL), washed with iN KHSO 4 (2×20 mL), saturated sodium bicarbonate (2×20 mL), water (20 mL), brine (20 mL), dried and concentrated to afford 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 (300 MHz, DMSO-d 6 ) δ 6.72 (s, 1H), 6.69 (d, J=1.4 Hz, 1H), 3.77 (s, 3H), 3.66 (s, 2H), 3.57 (t, J=5.3 Hz, 2H), 3.49-3.24 (m, 6H), 1.41 (s, 9H); MS (ES+): 393.5 (+Na) (ES−): 369.3 (M−1).

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 vacuum to afford 2-(2,6-difluoro-4-methoxyphenyl)-1-(piperazin-1-yl)ethanone 2,2,2-trifluoroacetate (45c) (800 mg, 81% yield) as an oil; 1H NMR (300 MHz, DMSO-d 6 ) δ 8.94 (s, 2H), 6.88-6.43 (m, 2H), 3.77 (s, 5H), 3.72 (s, 2H), 3.63 (d, J=5.6 Hz, 2H), 3.14 (d, J=27.6 Hz, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) 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).

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.30 (s, 1H, D 2 O exchangeable), 8.29 (d, J=1.7 Hz, 1H), 7.87 (d, J=1.7 Hz, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.70-7.64 (m, 2H), 7.57 (t, J=7.9 Hz, 2H), 7.43-7.34 (m, 1H), 7.15 (d, J=6.0 Hz, 1H), 6.71 (d, J=9.5 Hz, 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 (282 MHz, DMSO-d 6 ) δ −113.98; MS (ES+): 562.6 (M+1), 584.6 (M+Na).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.42 (s, 1H, D 2 O exchangeable), 8.06 (s, 1H), 7.44 (s, 1H), 7.38-7.13 (m, 6H), 6.98 (dd, J=4.5, 1.6 Hz, 1H), 6.42 (dd, J=4.4, 2.5 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 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). This gave 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 (300 MHz, DMSO-d 6 ) δ 11.37 (s, 1H, D 2 O exchangeable), 8.38 (d, J=1.6 Hz, 1H), 8.14 (t, J=1.9 Hz, 1H), 8.01-7.97 (m, 1H), 7.97-7.89 (m, 2H), 7.78 (dd, J=2.6, 1.5 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.40 (d, J=4.3 Hz, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H), 2.68 (s, 3H); MS (ES+): 353.3 (M+1); MS (ES−): 351.4 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.58 (s, 1H, D 2 O exchangeable), 8.38 (d, J=1.5 Hz, 1H), 8.24-8.16 (m, 1H), 8.07 (d, J=1.6 Hz, 1H), 8.06-7.98 (m, 1H), 7.98-7.84 (m, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.40 (dd, J=2.4, 1.6 Hz, 1H), 7.15 (dd, J=4.5, 1.6 Hz, 1H), 6.40 (dd, J=4.4, 2.5 Hz, 1H), 4.87 (t, J=5.0 Hz, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 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). 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 solid with a little pink color; 1 H NMR (300 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.78 (s, 1H), 8.04 (d, J=1.6 Hz, 1H), 7.77 (d, J=1.6 Hz, 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, 2.6 Hz, 1H); MS (ES+): 327.3 (M+1); MS (ES−): 325.2 (M−1), 361.2 (M+Cl).

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 reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.46 (s, 1H, D 2 O exchangeable), 9.69 (s, 1H, D 2 O exchangeable), 8.02 (d, J=1.5 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.38 (dd, J=2.4, 1.6 Hz, 1H), 7.14 (dd, J=4.4, 1.7 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 6.38 (dd, J=4.4, 2.4 Hz, 1H), 4.85 (t, J=5.0 Hz, 1H, D 2 O 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 calculated for C 20 H 21 N 7 O 2 : C, 61.37; H, 5.41; N, 25.05. Found: C, 60.88; H, 5.54; N, 24.96.

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.36 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 7.91 (d, J=1.7 Hz, 1H), 7.78 (dd, J=2.6, 1.5 Hz, 1H), 7.74-7.68 (m, 2H), 7.66-7.60 (m, 2H), 7.40 (d, J=4.5 Hz, 1H), 6.72 (dd, J=4.5, 2.6 Hz, 1H); 1H NMR (300 MHz, DMSO-d 6 /D 2 O) δ 8.19 (d, J=1.7 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.73 (dd, J=2.6, 1.5 Hz, 1H), 7.70-7.64 (m, 2H), 7.62-7.56 (m, 2H), 7.32 (d, J=4.3 Hz, 1H), 6.71 (dd, J=4.5, 2.6 Hz, 1H); MS (ES+): 345.3, 347.3 (M+1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.55 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.5 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.86-7.77 (m, 2H), 7.63-7.50 (m, 2H), 7.39 (dd, J=2.4, 1.6 Hz, 1H), 7.15 (dd, J=4.5, 1.7 Hz, 1H), 6.39 (dd, J=4.4, 2.5 Hz, 1H), 5.03-4.80 (m, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 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). 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-off yellow colored solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.17 (s, 1H, D 2 O exchangeable), 7.72 (dd, J=2.6, 1.5 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.35 (dd, J=4.5, 1.5 Hz, 1H), 6.68 (dd, J=4.5, 2.6 Hz, 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)

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.32 (s, 1H, D 2 O exchangeable), 7.59 (d, J=1.5 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.35 (dd, J=2.4, 1.7 Hz, 1H), 7.09 (dd, J=4.6, 1.7 Hz, 1H), 6.35 (dd, J=4.4, 2.4 Hz, 1H), 4.78 (t, J=5.1 Hz, 1H, D 2 O exchangeable), 4.52 (p, J=7.3 Hz, 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).

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.54 (s, 1H, D 2 O exchangeable), 8.10 (s, 1H), 7.54-7.40 (m, 2H), 7.11-6.97 (m, 1H), 6.72 (d, J=9.4 Hz, 2H), 6.49 (dd, J=4.5, 2.4 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 4H), 3.71 (s, 3H), 3.64 (d, J=4.6 Hz, 2H), 3.57 (s, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −114.02; MS (ES+): 483.5 (M+1), 505.5 (M+Na).

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.63 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.6 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.72-7.64 (m, 2H), 7.57 (dd, J=8.6, 7.2 Hz, 2H), 7.47 (dd, J=2.5, 1.7 Hz, 1H), 7.43-7.34 (m, 1H), 7.19 (s, 1H), 6.72 (d, J=9.5 Hz, 2H), 6.47 (dd, J=4.5, 2.5 Hz, 1H), 3.77 (s, 3H), 3.76-3.65 (m, 6H), 3.64-3.58 (m, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −114.00 (d, J=9.4 Hz); MS (ES+): 545.6 (M+1), 567.6 (M+Na), (ES−): 543.5 (M−1).

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 Levy, Daniel E. et al; in PCT Int. Appl., 2003/022214, 20 Mar. 2003) and DIPEA (0.28 mL, 1.61 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.38 (s, 1H, D 2 O exchangeable), 7.50 (d, J=1.4 Hz, 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, 2.5 Hz, 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).

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), tert-butyl piperazine-1-carboxylate (170 mg, 0.92 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), D 2 O exchangeable, 8.22 (d, J=1.5 Hz, 1H), 7.97 (d, J=5.4 Hz, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.4 Hz, 1H), 7.65 (dd, J=1.9, 0.9 Hz, 1H), 7.55 (dd, J=8.7, 7.1 Hz, 2H), 7.43-7.35 (m, 1H), 7.12 (d, J=5.4 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.33 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.76 (dd, J=2.6, 1.5 Hz, 1H), 7.63-7.49 (m, 2H), 7.40 (dd, J=4.6, 1.5 Hz, 1H), 7.19-7.06 (m, 2H), 6.71 (dd, J=4.5, 2.6 Hz, 1H), 3.81 (s, 3H); 1 H NMR (300 MHz, DMSO-d-D 2 O) δ 8.02 (d, J=1.2 Hz, 1H), 7.77 (dd, J=1.6, 0.8 Hz, 1H), 7.74-7.67 (m, 1H), 7.56-7.47 (m, 2H), 7.30 (d, J=4.4 Hz, 1H), 7.12-7.00 (m, 2H), 6.70 (dd, J=4.6, 2.7 Hz, 1H), 3.80 (s, 3H). MS (ES+): 341.3 (M+1), 363.4 (M+Na); MS (ES−): 339.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.49 (s, 1H, D 2 O exchangeable), 8.11 (d, J=1.5 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.65 (d, J=9.0 Hz, 2H), 7.38 (t, J=2.0 Hz, 1H), 7.15 (dd, J=4.5, 1.7 Hz, 1H), 7.04 (d, J=9.0 Hz, 2H), 6.39 (dd, J=4.4, 2.5 Hz, 1H), 4.94-4.81 (m, 1H, D 2 O exchangeable), 4.27-4.08 (m, 1H), 3.80 (s, 3H), 3.80-3.70 (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).

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)

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 according to the procedure reported in Scheme 1 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). 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 off-yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.34 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.77 (dd, J=2.6, 1.5 Hz, 1H), 7.47 (t, J=8.1 Hz, 1H), 7.40 (d, J=4.3 Hz, 1H), 7.23 (t, J=2.2 Hz, 1H), 7.22-7.16 (m, 1H), 7.03-6.93 (m, 1H), 6.72 (dd, J=4.5, 2.6 Hz, 1H), 3.85 (s, 3H); 1 H NMR (300 MHz, DMSO-d-D 2 O) δ 8.22 (d, J=1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.74 (dd, J=2.6, 1.5 Hz, 1H), 7.53-7.41 (m, 1H), 7.34 (d, J=4.4 Hz, 1H), 7.21-7.14 (m, 2H), 7.03-6.93 (m, 1H), 6.71 (dd, J=4.5, 2.6 Hz, 1H), 3.82 (s, 3H); MS (ES+): 341.4 (M+1); MS (ES−): 339.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.53 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.45-7.34 (m, 2H), 7.35-7.23 (m, 2H), 7.15 (dd, J=4.4, 1.7 Hz, 1H), 6.97-6.86 (m, 1H), 6.39 (dd, J=4.5, 2.4 Hz, 1H), 5.02-4.68 (m, 1H, D 2 O exchangeable), 4.30-4.11 (m, 1H), 3.85 (s, 3H), 3.74 (dd, J=9.9, 3.5 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 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). 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 white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.31 (s, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.77 (dd, J=2.6, 1.6 Hz, 1H), 7.39 (d, J=4.4 Hz, 1H), 6.93 (s, 2H), 6.72 (dd, J=4.4, 2.6 Hz, 1H), 3.87 (s, 6H), 3.69 (s, 3H); 1 H NMR (300 MHz, DMSO-d 6 -D 2 O) δ 8.14 (d, J=1.6 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.72 (dd, J=2.6, 1.6 Hz, 1H), 7.35-7.28 (m, 1H), 6.88 (s, 2H), 6.71 (dd, J=4.5, 2.6 Hz, 1H), 3.84 (s, 6H), 3.67 (s, 3H); MS (ES+): 401.4 (M+1); MS (ES−): 399.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.54 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.39 (dd, J=2.4, 1.6 Hz, 1H), 7.14 (dd, J=4.4, 1.7 Hz, 1H), 6.96 (s, 2H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 4.84 (t, J=5.1 Hz, 1H, D 2 O 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); Hydrochloride salt of compound 57c was obtained by purification of 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; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.78 (s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 7.44 (s, 1H), 7.12 (d, J=4.5 Hz, 1H), 7.02 (s, 2H), 6.43 (dd, J=4.4, 2.5 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 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). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.96 (s, 1H, D 2 O exchangeable), 8.29-8.18 (m, 2H), 7.91 (d, J=1.6 Hz, 1H), 7.78-7.65 (m, 2H), 7.48-7.35 (m, 3H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −115.27; MS (ES+): 346.3 (M+1), 368.3 (M+Na); (ES−): 344.2 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.14 (s, 1H, D 2 O exchangeable), 8.15 (d, J=1.5 Hz, 1H), 8.01-7.88 (m, 2H), 7.77 (s, 2H), 7.36 (t, J=8.4 Hz, 2H), 7.10 (d, J=5.3 Hz, 1H), 5.35-4.91 (m, 1H, D 2 O 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 (282 MHz, DMSO-d 6 ) δ −116.11; MS (ES+): 411.4 (M+1), 433.4 (M+Na); (ES−): 409.4 (M−1).

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.17 (s, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.73 (dt, J=2.9, 1.4 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.35 (d, J=4.4 Hz, 1H), 6.77-6.60 (m, 1H), 4.77 (p, J=8.6 Hz, 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%.

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.31 (s, 1H, D 2 O exchangeable), 8.62 (d, J=4.8 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.66 (td, J=7.7, 1.8 Hz, 1H), 7.37 (s, 1H), 7.25-7.19 (m, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.16-6.97 (m, 2H), 6.36 (dd, J=4.4, 2.5 Hz, 1H), 5.32 (d, J=8.2 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 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), and 1-(4-fluorophenyl)-1H-imidazol-4-amine (25a) (225 mg, 1.27 mmol). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.06 (s, 1H, D 2 O exchangeable), 8.21 (d, J=1.6 Hz, 1H), 8.04 (d, J=5.8 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.76-7.67 (m, 3H), 7.48-7.37 (m, 2H); 1 9 F NMR (282 MHz, DMSO-d 6 ) δ −115.31; MS (ES+): 346.3 (M+1), 368.3 (M+Na); (ES−): 344.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.17 (s, 1H, D 2 O exchangeable), 8.17 (s, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.91-7.61 (m, 2H), 7.47-7.21 (m, 3H), 7.03 (d, J=6.0 Hz, 1H), 5.17-4.77 (m, 1H, D 2 O exchangeable), 4.39-3.99 (m, 1H), 3.89-3.19 (m, 4H), 2.13-1.81 (m, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −73.43; MS (ES+) 411.4 (M+1), 433.4 (M+Na).

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 10.26 (s, 1H, D 2 O exchangeable), 8.25 (d, J=1.6 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.70-7.63 (m, 2H), 7.61-7.52 (m, 2H), 7.45-7.34 (m, 1H), 7.13 (d, J=6.0 Hz, 1H), 3.87-3.74 (m, 4H), 3.71-3.54 (m, 4H), 2.30 (s, 2H), 1.01 (s, 9H); MS (ES+): 476.6 (M+1), 498.5 (M+Na), (ES−): 474.6 (M−1).

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), 2-(ethylamino)ethanol (62a) (82 mg, 0.92 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 , 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; 1H NMR (300 MHz, DMSO-d 6 ) δ 10.16 (s, 1H, D 2 O exchangeable), 8.23 (d, J=1.5 Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.75-7.59 (m, 2H), 7.53 (t, J=7.7 Hz, 2H), 7.42-7.27 (m, 1H), 7.02 (d, J=6.0 Hz, 1H), 4.82 (s, 1H, D 2 O exchangeable), 3.82-3.54 (m, 6H), 1.31-1.06 (m, 3H); MS (ES+): 381.4 (M+1), 403.4 (M+Na), (ES−): 379.4 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.32 (s, 1H, D 2 O 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, 2.5 Hz, 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%.

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 reported 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 free base using NaHCO 3 , (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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.26 (s, 1H, D 2 O exchangeable), 8.67-8.48 (m, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.38 (s, 1H), 7.30-7.13 (m, 2H), 7.08 (dd, J=4.4, 1.7 Hz, 1H), 7.05-6.89 (m, 1H), 6.36 (dd, J=4.4, 2.5 Hz, 1H), 5.35 (d, J=8.1 Hz, 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, 1H), 2.12-1.99 (m, 1H), 2.01-1.90 (m, 1H), 1.90-1.65 (m, 3H). MS (ES+): 401.5 (M+1), 423.5 (M+Na); HPLC purity: 96.63%.

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)

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 according to the procedure reported in Scheme 1 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). This gave N-(1-(1H-indol-6-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (65b) (271 mg, 73% yield) as light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.36 (s, 2H), 8.18 (d, J=1.6 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.77 (dd, J=2.6, 1.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.46 (dd, J=3.1, 2.4 Hz, 1H), 7.41 (d, J=4.1 Hz, 1H), 7.27 (dd, J=8.4, 2.0 Hz, 1H), 6.72 (dd, J=4.4, 2.6 Hz, 1H), 6.52 (ddd, J=3.0, 2.0, 0.9 Hz, 1H); MS (ES+): 350.4 (M+1); MS (ES−): 348.3 (M−1), 384.3 (M+Cl).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 11.26 (s, 1H, D 2 O exchangeable), 10.50 (s, 1H, D 2 O exchangeable), 8.14 (s, 1H), 7.95 (d, J=1.6 Hz, 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, 2.0 Hz, 1H), 7.20-7.11 (m, 1H), 6.53-6.46 (m, 1H), 6.40 (dd, J=4.4, 2.4 Hz, 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%.

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)

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 according to the procedure reported in Scheme 1 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 Bleicher, Konrad et al; in PCT Int. Appl., 2011089132, 28 Jul. 2011). This gave after purification by flash column chromatography [silica (24 g), eluting with DMA-80 in DCM from 0 to 40%] 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 (300 MHz, DMSO-d 6 ) δ 11.37 (s, 1H), 8.64-8.49 (m, 2H), 8.25 (d, J=1.5 Hz, 1H), 8.11-7.97 (m, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.80-7.75 (m, 1H), 7.48-7.33 (m, 2H), 6.72 (dd, J=4.5, 2.6 Hz, 1H); MS (ES+): 312.3 (M+1); MS (ES−): 310.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.58 (s, 1H, D 2 O exchangeable), 8.51 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.19 (s, 1H), 7.98 (t, J=7.7 Hz, 1H), 7.90 (d, J=8.2 Hz, 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, D 2 O 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%.

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)

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 according to the procedure reported in Scheme 1 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). This gave N-(1-(1H-indol-5-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (67b) (314 mg, 79% yield) as light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.36 (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, 2.9 Hz, 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%.

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 11.30 (s, 1H, D 2 O exchangeable), 10.48 (s, 1H, D 2 O exchangeable), 8.09 (d, J=1.5 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.87 (d, J=2.0 Hz, 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, 2.4 Hz, 1H), 4.87 (t, J=5.1 Hz, 1H, D 2 O 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%.

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)

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 reported 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 free base using NaHCO 3 , (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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.38 (s, 1H, D 2 O exchangeable), 7.72 (d, J=1.5 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.36 (dd, J=2.4, 1.6 Hz, 1H), 7.09 (dd, J=4.5, 1.7 Hz, 1H), 6.36 (dd, J=4.4, 2.4 Hz, 1H), 4.80 (t, J=5.2 Hz, 1H, D 2 O 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).

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 reported 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 free base using NaHCO 3 , 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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.26 (s, 1H, D 2 O exchangeable), 8.61-8.50 (m, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.51 (d, J=1.5 Hz, 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, 2.4 Hz, 1H), 5.31 (d, J=8.1 Hz, 1H), 4.43-4.23 (m, 1H), 3.79 (t, J=9.3 Hz, 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%.

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)

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 THE (100 mL) at 0° C. was added sodium thiomethoxide (1.418 g, 19.51 mmol) and allowed to come to room temperature. Reaction mixture was quenched by adding 1 N HCl and poured into water (200 mL). The solid separated was collected by filtration, dried in vacuum to afford 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine (70a) (3.76 g, 89% yield) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.96 (d, J=6.0 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 2.68 (s, 3H).

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 THE (100 mL) at −78° C. under nitrogen was added dropwise n-butyl lithium (1.6 M solution in hexanes, 21.25 mL, 34.0 mmol). Reaction was stirred at −78° C. for 1.5 h and quenched slowly by 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. and quenched with 1 N HCl and extracted with ethyl acetate (2×100 mL). The organic layer was separated, washed with water (2×20 mL); brine (20 mL) dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel, (40 g) eluting with 0-100% ethyl acetate in hexanes] to afford 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (70b) (2.48 g, 60% yield) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.13 (s, 1H), 8.55 (s, 1H), 2.73 (s, 3H); MS (ES+): 277.2 (M+Na).

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. was added sulfuryl chloride (3.32 mL, 40.9 mmol) in dichloromethane (20 mL) over a period of 30 min. The reaction mixture was stirred for 10 min at 0° C. and quenched with saturated sodium bicarbonate solution. The reaction mixture was concentrated in vacuum to remove organic solvents and the aqueous residue was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried, filtered, and concentrated under reduced pressure to afford 2,4-dichlorothieno[2,3-d]pyrimidine-6-carbaldehyde (70c) (1.9 g, 100% yield) as a dark brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 8.62 (s, 1H).

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) was added sodium borohydride (162 mg, 4.29 mmol) at room temperature and stirred for 20 min. The reaction mixture was diluted with ethyl acetate (100 mL), quenched with 1 N HCl. The organic layer was separated washed with brine, dried and concentrated. The residue obtained was purified by flash column chromatography [silica gel (25 g), eluting with 0-100% ethyl acetate in hexanes] to afford (2,4-dichlorothieno[2,3-d]pyrimidin-6-yl)methanol (70d) (450 mg, 45% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.43 (t, J=1.3 Hz, 1H), 6.07 (t, J=5.7 Hz, 1H, D 2 O exchangeable), 4.83 (dd, J=5.8, 1.3 Hz, 2H).

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 according to the procedure reported in Scheme 1 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). 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 light pink solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.95 (s, 1H, D 2 O exchangeable), 8.25 (d, J=1.6 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.87 (s, 1H), 7.66 (dd, J=8.4, 1.4 Hz, 2H), 7.57 (t, J=7.9 Hz, 2H), 7.46-7.35 (m, 1H), 5.83 (t, J=5.8 Hz, 1H, D 2 O exchangeable), 4.72 (d, J=5.6 Hz, 2H); MS (ES+): 380.3 (M+Na), (ES−): 356.2 (M−1).

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 reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.07 (s, 1H, D 2 O exchangeable), 8.20 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.85-7.67 (m, 2H), 7.65 (s, 1H), 7.58-7.42 (m, 2H), 7.39-7.28 (m, 1H), 5.50 (t, J=5.7 Hz, 1H, D 2 O exchangeable), 5.05-4.82 (m, 1H, D 2 O exchangeable), 4.57 (d, J=5.7 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 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). This gave N-(1-(1H-pyrazol-3-yl)-1H-imidazol-4-yl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (71b) (496 mg, 87% yield) as yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.92 (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 (300 MHz, DMSO-d 6 /D 2 O) δ 8.14 (d, J=1.6 Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.6, 1.5 Hz, 1H), 7.33-7.26 (m, 1H), 6.71 (dd, J=4.5, 2.6 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H); MS (ES+): 301.3 (M+1); MS (ES−): 299.3 (M−1); HPLC purity: 98.56%.

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 reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.94 (s, 1H, D 2 O exchangeable), 10.54 (s, 1H, D 2 O exchangeable), 8.15 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.86 (dd, J=2.4, 1.1 Hz, 1H), 7.39 (dd, J=2.4, 1.7 Hz, 1H), 7.13 (dd, J=4.4, 1.7 Hz, 1H), 6.69 (s, 1H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 4.86 (t, J=5.6 Hz, 1H, D 2 O exchangeable), 4.25-4.04 (m, 1H), 3.88-3.71 (m, 1H), 3.58-3.45 (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%.

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.32 (s, 1H, D 2 O exchangeable), 8.29 (d, J=1.6 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.77 (dd, J=2.6, 1.6 Hz, 1H), 7.39 (d, J=4.4 Hz, 1H), 6.80 (d, J=2.2 Hz, 2H), 6.72 (dd, J=4.5, 2.6 Hz, 1H), 6.54 (t, J=2.2 Hz, 1H), 3.83 (s, 6H); MS (ES+): 371.4 (M+1); MS (ES−): 369.3 (M−1); HPLC purity: 98.98%.

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 reported 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 free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.53 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.39 (dd, J=2.4, 1.7 Hz, 1H), 7.14 (dd, J=4.5, 1.7 Hz, 1H), 6.86 (d, J=2.2 Hz, 2H), 6.47 (t, J=2.2 Hz, 1H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 4.82 (t, J=5.1 Hz, 1H, D 2 O exchangeable), 4.27-4.13 (m, 1H), 3.82 (s, 6H), 3.78-3.65 (m, 1H), 3.62-3.48 (m, 1H), 3.49-3.24 (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%.

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.32 (s, 1H, D 2 O exchangeable), 8.16 (d, J=1.6 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.76 (dd, J=2.6, 1.5 Hz, 1H), 7.49-7.34 (m, 1H), 7.25 (t, J=1.3 Hz, 1H), 7.16-7.06 (m, 2H), 6.72 (dd, J=4.4, 2.6 Hz, 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%.

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.51 (s, 1H, D 2 O exchangeable), 8.16 (d, J=1.5 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.42-7.35 (m, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.14 (dd, J=4.4, 1.7 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 4.85 (t, J=5.1 Hz, 1H, D 2 O 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).

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 reported 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 free base using NaHCO 3 , 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 (300 MHz, DMSO-d 6 ) δ 12.93 (s, 1H, D 2 O exchangeable), 10.43 (s, 1H, D 2 O exchangeable), 8.40 (d, J=4.8 Hz, 1H), 8.03 (s, 1H), 7.93 (t, J=2.0 Hz, 1H), 7.73-7.46 (m, 2H), 7.37 (s, 1H), 7.20 (d, J=7.9 Hz, 1H), 7.17-7.03 (m, 2H), 6.69 (t, J=2.2 Hz, 1H), 6.38 (dd, J=4.4, 2.4 Hz, 1H), 5.34 (d, J=8.1 Hz, 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%.

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)

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 according to the procedure reported in Scheme 1 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). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.86 (s, 1H, D 2 O exchangeable), 8.24 (d, J=6.0 Hz, 2H), 7.95 (s, 1H), 7.39 (d, J=5.4 Hz, 1H), 6.96 (s, 2H), 3.87 (s, 6H), 3.69 (s, 3H); MS (ES+): 440.3 (M+Na), (ES−): 416.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.19 (s, 1H, D 2 O exchangeable), 8.22 (d, J=1.5 Hz, 1H), 8.09-7.98 (m, 1H), 7.93 (d, J=5.4 Hz, 1H), 7.10 (d, J=5.3 Hz, 1H), 6.95 (s, 2H), 5.29-4.79 (m, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 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). This gave after work up 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]triazin-4-amine (76b) (300 mg, 31% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.45 (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).

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 layers were washed with a brine solution (100 mL), dried, filtered and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (silica gel, eluting with 0-10% ethyl acetate in methanol) to afford (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 (300 MHz, DMSO-d6) δ 10.63 (s, 1H, D 2 O exchangeable), 9.03 (dd, J=4.1, 1.6 Hz, 1H), 8.30-8.10 (m, 2H), 8.02 (d, J=1.4 Hz, 1H), 7.96-7.86 (m, 2H), 7.80 (dd, J=7.4, 1.2 Hz, 1H), 7.66 (dd, J=8.6, 4.2 Hz, 1H), 7.40 (t, J=2.0 Hz, 1H), 7.18 (dd, J=4.5, 1.7 Hz, 1H), 6.41 (dd, J=4.4, 2.4 Hz, 1H), 4.51 (t, J=5.3 Hz, 1H, D 2 O exchangeable), 4.10-3.96 (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%.

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)

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 according to the procedure reported in Scheme 1 from 7-bromo-2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (77a) (50 mg, 0.19 mmol; CAS #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). 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 hexanes (0 to 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 (300 MHz, DMSO-d 6 ) δ 11.50 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.6 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.71-7.63 (m, 2H), 7.57 (dd, J=8.8, 7.1 Hz, 2H), 7.52 (d, J=4.7 Hz, 1H), 7.46-7.37 (m, 1H), 6.91 (d, J=4.7 Hz, 1H). MS (ES+): 389.2, 391.3 (M+2); MS (ES−): 387.2, 389.1 (M+2).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (4 g), eluting with DMA-80 in CHCl 3 from 0 to 20%] (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 as such in next step without further purification.

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 2 (7 mg, 8.80 μmol), sodium carbonate (12 mg, 0.11 mmol) in a sealed reactor under a positive flow of nitrogen in Dioxane (3 mL) and Water (1 mL) was stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and filtered though a Celite pad. 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 fractions containing the product were combined and concentrated to remove acetonitrile. The aqueous solution was basified with saturated sodium bicarbonate and the solid obtained was collected by filtration, dried in vacuum to afford (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 (300 MHz, DMSO-d 6 ): δ 10.53 (s, 1H, D 2 O exchangeable), 8.29 (d, J=1.5 Hz, 1H), 8.22-8.13 (m, 2H), 8.01 (d, J=1.7 Hz, 1H), 7.76 (d, J=7.9 Hz, 2H), 7.51 (t, J=7.8 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H), 7.04-6.96 (m, 2H), 6.81 (d, J=4.6 Hz, 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, 9.2 Hz, 2H), 2.16-1.82 (m, 4H); MS (ES+): 482.6 (M+1).

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)

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 reported 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 (300 MHz, DMSO-d 6 ) δ 8.47 (d, J=5.4 Hz, 1H), 7.60 (d, J=5.4 Hz, 1H), 2.75 (s, 3H).

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 reported 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 (300 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 8.50 (s, 1H), 2.77 (s, 3H).

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 reported 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 (300 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.63 (s, 1H).

Compound 78d was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine-6-carbaldehyde (78c) (70 mg, 0.3 mmol) according to the procedure reported in step-4 of Scheme 70. This gave after workup (2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)methanol (78d) (95 mg) as a light orange solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.43 (t, J=1.3 Hz, 1H), 6.07 (t, J=5.7 Hz, 1H, D 2 O exchangeable), 4.83 (dd, J=5.8, 1.3 Hz, 2H).

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 10.99-10.67 (m, 1H, D 2 O exchangeable), 8.27 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.68 (d, J=7.9 Hz, 2H), 7.57 (t, J=7.8 Hz, 2H), 7.41 (t, J=7.3 Hz, 1H), 7.21 (s, 1H), 5.92 (s, 1H, D 2 O exchangeable), 4.78 (d, J=5.4 Hz, 2H); MS (ES+): 358.3 (M+1), (ES−): 356.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.00 (s, 1H, D 2 O exchangeable), 8.20 (d, J=1.7 Hz, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.81-7.59 (m, 2H), 7.51 (t, J=7.7 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 6.93 (d, J=1.1 Hz, 1H), 5.72 (t, J=5.8 Hz, 1H, D 2 O exchangeable), 5.04 (s, 1H, D 2 O exchangeable), 4.70 (dd, J=5.8, 1.2 Hz, 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%.

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.81 (s, 1H), 10.21 (s, 1H), 9.46 (s, OH), 8.25 (d, J=1.5 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.50 (d, J=4.9 Hz, 1H), 7.35 (d, J=4.8 Hz, 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).

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. was added n-BuLi (1.6 M, 0.32 mL, 0.51 mmol) and stirred at −78° C. for 4 h. The reaction mixture was quenched with Sat. NH 4 Cl and extracted with ethyl acetate (3×30 mL).

The combined organic layers were washed with brine, dried, filtered, concentrated under vacuum and purified by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0 to 20%) to afford 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 yellow solid; 1 H NMR (300 MHz, Chloroform-d) δ 10.51 (s, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 6.84 (d, J=4.5 Hz, 1H), 6.65 (s, 2H), 6.58 (d, J=4.4 Hz, 1H), 5.16 (dd, J=7.5, 6.1 Hz, 1H), 3.92 (s, 6H), 3.88 (s, 3H), 2.14-1.79 (m, 2H), 1.65-1.21 (m, 4H), 0.91 (t, J=7.0 Hz, 3H); MS (ES+): 487.5 (M+1); MS (ES−): 485.5 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.47 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.14 (d, J=4.6 Hz, 1H), 6.95 (s, 2H), 6.70 (d, J=16.1 Hz, 1H), 6.55 (d, J=4.6 Hz, 1H), 6.52-6.40 (m, 1H), 4.84 (t, J=5.1 Hz, 1H, D 2 O 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=7.1 Hz, 2H), 2.10-1.81 (m, 4H), 1.56-1.39 (m, 2H), 0.93 (t, J=7.2 Hz, 3H); MS (ES+): 534.6 (M+1); MS (ES−): 532.7 (M−1), 568.6 (M+Cl); HPLC purity: 94.02%.

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 2 (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 reported 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 (300 MHz, DMSO-d 6 ): δ 10.52 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.6 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.75 (d, J=7.9 Hz, 2H), 7.51 (t, J=7.8 Hz, 2H), 7.35 (t, J=7.3 Hz, 1H), 7.21 (d, J=4.9 Hz, 1H), 6.50 (d, J=4.7 Hz, 1H), 4.19 (s, 3H), 4.06 (s, 3H), 3.78 (d, J=9.8 Hz, 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). 19 F NMR (282 MHz, DMSO-d 6 ) δ −73.99; MS (ES+): 557.6 (M+1); 579.6 (M+Na).

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)

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 according to the procedure reported in Scheme 1 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). This gave 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 (300 MHz, DMSO-d 6 ) δ 11.31 (s, 1H, D 2 O exchangeable), 8.03 (d, J=1.5 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.76 (dd, J=2.6, 1.5 Hz, 1H), 7.65 (d, J=1.4 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.39 (dd, J=4.5, 1.6 Hz, 1H), 6.71 (dd, J=4.4, 2.6 Hz, 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%.

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 reported 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 free base using NaHCO 3 , 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 a off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.40 (s, 1H, D 2 O exchangeable), 8.44 (d, J=4.8 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.64-7.55 (m, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.42-7.33 (m, 2H), 7.20 (d, J=7.9 Hz, 1H), 7.21-7.10 (m, 1H), 7.12-7.08 (m, 1H), 6.38 (dd, J=4.5, 2.4 Hz, 1H), 5.34 (d, J=8.1 Hz, 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%.

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.71-7.58 (m, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.39 (dd, J=2.4, 1.6 Hz, 1H), 7.12 (dd, J=4.4, 1.7 Hz, 1H), 6.39 (dd, J=4.4, 2.5 Hz, 1H), 5.26-4.98 (m, 1H), 4.31-4.00 (m, 1H), 3.95-3.76 (m, 1H), 3.73-3.65 (m, 3H), 3.53-3.25 (m, 3H), 2.16-1.84 (m, 4H); MS (ES+): 380.4 (M+1), 402.4 (M+Na); HPLC purity: 99.92%.

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)

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 according to the procedure reported in Scheme 1 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). This gave 2-chloro-N-(1-(3,5-difluorophenyl)-1H-imidazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine (83b) (521 mg, 77% yield) as a solid; 1 H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H, D 2 O exchangeable), 8.38 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.79 (dd, J=2.6, 1.5 Hz, 1H), 7.65-7.53 (m, 2H), 7.45-7.36 (m, 1H), 7.31 (tt, J=9.3, 2.2 Hz, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −107.50; MS (ES+): 347.3 (M+1); MS (ES−): 345.2 (M−1); HPLC purity: 98.86%.

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 reported 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 free base using NaHCO 3 , ((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 (300 MHz, DMSO-d 6 ) δ 10.55 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.5 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.39 (dd, J=2.5, 1.7 Hz, 1H), 7.14 (dd, J=4.5, 1.7 Hz, 1H), 6.90-6.77 (m, 1H), 6.60 (s, 1H), 6.46-6.33 (m, 2H), 4.83 (t, J=6.1 Hz, 2H, D 2 O 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); 19 F NMR (282 MHz, DMSO-d 6 ) δ −110.98-111.15 (m); 19 FCPD NMR (282 MHz, DMSO-d 6 ) δ −111.06; MS (ES+): 493.5 (M+1); MS (ES−): 491.4 (M−1), 527.6 (M+Cl); HPLC purity: 96.03%.

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)

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 according to the procedure reported in Scheme 1 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). 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 (300 MHz, DMSO-d 6 ) δ 11.01 (s, 1H, D 2 O exchangeable), 8.21 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.71 (d, J=5.9 Hz, 1H), 6.93 (s, 2H), 3.87 (s, 6H), 3.69 (s, 3H); MS (ES+): 440.3 (M+Na), (ES−): 416.2 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ) δ 10.17 (s, 1H, D 2 O exchangeable), 8.23 (d, J=1.7 Hz, 1H), 8.08-7.94 (m, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H), 6.95 (s, 2H), 4.90 (s, 1H, D 2 O 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); Hydrochloride salt of compound 84b was prepared by purification of 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; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.36 (s, 1H), 8.45 (s, 1H), 8.20-7.84 (m, 2H), 7.37 (d, J=5.8 Hz, 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%.

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)

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 according to the procedure reported in Scheme 1 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). This gave after workup and purification by flash column chromatography [silica gel, 40 g eluting with a DCM and methanol (0 to 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.46 (s, 1H, D 2 O exchangeable), 8.22 (d, J=1.6 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.51 (d, J=4.7 Hz, 1H), 6.93 (s, 2H), 6.90 (d, J=4.6 Hz, 1H), 3.87 (s, 6H), 3.69 (s, 3H). MS (ES+): 481.3 (M+2); MS (ES−): 479.2, 481.2 (M+2).

Step-2: Preparation (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 reported in Scheme 2. This gave after workup 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) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.68 (s, 1H, D 2 O exchangeable), 8.26 (d, J=1.5 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.96 (s, 2H), 6.55 (d, J=4.6 Hz, 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 (282 MHz, DMSO-d 6 ) δ −74.03; MS (ES+): 544.4, 546.4 (M+2); MS (ES−): 542.4, 544.3 (M+2).

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

Step-1: Preparation of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (86a)

Compound 86a was prepared according to the procedure reported in Scheme 1 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). 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 light pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.12 (s, 1H, D 2 O exchangeable), 8.75 (d, J=8.3 Hz, 1H), 8.24 (s, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.7 Hz, 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).

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 reported 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 free base using NaHCO 3 , (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 color solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.59-10.09 (m, 1H, D 2 O exchangeable), 8.47 (d, J=8.1 Hz, 1H), 8.27 (s, 1H), 8.20-7.94 (m, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 6.98 (s, 2H), 5.09-4.67 (m, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 from 7-bromo-2,4-dichlorothieno[3,2-d]pyrimidine (87a) (0.2 g, 0.70 mmol; CAS #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). This gave after workup and purification by flash column chromatography [silica gel 12 g, eluting with a 9:1 mixture of ethyl acetate and methanol in hexanes (0 to 100%)] 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; 1 HNMR (300 MHz, DMSO-d 6 ) δ 11.34 (s, 1H, D 2 O 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).

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 reported in Scheme 2. This gave after workup 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 light yellow solid; 1 H NMR (300 MHz, Methanol-d 4 ) δ 8.78-8.54 (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-d 4 ) δ −77.25; MS (ES+): 471.3, 473.3 (M+2). HPLC purity: 97.84%.

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 2 (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 reported 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 (300 MHz, DMSO-d 6 ) δ 10.89 (s, 1H, D 2 O 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); MS (ES+): 473.5 (M+1), 495.4 (M+Na), MS (ES−): 471.4 (M−1), 507.4 (M+Cl).

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 2 (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 reported 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 (300 MHz, Methanol-d 4 ): δ 8.20 (s, 1H), 8.03 (d, J=12.4 Hz, 2H), 7.61 (dd, J=11.6, 7.7 Hz, 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, 2.4 Hz, 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-d 4 ) δ −77.28; MS (ES+): 499.5 (M+1), 521.5 (M+Na); MS (ES−): 497.5 (M−1).

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 2 (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 reported 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 (300 MHz, DMSO-d 6 ): δ 10.57 (s, 1H, D 2 O exchangeable), 8.33 (s, 1H), 8.17 (d, J=8.7 Hz, 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 (282 MHz, DMSO-d 6 ) δ −74.45; MS (ES+): 572.6, 594.6 (M+Na), 610.4 (M+K).

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 the 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 reported in Scheme 2. This gave after workup 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-(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) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.50 (s, 1H, D 2 O exchangeable), 8.22 (d, J=5.6 Hz, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.42 (d, J=5.4 Hz, 1H), 7.23 (s, 1H, D 2 O exchangeable), 7.17 (s, 1H), 7.12-7.05 (m, 2H), 7.02 (s, 1H, D 2 O exchangeable), 6.41 (d, J=5.6 Hz, 1H), 4.41 (s, 1H), 3.93 (t, J=4.2 Hz, 6H), 3.68 (t, J=4.2 Hz, 3H), 3.35 (s, 1H), 2.19 (s, 1H), 1.95 (d, J=13.6 Hz, 4H); MS (ES+): 479.5 (M+1).

Preparation of (S)-isobutyl 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)

Step-1: Preparation of isobutyl 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylate (92a)

Compound 92a was prepared according to the procedure reported in step-2 of Scheme 70 from 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine (70a) (0.5 g, 2.31 mmol) in THE (20 mL) using n-butyl lithium (1.6 M solution in hexanes, 3.03 mL, 4.85 mmol) and quenching with Isobutyl chloroformate (0.6 mL, 4.61 mmol). This gave after workup and purification by flash column chromatography [silica gel, (25 g) eluting with 0-100% ethyl acetate in hexanes]isobutyl 2-chloro-4-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylate (92a) (403 mg, 55% yield) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.09 (s, 1H), 4.14 (d, J=6.6 Hz, 2H), 2.70 (s, 3H), 2.04 (hept, J=6.6 Hz, 1H), 0.97 (d, J=6.7 Hz, 6H); MS (ES+): 339.2 (M+Na).

Step-2: Preparation of isobutyl 2,4-dichlorothieno[2,3-d]pyrimidine-6-carboxylate (92b)

Compound 92b was prepared according to the procedure reported in step-3 of Scheme 70 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). 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 (300 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 4.17 (d, J=6.6 Hz, 2H), 2.06 (dt, J=13.4, 6.7 Hz, 1H), 0.99 (d, J=6.8 Hz, 6H).

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 according to the procedure reported in Scheme 1 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). 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.43 (s, 1H, D 2 O exchangeable), 8.87 (s, 1H), 8.22 (d, J=1.6 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 6.94 (s, 2H), 4.12 (d, J=6.5 Hz, 2H), 3.88 (s, 6H), 3.70 (s, 3H), 2.09-1.96 (m, 1H), 1.01 (d, J=6.7 Hz, 6H); MS (ES+): 540.5 (M+Na), (ES−): 516.5 (M−1).

Step 4: Preparation of (S)-isobutyl 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 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 reported in Scheme 2. This gave after workup by pouring reaction the mixture into water and collecting the solid that separated out by filtration followed by drying in vacuum (S)-isobutyl 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 (300 MHz, DMSO-d 6 ) δ 10.32 (s, 1H, D 2 O exchangeable), 8.63 (s, 1H), 8.12 (d, J=1.7 Hz, 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, 1.6 Hz, 6H); MS (ES+): 583.6 (M+1).

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)

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 according to the procedure reported in Scheme 1 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). This gave after work up and purification by flash column chromatography [silica gel, (40 g) eluting with DCM and methanol (0 to 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 (300 MHz, DMSO-d 6 ): δ 11.37 (s, 1H, D 2 O exchangeable), 8.38 (d, J=1.7 Hz, 1H), 8.09 (s, 1H, D 2 O exchangeable), 8.08-8.01 (m, 2H), 7.98 (d, J=1.7 Hz, 1H), 7.78 (d, J=2.3 Hz, 2H), 7.75 (s, 1H), 7.50 (s, 1H, D 2 O exchangeable), 7.40 (d, J=4.4 Hz, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H). MS (ES+): 354.4; MS (ES−): 352.3.

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ): δ 10.57 (s, 1H, D 2 O exchangeable), 8.37 (d, J=1.5 Hz, 1H), 8.08 (s, 1H, D 2 O exchangeable), 8.05-8.01 (m, 2H), 7.99 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.44 (s, 1H, D 2 O exchangeable), 7.40 (t, J=2.0 Hz, 1H), 7.16 (dd, J=4.4, 1.7 Hz, 1H), 6.40 (dd, J=4.5, 2.4 Hz, 1H), 4.99 (s, 1H, D 2 O 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).

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)

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 according to the procedure reported in Scheme 1 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). This gave after work up and purification by flash column chromatography [silica gel, (40 g) eluting with DCM and methanol (0 to 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 (300 MHz, DMSO-d 6 ): δ 11.36 (s, 1H, D 2 O exchangeable), 8.31 (d, J=1.6 Hz, 1H), 8.18 (s, 1H), 8.11 (t, J=1.9 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.89 (dt, J=7.6, 1.3 Hz, 1H), 7.86-7.80 (m, 1H), 7.78 (dd, J=2.6, 1.5 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.41 (d, J=4.4 Hz, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H). MS (ES+): 354.3 (M+1); MS (ES−): 352.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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 (300 MHz, DMSO-d 6 ): δ 10.57 (s, 1H, D 2 O exchangeable), 8.30 (d, J=1.5 Hz, 1H), 8.15-8.08 (m, 2H), 8.04 (d, J=1.6 Hz, 1H), 7.92 (dd, J=8.0, 2.1 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.69-7.53 (m, 2H), 7.39 (t, J=2.0 Hz, 1H), 7.14 (dd, J=4.4, 1.6 Hz, 1H), 6.40 (dd, J=4.5, 2.4 Hz, 1H), 4.97 (s, 1H, D 2 O exchangeable), 4.21 (s, 1H), 3.78 (dd, J=10.0, 3.5 Hz, 1H), 3.51 (d, J=18.1 Hz, 2H), 3.35 (s, 1H), 2.11-1.82 (m, 4H). 19 F NMR (282 MHz, DMSO-d 6 ) δ −73.49; MS (ES+): 419.5 (M+1); MS (ES−): 453.4 (M+Cl).

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)

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 according to the procedure reported in Scheme 1 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). This gave after work up and purification by flash column chromatography [silica gel, (40 g) eluting with DCM and methanol (0 to 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 (300 MHz, DMSO-d 6 ): δ 11.40 (s, 1H, D 2 O exchangeable), 8.45 (d, J=1.6 Hz, 1H), 8.18-8.09 (m, 2H), 8.01 (d, J=1.6 Hz, 1H), 7.86-7.80 (m, 2H), 7.79 (dd, J=2.6, 1.5 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H), 2.62 (s, 3H). MS (ES−): 351.3, 353.3 (M−1).

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 reported 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 free base using NaHCO 3 , (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) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.79 (s, 1H, D 2 O exchangeable), 8.64 (s, 1H), 8.13-8.05 (m, 3H), 7.95 (d, J=8.5 Hz, 2H), 7.44 (t, J=2.0 Hz, 1H), 7.16 (dd, J=4.5, 1.6 Hz, 1H), 6.43 (dd, J=4.4, 2.4 Hz, 1H), 4.19 (s, 1H), 3.76 (dd, J=10.0, 3.6 Hz, 1H), 3.58-3.42 (m, 1H), 3.36 (dd, J=11.7, 7.1 Hz, 2H), 2.62 (s, 3H), 2.11-1.83 (m, 4H). MS (ES+): 418.5 (M+1); MS (ES−): 452.5 (M+Cl).

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)

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 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (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 (300 MHz, DMSO-d 6 ): δ 7.70 (dd, J=2.6, 1.4 Hz, 1H), 6.97 (dd, J=4.7, 1.6 Hz, 1H), 6.80-6.57 (m, 1H), 5.15 (t, J=5.7 Hz, 1H, D 2 O exchangeable), 4.87 (t, J=5.7 Hz, 1H), 4.44 (d, J=17.8 Hz, 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).

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 2-methylpropan-2-olate (80 mg, 0.79 mmol), Pd 2 (dba) 3 (40 mg, 0.04 mmol) in anhydrous Dioxane (4 mL) was heated in a sealed reactor under a positive flow of nitrogen at 90° C. for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and organic layer was separated. The organic layer was washed with water (3 xs), brine, dried, filtered and concentrated in vacuum to dryness. The residue was purified by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water] and lyophilized to afford (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 salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.72 (s, 1H, D 2 O exchangeable), 9.63 (s, 1H, D 2 O exchangeable), 9.38 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 7.15 (s, 2H), 6.90 (d, J=4.5 Hz, 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).

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)

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 according to the procedure reported in Scheme 1 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). 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 light brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.90 (s, 1H, D 2 O exchangeable), 8.19 (d, J=1.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.84 (s, 1H), 6.93 (s, 2H), 5.82 (t, J=5.8 Hz, 1H, D 2 O exchangeable), 4.72 (dd, J=5.8, 1.2 Hz, 2H), 3.87 (s, 6H), 3.69 (s, 3H); MS (ES+): 448.3 (M+1), 470.3 (M+Na), (ES−): 446.3 (M−1).

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. was added N,N-Dimethylformamide (5 mL) and thionyl chloride (0.2 mL, 2.79 mmol). The reaction mixture was allowed to warm to room temperature overnight, concentrated in vacuum to dryness triturated with hexanes and filtered to afford 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 as such for next step; 1 H NMR (300 MHz, DMSO-d 6 /D 2 O) δ 11.26 (s, 1H, D 2 O 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).

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 THE (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 vacuum and purified by flash column chromatography to afford 2-chloro-6-(morpholinomethyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (97c); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 8.19 (d, J=1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 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).

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 reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel C-18, 24 g), eluting with eluting with acetonitrile and 0.1% HCl in water] followed by lyophilization (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) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.70 (s, 1H, D 2 O exchangeable), 11.49 (s, 1H, D 2 O exchangeable), 8.52 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H, D 2 O 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).

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 2 (10 mg, 0.01 mmol), sodium carbonate (73 mg, 0.69 mmol) in Dioxane (3 mL) and Water (1 mL) according to the procedure reported 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] followed by conversion to free base using NaHCO 3 , (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; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.53 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.5 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.20 (d, J=4.6 Hz, 2H), 6.96 (s, 2H), 6.50 (d, J=4.6 Hz, 1H), 4.85 (s, 1H, D 2 O 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=6.9 Hz, 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).

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)

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 according to the procedure reported in step-2 of Scheme 79 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 THE (10 mL) using MeLi (3 M in THF, 0.33 mL, 1.03 mmol). This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0 to 10%) 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 light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.21 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.36 (d, J=4.5 Hz, 1H), 6.93 (s, 2H), 6.68 (d, J=4.5 Hz, 1H), 5.31 (d, J=5.0 Hz, 1H), 5.16 (p, J=6.4 Hz, 1H), 3.87 (s, 6H), 3.69 (s, 3H), 1.45 (d, J=6.5 Hz, 3H); MS (ES+): 445.5 (M+1), 467.4 (M+Na).

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 reported 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 lyophilization 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) TFA salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.79 (s, 1H, D 2 O exchangeable), 9.32 (s, 1H, D 2 O exchangeable), 9.20 (s, 1H, D 2 O exchangeable), 8.37-8.15 (m, 1H), 8.07-7.90 (m, 1H), 7.25 (dd, J=10.5, 4.6 Hz, 1H), 6.96 (s, 2H), 6.77 (dd, J=16.6, 4.6 Hz, 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 (282 MHz, DMSO-d 6 ) δ −74.28; HPLC purity: 92.61%; Elemental Analysis: Calculated for: C 25 H 31 N 7 O 5 ·2CF 3 COOH·3H 2 O: C, 42.29; H, 4.77; N, 11.90; Found: C, 42.02; H, 4.79; N, 12.08.

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 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 (300 MHz, DMSO-d 6 ) δ 13.54 (s, 1H, D 2 O exchangeable), 7.61 (d, J=5.8 Hz, 1H), 7.39 (d, J=5.8 Hz, 1H); MS (ES−): 185.1 (M−1).

To a solution of 2-chlorothieno[2,3-d]pyrimidin-4-ol (100a) (2.43 g, 13.02 mmol) in acetic acid (30 mL) was added bromine (2.01 mL, 39.1 mmol) and stirred at room temperature for 10 h. The resulting solid was collected by filtration, washed with water, and dried in 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 (300 MHz, DMSO-d 6 ) δ 7.94 (s, 1H).

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 at reflux for 30 h. The mixture was concentrated to remove excess phosphorus oxychloride, diluted with ice cold water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (20 mL), brine (30 mL), dried, filtered and concentrated in vacuum to afford 6-bromo-2,4-dichlorothieno[2,3-d]pyrimidine (100c) (1.4 g, 46% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.94 (s, 1H).

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 according to the procedure reported in Scheme 1 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). 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 light purple solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.04 (s, 1H, D 2 O exchangeable), 8.21 (d, J=1.6 Hz, 2H), 7.88 (d, J=1.6 Hz, 1H), 6.93 (s, 2H), 3.87 (s, 6H), 3.70 (s, 3H); MS (ES−): 494.2, 496.3 (M−1).

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 reported in Scheme 2. This gave after workup by pouring into water and collecting the solid that separated by filtration followed by drying in vacuum (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; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.08 (s, 1H, D 2 O exchangeable), 8.57 (s, 1H), 8.04 (d, J=15.7 Hz, 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=9.3 Hz, 1H), 2.12-1.85 (m, 4H). MS (ES+): 561.3, 564.3 (M+1), (ES−) 595.3 597.4 (M+Cl).

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)

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 reported in step-4 of Scheme 70. This gave after workup (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).

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 according to the procedure reported in Scheme 1 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). This gave (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 (300 MHz, DMSO-d 6 ) δ 11.24 (s, 1H, D 2 O exchangeable), 8.20 (d, J=1.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.37 (d, J=4.3 Hz, 1H), 6.93 (s, 2H), 6.69 (d, J=4.4 Hz, 1H), 5.24 (t, J=5.6 Hz, 1H, D 2 O exchangeable), 4.70 (d, J=5.5 Hz, 2H), 3.87 (s, 6H), 3.69 (s, 3H); MS (ES+): 431.4 (M+1), 453.4 (M+Na); MS (ES−): 429.3 (M−1); HPLC: 98.24%.

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 2 (dba) 3 (14 mg, 0.016 mmol), 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 hr, cooled to room temperature, quenched with saturated aqueous NH 4 Cl and extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with water, brine, dried, filtered and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0 to 40%) 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 (300 MHz, DMSO-d 6 ) δ 10.47 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.5 Hz, 1H), 7.97 (s, 1H), 7.10 (d, J=4.4 Hz, 1H), 6.96 (s, 2H), 6.37 (d, J=4.4 Hz, 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).

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)

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 reported 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).

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 reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel C-18, 24 g), eluting with eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (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) HCl salt as a solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.40 (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, 6H), 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).

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)

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 according to the procedure reported in Scheme 1 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). This gave after work up (2-chloro-furo[3,2-d]pyrimidin-4-yl)-[1-(3,4,5-trimethoxy-phenyl)-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).

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 according to the procedure reported in step-2 of Scheme 76 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). This gave after workup and purification by flash chromatography (silica gel, eluting with 0-10% methanol in ethyl acetate) (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%) free base as a white solid. The free base was re-purified by reverse phase flash column chromatography [(silica gel C-18 column, 24 g) eluting with acetonitrile and 0.1% HCl water (0-50%)] followed by lyophilization to afford (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 mgs) HCl salt as a light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 13.40 (s, 1H), 11.91 (s, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.01 (d, J=10.6 Hz, 3H), 4.44 (s, 1H), 3.87 (d, J=3.8 Hz, 6H), 3.75 (s, 1H), 3.68 (d, J=3.7 Hz, 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%.

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)

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 THE (3 mL) according to the procedure reported 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).

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 reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel C-18, 24 g), eluting with eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (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) HCl salt as a tan colored solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.14 (s, 1H), 8.43 (s, 1H), 8.07-7.85 (m, 2H), 6.98 (d, J=4.6 Hz, 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).

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)

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) 3 (64 mg, 0.3 mmol) and the reaction was stirred for 8 h. An additional amount of NaBH(OAc) 3 (64 mg, 0.3) was added and the reaction was allowed to stir for 8 h. The reaction was quenched with 1 N NaOH (2 mL), the organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (3×10 mL). The combined organic layers were dried, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0% to 10%) to afford 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 pale off-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).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography (Silica gel 4 g, eluting with MeOH in DCM from 0% to 10%) (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-d 4 ) 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). Hydrochloride salt of compound 105b was obtained by purification of 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 as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.90 (s, 1H), 10.36 (s, 1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.23 (d, J=4.6 Hz, 1H), 6.99 (s, 2H), 6.72 (d, J=4.5 Hz, 1H), 4.49 (s, 2H), 4.29-4.14 (m, 1H), 3.88 (s, 6H), 3.84-3.26 (m, 9H), 2.86 (d, J=11.4 Hz, 2H), 2.13-1.16 (m, 10H). MS (ES+): 563.3 (M+1); MS (ES−): 597.4 (M+Cl). HPLC purity: 95.10%.

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)

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 according to the procedure reported for reductive amination in step-1 of Scheme 105 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) 3 (74 mg, 0.35 mmol). This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with DMA-80 in DCM from 0% to 10%) to afford 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).

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 reported 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 of acetonitrile and 0.1% TFA 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 (300 MHz, DMSO-d 6 ) δ 10.47 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.13 (d, J=4.4 Hz, 1H), 6.95 (s, 2H), 6.33 (d, J=4.5 Hz, 1H), 4.89-4.79 (m, 1H, D 2 O 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); Hydrochloride salt of compound 106b was obtained by purification of 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 water] followed by lyophilization as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.49 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.13 (d, J=4.4 Hz, 1H), 6.95 (s, 2H), 6.34 (d, J=4.2 Hz, 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%.

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×), brine, dried, filtered and concentrated in vacuum. The residue was purified by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] and lyophilized to afford (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 a HCl salt; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 9.16 (s, 2H), 8.37 (s, 1H), 8.01 (s, 1H), 7.29 (s, 1H), 7.22 (d, J=4.6 Hz, 1H), 6.98 (s, 2H), 6.58 (d, J=4.7 Hz, 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%.

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)

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 reported 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 mgs, 47%) as a solid. MS (ES+): 593.5 (M+1), (ES−): 591.4 (M−1), 627.5, 629.5 (M+Cl).

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 reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel 18, 24 g), eluting with eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (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) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.16 (s, 1H), 11.60 (s, 1H), 8.58 (s, 1H), 8.19-7.93 (m, 5H), 7.37 (d, J=8.9 Hz, 1H), 7.00 (d, J=8.5 Hz, 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%.

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 2 (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 reported in step-3 of Scheme 77. This gave after workup, purification by flash column chromatography [(silica gel, 12 g) eluting with DMA 80 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 (300 MHz, DMSO-d 6 ) δ 10.63 (s, 1H, D 2 O exchangeable), 10.14 (s, 1H), 8.95 (d, J=1.9 Hz, 1H), 8.76 (d, J=7.8 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.03 (s, 2H), 5.84 (s, 1H, D 2 O 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).

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 2 (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 reported in step-3 of Scheme 77. This gave after workup, purification by flash column chromatography [(silica gel, 12 g) eluting with DMA 80 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 (300 MHz, DMSO-d 6 ) δ 11.02 (s, 1H, D 2 O exchangeable), 10.13 (s, 1H), 8.82 (t, J=1.7 Hz, 1H), 8.64 (dt, J=7.8, 1.5 Hz, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.04 (dt, J=7.7, 1.4 Hz, 1H), 7.88 (dd, J=2.6, 1.6 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.51-7.25 (m, 1H), 7.03 (s, 2H), 6.77 (dd, J=4.4, 2.6 Hz, 1H), 3.90 (s, 6H), 3.71 (s, 3H); MS (ES+): 471.4 (M+1), (ES−): 469.4 (M−1).

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)

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 according to the procedure reported for reductive amination in step-1 of Scheme 105 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) 3 (129 mg, 0.61 mmol). This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0% to 10%) 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 little pink solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.24 (s, 1H, D 2 O exchangeable), 8.20 (d, J=1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.40 (d, J=4.4 Hz, 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=4.6 Hz, 4H), 2.47-2.37 (m, 4H); MS (ES+): 500.4 (M+1), 522.4 (M+Na); HPLC purity: 95.21%.

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 2 (dba) 3 (14 mg, 0.015 mmol) and sodium tert-butoxide (153 mg, 1.59 mmol) in toluene (5 mL) according to the procedure reported in step-3 on Scheme 101. This gave after workup and purification by flash chromatography (Silica gel 24 g, eluting with MeOH in DCM from 0% to 10%) (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) (75 mg, 63% yield) as a solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.48 (s, 1H, D 2 O exchangeable), 8.24 (s, 1H), 7.98 (s, 1H), 7.14 (d, J=4.4 Hz, 1H), 6.95 (s, 2H), 6.35 (d, J=4.4 Hz, 1H), 4.83 (t, J=5.2 Hz, 1H, D 2 O 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%. Hydrochloride salt of compound 111b was obtained by purification of 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; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.51 (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=4.4 Hz, 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%.

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)

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 according to the procedure reported for reductive amination in step-1 of Scheme 105 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) 3 (148 mg, 0.7 mmol).

The combined organic layers were dried, filtered and concentrated in vacuum. This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with DMA-80 in DCM from 0 to 50%) to afford 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 (300 MHz, Chloroform-d) δ 10.13 (s, 1H), 7.94 (d, J=1.5 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 6.87 (d, J=4.5 Hz, 1H), 6.66 (s, 2H), 6.63 (d, J=4.5 Hz, 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).

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 2 (dba) 3 (13 mg, 0.015 mmol) and sodium tert-butoxide (149 mg, 1.55 mmol) in toluene (5 mL) according to the procedure reported in step-3 on Scheme 101. This gave after workup and purification by flash chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0 to 40%) (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 (300 MHz, DMSO-d 6 ) δ 10.47 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.13 (d, J=4.4 Hz, 1H), 6.95 (s, 2H), 6.33 (d, J=4.4 Hz, 1H), 4.83 (t, J=5.2 Hz, 1H, D 2 O 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), 2.55-2.18 (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%.

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)

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 THE (3 mL) according to the procedure reported 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 mgs, 60%) as a solid, which was used for next step without further purification; MS (ES−): 514.4 (M−1).

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 reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (4 g), eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%] (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 (300 MHz, Chloroform-d) δ 7.88 (d, J=1.6 Hz, 1H), 7.75 (s, 1H), 7.62 (d, J=1.6 Hz, 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); Hydrochloride salt of compound 113b was obtained by purification of 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.36 (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%.

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)

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 according to the procedure reported for reductive amination in step-1 of Scheme 105 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) 3 (148 mg, 0.7 mmol). This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with DMA-80 in DCM from 0 to 50%) 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).

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 2 (dba) 3 (8 mg, 0.009 mmol) and sodium tert-butoxide (93 mg, 0.97 mmol) in PhMe (5 mL) according to the procedure reported in step-3 on Scheme 101. This gave after workup and purification by flash chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0 to 50%) (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 (300 MHz, DMSO-d 6 ) δ 10.50 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.6 Hz, 1H), 7.97 (s, 1H), 7.14 (d, J=4.4 Hz, 1H), 6.95 (s, 2H), 6.35 (s, 1H), 4.96-4.75 (m, 1H, D 2 O exchangeable), 4.30-4.06 (m, 1H), 3.54-3.25 (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).

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

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), DIPEA (3.5 mL, 27.15 mmol) and stirred at room temperature for 1 h. The reaction was diluted with water (50 mL) extracted with DCM (2×100 mL). The organic layers were combined dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel, eluting with ethyl acetate in hexanes 0-40%) to afford (S)-(1-(2-chloroquinazolin-4-yl)pyrrolidin-2-yl)methanol (115a) (1.4 g, 54% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.33-8.22 (m, 1H), 7.78 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 7.62 (dd, J=8.4, 1.3 Hz, 1H), 7.47 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 4.85 (t, J=5.8 Hz, 1H), 4.57 (t, J=5.7 Hz, 1H), 4.11-3.87 (m, 2H), 3.64 (t, J=5.2 Hz, 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).

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 2 (dba) 3 (0.09 g, 0.1 mmol) and sodium tert-butoxide (0.18 g, 1.9 mmol) in PhMe (4 mL) according to the procedure reported in step-2 on Scheme 96. This gave after workup and purification by flash column chromatography [silica (4 g), eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%] (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 (300 MHz, DMSO-d 6 ) δ 9.01 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.56 (td, J=7.4, 6.8, 1.2 Hz, 1H), 7.48 (s, 1H), 7.10 (t, J=7.6 Hz, 1H), 6.93 (s, 2H), 4.87 (s, 1H), 4.72 (s, 1H), 4.10-3.97 (m, 1H), 3.96 (s, 1H), 3.89 (s, 6H), 3.85-3.73 (m, 1H), 3.68 (s, 3H), 3.63-3.50 (m, 1H), 2.12-1.78 (m, 4H). MS (ES+): 477.5 (M+1); MS (ES−): 511.5 (M+Cl).

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)benzonitrile (116c)

Step-1: Preparation of 4-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (116b)

Compound 116b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (340 mg, 1.81 mmol) in 2-Propanol (10 mL) using DIPEA (0.95 mL, 5.44 mmol) and 4-(4-amino-1H-imidazol-1-yl)benzonitrile hydrochloride (116a) (0.4 g, 1.81 mmol; prepared according to the procedure reported in Jones, Alison et al; in PCT Int. Appl., 2016046530, 31 Mar. 2016). This gave after work up and purification by flash column chromatography [silica gel, (12 g) eluting with DCM and methanol (0 to 50%)]4-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (116b) (0.55 g, 91% yield) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.39 (s, 1H), 8.47 (d, J=1.6 Hz, 1H), 8.09-8.02 (m, 2H), 8.01 (d, J=1.6 Hz, 1H), 7.94-7.87 (m, 2H), 7.79 (dd, J=2.6, 1.6 Hz, 1H), 7.40 (s, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H). MS (ES−): 334.3, 336.3 (M+2).

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)benzonitrile (116c)

Compound 116c was prepared from 4-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (116b) (100 mg, 0.3 mmol), (S)-pyrrolidin-2-ylmethanol (0.09 mL, 0.9 mmol), and DIPEA (0.16 mL, 0.9 mmol) in NMP (1.5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel C-18, 24 g), eluting with eluting with acetonitrile and 0.1% HCl water], followed by lyophilization (S)-4-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (116c) (20 mg, 18% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.67 (s, 1H), 8.53 (s, 1H), 8.15-7.92 (m, 5H), 7.42 (s, 1H), 7.15 (d, J=4.2 Hz, 1H), 6.41 (d, J=4.4 Hz, 1H), 4.18 (s, 1H), 3.56-3.43 (m, 1H), 3.42-3.27 (m, 2H), 2.13-1.81 (m, 4H); MS (ES+): 401.5. IR (film): 2230 cm −1 . HPLC purity: 94.20%.

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)pyrrolidine-2-carboxamide (117a)

Compound 117a 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) (52 mg, 0.104 mmol), (S)-pyrrolidine-2-carboxamide (119 mg, 1.04 mmol) in NMP (1 mL) according to the procedure reported 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 free base using NaHCO 3 (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)pyrrolidine-2-carboxamide (117a) (7 mg, 12% yield) as a pale off-white solid; 1 H NMR (300 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.80 (s, 1H), 7.69-7.58 (m, 1H), 6.76 (s, 2H), 6.63 (d, J=4.4 Hz, 1H), 6.51 (d, J=4.5 Hz, 1H), 5.54-5.32 (m, 1H), 4.66-4.54 (m, 1H), 4.28-3.67 (m, 12H), 3.70-3.57 (m, 1H), 2.77-2.43 (m, 4H), 2.40-2.14 (m, 2H), 2.16-1.93 (m, 2H), 1.81-1.50 (m, 4H), 1.52-1.35 (m, 2H); MS (ES+): 576.6 (M+1).

Preparation of (S)-1-((2-((S)-2-carbamoylpyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl)pyrrolidine-2-carboxamide (118b)

Step-1: Preparation of 2-chloro-7-(((cyclopropylmethyl)amino)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (118a)

Compound 118a was prepared according to the procedure reported for reductive amination in step-1 of Scheme 105 from 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (400 mg, 0.93 mmol) in dichloroethane (10 mL) using 1-cyclopropylmethylamine (0.24 mL, 2.8 mmol), acetic acid (0.11 mL) and NaBH(OAc) 3 (297 mg, 1.4 mmol). This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0% to 40%) 2-chloro-7-(((cyclopropylmethyl)amino)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (118a) (218 mg, 48% yield) as a solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.35 (d, J=4.4 Hz, 1H), 6.93 (s, 2H), 6.65 (d, J=4.4 Hz, 1H), 3.96 (s, 2H), 3.87 (s, 6H), 3.69 (s, 3H), 2.39 (d, J=6.7 Hz, 2H), 0.99-0.78 (m, 1H), 0.46-0.31 (m, 2H), 0.14-0.02 (m, 2H); MS (ES+): 484.4 (M+1), 506.4 (M+Na); MS (ES−): 482.4 (M−1), 518.4 (M+Cl).

Step 2: Preparation of (S)-1-((2-((S)-2-carbamoylpyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl)pyrrolidine-2-carboxamide (118b)

Compound 118b was prepared from 2-chloro-7-(((cyclopropylmethyl)amino)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (118a) (98 mg, 0.2 mmol), (S)-pyrrolidine-2-carboxamide (0.462 g, 4.1 mmol) in NMP (1.5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash chromatography [silica gel (12 g), eluting with MeOH in DCM from 0% to 40%] (S)-1-((2-((S)-2-carbamoylpyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl)pyrrolidine-2-carboxamide (118b) (10 mg, 8% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.43 (s, 1H, D 2 O exchangeable), 8.21 (d, J=1.5 Hz, 1H), 7.91 (s, 1H), 7.63-7.43 (m, 1H, D 2 O exchangeable), 7.37-7.15 (m, 2H, D 2 O exchangeable), 7.16 (d, J=4.4 Hz, 1H), 7.08 (s, 2H), 7.04 (s, 1H, D 2 O exchangeable), 6.39 (d, J=4.4 Hz, 1H), 4.49-4.35 (m, 1H), 4.23-4.06 (m, 1H), 3.93 (s, 6H), 3.68 (s, 3H), 3.64-3.52 (m, 1H), 3.02-2.89 (m, 1H), 2.89-2.78 (m, 1H), 2.45-2.30 (m, 1H), 2.32-1.98 (m, 2H), 2.00-1.85 (m, 4H), 1.81-1.48 (m, 4H); MS (ES+): 605.6 (M+1), 627.6 (M+Na); HPLC purity: 95.61%.

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)benzonitrile (119c)

Step-1: Preparation of 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (119b)

Compound 119b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (852 mg, 4.53 mmol) in 2-Propanol (10 mL) using DIPEA (2.38 mL, 13.6 mmol) and 3-(4-amino-1H-imidazol-1-yl)benzonitrile hydrochloride (119a) (1 g, 4.53 mmol; can be prepared according to the procedure reported by Jones, Alison et al; in PCT Int. Appl., 2016046530, 31 Mar. 2016). This gave after work up and purification by flash column chromatography [silica gel, (40 g) eluting with DCM and methanol (0 to 30%)]3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (119b) (0.9 g, 59% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.35 (s, 1H), 8.37 (d, J=1.6 Hz, 1H), 8.29 (t, J=1.8 Hz, 1H), 8.02 (ddd, J=8.1, 2.4, 1.1 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.86 (dt, J=7.7, 1.3 Hz, 1H), 7.80-7.72 (m, 2H), 7.40 (d, J=4.4 Hz, 1H), 6.73 (dd, J=4.5, 2.6 Hz, 1H); MS (ES−): 335.3, 337.3 (M+2).

Step-2: 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)benzonitrile (119c)

Compound 119c was prepared from 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (119b) (300 mg, 0.89 mmol), (S)-pyrrolidin-2-ylmethanol (0.27 mL, 2.68 mmol), and DIPEA (0.47 mL, 2.68 mmol) in NMP (1.5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel C-18, 24 g), eluting with eluting with acetonitrile and 0.1% HCl water], followed by lyophilization (S)-3-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (119c) (22 mg, 6% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.28 (s, 1H), 8.94 (s, 1H), 8.37 (s, 1H), 8.25-8.06 (m, 2H), 7.90 (d, J=6.6 Hz, 1H), 7.83-7.68 (m, 1H), 7.49 (s, 1H), 7.17 (s, 1H), 6.46 (s, 1H), 4.15 (s, 1H), 3.77-3.63 (m, 1H), 3.55-3.19 (m, 3H), 2.10-1.73 (m, 4H); MS (ES+): 401.5; MS (ES−): 399.5 (M−1), 435.5 (M+Cl). HPLC purity: 96.43%.

Preparation of (S)-(1-(7-(((cyclopropylmethyl)amino)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 (120a)

Compound 120a was prepared from 2-chloro-7-(((cyclopropylmethyl)amino)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (118a) (103 mg, 0.21 mmol), (S)-pyrrolidin-2-ylmethanol (431 mg, 4.26 mmol) in NMP (1.5 mL) according to the procedure reported 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] (S)-(1-(7-(((cyclopropylmethyl)amino)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 (120a) (10 mg, 7% yield) TFA salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.76 (s, 1H, D 2 O exchangeable), 8.79 (s, 2H, D 2 O exchangeable), 8.28 (d, J=1.5 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.20 (d, J=4.5 Hz, 1H), 6.96 (s, 2H), 6.60 (d, J=4.5 Hz, 1H), 4.48-4.39 (m, 2H), 4.31-4.20 (m, 1H), 3.88 (s, 6H), 3.81-3.70 (m, 1H), 3.68 (s, 3H), 3.67-3.56 (m, 1H), 3.56-3.43 (m, 1H), 3.35 (t, J=9.3 Hz, 1H), 2.88 (q, J=6.1 Hz, 2H), 2.20-1.75 (m, 4H), 1.21-1.01 (m, 1H), 0.69-0.52 (m, 2H), 0.48-0.30 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −74.16; MS (ES+): 549.5 (M+1), 571.6 (M+Na); HPLC purity: 94.26%.

Preparation of (S)-tert-butyl 4-((2-(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)methyl)piperazine-1-carboxylate (121b)

Step-1: Preparation of tert-butyl 4-((2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl)piperazine-1-carboxylate (121a)

Compound 121a was prepared according to the procedure reported for reductive amination in step-1 of Scheme 105 from 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (400 mg, 0.93 mmol) in dichloroethane (10 mL) using tert-butyl piperazine-1-carboxylate (521 mg, 2.8 mmol), acetic acid (0.064 mL) and NaBH(OAc) 3 (297 mg, 1.4 mmol). This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0 to 40%) tert-butyl 4-((2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl)piperazine-1-carboxylate (121a) (218 mg, 39% yield) as a solid; 1 H NMR (300 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.64 (d, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.74-6.58 (m, 3H), 4.09-3.79 (m, 11H), 3.53-3.34 (m, 4H), 2.65-2.39 (m, 4H), 1.44 (s, 9H); MS (ES+): 599.6 (M+1), 621.6 (M+Na); MS (ES−): 597.5 (M−1).

Step 2: Preparation of (S)-tert-butyl 4-((2-(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)methyl)piperazine-1-carboxylate (121b)

Compound 121b was prepared from tert-butyl 4-((2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl)piperazine-1-carboxylate (121a) (148 mg, 0.25 mmol), (S)-pyrrolidin-2-ylmethanol (187 mg, 1.85 mmol), (di-t-Bu-XPhos) (16 mg, 0.087 mmol), Pd 2 (dba) 3 (16 mg, 0.087 mmol) and sodium tert-butoxide (178 mg, 1.85 mmol) in PhMe (5 mL) according to the procedure reported in step-3 on Scheme 101. This gave after workup and purification by flash chromatography (Silica gel 24 g, eluting with MeOH in DCM from 0 to 50%) (S)-tert-butyl 4-((2-(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)methyl)piperazine-1-carboxylate (121b) (86 mg, 52% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.49 (s, 1H, D 2 O exchangeable), 8.24 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.13 (d, J=4.5 Hz, 1H), 6.95 (s, 2H), 6.34 (d, J=4.4 Hz, 1H), 4.84 (t, J=5.2 Hz, 1H, D 2 O exchangeable), 4.26-4.12 (m, 1H), 3.87 (s, 6H), 3.87-3.71 (m, 2H), 3.80-3.67 (m, 1H), 3.68 (s, 3H), 3.66-3.53 (m, 1H), 3.51-3.22 (m, 6H), 2.38 (s, 4H), 2.12-1.69 (m, 4H), 1.36 (s, 9H); MS (ES+): 664.7 (M+1), 686.7 (M+Na); MS (ES−): 662.7 (M+1), 698.8 (M+Cl); HPLC purity: 88.43%.

Preparation of (S)-(1-(7-(piperazin-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 (122a)

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[2,1-f][1,2,4]triazin-7-yl)methyl)piperazine-1-carboxylate (121b) (66 mg, 0.1 mmol) in DCM (5 mL) was added TFA (0.15 mL, 1.99 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuum and the residue was dissolved in DCM, washed with saturated aqueous NaHCO 3 , brine, dried, and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 12 g, eluting with DMA80 in DCM 0-50%) to afford (S)-(1-(7-(piperazin-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 (122a) (22 mg, 39% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.45 (s, 1H, D 2 O exchangeable), 8.23 (d, J=1.5 Hz, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.12 (dd, J=4.5, 2.1 Hz, 1H), 6.95 (s, 2H), 6.32 (d, J=4.4 Hz, 1H), 4.93-4.72 (m, 1H, D 2 O exchangeable), 4.32-4.13 (m, 1H), 3.87 (s, 6H), 3.80-3.70 (m, 3H), 3.68 (s, 3H), 3.66-3.52 (m, 1H), 3.54-3.24 (m, 2H), 2.71-2.59 (m, 4H), 2.41-2.27 (m, 4H), 2.10-1.82 (m, 4H); MS (ES+): 564.7 (M+1); MS (ES−): 598.9 (M+Cl); HPLC purity: 98.11%.

Preparation of (S)-1-(2-hydroxy-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (123c)

Step-1: Preparation of 1-(5-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2-methoxyphenyl)ethanone (123b)

Compound 123b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (240 mg, 1.30 mmol) in 2-Propanol (10 mL) using DIPEA (0.68 mL, 3.89 mmol) and 1-(5-(4-amino-1H-imidazol-1-yl)-2-methoxyphenyl)ethanone hydrochloride (123a) (0.3 g, 1.3 mmol). This gave after work up and purification by flash column chromatography [silica gel, (12 g) eluting with DCM and methanol (0 to 50%)] 1-(5-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2-methoxyphenyl)ethanone (123b) (0.35 g, 71% yield) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.41-11.28 (m, 1H), 8.19 (t, J=2.1 Hz, 1H), 7.91-7.79 (m, 2H), 7.76 (dt, J=5.9, 2.4 Hz, 2H), 7.45-7.31 (m, 2H), 6.72 (q, J=2.6 Hz, 1H), 3.96 (d, J=2.5 Hz, 3H), 2.59 (d, J=2.6 Hz, 3H). MS (ES+): 405.4 (M+Na); MS (ES−): 381.4, 383.4 (M−1).

Step-2: Preparation of (S)-1-(2-hydroxy-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (123c)

Compound 123c was prepared from 1-(5-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2-methoxyphenyl)ethanone (123b) (100 mg, 0.26 mmol), (S)-pyrrolidin-2-ylmethanol (0.08 mL, 0.78 mmol), and DIPEA (0.14 mL, 0.78 mmol) in NMP (1.5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel C-18, 24 g), eluting with acetonitrile and 0.1% HCl water], followed by lyophilization (S)-1-(2-hydroxy-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)phenyl)ethanone (123c) (10 mg, 10% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.92 (s, 1H), 10.63 (s, 1H), 8.37 (s, 1H), 8.09 (d, J=2.8 Hz, 1H), 8.00 (s, 1H), 7.92 (dd, J=8.9, 2.7 Hz, 1H), 7.41 (t, J=2.0 Hz, 1H), 7.17-7.07 (m, 2H), 6.41 (dd, J=4.4, 2.4 Hz, 1H), 4.27-4.12 (m, 2H), 3.73 (dd, J=10.0, 3.5 Hz, 1H), 3.50 (s, 1H), 3.45-3.26 (m, 2H), 2.75 (s, 3H), 2.10-1.81 (m, 4H). MS (ES+): 434.5 (M+1); MS (ES−): 432.5 (M−1), 468.6 (M+Cl). HPLC purity: 88.85%.

Preparation of (3-(6-(hydroxymethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)phenyl)methanol (124a)

Compound 124a was prepared from 3-(6-(hydroxymethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)benzaldehyde (109a) (50 mg, 0.1 mmol) according to the procedure reported in step-4 of Scheme 70 using NaBH 4 (4 mg, 0.1 mmol) in MeOH (10 mL). This gave after workup (3-(6-(hydroxymethyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)phenyl)methanol (124a) (0.03 g, 58% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.54 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.44 (d, J=4.5 Hz, 2H), 7.01 (s, 2H), 5.79 (s, 1H), 5.30 (s, 1H), 4.74 (s, 2H), 4.59 (s, 2H), 3.91 (s, 6H), 3.71 (s, 3H); MS (ES+): 501.6 (M−18); HPLC purity: 93.11%.

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)-5-methoxybenzamide (125c)

Step-1: Preparation of 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzamide (125b)

Compound 125b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (350 mg, 1.86 mmol) in 2-Propanol (10 mL) using DIPEA (0.98 mL, 5.58 mmol) and 3-(4-amino-1H-imidazol-1-yl)-5-methoxybenzamide (125a) (0.4 g, 1.86 mmol). This gave after work up and purification by flash column chromatography [silica gel, (12 g) eluting with DCM and methanol (0 to 50%)] 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzamide (125b) (0.52 g, 75% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.34 (s, 1H), 8.38-8.28 (m, 1H), 8.17 (s, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.78 (dd, J=2.6, 1.5 Hz, 1H), 7.69 (t, J=1.6 Hz, 1H), 7.60 (s, 1H), 7.45 (t, J=1.7 Hz, 1H), 7.40 (t, J=2.3 Hz, 2H), 6.73 (dd, J=4.4, 2.6 Hz, 1H), 3.90 (s, 3H). MS (ES+): 384.2, 386.5 (M+1), 406.3 (M+Na); MS (ES−): 382.4, 384.4 (M−1).

Step-2: 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)-5-methoxybenzamide (125c)

Compound 125c was prepared from 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzamide (125b) (100 mg, 0.26 mmol), (S)-pyrrolidin-2-ylmethanol (0.08 mL, 0.78 mmol), and DIPEA (0.14 mL, 0.78 mmol) in NMP (1.5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash chromatography [silica gel (4 g), eluting with ethyl acetate/methanol (9:1) in hexane from 0 to 100%], (S)-3-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzamide (125c) (14 mg, 12% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.32 (dd, J=4.5, 1.6 Hz, 1H), 8.10-8.00 (m, 2H), 7.70 (t, J=1.7 Hz, 1H), 7.59 (s, 1H), 7.47-7.33 (m, 3H), 7.14 (dd, J=4.4, 1.7 Hz, 1H), 6.40 (dd, J=4.4, 2.5 Hz, 1H), 4.89 (t, J=5.0 Hz, 1H), 4.28-4.15 (m, 1H), 3.89 (s, 3H), 3.82-3.69 (m, 1H), 3.61-3.47 (m, 1H), 3.48-3.34 (m, 2H), 2.11-1.82 (m, 4H); MS (ES+): 449.5 (M+1); MS (ES−): 447.5 (M−1). HPLC purity: 87.51%.

Preparation of (S)-1-(7-(piperidine-1-carbonyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-2-carboxamide (126c)

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-carboxylic acid (126a)

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) (1 g, 2.33 mmol) in acetonitrile (4 ml), t-BuOH (28 mL), Water (4 mL) was added sodium dihydrogenphosphate (0.56 g, 4.66 mmol) and 2-methylbut-2-ene (2.63 mL, 23.32 mmol). The reaction mixture was cooled with ice-water bath and added a solution of sodium chlorite (1.055 g, 11.66 mmol) in Water (4 mL). The reaction mixture was allowed to warm to room temperature overnight and diluted with water. The solid obtained was collected by filtration dried in air to afford 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (126a) (1.037 g, 100% yield, contaminated with 30% starting material 79b based on NMR data) as a white solid, which was used directly for next step without further purification; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.77, 11.55 (2s, 1H), 8.25 (dd, J=4.8, 1.6 Hz, 1H), 7.93 (dd, J=5.2, 1.6 Hz, 1H), 7.49 (dd, J=14.2, 4.8 Hz, 1H), 7.32 (dd, J=20.8, 4.8 Hz, 1H), 6.95 (s, 2H), 3.88 (s, 6H), 3.70 (s, 3H).

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)(piperidin-1-yl)methanone (126b)

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-carboxylic acid (126a) (0.75 g, 1.69 mmol) and piperidine (0.2 mL, 2.02 mmol) in DMF (50 mL) was added HATU (769 mg, 2.02 mmol) and DIPEA (0.883 mL, 5.06 mmol), stirred at room temperature overnight and diluted with EtOAc (200 mL). The organic layer was washed with water, brine, dried, filtered and concentrated in vacuum. The residue obtained was purified twice by flash column chromatography [silica (40 g), eluting with DMA80 in DCM from 0 to 30%] followed by [silica (40 g), eluting with EtOAc/MeOH (9:1) in hexane from 0 to 100%] to afford (2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)(piperidin-1-yl)methanone (126b) (219 mg, 25% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.46 (s, 1H), 8.22 (d, J=1.6 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.44 (d, J=4.6 Hz, 1H), 6.94 (s, 2H), 6.85 (d, J=4.6 Hz, 1H), 3.87 (s, 6H), 3.69 (s, 3H), 3.69-3.58 (m, 2H), 3.26-3.04 (m, 2H), 1.77-1.39 (m, 6H); MS (ES+): 512.5 (M+1), 534.5 (M+1); MS (ES−): 510.5 (M−1).

Step 3: Preparation of (S)-1-(7-(piperidine-1-carbonyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-2-carboxamide (126c)

Compound 126c was prepared from (2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)(piperidin-1-yl)methanone (126b) (253 mg, 0.49 mmol), (S)-pyrrolidine-2-carboxamide (169 mg, 1.48 mmol), (di-t-Bu-XPhos) (32 mg, 0.074 mmol), Pd 2 (dba) 3 (32 mg, 0.035 mmol) and Cs 2 CO 3 (483 mg, 1.48 mmol) in PhMe (5 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash chromatography (Silica gel 24 g, eluting with MeOH in DCM from 0 to 10%), followed by purification by reverse phase chromatography [(silica gel C-18, 24 g) eluting with 0.1% TFA in acetonitrile and 0.1% TFA in water] (S)-1-(7-(piperidine-1-carbonyl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-2-carboxamide (126c) (6 mg, 2% yield) TFA salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.65 (s, 1H, D 2 O exchangeable), 8.26 (s, 1H), 7.95 (s, 1H), 7.24 (s, 2H, 1H D 2 O exchangeable), 7.15-6.95 (m, 3H, 1H D 2 O exchangeable), 6.55 (s, 1H), 4.52-4.27 (m, 1H), 3.92 (s, 6H), 3.86-3.70 (m, 2H), 3.68 (s, 3H), 3.64-3.36 (m, 2H), 3.34-3.01 (m, 2H), 2.31-1.79 (m, 4H), 1.72-1.29 (m, 6H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −74.12; MS (ES+): 590.6 (M+1), 612.6 (M+Na); MS (ES−): 624.0 (M+Cl); HPLC purity: 83.3%; Hydrochloride salt of compound 126c was obtained by purification of 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; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.10 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.29 (s, 1H), 7.22 (d, J=4.6 Hz, 1H), 7.17 (s, 2H), 7.03 (s, 1H), 6.60 (d, J=4.5 Hz, 1H), 4.38 (d, J=8.6 Hz, 1H), 4.06-2.97 (m, 15H), 2.28-1.79 (m, 4H), 1.69-1.32 (m, 6H). MS (ES−): 588.3 (M−1). HPLC purity: 94.09%.

Preparation of (S)-3-hydroxy-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (127b)

Step-1: Preparation of 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzonitrile (127a)

To a solution of 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzamide (125b) (0.06 g, 0.14 mmol) in THE (5 mL) was added pyridine (0.02 mL, 0.29 mmol), 2,2,2-trifluoroacetic anhydride (0.02 mL, 0.17 mmol) and stirred at room temperature for 1 h. The mixture was quenched with water (1 mL) and concentrated in vacuum to dryness. To the residue was added saturated aqueous NaHCO 3 (20 mL) and extracted with chloroform (2×30 mL). The organic layers were combined washed with brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to 2:1)] to afford 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzonitrile (127a) (31 mg, 59% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.32 (s, 1H), 8.38 (d, J=1.6 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.88-7.73 (m, 2H), 7.59 (d, J=2.1 Hz, 1H), 7.49 (t, J=1.6 Hz, 1H), 7.39 (s, 1H), 6.73 (dd, J=4.4, 2.6 Hz, 1H), 3.91 (s, 3H). MS (ES+): 366.4; MS (ES−): 364.4.

Step-2: Preparation of (S)-3-hydroxy-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (127b)

Compound 127b was prepared from 3-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-5-methoxybenzonitrile (127a) (100 mg, 0.27 mmol), (S)-pyrrolidin-2-ylmethanol (0.08 mL, 0.78 mmol), and DIPEA (0.14 mL, 0.78 mmol) in NMP (1.5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash chromatography [silica (4 g), eluting with ethyl acetate/methanol (9:1) in hexane from 0 to 100%] (S)-3-hydroxy-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)benzonitrile (127b) (10 mg, 9% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.76-10.58 (m, 1H), 10.54 (s, 1H), 8.29 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.45-7.35 (m, 2H), 7.19-7.07 (m, 2H), 6.44-6.34 (m, 1H), 4.96-4.81 (m, 1H), 4.25-4.08 (m, 1H), 3.81-3.68 (m, 1H), 3.58-3.42 (m, 1H), 3.44-3.33 (m, 1H), 2.23-1.82 (m, 4H); MS (ES+): 417.5 (M+1), 439.5 (M+Na); MS (ES−): 415.5 (M-1).

Preparation of (S)-(1-(4-((1-(3,4-difluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (128c)

Step-1: Preparation of 2-chloro-N-(1-(3,4-difluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (128b)

Compound 128b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (366 mg, 1.95 mmol) in 2-Propanol (10 mL) using DIPEA (1.02 mL, 5.84 mmol) and 1-(3,4-difluorophenyl)-1H-imidazol-4-amine (128a) (0.38 g, 1.95 mmol). This gave after work up 2-chloro-N-(1-(3,4-difluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (128b) (566 mg, 84% yield) as an off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.34 (s, 1H, D 2 O exchangeable), 8.26 (d, J=1.6 Hz, 1H), 7.95 (ddd, J=11.9, 7.0, 2.8 Hz, 1H), 7.90 (d, J=1.7 Hz, 1H), 7.78 (dd, J=2.6, 1.5 Hz, 1H), 7.65 (dt, J=10.4, 8.8 Hz, 1H), 7.58-7.48 (m, 1H), 7.40 (d, J=4.4 Hz, 1H), 6.72 (dd, J=4.4, 2.6 Hz, 1H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −135.50, −135.68 (m), −139.73, −141.11 (m); 19 F CPD NMR (282 MHz, DMSO-d 6 ) δ −135.59 (d, J=22.9 Hz), −140.48 (d, J=22.9 Hz); MS (ES+): 347.3 (M+1); MS (ES−): 345.3 (M−1); HPLC purity: 99.39%.

Step-2: Preparation of (S)-(1-(4-((1-(3,4-difluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (128c)

Compound 128c was prepared from 2-chloro-N-(1-(3,4-difluorophenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (128b) (100 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (146 mg, 1.44 mmol), and DIPEA (0.15 mL, 0.87 mmol) in NMP (1.5 mL) according to the procedure reported 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 free base using saturated sodium bicarbonate gave (S)-(1-(4-((1-(3,4-difluorophenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-2-yl)methanol (128c) (24 mg, 20% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.55 (s, 1H, D 2 O exchangeable), 8.27 (d, J=1.6 Hz, 1H), 8.07-7.96 (m, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.65 (dt, J=5.7, 2.9 Hz, 1H), 7.63-7.47 (m, 1H), 7.40 (dd, J=2.4, 1.6 Hz, 1H), 7.15 (dd, J=4.4, 1.7 Hz, 1H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 5.01 (t, J=4.7 Hz, 1H, D 2 O exchangeable), 4.30-4.08 (m, 1H), 3.88-3.69 (m, 1H), 3.58-3.43 (m, 1H), 3.45-3.20 (m, 2H), 2.17-1.77 (m, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) δ −133.86-−137.91 (m), −139.79-−143.07 (m); 19 FCPD NMR (282 MHz, DMSO-d 6 ) δ −135.89 (d, J=22.6 Hz), −141.35 (d, J=22.6 Hz); MS (ES+): 412.4 (M+1); MS (ES−): 410.4 (M−1), 446.3 (M+Cl); HPLC purity: 97.91%.

Preparation of (S)-(1-(7-((isopropylamino)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 (129b)

Step-1: Preparation of 2-chloro-7-((isopropylamino)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (129a)

Compound 129a was prepared according to the procedure reported for reductive amination in step-1 of Scheme 105 from 2-chloro-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)pyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde (79b) (400 mg, 0.93 mmol) in dichloroethane (10 mL) using 1-isopropylamine (0.24 mL, 2.8 mmol), acetic acid (0.064 mL) and NaBH(OAc) 3 (297 mg, 1.4 mmol). This gave after workup and purification by flash column chromatography (Silica gel 12 g, eluting with MeOH in DCM from 0% to 50%) 2-chloro-7-((isopropylamino)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (129a) (217 mg, 49% yield) as a solid; 1 HNMR (300 MHz, CDCl 3 ) δ 8.98 (br, s, 1H), 7.91 (d, J=1.3 Hz, 1H), 7.72-7.57 (m, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.66 (d, J=0.9 Hz, 2H), 6.63 (d, J=4.5 Hz, 1H), 4.13 (s, 2H), 3.94 (s, 6H), 3.89 (s, 3H), 2.95-2.74 (m, 1H), 1.79 (br, s, 1H), 1.13 (d, J=6.2 Hz, 6H); MS (ES+): 472.5 (M+1), 494.5 (M+Na); MS (ES−): 470.5 (M−1).

Step 2: Preparation of (S)-(1-(7-((isopropylamino)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 (129b)

Compound 129b was prepared from 2-chloro-7-((isopropylamino)methyl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (129a) (103 mg, 0.22 mmol), (S)-pyrrolidin-2-ylmethanol (221 mg, 2.18 mmol) in NMP (1.5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash chromatography [silica gel (4 g), eluting with DMA80 in DCM from 0 to 50%], followed by purification by reverse phase flash chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water] (S)-(1-(7-((isopropylamino)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 (129b) (8 mg, 7% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) (a mixture of two rotamers) δ 11.21 and 11.18 (2s, 1H), 9.17 (s, 1H), 8.85 and 8.82 (2s, 1H), 8.12-8.05 (m, 1H), 7.24 and 7.20 (2d, J=4.5 Hz, 1H), 7.10-7.01 (m, 2H), 6.77 and 6.73 (d, J=4.5 Hz, 1H), 4.66-4.52 (m, 1H), 4.45-4.29 (m, 2H), 4.22 (s, 1H), 3.98-3.12 (m, 13H), 2.13-1.68 (m, 4H), 1.35-1.28 (m, 6H); MS (ES+): 559.5 (M+Na); MS (ES−): 571.6 (M+Cl). HPLC purity: 96.89%.

Preparation (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (130a)

Compound 130a was prepared according to the procedure reported in step-2 of Scheme 76 from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (86a) (100 mg, 0.24 mmol), DIPEA (0.11 mL, 0.85 mmol), and (S)-pyrrolidine-2-carboxamide (0.15 g, 1.31 mmol) in NMP (10 mL). This gave after workup and purification by flash chromatography (silica gel, eluting with 0-80% ethyl acetate in hexanes) (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (130a) (50 mg, 43%) free base as a white solid. This was re-purified by reverse phase flash column chromatography [(silica gel C-18 column 24 g), eluting with acetonitrile and 0.1% HCl water (0-50%)] followed by lyophilization to afford (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (130a) (20 mgs) HCl salt as a light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.29 (s, 1H), 11.65 (s, 1H), 8.77 (d, J=8.0 Hz, 1H), 8.38 (s, 1H), 8.13-7.99 (m, 1H), 7.99-7.81 (m, 1H), 7.62 (s, 1H), 7.57-7.40 (m, 2H), 7.37-7.24 (m, 1H), 7.14 (s, 2H), 4.75 (d, J=9.0 Hz, 1H), 4.10-4.01 (m, 2H), 3.94 (s, 6H), 3.69 (s, 3H), 2.40-1.95 (m, 4H) MS (ES+): 490.5 (M+1), 512.5 (M+Na); MS (ES−): 524.5 (M+Cl). HPLC purity: 98.13%.

Preparation of (S)-1-(4-((1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-2-carboxamide (131a)

Compound 131a 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) (150 mg, 0.41 mmol), (S)-pyrrolidine-2-carboxamide (0.14 g, 1.21 mmol), and DIPEA (0.21 mL, 1.21 mmol) in NMP (2 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by reverse phase flash chromatography [(silica gel C-18, 24 g), eluting with acetonitrile and 0.1% HCl in water], followed by lyophilization (S)-1-(4-((1-(3,5-dimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-2-carboxamide (131a) (50 mg, 25% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.53 (s, 1H), 8.35 (d, J=1.5 Hz, 1H), 7.95 (s, 1H), 7.48-7.37 (m, 1H), 7.22 (s, 1H), 7.16 (dd, J=4.6, 1.7 Hz, 1H), 7.00 (s, 3H), 6.47 (t, J=2.2 Hz, 1H), 6.43 (dd, J=4.4, 2.4 Hz, 1H), 4.39 (d, J=9.0 Hz, 1H), 3.86 (s, 6H), 3.78 (m, 1H), 3.48 (m, 1H), 2.31-1.82 (m, 4H). MS (ES+): 449.4; MS (ES−): 483.3 (M+Cl). HPLC purity: 94.06%.

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (132b)

Step-1: Preparation of (S)-1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (132a)

Compound 132a was prepared from 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (2 g, 9.75 mmol) in 2-Propanol (20 mL) was added (S)-pyrrolidine-2-carboxamide (1.11 g, 9.75 mmol), DIPEA (5.11 mL, 29.3 mmol) according to the procedure reported in step-1 of Scheme 96. This gave (S)-1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (132a) (1.28 g, 46% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.71-7.66 (m, 1H), 7.58 (d, J=6.0 Hz, 1H), 7.52 (s, 1H), 7.07-6.97 (m, 1H), 4.63 (s, 1H), 4.19-3.77 (m, 2H), 2.25-1.86 (m, 4H). MS (ES−): 281.3, 317.3 (M+Cl).

Step-2: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (132b)

Compound 132b was prepared from (S)-1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (132a) (0.3 g, 1.06 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.3 g, 1.06 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (50 mg, 0.13 mmol), sodium 2-methylpropan-2-olate (610 mg, 6.4 mmol), Pd 2 (dba) 3 (60 mg, 0.06 mmol) in anhydrous Dioxane (15 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (132b) (0.03 g, 6% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.18 (s, 1H), 9.29 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.31 (d, J=6.0 Hz, 1H), 7.28 (s, 2H), 7.08 (s, 1H), 4.73 (s, 1H), 4.25 (m, 1H), 4.03-3.84 (m, 7H), 3.71 (s, 3H), 2.34-1.86 (m, 4H). MS (ES+): 496.3; MS (ES−): 530.3 (M+Cl).

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (133b)

Step-1: Preparation of (S)-(1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (133a) Compound 133a was prepared from 2,4-dichlorothieno[2,3-d]pyrimidine (31a) (2 g, 9.75 mmol) in 2-Propanol (20 mL), (S)-pyrrolidin-2-ylmethanol (0.96 mL, 9.75 mmol), DIPEA (5.11 mL, 29.3 mmol) according to the procedure reported in step-1 of Scheme 96. This gave (S)-(1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (133a) (1.52 g, 58% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.61 (d, J=5.3 Hz, 1H), 7.55 (d, J=6.2 Hz, 1H), 4.96-4.73 (m, 1H), 4.48-4.34 (m, 1H), 4.05-3.67 (m, 2H), 3.66-3.38 (m, 2H), 2.22-1.81 (m, 4H). MS (ES+): 292.2 (M+Na). MS (ES−): 268.3 (M−1), 304.3 (M+Cl).

Step-2: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (133b)

Compound 133b was prepared from (S)-(1-(2-chlorothieno[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (133a) (0.5 g, 1.85 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.53 g, 1.85 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.094 g, 0.22 mmol), sodium 2-methylpropan-2-olate (1.07 g, 11.12 mmol), Pd 2 (dba) 3 (0.1 g, 0.11 mmol) in anhydrous Dioxane (15 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (133b) (100 mg, 12% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.26 (s, 1H), 9.15 (s, 1H), 7.92 (s, 1H), 7.57 (d, J=6.1 Hz, 1H), 7.32 (d, J=5.9 Hz, 1H), 7.12 (s, 2H), 4.68-4.50 (m, 1H), 4.07-3.93 (m, 1H), 3.89 (s, 6H), 3.85-3.76 (m, 1H), 3.70 (s, 3H), 3.66-3.58 (m, 1H), 3.47 (t, J=9.3 Hz, 1H), 2.20-1.83 (m, 4H). MS (ES+): 483.4 (M+1); MS (ES−): 517.3 (M+Cl). HPLC purity: 98.94%.

Preparation of (3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)methanol (134a)

Compound 134a 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) (0.3 g, 0.75 mmol), using 3-(hydroxymethyl)phenylboronic acid (171 mg, 1.10 mmol), Pd(Ph 3 P) 4 (86 mg, 0.075 mmol), potassium carbonate (207 mg, 1.5 mmol) in 1,4-Dioxane (8 mL) and Water (2 mL) according to the procedure reported in step-3 of Scheme 77. This gave after workup, purification by flash column chromatography [(silica gel, 12 g) eluting with ethyl acetate/MeOH (9:1) in hexane from 0-100%] then [(silica, 12 g), eluting with MeOH in DCM from 0-15%] (3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)methanol (134a) (54 mg, 15% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.93 (s, 1H, D 2 O exchangeable), 8.28 (s, 2H), 8.24-8.15 (m, 2H), 7.83 (t, J=2.0 Hz, 1H), 7.43 (d, J=4.7 Hz, 2H), 7.41-7.34 (m, 1H), 7.01 (s, 2H), 6.76-6.68 (m, 1H), 5.30 (t, J=5.7 Hz, 1H, D 2 O exchangeable), 4.58 (d, J=5.8 Hz, 2H), 3.88 (s, 6H), 3.71 (s, 3H); MS (ES+): 495.3 (M+1); (ES−): 471.4 (M−1).

Preparation of 2-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzamide (135a)

Compound 135a 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) (0.3 g, 0.75 mmol), using 2-carbamoylphenylboronic acid (185 mg, 1.12 mmol), Pd(Ph 3 P) 4 (86 mg, 0.075 mmol), potassium carbonate (207 mg, 1.5 mmol) in 1,4-Dioxane (8 mL) and Water (2 mL) according to the procedure reported in step-3 of Scheme 77. This gave after workup, purification by flash column chromatography [(silica gel, 12 g) eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] 2-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzamide (135a) (26 mg, 7% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.77 (s, 1H, D 2 O exchangeable), 8.25-8.16 (m, 2H, D 2 O exchangeable), 7.83-7.74 (m, 2H), 7.60 (s, 1H), 7.56-7.46 (m, 3H), 7.41-7.30 (m, 2H), 7.15 (s, 2H), 6.79-6.70 (m, 1H), 3.91 (s, 6H), 3.67 (s, 3H); MS (ES+): 486.3 (M+1); 508.3 (M+Na); HPLC purity; 95.32%

Preparation of 3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzamide (136a)

Compound 136a 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) (0.3 g, 0.75 mmol), using 3-carbamoylphenylboronic acid (185 mg, 1.12 mmol), Pd(Ph 3 P) 4 (86 mg, 0.075 mmol), potassium carbonate (207 mg, 1.5 mmol) in 1,4-dioxane (8 mL) and water (2 mL) according to the procedure reported in step-3 of Scheme 77. This gave after workup, 3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzamide (136a) (250 mg, 69% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.97 (s, 1H, D 2 O exchangeable), 8.81 (d, J=2.4 Hz, 1H), 8.45 (d, J=7.9 Hz, 1H), 8.33-8.27 (m, 1H), 8.23-8.09 (m, 2H, D 2 O exchangeable), 7.98 (d, J=8.0 Hz, 1H), 7.89-7.82 (m, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.99 (s, 2H), 6.81-6.69 (m, 1H), 3.90 (s, 6H), 3.71 (s, 3H); MS (ES+): 508.3 (M+Na); (ES−): 484.4 (M−1); HPLC purity; 98.25%.

Preparation of (2-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)methanol (137a)

Compound 137a 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) (0.3 g, 0.75 mmol), using 2-(hydroxymethyl)phenylboronic acid (171 mg, 1.10 mmol), Pd(Ph 3 P) 4 (86 mg, 0.075 mmol), potassium carbonate (207 mg, 1.5 mmol) in 1,4-dioxane (8 mL) and water (2 mL) according to the procedure reported in step-3 of Scheme 77. This gave after workup, purification by flash column chromatography [(silica gel, 12 g) eluting with ethyl acetate/MeOH (9:1) in hexane from 0-100%] (2-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)methanol (137a) (65 mg, 18% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.93 (s, 1H, D 2 O exchangeable), 8.27 (s, 1H), 8.06 (s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.80 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.42-7.30 (m, 2H), 6.91 (s, 2H), 6.75 (t, J=3.5 Hz, 1H), 5.19 (t, J=5.6 Hz, 1H, D 2 O exchangeable), 4.86 (d, J=5.5 Hz, 2H), 3.85 (s, 6H), 3.68 (s, 3H); MS (ES+): 495.3 (M+1); (ES−): 471.4 (M−1); HPLC purity; 97.31%.

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (138b)

Step-1: Preparation of (S)-(1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (138a) Compound 138a was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (2 g, 9.75 mmol) in 2-Propanol (20 mL), (S)-pyrrolidin-2-ylmethanol (0.96 mL, 9.75 mmol), DIPEA (5.11 mL, 29.3 mmol) according to the procedure reported in step-1 of Scheme 96. This gave (S)-(1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (138a) (1.17 g, 45% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.27 (d, J=5.5 Hz, 1H), 7.34 (d, J=5.5 Hz, 1H), 4.89 (s, 1H), 4.40 (s, 1H), 3.92 (s, 2H), 3.68-3.56 (m, 1H), 3.56-3.42 (m, 1H), 2.20-1.85 (m, 4H). MS (ES+): 270.2 (M+1); MS (ES−): 268.2, 304.2 (M+Cl).

Step-2: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (138b)

Compound 138b was prepared from (S)-(1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (138a) (500 mg, 1.85 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (508 mg, 2.32 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 398 mg, 0.834 mmol), cesium carbonate (1.81 g, 5.56 mmol), Pd 2 (dba) 3 (260 mg, 0.28 mmol) in anhydrous Dioxane (15 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (138b) (410 mg, 46% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.82-10.49 (m, 1H, D 2 O exchangeable), 8.43 (d, J=5.5 Hz, 1H), 8.36 (s, 1H), 7.74 (s, 1H), 7.45 (d, J=5.5 Hz, 1H), 6.98 (s, 2H), 4.77-4.54 (m, 1H), 4.17-3.93 (m, 1H), 3.88 (s, 6H), 3.79-3.71 (m, 1H), 3.69 (s, 3H), 3.65-3.50 (m, 2H), 2.31-1.96 (m, 4H); MS (ES+) 483.3 (M+1), 505.3 (M+Na), (ES−) 517.3 (M+Cl); HPLC purity, 96.8%.

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (139b)

Step-1: Preparation of (S)-1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (139a)

Compound 139a was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (2 g, 9.75 mmol) in 2-Propanol (20 mL) was added (S)-pyrrolidine-2-carboxamide (1.11 g, 9.75 mmol), DIPEA (5.11 mL, 29.3 mmol) according to the procedure reported in step-1 of Scheme 96. This gave (S)-1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (139a) (2.2 g, 80% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.29 (d, J=5.4 Hz, 1H), 7.55 (s, 1H), 7.36 (d, J=5.4 Hz, 1H), 7.04 (s, 1H), 4.58 (d, J=7.8 Hz, 1H), 4.25-3.87 (m, 2H), 2.35-1.67 (m, 4H). MS (ES−): 317.2 (M+Cl).

Step-2: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (139b)

Compound 139b was prepared from (S)-1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (139a) (0.5 g, 1.85 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.53 g, 1.85 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.094 g, 0.22 mmol), sodium 2-methylpropan-2-olate (1.07 g, 11.12 mmol), Pd 2 (dba) 3 (102 mg, 0.111 mmol) in anhydrous Dioxane (15 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (139b) (38 mg, 4% yield) as a white HCl salt; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.54 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.31 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.44 (d, J=5.4 Hz, 2H), 7.29 (s, 1H), 7.11 (s, 2H), 4.88-4.76 (m, 1H), 4.45-4.30 (m, 1H), 4.11-3.96 (m, 1H), 3.92 (s, 6H), 3.68 (s, 3H), 2.21-1.99 (m, 4H); MS (ES+): 496.4 (M+1); MS (ES−): 494.3 (M−1).

Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (140c)

Step-1: Preparation of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (140b)

Compound 140b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrido[3,2-d]pyrimidine (140a) (0.5 g, 2.5 mmol, CAS #39551-54-7) in 2-Propanol (10 mL) using DIPEA (1.31 mL, 7.50 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.79 g, 2.75 mmol). This gave after workup and purification by flash column chromatography [Silica gel, (24 g) eluting with DCM in MeOH 0 to 30%], 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (140b) (0.58 g, 56% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.36 (s, 1H), 8.93 (dd, J=4.3, 1.5 Hz, 1H), 8.30-8.13 (m, 2H), 8.02-7.87 (m, 2H), 6.96 (s, 2H), 3.88 (s, 6H), 3.70 (s, 3H). MS (ES+): 435.3 (M+Na).

Step-2: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (140c)

Compound 140c was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (140b) (0.15 g, 0.36 mmol), (S)-pyrrolidin-2-ylmethanol (0.04 mL, 0.36 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 0.03 g, 0.04 mmol), sodium 2-methylpropan-2-olate (0.11 g, 1.09 mmol), Pd 2 (dba) 3 (30 mg, 0.04 mmol) in degassed toluene (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by reverse phase flash column chromatography [silica (12 g), eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%] (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (140c) (50 mg, 29% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ (mixture of rotamers) δ 9.44 and 9.29 (2s, 1H), 8.45-8.42 and 8.42-8.41 (2m, 1H), 8.24 (s, 1H), 8.05 and 7.97 (2s, 1H), 7.75 and 7.73 (2s, 1H), 7.62 and 7.59 (2d, J=4.2 Hz, 1H), 6.97 and 6.95 (2s, 2H), 5.15 and 4.99 (2s, 1H), 4.40 and 4.24 (2s, 1H), 3.96-3.34 (m, 13H), 2.14-1.81 (m, 4H); MS (ES+): 478.3 (M+1); MS (ES−): 476.3 (M−1); 512.5 (M+Cl).

Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (141d)

Step-1: Preparation of 2-chloro-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (141b)

Compound 141b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (141a) (100 mg, 0.29 mmol, prepared according to procedure reported by Su, Qibin et al; Journal of Medicinal Chemistry, 57(1), 144-158; 2014) in 2-Propanol (5 mL) using DIPEA (0.15 mL, 0.88 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (93 mg, 0.29 mmol). This gave after filtration 2-chloro-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (141b) (122 mg, 75% yield) as white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.92 (s, 1H), 8.16 (s, 1H), 8.01-7.92 (m, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.66 (d, J=4.0 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.23 (s, 1H), 6.90 (s, 2H), 3.86 (s, 6H), 3.69 (s, 3H), 2.37 (s, 3H); MS (ES+) 556.1 (M+1); 577.2 (M+Na).

Step-2: Preparation of (S)-(1-(7-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (141c)

Compound 141c was prepared from 2-chloro-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (141b) (150 mg, 0.27 mmol), DIPEA (0.14 mL, 0.81 mmol) and (S)-pyrrolidin-2-ylmethanol (82 mg, 0.81 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] (S)-(1-(7-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (141c) (130 mg, 78% yield) as white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.25-10.07 (m, 1H, D 2 O exchangeable), 8.18 (s, 1H), 8.02 (d, J=8.0 Hz, 2H), 8.00-7.80 (m, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.20 (d, J=3.9 Hz, 1H), 7.05 (s, 1H), 6.91 (s, 2H), 4.98-4.76 (m, 1H, D 2 O exchangeable), 4.34-4.04 (m, 1H), 3.86 (s, 6H), 3.80-3.71 (m, 2H), 3.67 (s, 3H), 3.64-3.55 (m, 1H), 3.47-3.37 (m, 1H), 2.37 (s, 3H), 2.10-1.83 (m, 4H); MS (ES + ) 642.3 (M+Na); (ES−): δ 18.4 (M−1).

Step-3: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (141d)

To a solution of(S)-(1-(7-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (141c) (650 mg, 1.05 mmol) in MeOH/THF (50 mL) was added Cs 2 CO 3 (1025 mg, 3.15 mmol). The resulting mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature, concentrated in vacuum and the resulting residue was dissolved in ethyl acetate, washed with water, brine, filtered and concentrated in vacuum. The residue was purified by chromatography [silica (24 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] then further purified by reverse phase column chromatography [(silica gel C-18 50 g), eluting with CH 3 CN in water (containing 0.1% HCl) from 0-100%] to give (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (141d) (320 mg, 66% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.42 (s, 2H, D 2 O exchangeable), 8.45 (s, 1H), 7.94 (s, 1H), 7.06-6.89 (m, 4H), 4.46-4.24 (m, 4H, 1H is D 2 O exchangeable), 3.88 (s, 6H), 3.68 (s, 3H), 3.64-3.48 (m, 2H), 2.16-1.92 (m, 4H); MS (ES + ) 466.3 (M+1); (ES−) 464.6 (M−1); 500.3 (M+Cl); HPLC purity, 97.94%.

Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (142b)

Step-1: Preparation of (S)-1-(7-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (142a)

Compound 142a was prepared from 2-chloro-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (141b) (150 mg, 0.27 mmol), DIPEA (0.14 mL, 0.81 mmol) and (S)-pyrrolidine-2-carboxamide (93 mg, 0.81 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] (S)-1-(7-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (142a) (80 mg, 47% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.31-9.92 (m, 1H, D 2 O exchangeable), 8.24-8.10 (m, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.90-7.72 (m, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.26-7.15 (m, 1H), 7.15-6.83 (m, 4H), 4.57-4.33 (m, 1H), 3.90 (s, 6H), 3.68 (s, 3H), 3.59-3.46 (m, 1H), 2.37 (s, 3H), 2.05-1.90 (m, 3H), 2.27-2.11 (m, 1H), 1.26-1.11 (m, 2H); MS (ES+): δ 33.3 (M+1); 656.3 (M+Na); (ES−): δ 31.4 (M−1).

Step-2: Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (142b)

Compound 142b was prepared from (S)-1-(7-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (142a) (50 mg, 0.79 mmol), in MeOH/THF (3 mL) using Cs 2 CO 3 (77 mg, 0.24 mmol) according to the procedure reported in step-3 of Scheme 141. This gave after work up and by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%](S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (142b) (28 mg, 74% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.03 (s, 1H, D 2 O exchangeable), 9.68 (s, 1H, D 2 O exchangeable), 8.14 (d, J=1.6 Hz, 1H), 7.96 (s, 1H), 7.14-6.97 (m, 3H), 6.91 (s, 1H), 6.81-6.68 (m, 2H), 4.47 (d, J=8.6 Hz, 1H), 3.92 (s, 7H), 3.69 (s, 3H), 3.64-3.50 (m, 1H), 2.29-2.09 (m, 1H), 2.04-1.81 (m, 3H); MS (ES+): 479.3 (M+1); (ES−): 477.4 (M−1); HPLC purity, 97.22%.

Preparation (S)-1-(8-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (143h)

Step-1: Preparation of isopropyl 3-isopropoxy-2-nitrobenzoate (143b)

To a stirred solution of 3-hydroxy-2-nitro-benzoic acid (143a) (10.0 g, 54.6 mmol) in DMF (40.0 mL) was added at room temperature potassium carbonate (30.14 g, 218 mmol) and isopropyl iodide (13.09 mL, 77.04 mmol). The reaction mixture was stirred at reflux for 4 h and poured into ice-water with vigorous stirring. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers was washed with brine (50.0 mL), dried, filtered and concentrated under vacuum to get afford isopropyl 3-isopropoxy-2-nitrobenzoate (143b) (8 g, 55%) as a brown liquid, which was used as such without further purification; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.90-7.59 (m, 2H), 7.53 (dd, J=7.0, 2.0 Hz, 1H), 5.09 (m, 1H), 4.95-4.57 (m, 1H), 1.26 (dd, J=6.1, 4.0 Hz, 12H); MS (ES+): 268 (M+1).

Step-2: Preparation of 3-isopropoxy-2-nitrobenzoic acid (143c)

To a stirred solution of isopropyl 3-isopropoxy-2-nitrobenzoate (143b) (8.0 g, 29.9 mmol) in methanol (32 mL) was added a solution of sodium hydroxide (5.9 g, 22.07 mmol) in water (32.0 mL) and stirred at room temperature for 5 h. The reaction mixture was acidified with 1 N HCl at 0° C. and the solid obtained was collected by filtration, dried in vacuum oven at 40° C. to get 3-isopropoxy-2-nitrobenzoic acid (143c) (5.5 g, 81%) as an off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.76-7.40 (m, 3H), 4.82 (m, 1H), 1.24 (d, J=6.0 Hz, 6H); MS (ES−): 224.0 (M−1).

Step-3: Preparation of 2-amino-3-isopropoxybenzoic acid (143d)

A solution of 3-isopropoxy-2-nitrobenzoic acid (143c) (5.5 g, 22.22 mmol) in ethanol (60 mL) was added 10% Pd/C (1.0 g, 0.94 mmol) and hydrogenated for 12 h at room temperature using a hydrogen balloon. The reaction mixture was filtered through a Celite bed to remove Pd/C. The filtrate was concentrated to dryness to furnish 2-amino-3-isopropoxybenzoic acid (143d) (3.5 g, 74%) as a yellowish solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.32 (dd, J=8.2, 1.4 Hz, 1H), 6.97 (dd, J=8.0, 1.4 Hz, 1H), 6.48 (t, J=8.0 Hz, 1H), 4.55 (m, 1H), 1.28 (d, J=6.0 Hz, 6H); MS (ES−): 194.0 (M−1).

Step-4: Preparation of 8-isopropoxyquinazoline-2,4-diol (143e)

To a stirred solution of 2-amino-3-isopropoxybenzoic acid (143d) (3.5 g, 17.92 mmol) in acetic acid (96.25 mL) was added urea (14.99 g, 248.08 mmol) and heated at 110° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue was diluted with water (250 mL) and solid obtained was collected by filtration, dried in vacuum to afford 8-isopropoxyquinazoline-2,4-diol (143e) (1.8 g, 42%) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.29 (s, 1H), 10.38 (s, 1H), 7.44 (dd, J=7.9, 1.2 Hz, 1H), 7.36-7.26 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 4.72 (dt, J=12.0, 6.0 Hz, 1H), 1.31 (dd, J=6.1, 1.0 Hz, 6H); MS (ES−): 219.0 (M−1).

Step-5: Preparation of 2,4-dichloro-8-isopropoxyquinazoline (143f)

To a stirred solution of 8-isopropoxyquinazoline-2,4-diol (143e) (1.5 g, 6.81 mmol) in toluene (9 mL) at room temperature was added DIPEA (3.5 mL, 27.08 mmol), POCl 3 (9 mL) and heated at 90° C. for 12 h. The reaction mixture was poured into ice-water with vigorous stirring and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (50.0 mL), dried, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography [silica gel, eluting with ethyl acetate in n-hexane (0-5%)] to furnish 2,4-dichloro-8-isopropoxyquinazoline (143f) (0.8 g, 46%) as a yellowish solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.84-7.74 (m, 2H), 7.67 (q, J=4.7 Hz, 1H), 4.91 (m, 1H), 1.39 (d, J=6.0 Hz, 6H).

Step-6: Preparation of 2-chloro-8-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (143g)

Compound 143g was prepared according to the procedure reported in Scheme 1 from 2,4-dichloro-8-isopropoxyquinazoline (143f) (1.0 g, 3.88 mmol) in IPA (15 mL) using DIPEA (2.03 mL, 15.71 mmol) and 1-(3,4,5-trimethoxy-phenyl)-1H-imidazol-4-ylamine (57a) (0.96 g, 3.88 mmol, free base). This gave after work up 2-chloro-8-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (143g) (600 mg, 33%) as an off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.78 (dd, J=8.1, 1.6 Hz, 1H), 7.47-7.13 (m, 2H), 4.80 (dt, J=19.9, 5.9 Hz, 2H), 4.56 (t, J=5.6 Hz, 1H), 4.09-3.82 (m, 2H), 3.63 (dd, J=5.7, 4.0 Hz, 2H), 2.24-1.93 (m, 3H), 1.82 (td, J=8.8, 8.2, 3.9 Hz, 1H), 1.33 (dd, J=6.0, 2.4 Hz, 6H); MS (ES+): 470.0 (M+1); HPLC purity: 98.63%.

Step-7: Preparation of (S)-1-(8-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (143h)

Compound 143h was prepared according to the procedure reported in step-2 of Scheme 76 from 2-chloro-8-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (143g) (350 mg, 0.74 mmol) and L-prolinamide (0.42 g, 3.71 mmol) in NMP (10 mL). This gave after workup and purification by flash chromatography (silica gel, eluting with 0-40% methanol in DCM) compound (143h) (0.06 g, 15%) as an off-white solid. The white solid was repurified by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water (0-50%)] to afford (S)-1-(8-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (143h) (60 mg) as a yellow HCl salt; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.34 (s, 1H), 10.02 (s, 1H), 8.23 (s, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.99 (s, 1H), 7.11 (d, J=8.9 Hz, 3H), 6.99 (q, J=8.6 Hz, 3H), 4.95-4.76 (m, 1H), 4.58 (d, J=7.6 Hz, 1H), 4.01-3.85 (m, 7H), 3.69 (s, 3H), 3.35-3.29 (m, 1H), 2.37-1.76 (m, 4H), 1.38-1.17 (m, 6H). MS (ES+): 570.3 (M+Na).

Preparation (S)-(1-(8-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (144a)

Compound 144a was prepared according to the procedure reported in step-2 of Scheme 76 from 2-chloro-8-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (143g) (300 mg, 0.63 mmol) and (S)-pyrrolidin-2-ylmethanol (0.64 g, 6.38 mmol) in NMP (10 mL). This gave after workup and purification by flash chromatography (silica gel, eluting with 0-40% methanol in DCM) compound (144a) (70 mg, 20%) as an off-white solid. The solid was repurified by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water (0-50%)] to afford (S)-(1-(8-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (144a) (80 mg) as a yellow HCl salt; 1 H NMR (300 MHz, DMSO-d 6 ) (mixture of rotamers) δ 10.35 and 10.11 (2s, 1H), 8.26 and 8.13 (s, 2H), 8.09 and 8.06 (2s, 1H), 7.12 and 7.10 (2s, 1H), 7.06-6.89 (m, 4H), 4.87-4.61 (m, 1H), 4.23-3.46 (m, 14H), 2.29-1.60 (m, 4H), 1.31 and 1.27 (d, J=6.0 Hz, 6H); MS (ES+): 535.3 (M+1); MS (ES−): 533.4 (M−1). HPLC purity: 96.15%.

Preparation (S)-(1-(7-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (145h)

Step-1: Preparation of isopropyl 4-isopropoxy-2-nitrobenzoate (145b)

Compound 145b was prepared from 4-hydroxy-2-nitrobenzoic acid (145a) (10.0 g, 54.60 mmol) in DMF (40 mL) using potassium carbonate (30.14 g, 218 mmol) and isopropyl iodide (13.09 mL, 77.04 mmol) according to the procedure reported in step-1 of Scheme 143. This gave after workup isopropyl 4-isopropoxy-2-nitrobenzoate (145b) (8 g, 55%) as a brown liquid, which was used as such without further purification; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.83-7.80 (d, 1H), 7.50-7.49 (d, 1H), 7.30-7.26 (m, 1H), 5.06 (m, 1H), 4.81 (m, 1H), 1.30-1.14 (d, 12H); MS ES (+): 268 (M+1).

Step-2: Preparation of 4-isopropoxy-2-nitrobenzoic acid (145c)

Compound 145c was prepared from isopropyl 4-isopropoxy-2-nitrobenzoate (145b) (8.0 g, 29.9 mmol) in methanol (32 mL) and water (32 mL) using sodium hydroxide (5.9 g, 22.07 mmol) according to the procedure reported in step-2 of Scheme 143. This gave after workup 4-isopropoxy-2-nitrobenzoic acid (145c) (5.5 g, 81%) as an off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.88-7.83 (d, 1H). 7.49-7.43 (d, 1H), 7.30-7.26 (m, 1H), 4.84-4.76 (m, 1H), 1.30-1.24 (d, 6H); MS (ES−): 224.0 (M−1).

Step-3: Preparation of 2-amino-4-isopropoxybenzoic acid (145d)

Compound 145d was prepared from 4-isopropoxy-2-nitrobenzoic acid (145c) according to the procedure reported in step-3 of Scheme 143. This gave after workup 2-amino-4-isopropoxybenzoic acid (145d) (3.5 g, 73%) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.55-8.10 (d, 2H), 7.33-7.30 (d, 1H), 6.99-6.66 (d, 1H), 6.50-6.45 (m, 1H), 4.59-4.51 (m, 1H), 1.29-1.27 (d, 6H); MS ES (−): 194.0 (M−1).

Step-4: Preparation of 7-isopropoxyquinazoline-2,4-diol (145e)

Compound 145e was prepared from 2-amino-4-isopropoxybenzoic acid (145d) (3.5 g, 17.92 mmol) in acetic acid (96.25 mL) using urea (14.99 g, 248.08 mmol) according to the procedure reported in step-4 of Scheme 143. This gave 7-isopropoxyquinazoline-2,4-diol (145e) (1.8 g, 46%) as a brown solid; MS (ES−): 219.2 (M−1).

Step-5: Preparation of 2,4-dichloro-7-isopropoxyquinazoline (145f)

Compound 145f was prepared from 7-isopropoxyquinazoline-2, 4-diol (145e) (1.5 g, 6.81 mmol) in toluene (9 mL) using DIPEA (3.5 mL, 27.08 mmol) and POCl 3 (9 mL) according to the procedure reported in step-5 of Scheme 143. This gave after work up and purification by flash column chromatography [silica gel, eluting with ethyl acetate in n-hexane (0-5%)] 2,4-dichloro-7-isopropoxyquinazoline (145f) (0.8 g, 46%) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.17-8.14 (d, 1H), 7.46-7.42 (m, 2H), 4.98-4.94 (m, 1H), 1.41-1.36 (d, 6H); MS (ES+): 258.0 (M+1).

Step-6: Preparation of 2-chloro-7-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (145g)

Compound 145g was prepared according to the procedure reported in Scheme 1 from 2,4-dichloro-7-isopropoxyquinazoline (145f) (1.0 g, 3.88 mmol) in IPA (15 mL) using DIPEA (2.03 mL, 15.71 mmol) and 1-(3,4,5-trimethoxy-phenyl)-1H-imidazol-4-ylamine (57a) (0.96 g, 3.88 mmol). This gave after work up 2-chloro-7-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (145g) (0.6 g, 33%) as an off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.88 (s, 1H), 8.64-8.61 (d, 1H). 8.21-8.20 (d, 1H), 7.95 (s, 1H), 7.17-7.13 (m, 2H), 6.93 (s, 2H), 4.87-4.83 (m, 1H), 3.88 (s, 6H). 3.70 (s, 3H), 1.35-1.33 (d, 6H); MS (ES−): 468.0 (M−1).

Step-7: Preparation of (S)-(1-(7-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (145h)

Compound 145h was prepared according to the procedure reported in step-2 of Scheme 76 from 2-chloro-7-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (145g) (180 mg, 0.38 mmol) and (S)-pyrrolidin-2-ylmethanol (0.38 g, 3.75 mmol) in NMP (10 mL). This gave after workup and purification by flash chromatography (Silica gel, eluting with 0-40% methanol in DCM) compound (145h) (0.11 g, 54%) as an off-white solid. The white solid was repurified by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water (0-50%)] to afford (S)-(1-(7-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidin-2-yl)methanol (145h) (90 mg) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.29 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 6.94 (s, 2H), 6.84-6.61 (m, 2H), 4.73 (p, J=5.9 Hz, 1H), 4.55-4.14 (m, 2H), 3.88 (s, 6H), 3.70 (s, 3H), 3.57-3.18 (m, 3H), 2.06-1.94 (m, 4H), 1.32 (d, J=5.9 Hz, 6H). MS (ES+): 535.4 (M+1); MS (ES−): 533.4 (M−1).

Preparation of 3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)benzamide (146a)

Compound 146a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (84a) (150 mg, 0.36 mmol), using 3-carbamoylphenylboronic acid (89 mg, 0.54 mmol), Pd(Ph 3 P) 4 (83 mg, 0.072 mmol) and potassium carbonate (99 mg, 0.72 mmol) in 1,4-Dioxane and Water (10 mL, 4:1) according to the procedure reported in step-3 of Scheme 77. This gave after workup and filtration followed by drying of solid, 3-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)benzamide (146a) (85 mg, 47% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H, D 2 O exchangeable), 8.95 (s, 1H), 8.60 (d, J=7.9 Hz, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.16-8.08 (m, 2H), 8.00 (d, J=7.7 Hz, 1H), 7.71 (d, J=5.9 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.43 (s, 1H), 7.00 (s, 2H), 3.91 (s, 6H), 3.72 (s, 3H); MS (ES+): 525.3 (M+Na); (ES−): 501.2 (M−1).

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)pyrrolidine-2-carboxamide (147b)

Step-1: Preparation of (S)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (147a) Compound 147a was prepared from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4a) (2 g, 9.75 mmol) in 2-Propanol (20 mL) was added (S)-pyrrolidine-2-carboxamide (1.21 g, 10.64 mmol), DIPEA (5.57 mL, 31.9 mmol) according to the procedure reported in step-1 of Scheme 96. This gave (S)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (147a) (2.2 g, 78% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.85-7.65 (m, 1H), 7.53 (s, 1H), 7.32 (s, 1H), 7.09-6.97 (m, 1H), 6.79-6.64 (m, 1H), 4.65 (dd, J=8.3, 2.9 Hz, 1H), 4.17-3.58 (m, 2H), 2.44-1.75 (m, 4H); MS (ES−): 300.3, 302.3 (M+Cl).

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)pyrrolidine-2-carboxamide (147b)

Compound 147b was prepared from (S)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (147a) (0.3 g, 1.13 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.5 g, 1.3 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 0.08 g, 0.14 mmol), sodium 2-methylpropan-2-olate (0.33 g, 3.39 mmol), Pd 2 (dba) 3 (100 mg, 0.11 mmol) in anhydrous toluene (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel, (12 g) eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%], reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (147b) (0.04 g, 6% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.88 (s, 1H), 7.84-7.47 (m, 2H), 7.47-6.78 (m, 5H), 6.69 (s, 1H), 6.65-6.59 (m, 1H), 4.91-4.78 (m, 1H), 4.47-4.02 (m, 1H), 3.74 (s, 9H), 3.26-2.88 (m, 1H), 2.36-1.56 (m, 4H). MS (ES+): 479.3 (M+1), 501.3 (M+Na); MS (ES−): 513.3 (M+Cl).

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (148b)

Step-1: Preparation of (S)-(1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (148a) Compound 148a was prepared from 2,4-dichlorofuro[3,2-d]pyrimidine (1a) (3 g, 15.87 mmol) in 2-Propanol (30 mL) using (S)-pyrrolidin-2-ylmethanol (1.57 mL, 15.87 mmol), DIPEA (8.32 mL, 47.6 mmol) according to the procedure reported in step-1 of Scheme 96. This gave (S)-(1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (148a) (3.07 g, 76% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.22 (d, J=2.1 Hz, 1H), 6.90 (d, 1H), 4.58-4.19 (m, 1H), 4.03-3.74 (m, 1H), 3.58 (d, J=27.4 Hz, 3H), 1.98 (d, J=27.9 Hz, 4H).

Step-2: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (148b)

Compound 148b was prepared from (S)-(1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (148a) (0.3 g, 1.18 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.34 g, 1.18 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 0.09 g, 0.14 mmol), sodium 2-methylpropan-2-olate (0.34 g, 3.6 mmol), Pd 2 (dba) 3 (0.10 g, 0.11 mmol) in anhydrous toluene (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel, (12 g) eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%], reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (148b) (80 mg, 14% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.85 (s, 1H), 8.81-8.66 (m, 1H), 8.37 (d, J=7.2 Hz, 1H), 7.96-7.82 (m, 1H), 7.08 (s, 1H), 7.03 (s, 2H), 4.62 (m, 1H), 4.20-3.42 (m, 13H), 2.26-1.86 (m, 4H); MS (ES+): 467.3 (M+1), 489.3 (M+Na); MS (ES−): 501.3 (M+Cl).

Preparation of (S)-(1-(6-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (149c)

Step-1: Preparation of 6-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (149b)

Compound 149b was prepared according to the procedure reported in Scheme 1 from 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (149a) (1 g, 3.4 mmol) in 2-Propanol (15 mL) using DIPEA (2.38 mL, 13.6 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (1.17 g, 4.08 mmol). This gave 6-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (149b) (320 mg, 19% yield) as a buff colored solid; 1 H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.14 (d, J=1.3 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.37 (d, J=8.2 Hz, 4H), 7.29 (d, J=7.0 Hz, 1H), 6.94-6.83 (m, 2H), 3.86 (d, J=1.2 Hz, 6H), 3.73 (s, 2H), 3.68 (d, J=1.1 Hz, 3H), 3.51 (s, 2H), 2.72 (s, 4H); MS (ES+): 507.3 (M+1), (ES−): 541.4 (M+Cl).

Step-2: Preparation of (S)-(1-(6-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (149c)

Compound 149c was prepared from 6-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (149b) (120 mg, 0.24 mmol), (S)-pyrrolidin-2-ylmethanol (72 mg, 0.71 mmol) in 2-Propanol (2 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (12 g), eluting with DMA 80 in dichloromethane (0 to 40%)], (S)-(1-(6-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (149c) (131 mg, 97% yield) as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.67 (s, 1H, D 2 O exchangeable), 8.15 (s, 1H), 7.91 (s, 1H), 7.51-7.09 (m, 5H), 6.90 (s, 2H), 5.31-4.80 (m, 1H, D 2 O exchangeable), 4.13 (d, J=19.8 Hz, 1H), 3.86 (s, 7H), 3.79-3.51 (m, 8H), 3.45 (s, 2H), 2.64 (d, J=5.3 Hz, 2H), 2.61-2.50 (m, 2H), 2.03-1.75 (m, 4H); MS (ES+): 572.4 (M+1), 594.4 (M+Na), (ES−): 570.5 (M−1).

Preparation of (S)-(1-(5-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)pyrrolidin-2-yl)methanol (150c)

Step-1: Preparation of (S)-(1-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)pyrrolidin-2-yl)methanol (150b) Compound 150b was prepared from 5,7-dichlorothiazolo[5,4-d]pyrimidine (150a) (500 mg, 15.87 mmol; CAS #13479-88-4) in 2-Propanol (10 mL) using (S)-pyrrolidin-2-ylmethanol (0.24 mL, 2.43 mmol), DIPEA (1.27 mL, 7.28 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after work up and purification by flash column chromatography [silica gel, (12 g) eluting with MeOH in CH 2 Cl 2 from 0 to 30%] (S)-(1-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)pyrrolidin-2-yl)methanol (150b) (0.33 g, 50% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.17 (d, J=13.2 Hz, 1H), 5.04 (q, J=5.5, 5.0 Hz, 1H), 4.85 (t, J=5.7 Hz, 1H), 4.40 (dt, J=10.4, 4.6 Hz, 1H), 4.23-3.96 (m, 1H), 3.75-3.49 (m, 2H), 2.20-1.83 (m, 4H). MS (ES+): 293.2 (M+Na).

Step-2: Preparation of (S)-(1-(5-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)pyrrolidin-2-yl)methanol (150c)

Compound 150c was prepared from (S)-(1-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)pyrrolidin-2-yl)methanol (150b) (0.15 g, 0.55 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.19 g, 0.67 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 0.04 g, 0.07 mmol), sodium 2-methylpropan-2-olate (0.16 g, 1.66 mmol), Pd 2 (dba) 3 (0.05 g, 0.06 mmol) in anhydrous toluene (7 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%], reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-(1-(5-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)pyrrolidin-2-yl)methanol (150c) (0.03 g, 10% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.14 (s, 1H), 9.20 (s, 1H), 8.90 (s, 1H), 7.93 (s, 1H), 7.12 (s, 2H), 5.19-4.98 (m, 1H), 4.70-4.47 (m, 1H), 4.31-4.14 (m, 1H), 4.13-3.96 (m, 1H), 3.94-3.55 (m, 11H), 2.15-1.81 (m, 4H); MS (ES+): 484.3 (M+1); MS (ES−): 518.3 (M+Cl). HPLC purity: 95.61%.

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (151b)

Step-1: Preparation of (S)-1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (151a) Compound 151a was prepared from 2,4-dichlorofuro[3,2-d]pyrimidine (1a) (800 mg, 4.23 mmol) in 2-Propanol (16 mL) using (S)-pyrrolidine-2-carboxamide (482 mg, 4.23 mmol), DIPEA (2.21 mL, 12.69 mmol) according to the procedure reported in step-1 of Scheme 96. This gave (S)-1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (151a) (600 mg, 53% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) (mixture of rotamers) δ 8.33, 8.25 (2s, 1H), 7.58, 7.53 (2s, 1H), 7.13, 7.05 (2s, 1H), 6.96 (2s, 1H), 4.87, 4.52 (2d, J=8.4 Hz, 1H), 4.18-3.86 (m, 1H), 3.81-3.52 (m, 1H), 2.38-1.70 (m, 4H); MS (ES+): 267.3 (M+1), (ES−): 301.2, 303.2 (M+Cl).

Step-2: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (151b)

Compound 151b was prepared from (S)-1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (151a) (0.3 g, 1.13 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (0.32 g, 1.13 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 100 mg, 0.11 mmol), sodium 2-methylpropan-2-olate (0.32 g, 3.37 mmol), Pd 2 (dba) 3 (100 mg, 0.11 mmol) in anhydrous toluene (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel, (12 g) eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%], reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] followed by lyophilization (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (151b) (60 mg, 10% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) (mixture of two rotamers) δ 10.94 and 10.78 (2s, 1H), 8.79 and 8.68 (2s, 1H), 8.43 and 8.33 (2d, J=2.1 Hz, 1H), 7.94 and 7.79 (2s, 1H), 7.60 and 7.26 (2s, 1H), 7.21 and 7.14 (2s, 2H), 7.10 and 7.09 (2s, 1H), 7.07-7.02 (m, 1H), 5.09-5.01 and 4.80-4.68 (2m, 1H), 4.40-4.26 (m, 1H), 4.12-3.99 (m, 1H), 3.92 and 3.88 (2s, 6H), 3.69 (s, 3H), 2.43-1.84 (m, 4H); MS (ES+): 480.3 (M+1); MS (ES−): 478.4 (M−1).

Preparation of (S)-1-(6-benzyl-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (152a)

Compound 152a was prepared from 6-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (149b) (120 mg, 0.24 mmol), (S)-pyrrolidine-2-carboxamide (81 mg, 0.71 mmol) in 2-Propanol (3 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (12 g), eluting with DMA 80 in dichloromethane (0 to 40%)], (S)-1-(6-benzyl-4-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-ylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (152a) (90 mg, 65% yield) as a light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.46 (s, 1H, D 2 O exchangeable), 8.12 (s, 1H), 7.97-7.72 (m, 1H), 7.49-7.24 (m, 5H), 7.20-6.98 (m, 2H), 6.95-6.80 (m, 2H), 4.39 (d, J=8.6 Hz, 1H), 3.99-3.84 (m, 7H), 3.83-3.76 (m, 1H), 3.78-3.63 (m, 3H), 3.55-3.41 (m, 3H), 3.42-3.32 (m, 1H), 2.78-2.56 (m, 4H), 2.30-2.02 (m, 1H), 2.02-1.76 (m, 3H); MS (ES+): 585.4 (M+1), (ES−): 583.4 (M−1).

Preparation of (S)-(1-(7-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (153c)

Step-1: Preparation of 7-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (153b)

Compound 153b was prepared according to the procedure reported in Scheme 1 from 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (153a) (1 g, 3.4 mmol; CAS #1059735-34-0) in 2-Propanol (15 mL) using DIPEA (2.38 mL, 13.6 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (1.17 g, 4.08 mmol). This gave 7-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (153b) (350 mg, 20% yield) as a buff colored solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.56 (s, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.78 (s, 1H), 7.45-7.23 (m, 5H), 6.90 (s, 2H), 3.86 (s, 6H), 3.68 (s, 3H), 3.67 (s, 2H), 3.39 (s, 2H), 2.78-2.68 (m, 2H), 2.68-2.58 (m, 2H); MS (ES+): 507.3 (M+1), 529.3 (M+Na), (ES−): 541.4 (M+Cl).

Step-2: Preparation of (S)-(1-(7-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (153c)

Compound 153c was prepared from 7-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (153b) (150 mg, 0.296 mmol), (S)-pyrrolidin-2-ylmethanol (90 mg, 0.89 mmol) in 2-Propanol (2 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel (25 g), eluting with DMA 80 in dichloromethane (0 to 40%)], (S)-(1-(7-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (153c) (110 mg, 65% yield) as an orange solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.65 (s, 1H, D 2 O exchangeable), 8.17 (s, 1H), 7.92 (s, 1H), 7.45-7.14 (m, 5H), 6.91 (s, 2H), 5.01 (s, 1H, D 2 O exchangeable), 4.33-3.97 (m, 1H), 3.67 (s, 3H), 3.63 (s, 2H), 3.32 (d, J=1.7 Hz, 4H), 3.22 (s, 2H), 2.69 (q, J=5.6 Hz, 2H), 2.56 (d, J=5.5 Hz, 2H), 2.02-1.72 (m, 4H); MS (ES+) 572.4 (M+1), 594.5 (M+Na), (ES−): 570.4 (M−1), 606.6 (M+Cl).

Preparation of (S)-1-(7-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (154a)

Compound 154a was prepared from 7-benzyl-2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (153b) (150 mg, 0.3 mmol), (S)-pyrrolidine-2-carboxamide (101 mg, 0.89 mmol) in 2-Propanol (4 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (12 g), eluting with DMA 80 in dichloromethane (0 to 40%)], (S)-1-(7-benzyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (154a) (100 mg, 58% yield) as an orange solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.44 (s, 1H, D 2 O exchangeable), 8.14 (s, 1H), 7.85 (s, 1H), 7.42-7.23 (m, 5H), 7.08 (s, 2H), 6.90 (s, 2H), 4.36 (s, 1H), 3.91 (s, 6H), 3.83-3.74 (m, 1H), 3.68 (s, 3H), 3.66-3.55 (m, 2H), 3.55-3.35 (m, 1H), 3.23 (s, 2H), 2.69 (d, J=6.3 Hz, 2H), 2.57 (d, J=5.4 Hz, 2H), 2.15 (s, 1H), 1.91 (d, J=14.8 Hz, 3H); MS (ES+): 585.4 (M+1), 607.4 (M+Na), (ES−): 583.4 (M−1).

Preparation (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (155a)

Compound 155a was prepared according to the procedure reported in step-2 of Scheme 76 from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (84a) (800 mg, 1.91 mmol), (S)-pyrrolidine-2-carboxamide (2.18 g, 19.1 mmol) and DIPEA (0.627 mL, 3.59 mmol) in NMP (40 mL). This gave after workup and purification by flash chromatography (Silica gel, eluting with 0-10% methanol in DCM) compound (155a) (0.43 g, 44%) as an off-white solid. The solid was repurified by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water (0-50%)] to afford (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (155a) (232 mg) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.29 (s, 1H), 8.43 (s, 1H), 7.99 (d, J=5.8 Hz, 1H), 7.90 (s, 1H), 7.53 (s, 1H), 7.40 (d, J=5.7 Hz, 1H), 7.17 (s, 1H), 7.14 (s, 2H), 4.62 (d, J=8.6 Hz, 1H), 3.94 (s, 7H), 3.69 (s, 3H), 3.66-3.51 (m, 1H), 2.38-1.86 (m, 4H). MS (ES+): 496.3 (M+1); MS (ES−): 494.4 (M−1), 530.3 (M+Cl).

Preparation of 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (156a)

Compound 156a 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) (150 mg, 0.37 mmol), pyrrolidine (0.09 mL, 1.12 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (12 g), eluting with DMA 80 in dichloromethane (0 to 30%)], 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (156a) (0.03 g, 19% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.56 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.39 (t, J=1.9 Hz, 1H), 7.11 (dd, J=4.5, 1.7 Hz, 1H), 6.93 (s, 2H), 6.39 (dd, J=4.4, 2.4 Hz, 1H), 3.87 (s, 6H), 3.69 (s, 3H), 3.55 (d, J=6.2 Hz, 4H), 1.91 (q, J=3.5 Hz, 4H). MS (ES+): 436.4 (M+1).

Preparation of 2-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)benzamide (157a)

Compound 157a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine (84a) (150 mg, 0.36 mmol), using 2-carbamoylphenylboronic acid (89 mg, 0.54 mmol), Pd(Ph 3 P) 4 (83 mg, 0.072 mmol) and potassium carbonate (99 mg, 0.72 mmol) in 1,4-Dioxane and Water (10 mL, 4:1) according to the procedure reported in step-3 of Scheme 77. This gave after workup and filtration followed by drying of solid, 2-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)benzamide (157a) (23 mg, 13% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.22 (d, J=1.5 Hz, 2H, D 2 O exchangeable), 8.10 (d, J=6.0 Hz, 1H), 7.95-7.87 (m, 1H), 7.71-7.64 (m, 1H), 7.57-7.40 (m, 4H), 7.33-7.18 (m, 1H), 7.16 (s, 2H), 3.91 (s, 6H), 3.68 (s, 3H); MS (ES+): 503.3 (M+1); 525.2 (M+Na); (ES−) 501.3 (M−1).

Preparation of (S)-1-(7-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-2-carboxamide (158b)

Step-1: Preparation of 5-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thiazolo[5,4-d]pyrimidin-7-amine (158a)

Compound 158a was prepared according to the procedure reported in Scheme 1 from 5,7-dichlorothiazolo[5,4-d]pyrimidine (150a) (0.3 g, 1.46 mmol) in 2-Propanol (10 mL) using DIPEA (0.76 mL, 4.37 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (0.46 g, 1.6 mmol, free base). This gave after workup and purification by flash column chromatography [silica gel, (40 g) eluting with methanol in DCM (0 to 30%)] 5-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thiazolo[5,4-d]pyrimidin-7-amine (158a) (0.41 g, 67% yield) as a brown solid; MS (ES+): 441.2 & 443.2 (M+Na); MS (ES−): 417.3 (M−1).

Step-2: Preparation of (S)-1-(7-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-2-carboxamide (158b)

Compound 158b was prepared from 5-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thiazolo[5,4-d]pyrimidin-7-amine (158a) (0.07 g, 0.16 mmol), (S)-pyrrolidine-2-carboxamide (0.05 g, 0.47 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (25 g), eluting with DMA 80 in dichloromethane (0 to 30%)], (S)-1-(7-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-2-carboxamide (158b) (0.04 g, 52% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): (a mixture of two rotamers) δ 9.79 and 9.26 (2s, 1H), 8.85 and 8.52 (2s, 1H), 8.18 and 8.09 (2s, 1H), 7.90 (s, 1H), 7.46-6.79 (m, 4H), 4.56-4.37 and 4.36-4.29 (2m, 1H), 3.91 (s, 7H), 3.72 and 3.69 (2s, 3H), 3.62-3.48 (m, 1H), 2.37-1.83 (m, 4H). MS (ES+): 497.3 (M+1); MS (ES−): 531.3 (M+Cl).

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159c)

Step-1: Preparation of (S)-(1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159a)

Compound 159a was prepared from 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (141a) (1 g, 2.92 mmol) in 2-Propanol (10 mL), (S)-pyrrolidin-2-ylmethanol (0.3 gm, 2.92 mmol), DIPEA (0.77 mL, 4.38 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] (S)-(1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159a) (865 mg, 73% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.96 (d, J=8.2 Hz, 2H), 7.58 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 6.88 (s, 1H), 5.10-4.66 (m, 1H, D 2 O exchangeable), 4.28 (s, 1H), 3.90-3.35 (m, 4H), 2.37 (s, 3H), 2.12-1.81 (m, 4H); MS (ES + ) 407.3 (M+1); (ES−) 441.2 (M+Cl).

Step-2: Preparation of (S)-(1-(7-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159b)

Compound 159b was prepared from (S)-(1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159a) (620 mg, 1.52 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (1085 mg, 3.05, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 327 mg, 0.69 mmol), cesium carbonate (1241 mg, 3.81 mmol), Pd 2 (dba) 3 (209 mg, 0.23 mmol) in toluene and t-BuOH (20 mL, 5:1) according to the procedure reported in step-3 of Scheme 101. This gave after workup and twice purification by flash column chromatography [silica (40 g), eluting with DMA80 in DCM from 0-60%], [silica (24 g), eluting with MeOH in DCM from 0-10%] (S)-(1-(7-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159b) (198 mg, 21% yield) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.33 (s, 1H, D 2 O exchangeable), 8.68-8.24 (m, 1H), 8.21 (s, 1H), 8.04 (s, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.25 (d, J=3.8 Hz, 1H), 6.97 (s, 2H), 6.72 (d, J=4.1 Hz, 1H), 5.04-4.55 (m, 1H, D 2 O exchangeable), 4.56-4.15 (m, 1H), 3.82 (s, 6H), 3.78-3.71 (m, 1H), 3.67 (s, 3H), 3.64-3.47 (m, 3H), 2.30 (s, 3H), 2.13-1.77 (m, 4H); MS (ES+): δ 20.8 (M+1); 642.4 (M+Na); (ES−): 618.4 (M−1).

Step-3: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159c)

Compound 159c was prepared from (S)-(1-(7-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159b) (150 mg, 0.24 mmol) and Cs 2 CO 3 (237 mg, 0.73 mmol) in MeOH/THF (5 mL, 3:2) according to the procedure reported in step-3 of Scheme 141. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] followed by prep-HPLC [(silica gel C-18, 24 g) eluting with ACN in water (contains 0.1% HCl) from 0-100%], (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (159c) (26 mg, 23% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.00 (s, 1H, D 2 O exchangeable), 10.40 (s, 1H, D 2 O exchangeable), 8.37 (s, 1H), 7.67 (s, 1H), 7.16-7.03 (m, 1H), 6.97 (s, 2H), 6.72-6.62 (m, 1H), 4.73-4.38 (m, 2H, D 2 O exchangeable), 4.06-3.93 (m, 2H), 3.88 (s, 6H), 3.69 (s, 3H), 3.61-3.53 (m, 2H), 2.22-1.92 (m, 4H); MS (ES+): 466.3 (M+1), 488.4 (M+Na); (ES−): 464.4 (M−1), 500.3 (M+Cl).

Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (160d)

Step-1: Preparation of 2-chloro-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (160b)

Compound 160b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidine (160a) (3 g, 8.77 mmol, prepared according to procedure reported by Su, Qibin et al; Journal of Medicinal Chemistry, 57(1), 144-158; 2014) in 2-Propanol (5 mL) using DIPEA (4.59 mL, 26.3 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine hydrochloride (57a) (4.17 g, 13.15 mmol). This gave after filtration 2-chloro-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (160b) (1.03 g, 21% yield) as white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.26 (d, J=3.7 Hz, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.86-7.74 (m, 3H), 7.46 (d, J=8.1 Hz, 2H), 6.98-6.90 (m, 3H), 3.89 (s, 6H), 3.72 (s, 3H), 2.34 (s, 3H); MS (ES+): 555.2 (M+1); 577.2 (M+Na).

Step-2: Preparation of (S)-(1-(5-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (160c)

Compound 160c was prepared from 2-chloro-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (160b) (400 mg, 0.72 mmol), (S)-pyrrolidin-2-ylmethanol (219 mg, 2.16 mmol) and DIPEA (0.378 mL, 2.162 mmol) in NMP (5 mL) according to the procedure reported in step-2 of Scheme 76. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] (S)-(1-(5-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (160c) (166 mg, 37% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.57 (s, 1H, D 2 O exchangeable), 8.22 (s, 1H), 7.88 (d, J=3.7 Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 6.95 (s, 2H), 6.64 (d, J=3.7 Hz, 1H), 4.93-4.80 (m, 1H, D 2 O exchangeable), 4.25 (s, 1H), 3.88 (s, 6H), 3.69 (s, 5H), 3.34-3.21 (m, 4H), 2.32 (s, 3H), 2.05-1.79 (m, 4H); MS (ES+): δ 20.4 (M+1); 642.3 (M+Na); (ES−): δ 18.3 (M−1).

Step-3: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (160d)

Compound 160d was prepared from (S)-(1-(5-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (160c) (120 mg, 0.19 mmol) and Cs 2 CO 3 (189 mg, 0.58 mmol) in MeOH/THF (5 mL, 3:2) according to the procedure reported in step-3 of Scheme 141. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-100%] (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (160d) (38 mg, 42% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.62 (s, 1H, D 2 O exchange), 9.69 (s, 1H, D 2 O exchange), 8.18 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.34 (t, J=2.9 Hz, 1H), 6.93 (s, 2H), 6.10 (d, J=2.5 Hz, 1H), 4.27-4.15 (m, 1H), 3.87 (s, 6H), 3.78-3.62 (m, 5H), 3.62-3.51 (m, 1H), 3.40-3.32 (m, 2H), 1.95-1.89 (m, 4H); MS (ES+): 466.4 (M+1); (ES−): 464.4 (M−1).

Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (161a)

Compound 161a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (140b) (0.06 g, 0.15 mmol), (S)-pyrrolidine-2-carboxamide (0.05 g, 0.47 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%] (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (161a) (26 mg, 37% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): (a mixture of two rotamers) δ 9.43 and 9.26 (2s, 1H), 8.47 and 8.46 (2s, 1H), 8.23 (s, 1H), 8.11 and 7.98 (2s, 1H), 7.83 and 7.80 (s, 1H), 7.71-7.59 (m, 1H), 7.37 and 7.28 (2s, 1H), 7.18-6.84 (m, 3H), 4.52 and 4.33 (2d, J=8.8 Hz, 1H), 3.94 and 3.89 (2s, 6H), 3.83-3.57 (m, 5H), 2.38-2.19 and 2.08-1.87 (2m, 4H); MS (ES+): 491.3 (M+1), MS (ES−): 525.3 (M+Cl).

Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (162b)

Step-1: Preparation of (S)-1-(5-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (162a)

Compound 162a was prepared from 2-chloro-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (160b) (327 mg, 0.59 mmol), (S)-pyrrolidine-2-carboxamide (269 mg, 2.36 mmol) in NMP (5 mL) according to the procedure reported in Scheme 2. This gave after workup and twice purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%]; [silica (12 g), eluting with MeOH in DCM from 0-20%] (S)-1-(5-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (162a) (162 mg, 44% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.60 (s, 1H, D 2 O exchangeable), 8.20 (s, 1H), 8.00-7.77 (m, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.30-6.80 (m, 4H; 2H, D 2 O exchangeable), 6.68 (s, 1H), 4.51-4.30 (m, 1H), 4.04-3.74 (m, 8H), 3.69 (s, 3H), 2.32 (s, 3H), 2.24-2.06 (m, 1H), 2.01-1.79 (m, 3H); MS (ES+): δ 33.2 (M+1); 655.2 (M+Na); (ES−): δ 31.5 (M−1).

Step-2: Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (162b)

Compound 162b was prepared from (S)-1-(5-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (162a) (130 mg, 0.21 mmol) and Cs 2 CO 3 (201 mg, 0.62 mmol) in MeOH/THF (5 mL, 3:2) according to the procedure reported in step-3 of Scheme 141. This gave after workup and purification twice by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-100%], [silica (12 g), eluting with DMA-80 in DCM from 0-60%], followed by conversion of free base to HCl salt using 1 N HCl (2 mL) in CH 3 CN, (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (162b) (30 mg, 31% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.52 (s, 1H, D 2 O exchangeable), 12.02 (s, 1H, D 2 O exchangeable), 11.14 (s, 1H, D 2 O exchangeable), 8.29 (s, 1H), 7.84 (s, 1H), 7.67-7.59 (m, 1H), 7.56 (s, 1H, D 2 O exchangeable), 7.26-7.16 (m, 1H, D 2 O exchangeable), 7.12 (s, 2H), 6.41 (s, 1H), 4.61 (d, J=8.9 Hz, 2H), 4.52 (brs, 2H, D 2 O exchangeable), 3.93 (s, 6H), 3.69 (s, 3H), 3.62-3.49 (m, 1H), 2.36-2.24 (m, 1H), 2.13-1.97 (m, 3H); MS (ES+): 479.4 (M+1), 501.3 (M+Na); (ES−): 513.3 (M+Cl).

Preparation of 2-(pyrrolidin-1-yl)-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (163a)

Compound 163a was prepared from 2-chloro-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (141b) (80 mg, 0.14 mmol), pyrrolidine (62 mg, 0.87 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] 2-(pyrrolidin-1-yl)-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (163a) (65 mg, 76% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.15 (s, 1H, D 2 O exchangeable), 8.18 (s, 1H), 8.05-7.96 (m, 3H), 7.43 (d, J=8.1 Hz, 2H), 7.18 (d, J=4.0 Hz, 1H), 7.02 (d, J=4.0 Hz, 1H), 6.89 (s, 2H), 3.85 (s, 6H), 3.75-3.50 (m, 7H), 2.36 (s, 3H), 2.02-1.87 (m, 4H); MS (ES+): 590.3 (M+1); 612.3 (M+Na); (ES−): 588.5 (M−1).

Preparation of (S)-(1-(7-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (164a)

Compound 164a was prepared from 5-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thiazolo[5,4-d]pyrimidin-7-amine (158a) (120 mg, 0.29 mmol), (S)-pyrrolidin-2-ylmethanol (0.09 mL, 0.86 mmol), DIPEA (0.15 mL, 0.86 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%](S)-(1-(7-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (164a) (31 mg, 23% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.84-9.29 (m, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 8.10-7.78 (m, 1H), 6.96 (s, 2H), 5.08-4.61 (m, 1H), 4.46-4.05 (m, 1H), 4.01-3.22 (m, 13H), 2.11-1.78 (m, 4H); MS (ES+): 484.3 (M+1); MS (ES−): 482.3 (M−1); 518.2 (M+Cl). HPLC purity: 94.37%.

Preparation of (S)-(1-(7-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (165b)

Step-1: Preparation of (S)-(1-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (165a)

Compound 165a was prepared from 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (153a) (1 g, 3.4 mmol) in 2-Propanol (5 mL), (S)-pyrrolidin-2-ylmethanol (344 mg, 3.4 mmol), DIPEA (0.89 mL, 5.1 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA-80 in dichloromethane] (S)-(1-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (165a) (1.13 g, 93% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.45-7.17 (m, 5H), 4.71 (t, J=5.9 Hz, 1H, D 2 O exchangeable), 4.40-4.23 (m, 1H), 3.76-3.56 (m, 4H), 3.56-3.42 (m, 2H), 3.43-3.26 (m, 1H), 3.21 (d, J=17.3 Hz, 1H), 3.03-2.78 (m, 2H), 2.76-2.57 (m, 1H), 2.41-2.24 (m, 1H), 1.99-1.83 (m, 3H), 1.81-1.69 (m, 1H).

Step-2: Preparation of (S)-(1-(7-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (165b)

Compound 165b was prepared from (S)-(1-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (165a) (300 mg, 0.84 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (313 mg, 1.25 mmol, free base), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 104 mg, 0.167 mmol), cesium carbonate (817 mg, 2.51 mmol) and Pd 2 (dba) 3 (115 mg, 0.125 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%] followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-(1-(7-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (165b) (235 mg, 49% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.74-11.60 (m, 1H, D 2 O exchangeable), 10.20 (s, 1H, D 2 O exchangeable), 8.71 (s, 1H), 7.88-7.59 (m, 3H), 7.59-7.36 (m, 3H), 7.02 (s, 2H), 4.58 (s, 1H), 4.50 (s, 2H), 4.33-4.03 (m, 2H), 3.87 (s, 6H), 3.69 (s, 3H), 3.67-3.53 (m, 2H), 3.53-3.39 (m, 2H), 3.39-3.22 (m, 2H), 3.26-2.92 (m, 1H), 2.11-1.76 (m, 4H); MS (ES+): 572.4 (M+1), 594.3 (M+Na).

Preparation of (S)-1-(7-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (166b)

Step-1: Preparation of (S)-1-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (166a)

Compound 166a was prepared from 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (153a) (1 g, 3.4 mmol) in 2-Propanol (5 mL), (S)-pyrrolidine-2-carboxamide (388 mg, 3.4 mmol), DIPEA (0.89 mL, 5.1 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA-80 in dichloromethane] (S)-1-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (166a) (1.1 g, 87% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.43-7.24 (m, 6H), 6.94 (s, 1H), 4.60-4.46 (m, 1H), 3.97-3.70 (m, 2H), 3.63 (s, 2H), 3.49-3.23 (m, 2H), 2.98-2.84 (m, 3H), 2.78-2.60 (m, 1H), 2.21-2.04 (m, 1H), 1.96-1.72 (m, 3H).

Step-2: Preparation of (S)-1-(7-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (166b)

Compound 166b was prepared from (S)-1-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (166a) (400 mg, 1.07 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (402 mg, 1.61, free base), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 134 mg, 0.21 mmol), cesium carbonate (1.05 g, 3.23 mmol) and Pd 2 (dba) 3 (148 mg, 0.161 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%] followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-1-(7-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (166b) (105 mg, 17% yield) light yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.25 (s, 1H, D 2 O exchangeable), 10.11 (s, 1H, D 2 O exchangeable), 8.91 (s, 1H), 7.89 (s, 1H, D 2 O exchangeable), 7.74 (dd, J=6.5, 2.9 Hz, 2H), 7.63-7.44 (m, 5H), 7.24 (s, 2H), 7.11 (s, 1H, D 2 O exchangeable), 4.74-4.59 (m, 1H), 4.51 (s, 2H), 4.36-3.97 (m, 4H), 3.91 (s, 6H), 3.82-3.47 (m, 5H), 3.47-3.00 (m, 4H), 2.38-2.11 (m, 1H), 2.08-1.69 (m, 3H); FREE BASE 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 7.39-7.24 (m, 5H), 7.21 (s, 1H), 7.10 (s, 2H), 6.92 (s, 1H), 4.72-4.58 (m, 1H), 4.07-3.89 (m, 2H), 3.90 (s, 6H), 3.67 (s, 3H), 3.62 (s, 2H), 3.42 (d, J=16.5 Hz, 1H), 3.16 (d, J=16.6 Hz, 1H), 2.87 (d, J=10.1 Hz, 2H), 2.46-2.34 (m, 1H), 2.29-2.07 (m, 1H), 1.99-1.72 (m, 4H); MS (ES+): 585.4 (M+1), (ES−): 619.5 (M+Cl).

Preparation of (S)-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2,3-dimethoxybenzonitrile (167f)

Step-1: Preparation of 5-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2,3-dimethoxybenzonitrile (167e)

Compound 167e was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4a) (670 mg, 2.38 mmol) in DCM (20 mL) using DIPEA (1.38 g, 10.72 mmol) and 5-(4-amino-1H-imidazol-1-yl)-2,3-dimethoxybenzonitrile hydrochloride (167d) (1.0 g, 5.31 mmol). This gave after workup 5-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2,3-dimethoxybenzonitrile (167e) (1.03 g, 21% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.66 (s, 1H), 9.22 (m, 1H), 7.92 (s, 2H), 7.83 (s, 2H), 7.35-7.34 (s, 1H), 6.79 (s, 1H) 3.92 (s, 3H), 3.90 (s, 3H).

Step-2: Preparation of (S)-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2,3-dimethoxybenzonitrile (167f)

Compound 167f was prepared from 5-(4-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2,3-dimethoxybenzonitrile (167e) (300 mg, 0.76 mmol), (S)-pyrrolidin-2-ylmethanol (770 mg, 7.58 mmol) in NMP (12 mL) according to the procedure reported in step-2 of Scheme 76. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with methanol in ethyl acetate 0-10%] (S)-5-(4-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-imidazol-1-yl)-2,3-dimethoxybenzonitrile (167f) (50 mg, 14% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.66 (s, 1H), 7.92 (s, 2H), 7.45 (t, J=2.1 Hz, 1H), 6.97 (dd, J=4.5, 1.6 Hz, 1H), 6.48 (dd, J=4.5, 2.5 Hz, 1H), 4.64 (t, J=4.8 Hz, 1H), 4.12-4.01 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.66-3.56 (m, 1H), 3.55-3.38 (m, 3H), 2.08-1.74 (m, 4H).

Preparation of 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (168b)

Step-1: Preparation of 2-chloro-4-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine (168a)

Compound 168a was prepared from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4a) (1.02 g, 5.44 mmol) in 2-Propanol (30 mL), pyrrolidine (0.49 mL, 5.98 mmol), TEA (1.52 mL, 10.87 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA-80 in dichloromethane] 2-chloro-4-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine (168a) (550 mg, 45% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.69 (dd, J=2.7, 1.5 Hz, 1H), 6.96 (dd, J=4.6, 1.6 Hz, 1H), 6.66 (dd, J=4.6, 2.7 Hz, 1H), 3.93 (t, J=6.9 Hz, 2H), 3.64 (t, J=6.8 Hz, 2H), 2.05 (p, J=6.8 Hz, 2H), 1.90 (p, J=6.8 Hz, 2H).

Step-2: Preparation of 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (168b)

Compound 168b was prepared from 2-chloro-4-(pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine (168a) (0.5 g, 2.25 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (840 mg, 3.37, free base), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 280 mg, 0.45 mmol), cesium carbonate (2195 mg, 6.74 mmol) and Pd 2 (dba) 3 (308 mg, 0.34 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification twice by flash column chromatography [silica (40 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%], [silica (25 g), eluting with (9:1) ethyl acetate/methanol in hexane from 0 to 100%], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (168b) (21 mg, 2% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.55 (t, J=2.0 Hz, 1H), 6.89 (s, 2H), 6.75 (dd, J=4.5, 1.6 Hz, 1H), 6.46 (dd, J=4.5, 2.5 Hz, 1H), 3.88 (s, 6H), 3.83-3.71 (m, 4H), 3.68 (s, 3H), 2.15-1.85 (m, 4H); MS (ES+): 436.3 (M+1), 458.3 (M+Na).

Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (169c)

Step-1: Preparation of 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine (169b)

Compound 169b was prepared according to the procedure reported in Scheme 1 from 2,4-dichloropyrido[2,3-d]pyrimidine (169a) (0.5 g, 2.5 mmol; CAS #126728-20-9) in 2-Propanol (10 mL) using DIPEA (1.31 mL, 7.5 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (0.86 g, 3.0 mmol). This gave after workup and purification by flash column chromatography [silica gel, (40 g) eluting with methanol in DCM (0 to 30%)] 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine (169b) (0.7 g, 68% yield) as a brown solid; MS (ES+): 435.7 (M+Na); MS (ES−): 411.3 & 413.3 (M−1).

Step-2: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (169c)

Compound 169c was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine (169b) (0.15 g, 0.36 mmol), (S)-pyrrolidin-2-ylmethanol (0.11 mL, 1.09 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (25 g), eluting with DMA-80 in dichloromethane (0 to 30%)], (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (169c) (06 mg, 35% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): (as a mixture of two rotamers) 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.70 and 10.49 (s, 1H), 8.88 and 8.86 (2d, J=2.0 Hz, 1H), 8.71-8.63 (m, 1H), 8.32-8.23 (m, 1H), 8.13 and 8.04 (2s, 1H), 7.16-7.02 (m, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 5.72-5.59 and 5.01-4.88 (2m, 1H), 4.54-4.40 and 4.33-4.17 (2m, 1H), 3.99-3.35 (m, 13H), 2.14-1.79 (m, 4H); MS (ES+): 478.3 (M+1); MS (ES−): 512.3 (M+Cl).

Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (170a)

Compound 170a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine (169b) (0.15 g, 0.36 mmol), (S)-pyrrolidine-2-carboxamide (124 mg, 1.09 mmol), DIPEA (0.19 mL, 1.09 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (12 g), eluting with DMA-80 in dichloromethane (0 to 30%)], followed by reverse phase flash column chromatography [(silica gel, C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (170a) (31 mg, 17% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.93 (s, 1H), 9.60-9.20 (m, 1H), 9.01-7.93 (m, 2H), 7.63-7.45 (m, 2H), 7.30-7.11 (m, 3H), 7.00 (s, 1H), 4.82-4.68 (m, 1H), 4.12-3.81 (m, 7H), 3.79-3.64 (m, 4H), 2.40-1.88 (m, 4H); MS (ES+): 491.3 (M+1), 513.3 (M+Na); MS (ES−): 489.4 (M−1), 525.4 (M+Cl). HPLC purity: 97.96%.

Preparation (S)-1-(7-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (171a)

Compound 171a was prepared according to the procedure reported in step-2 of Scheme 76 from 2-chloro-7-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine (145g) (300 mg, 0.63 mmol) and (S)-pyrrolidine-2-carboxamide (0.65 g, 5.75 mmol) in NMP (10 mL). This gave after workup and purification by flash chromatography. (Silica gel, eluting with 0-4% methanol in DCM) compound (171a) (0.28 g, 77%) as an off-white solid. The solid was repurified by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water (0-50%)] to afford (S)-1-(7-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide (171a) (34 mg) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 12.31 (s, 1H), 11.37 (s, 1H), 8.66 (d, J=9.2 Hz, 1H), 8.36 (s, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.22 (s, 1H), 7.13 (s, 2H), 7.08-6.94 (m, 1H), 4.80-4.68 (m, 1H), 4.14-4.00 (m, 1H), 3.94 (s, 7H), 3.69 (s, 4H), 2.38-1.94 (m, 4H), 1.37 (d, J=5.9 Hz, 6H); MS (ES+): 548.4 (M+1); MS (ES−): 582.4 (M+Cl). HPLC purity: 97.90%.

Preparation of (S)-(1-(2-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (172a)

Compound 172a was prepared from (S)-(1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (96a) (0.91 g, 3.6 mmol), 1-phenyl-1H-imidazol-4-amine (8a) (860 mg, 5.40, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 0.77 g, 1.62 mmol), cesium carbonate (3.52 g, 10.8 mmol) and Pd 2 (dba) 3 (490 mg, 0.54 mmol) in 1,4-dioxane (30 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (80 g), eluting with DMA-80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-(1-(2-((1-phenyl-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2-yl)methanol (172a) (370 mg, 27% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.12 (s, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.68-7.49 (m, 5H), 6.85 (d, J=4.6 Hz, 1H), 6.54 (s, 1H), 4.59-4.33 (m, 1H), 4.09-3.34 (m, 4H), 2.26-1.65 (m, 4H); MS (ES+): 376.3 (M+1), 398.3 (M+Na).

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173c)

Step-1: Preparation of (S)-1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173a)

Compound 173a was prepared from 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (141a) (1.54 g, 4.5 mmol) in 2-Propanol (10 mL), (S)-pyrrolidine-2-carboxamide (0.51 g, 4.50 mmol), DIPEA (1.18 mL, 6.75 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] (S)-1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173a) (600 mg, 32% yield) as a white solid; MS (ES−): 418.4 (M−1), 454.2, 456.3 (M+Cl).

Step-2: Preparation of (S)-1-(7-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173b)

Compound 173b was prepared from (S)-1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173a) (500 mg, 1.19 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (848 mg, 2.38, free base), Pd 2 (dba) 3 (109 mg, 0.12 mmol), BrettPhos (63.9 mg, 0.12 mmol), BrettPhos Palladacycle (64.8 mg, 0.071 mmol) and Cs 2 CO 3 (776 mg, 2.38 mmol) in t-BuOH (15 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification twice by flash column chromatography [silica (40 g), eluting with DMA 80 in CH 2 Cl 2 from 0 to 50%]; [silica (24 g), eluting with EtOAc/MeOH (9:1) in hexane from 0-100%] (S)-1-(7-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173b) (420 mg, 56% yield) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.52 (s, 1H, D 2 O exchangeable), 8.65-8.34 (m, 1H), 8.34-8.17 (m, 1H), 8.14-7.88 (m, 2H), 7.36 (d, J=8.1 Hz, 3H, 1H is D 2 O exchangeable), 7.26 (d, J=3.9 Hz, 1H), 7.15-6.91 (m, 3H, 1H is D 2 O exchangeable), 6.84-6.68 (m, 1H), 4.72-4.51 (m, 1H), 3.84 (s, 6H), 3.70-3.62 (m, 5H), 2.30 (s, 3H), 2.12-1.87 (m, 4H); MS (ES+): δ 33.3 (M+1), 655.3 (M+Na).

Step-3: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173c)

Compound 173c was prepared from (S)-1-(7-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173b) (220 mg, 0.35 mmol), in MeOH/THF (5 mL, 1:1) using Cs 2 CO 3 (340 mg, 1.04 mmol) according to the procedure reported in step-3 of Scheme 141. This gave after work up and purification twice by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-100%], [silica (12 g), eluting with DMA-80 in DCM from 0-60%], free base of compound 173c. The free base was stirred for 30 min in CH 3 CN in presence of HCl (1N, 2 mL) to afford after lyophilization (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (173c) (39 mg, 23% yield) HCl salt as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.24 (s, 1H, D 2 O exchangeable), 10.75 and 10.33 (2s, 1H, D 2 O exchangeable), 8.57 (s, 1H), 7.89-7.73 (m, 1H, D 2 O exchangeable), 7.48 and 7.34 (2 bs, 1H, D 2 O exchangeable), 7.21-6.94 (m, 4H, partially D 2 O exchangeable), 6.70 and 6.49 (2 bs, 1H), 4.92-4.72 (m, 2H), 4.31-4.20 (m, 2H), 3.91 (s, 7H), 3.70 (s, 3H), 2.37-2.18 (m, 1H), 2.14-1.92 (m, 3H); MS (ES+): 479.4 (M+1), 501.3 (M+Na); (ES−): 513.4 (M+Cl).

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (174b)

Step-1: Preparation of (S)-(1-(2-chloropyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (174a)

Compound 174a was prepared from 2,4-dichloropyrido[2,3-d]pyrimidine (169a) (0.5 g, 2.5 mmol) in 2-Propanol (10 mL) using (S)-pyrrolidin-2-ylmethanol (0.25 mL, 2.5 mmol) and DIPEA (1.31 mL, 7.5 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with MeOH in dichloromethane] (S)-(1-(2-chloropyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (174a) (0.46 g, 70% yield) as a white solid; MS (ES+): 265.3 (M+1), 287.2 (M+Na); MS (ES−): 263.2 (M−1), 299.3 (M+Cl).

Step-2: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (174b)

Compound 174b was prepared from (S)-(1-(2-chloropyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (174a) (0.25 g, 0.94 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (280 mg, 1.13, free base), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 0.071 g, 0.113 mmol), sodium tert-butoxide (0.27 g, 2.83 mmol) and Pd 2 (dba) 3 (90 mg, 0.09 mmol) in toluene (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (174b) (31 mg, 7% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.81 (s, 1H), 8.56 (d, J=8.3 Hz, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7.24 (dd, J=8.1, 4.5 Hz, 1H), 6.94 (s, 2H), 5.17-4.88 (m, 1H), 4.88-4.66 (m, 1H), 4.17-3.55 (m, 13H), 2.21-1.84 (m, 4H); MS (ES+): 478.3 (M+1), 500.3 (M+Na). HPLC purity: 96.94%.

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (175b)

Step-1: Preparation of (S)-(1-(2-chloropyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (175a) Compound 175a was prepared from 2,4-dichloropyrido[3,2-d]pyrimidine (140a) (0.3 g, 1.50 mmol) in 2-Propanol (10 mL) using (S)-pyrrolidin-2-ylmethanol (0.15 mL, 1.50 mmol) and DIPEA (0.79 mL, 4.50 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with MeOH in dichloromethane 0-30%] (S)-(1-(2-chloropyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (175a) (0.21 g, 53% yield) as a white solid; MS (ES+): 265.3 (M+1), 287.2 (M+Na); MS (ES−): 263.3 & 265.3 (M−1).

Step-2: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (175b)

Compound 175b was prepared from (S)-(1-(2-chloropyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (175a) (0.2 g, 0.76 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (280 mg, 1.13, free base), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, 0.06 g, 0.09 mmol), sodium tert-butoxide (0.22 g, 2.27 mmol) and Pd 2 (dba) 3 (70 mg, 0.08 mmol) in toluene (15 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (175b) (33 mg, 9% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.77-8.68 (m, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.89-7.79 (m, 1H), 7.77 (s, 1H), 7.00 (s, 1H), 6.96 (s, 1H), 4.85 (s, 1H), 4.63-4.46 (m, 1H), 4.46-4.31 (m, 1H), 4.18-3.99 (m, 1H), 3.89 (s, 6H), 3.87-3.75 (m, 1H), 3.75-3.59 (m, 4H), 2.34-1.84 (m, 4H); MS (ES+): 478.3 (M+1), 500.3 (M+Na); MS (ES−): 512.3 (M+Cl). HPLC purity: 97.16%.

Preparation of (R)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (176b)

Step-1: Preparation of (R)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (176a) Compound 176a was prepared from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4a) (3 g, 15.96 mmol) in 2-Propanol (10 mL) using (R)-pyrrolidine-2-carboxamide (2.0 g, 17.55 mmol) and TEA (4.45 mL, 31.9 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (80 g), eluting with 9:1 mixture of ethyl acetate and methanol in hexanes] (R)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (176a) (3.85 g, 91% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.83-7.62 (m, 1H), 7.41 (d, J=70.7 Hz, 1H), 7.01 (dd, J=4.6, 1.6 Hz, 1H), 6.74 (dd, J=19.1, 3.6 Hz, 1H), 6.70-6.57 (m, 1H), 5.01-4.51 (m, 1H), 4.22-3.56 (m, 2H), 2.43-1.72 (m, 4H).

Step-2: Preparation of (R)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (176b)

Compound 176b was prepared from (R)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (176a) (0.5 g, 1.88 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (700 mg, 2.82 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 0.40 g, 0.84 mmol), cesium carbonate (1.83 g, 5.65 mmol) and Pd 2 (dba) 3 (250 mg, 0.28 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (80 g), eluting with DMA-80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C18, 150 g) eluting with acetonitrile and 0.1% HCl water] (R)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidine-2-carboxamide (176b) (394 mg, 43.8% yield) as awhite solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.66-9.46, 9.46-9.27 (2m, 1H), 9.22 (s, 1H), 7.90, 7.85 (2s, 1H), 7.78-7.67, 7.67-7.57 (2m, 1H), 7.43 (s, 1H), 7.30-7.08 (m, 2H), 7.08-6.85 (m, 1H), 6.75-6.46 (m, 1H), 4.95-4.82, 4.75-4.59 (2m, 1H), 4.33-4.05 (m, 1H), 4.01-3.75 (m, 7H), 3.72 (s, 3H), 2.30-1.81 (m, 4H); 1 H NMR (300 MHz, DMSO-d 6 -D 2 O) δ 9.11 (s, 1H), 7.72-7.55, 7.87-7.72 (2m, 1H), 7.18-7.05 (m, 2H), 6.91 (d, J=4.6 Hz, 1H), 6.73-6.50 (m, 2H), 4.74-4.61, 4.94-4.88 (2m, 1H), 4.25-4.13 (m, 1H), 4.01-3.93 (m, 1H), 3.91 (s, 6H), 3.73 (s, 3H), 2.32-1.91 (m, 4H); MS (ES+): 479.4 (M+1), 501.4 (M+Na), (ES−): 513.4 (M+Cl).

Preparation of (S)-(1-(6-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (177b)

Step-1: Preparation of (S)-(1-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (177a)

Compound 177a was prepared from 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (149a) (0.5 g, 1.7 mmol) in 2-Propanol (5 mL) using (S)-pyrrolidin-2-ylmethanol (172 mg, 1.7 mmol) and DIPEA (0.45 mL, 2.55 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA 80 in chloroform (0 to 50%) (S)-(1-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (177a) (511 mg, 84% yield) as an oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.40-7.18 (m, 5H), 4.79-4.63 (m, 1H, D 2 O exchangeable), 4.37-4.18 (m, 1H), 3.78-3.64 (m, 2H), 3.65-3.49 (m, 4H), 3.52-3.34 (m, 2H), 2.89-2.72 (m, 1H), 2.72-2.54 (m, 2H), 2.47-2.32 (m, 1H), 1.97-1.79 (m, 3H), 1.78-1.63 (m, 1H).

Step-2: Preparation of (S)-(1-(6-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (177b)

Compound 177b was prepared from (S)-(1-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (177a) (0.33 g, 0.91 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (340 mg, 1.36 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 195 mg, 0.41 mmol), cesium carbonate (890 mg, 2.73 mmol) and Pd 2 (dba) 3 (125 mg, 0.14 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (80 g), eluting with DMA 80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-(1-(6-benzyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (177b) (140 mg, 27% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.50-11.73 (m, 1H, D 2 O exchangeable), 10.61-10.07 (m, 1H, D 2 O exchangeable), 8.58-8.26 (m, 1H), 7.79-7.65 (m, 3H), 7.55-7.42 (m, 3H), 6.98 (s, 2H), 4.67-4.30 (m, 7H), 3.87 (s, 6H), 3.83-3.72 (m, 2H), 3.68 (s, 3H), 3.66-3.38 (m, 2H), 3.37-2.95 (m, 2H), 2.10-1.75 (m, 4H); 1 H NMR (300 MHz, DMSO-d-D 2 O) δ 8.45 (s, 1H), 7.71 (s, 1H), 7.68-7.59 (m, 2H), 7.57-7.47 (m, 3H), 6.96 (s, 2H), 4.65-4.36 (m, 7H), 3.87 (s, 6H), 3.70-3.68 (m, 4H), 3.67-3.56 (m, 1H), 3.57-3.40 (m, 2H), 3.11 (s, 2H), 2.14-1.79 (m, 4H); MS (ES+): 572.4 (M+1), 595.5 (M+Na), (ES−): 606.4 (M+Cl); HPLC purity: 98.17%.

Preparation of N-(naphthalen-2-yl)-1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (178b)

To a solution of 2-bromonaphthalene (178a) (100 mg, 0.48 mmol, in a 40 mL vial) in dioxane (5 mL) was added 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (181 mg, 0.72 mmol, free base), BrettPhos Palladacycle (22 mg, 0.024 mmol), BrettPhos (23 mg, 0.048 mmol) and Cs 2 CO 3 (393 mg, 1.21 mmol). The reaction mixture was fully degassed with argon and heated at 95° C. for 12 h. The reaction mixture was diluted with EtOAc (120 mL), filtered to remove inorganic solids. The filtrate was washed with water, brine, dried, filtered and concentrated in vacuum. The residue obtained was purified twice by flash column chromatography [silica (12 g), eluting with DMA80 in DCM 0-60%] to furnish compound 178b as a free base. The free base was stirred for 30 min in CH 3 CN in presence of HCl (1N, 2 mL) to afford after lyophilization N-(naphthalen-2-yl)-1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (178b) (26 mg, 14% yield) HCl salt as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.23 (s, 1H), 8.99 (brs, 1H, D 2 O exchangeable), 8.02 (s, 1H, D 2 O exchangeable), 7.87-7.70 (m, 3H), 7.45-7.40 (m, 1H), 7.40-7.33 (m, 2H), 7.33-7.22 (m, 2H), 7.16 (s, 2H), 3.90 (s, 6H), 3.72 (s, 3H); MS (ES + ) 376.3 (M+1); (ES−) 410.3 (M+Cl).

Preparation of N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinolin-2-amine (179b)

Compound 179b was prepared from 2-chloroquinoline (179a) (75 mg, 0.46 mmol) in dioxane (5 mL), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (171 mg, 0.69 mmol), BrettPhos Palladacycle (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol) and Cs 2 CO 3 (299 mg, 0.92 mmol) according to the procedure reported in Scheme 178. This gave after workup and purification by flash column chromatography [silica (24 g), eluting with EtOAc/MeOH (9:1) in hexane from 0-100%] N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinolin-2-amine (179b) (138 mg, 80% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.86 (s, 1H, D 2 O exchangeable), 8.21-8.15 (m, 1H), 8.13-8.06 (m, 1H), 7.98 (d, J=8.9 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.69 (dd, J=8.1, 1.5 Hz, 1H), 7.62-7.51 (m, 1H), 7.29-7.18 (m, 1H), 7.14 (d, J=8.9 Hz, 1H), 6.95 (s, 2H), 3.91 (s, 6H), 3.70 (s, 3H); MS (ES+): 377.3 (M+1); 399.3 (M+Na); (ES−): 375.3 (M−1).

Preparation of (S)-(1-(5-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (180b)

Step-1: Preparation of (S)-(1-(2-chloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (180a)

Compound 180a was prepared from 2,4-dichloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidine (160a) (1.23 g, 3.59 mmol) in IPA (15 mL), (S)-pyrrolidin-2-ylmethanol (0.36 g, 3.59 mmol), DIPEA (0.94 mL, 5.39 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] (S)-(1-(2-chloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (180a) (1.21 g, 83% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.88 (d, J=3.7 Hz, 1H), 7.47-7.36 (m, 2H), 7.33-7.23 (m, 2H), 6.67 (d, J=3.7 Hz, 1H), 4.80 (t, 1H, D 2 O exchangeable), 4.61-4.45 (m, 1H), 4.07-3.93 (m, 1H), 3.65-3.48 (m, 2H), 3.44-3.34 (m, 1H), 2.31 (s, 3H), 2.11-1.84 (m, 3H), 1.82-1.66 (m, 1H).

Step-2: Preparation of (S)-(1-(5-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (180b)

Compound 180b was prepared from (S)-(1-(2-chloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (180a) (350 mg, 0.86 mmol) in dioxane (15 mL), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (322 mg, 1.29 mmol), BrettPhos Palladacycle (39 mg, 0.043 mmol), BrettPhos (46 mg, 0.086 mmol) and Cs 2 CO 3 (561 mg, 1.72 mmol) according to the procedure reported in Scheme 178. This gave after workup and twice purification by flash column chromatography [silica (40 g), eluting with DMA-80 in DCM from 0-60%], [silica (24 g), eluting with EtOAc/MeOH (9:1) in hexane from 0-100%] compound 180b as a free base. The free base was converted to HCl salt using 1 N HCl (2 mL) in acetonitrile to afford (S)-(1-(5-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (180b) (75 mg, 14% yield) HCl salt as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.32-12.00 (m, 1H, D 2 O exchangeable), 10.83-10.49 (m, 1H, D 2 O exchangeable), 8.52 (s, 1H), 8.05-7.88 (m, 2H), 7.77 (s, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.09-6.96 (m, 3H), 4.84-4.57 (m, 1H), 4.28-4.08 (m, 1H), 3.98-3.83 (m, 8H), 3.72-3.62 (m, 5H), 2.39 (s, 3H), 2.13-1.91 (m, 4H); MS (ES+): δ 20.3 (M+1); (ES−): δ 18.4 (M−1).

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (181d)

Step-1: Preparation of (S)-tert-butyl 2-chloro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181b)

Compound 181b was prepared from tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181a) (2.0 g, 6.58 mmol, CAS #635698-56-5) in 2-Propanol (20 mL) using (S)-pyrrolidin-2-ylmethanol (0.67 g, 6.58 mmol) and DIPEA (1.72 mL, 9.86 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA 80 in chloroform (0 to 50%)] (S)-tert-butyl 2-chloro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181b) (511 mg, 84% yield) as an oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 4.79-4.71 (m, 1H, D 2 O exchangeable), 4.56 (m, 2H), 4.31 (dd, J=6.3, 3.9 Hz, 1H), 3.83-3.55 (m, 2H), 3.57-3.28 (m, 4H), 2.67 (t, J=6.1 Hz, 2H), 2.04-1.85 (m, 3H), 1.85-1.69 (m, 1H), 1.41 (s, 9H).

Step-2: Preparation of (S)-tert-butyl 4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181c)

Compound 181c was prepared from (S)-tert-butyl 2-chloro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181b) (0.5 g, 1.36 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (422 mg, 1.69 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 0.29 g, 0.61 mmol), cesium carbonate (1.33 g, 4.07 mmol) and Pd 2 (dba) 3 (186 mg, 0.2 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (80 g), eluting with DMA 80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-tert-butyl 4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181c) (350 mg, 44% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 -D 2 O) δ 8.33 (d, J=17.4 Hz, 1H), 7.74-7.56 (m, 1H), 6.94 (d, J=3.4 Hz, 2H), 4.80-4.44 (m, 3H), 3.93-3.84 (m, 8H), 3.84-3.71 (m, 2H), 3.69 (s, 3H), 3.65-3.22 (m, 2H), 2.89-2.71 (m, 2H), 2.21-1.79 (m, 4H), 1.43 (s, 9H); MS (ES+) 582.4 (M+1), 604.3 (M+Na), (ES−) 616.5 (M+Cl); HPLC purity: 90.07%.

Step-3: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (181d)

Compound 181d was prepared by hydrolysis of Boc of (S)-tert-butyl 4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181c) (260 mg, 0.45 mmol) in DCM using trifluoroacetic acid (0.69 mL, 8.94 mmol). This gave after purification by reverse phase column chromatography [(silica gel C-18, 100 g) eluting with 0.1% HCl and acetonitrile] (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido [4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (181d) (95 mg, 44% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.48-9.44 (m, 3H, D 2 O exchangeable), 8.41 (s, 1H), 7.70 (s, 1H), 6.97 (d, J=2.6 Hz, 2H), 4.74-4.47 (m, 2H), 4.47-4.22 (m, 2H), 3.87 (s, 6H), 3.68 (s, 3H), 3.69-3.54 (m, 4H), 3.55-3.36 (m, 2H), 3.36-3.16 (m, 1H), 3.12-2.95 (m, 2H), 2.14-1.71 (m, 4H); MS (ES+): 482.4 (M+1), 504.3 (M+Na), (ES−): 516.3 (M+Cl).

Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (182d)

Step-1: Preparation of (S)-tert-butyl 2-chloro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182b)

Compound 182b was prepared from tert-butyl 2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182a) (2.0 g, 6.58 mmol, CAS #916420-27-4) in 2-Propanol (20 mL) using (S)-pyrrolidin-2-ylmethanol (0.67 g, 6.58 mmol) and DIPEA (1.72 mL, 9.86 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA 80 in chloroform (0 to 50%)] (S)-tert-butyl 2-chloro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182b) (1.85 g, 76% yield) as an oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 4.77-4.62 (m, 1H), 4.47 (d, J=18.7 Hz, 1H), 4.39-4.26 (m, 1H), 4.23-4.01 (m, 1H), 4.00-3.84 (m, 2H), 3.76-3.55 (m, 2H), 3.54-3.34 (m, 1H), 3.12-2.79 (m, 2H), 2.76-2.62 (m, 1H), 2.03-1.83 (m, 3H), 1.81-1.63 (m, 1H), 1.43 (s, 9H).

Step-2: Preparation of (S)-tert-butyl 4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182c)

Compound 182c was prepared from (S)-tert-butyl 2-chloro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182b) (0.5 g, 1.36 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (422 mg, 1.69 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 290 mg, 0.61 mmol), cesium carbonate (1.33 g, 4.07 mmol) and Pd 2 (dba) 3 (186 mg, 0.2 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica (80 g), eluting with DMA-80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-tert-butyl 4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182c) (320 mg, 41% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 -D 2 O) δ 8.43 (s, 1H), 7.71 (s, 1H), 6.96 (s, 2H), 4.64-4.52 (m, 2H), 4.28-4.17 (m, 1H), 4.01-3.67 (m, 12H), 3.67-3.53 (m, 1H), 3.53-3.42 (m, 2H), 3.32-3.04 (m, 2H), 2.07-1.91 (m, 4H), 1.45 (s, 9H); MS (ES+): 582.4 (M+1), (ES−): δ 16.4 (M+Cl); HPLC purity: 90.76%.

Step-3: Preparation of (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (182d)

Compound 182d was prepared by hydrolysis of Boc of (S)-tert-butyl 4-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182c) (255 mg, 0.44 mmol) in DCM using trifluoroacetic acid (0.68 mL, 8.77 mmol) according to the procedure reported in Scheme 122. This gave after purification by reverse phase column chromatography [(silica gel C-18, 100 g) eluting with 0.1% HCl and acetonitrile] (S)-(1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (182d) (155 mg, 73% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 10.03-9.76 (m, 2H), 8.59 (s, 1H), 7.73 (s, 1H), 7.00 (s, 2H), 4.61 (s, 1H), 4.20 (s, 2H), 3.87 (s, 6H), 3.82-3.73 (m, 2H), 3.69 (s, 3H), 3.66-3.56 (m, 1H), 3.52-3.35 (m, 2H), 3.22-3.05 (m, 2H), 3.01-2.85 (m, 1H), 2.09-1.80 (m, 4H); MS (ES+): 482.4 (M+1), 504.4 (M+Na), (ES−): 516.4 (M+Cl); Analysis calculated for C 24 H 31 N 7 O 4 (HCl) 3 (H 2 O) 4 : C, 43.48; H, 6.39; Cl, 16.04; N, 14.79. Found: C, 43.49; H, 6.22; Cl, 15.85; N, 14.56.

Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (183c)

Step-1: Preparation of tert-butyl 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183a)

Compound 183a was prepared from tert-butyl 2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182a) (1.0 g, 3.29 mmol) in 2-Propanol (15 mL) using DIPEA (2.3 mL, 13.15 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (0.98 g, 3.95 mmol). This gave after workup and purification by flash column chromatography [silica gel, (12 g) eluting with DMA-80 in DCM (0 to 80%)] tert-butyl 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5, 6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183a) (0.87 g, 51% yield) as a buff solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.65 (s, 1H, D 2 O exchangeable), 8.16 (d, J=1.5 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 6.90 (s, 2H), 4.35 (s, 2H), 3.87 (s, 6H), 3.69 (s, 3H), 3.61 (t, J=5.8 Hz, 2H), 2.69-2.60 (m, 2H), 1.43 (s, 9H).

Step-2: Preparation of (S)-tert-butyl 2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5, 6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183b)

Compound 183b was prepared from tert-butyl 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183a) (0.4 g, 0.77 mmol), (S)-pyrrolidin-2-ylmethanol (235 mg, 2.32 mmol) in 2-Propanol (7 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (40 g), eluting with DMA 80 in dichloromethane], (S)-tert-butyl 2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183b) (0.41 g, 91% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.79 (s, 1H, D 2 O exchangeable), 8.18 (s, 1H), 7.93 (s, 1H), 6.92 (s, 2H), 5.26-4.70 (m, 1H, D 2 O exchangeable), 4.39-3.97 (m, 3H), 3.87 (s, 6H), 3.77-3.56 (m, 4H), 3.66-3.40 (m, 4H), 3.39-3.23 (m, 1H), 2.58-2.53 (m, 2H), 2.06-1.79 (m, 4H), 1.44 (s, 9H); MS (ES+): 582.4 (M+1), 604.3 (M+Na), (ES−): 580.4 (M−1); HPLC purity: 95.74%.

Step-3: Preparation of (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (183c)

Compound 183c was prepared by hydrolysis of Boc of (S)-tert-butyl 2-(2-(hydroxymethyl)pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183b) (363 mg, 0.624 mmol) in DCM (10 mL) using trifluoroacetic acid (0.96 mL, 12.48 mmol) according to the procedure reported in Scheme 122. This gave after purification by reverse phase column chromatography [(silica gel C-18, 100 g) eluting with 0.1% HCl and acetonitrile] (S)-(1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5, 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidin-2-yl)methanol (183c) (210 mg, 70% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d-D 2 O) δ 8.27 (s, 1H), 7.91 (s, 1H), 6.89 (s, 2H), 4.47-4.31 (m, 1H), 4.21-4.10 (m, 2H), 3.86-3.80 (m, 6H), 3.66 (s, 3H), 3.65-3.45 (m, 2H), 3.45-3.31 (m, 4H), 2.82-2.69 (m, 2H), 2.09-1.85 (m, 4H); MS (ES+): 482.3 (M+1), 504.4 (M+Na), (ES−): 516.4 (M+Cl); HPLC: 99.46%; Analysis calculated for C 24 H 31 N 7 O 4 (HCl) 2.75 (H 2 O) 3 : C, 45.33; H, 6.30; Cl, 15.33; N, 15.42. Found: C, 45.13; H, 6.18; Cl, 15.74; N, 15.22.

Preparation of 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (184b)

Step-1: Preparation of tert-butyl 2-(pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (184a)

Compound 184a was prepared from tert-butyl 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183a) (0.2 g, 0.39 mmol), pyrrolidine (83 mg, 1.16 mmol) in 2-Propanol (3 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (25 g), eluting with DMA 80 in dichloromethane], tert-butyl 2-(pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (184a) (0.18 g, 84% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.84 (s, 1H, D 2 O exchangeable), 8.18 (s, 1H), 8.01 (d, J=1.7 Hz, 1H), 6.89 (s, 2H), 4.20 (s, 2H), 3.86 (s, 6H), 3.68 (s, 3H), 3.56 (s, 6H), 2.61-2.40 (m, 2H), 1.98-1.81 (m, 4H), 1.43 (s, 9H); MS (ES+): 552.4 (M+1), 574.4 (M+Na); HPLC purity: 96.29%.

Step-2: Preparation of 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (184b)

Compound 184b was prepared by hydrolysis of Boc of tert-butyl 2-(pyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (184a) (150 mg, 0.27 mmol) in DCM (10 mL) using trifluoroacetic acid (0.42 mL, 5.44 mmol) according to the procedure reported in Scheme 122. This gave after workup and purification by reverse phase column chromatography [(silica gel C-18, 100 g) eluting with 0.1% HCl and acetonitrile] 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (184b) (91 mg, 74% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 -D 2 O) δ 10.61 (s, 1H, D 2 O exchangeable), 9.92 (s, 2H, D 2 O exchangeable), 8.39 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 6.95 (s, 2H), 4.29 (s, 2H), 3.87 (s, 6H), 3.69 (s, 3H), 3.70-3.52 (m, 2H), 3.47-3.31 (m, 4H), 2.91-2.78 (m, 2H), 1.99 (m, 4H); MS (ES+): 452.4 (M+1), (ES−): 486.4 (M+Cl); HPLC purity: 98.30%; Analysis calculated for C 23 H 29 N 7 O 3 (HCl) 2.5 (H 2 O) 3 : C, 46.29; H, 6.33; Cl, 14.85; N, 16.43; Found: C, 46.70; H, 6.22; Cl, 14.74; N, 16.51.

Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (185b)

Step-1: Preparation of (S)-tert-butyl 2-(2-carbamoylpyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5, 6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (185a)

Compound 185a was prepared from tert-butyl 2-chloro-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (183a) (293 mg, 0.57 mmol), (S)-pyrrolidine-2-carboxamide (194 mg, 1.7 mmol) in 2-Propanol (7 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (25 g), eluting with DMA 80 in dichloromethane], (S)-tert-butyl 2-(2-carbamoylpyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (185a) (0.29 g, 86% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.09-8.44 (m, 1H, D2O exchangeable), 8.15 (s, 1H), 7.99-7.71 (m, 1H), 7.29-6.75 (m, 4H), 4.45-4.34 (m, 1H), 4.33-4.10 (m, 2H), 3.91 (s, 6H), 3.68 (s, 3H), 3.57 (s, 2H), 3.41-3.27 (m, 2H), 2.62-2.44 (m, 2H), 2.30-2.07 (m, 1H), 2.02-1.76 (m, 3H), 1.43 (s, 9H); MS (ES+): 595.4 (M+1), 617.3 (M+Na); HPLC purity: 94.40%.

Step-2: Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (185b)

Compound 185b was prepared by hydrolysis of Boc of (S)-tert-butyl 2-(2-carbamoylpyrrolidin-1-yl)-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (185a) (260 mg, 0.44 mmol) in DCM (10 mL) using trifluoroacetic acid (0.674 mL, 8.74 mmol) according to the procedure reported in Scheme 122. This gave after workup and purification by reverse phase column chromatography [(silica gel C-18, 100 g) eluting with 0.1% HCl and acetonitrile] (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (185b) (133 mg, 62% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 -D 2 O) δ 10.49-10.12 (m, 1H, D 2 O exchangeable), 10.12-9.72 (m, 2H, D 2 O exchangeable), 8.44 (s, 1H), 7.88 (s, 1H), 7.50 (s, 1H), 7.26-6.90 (m, 3H), 4.82-4.43 (m, 1H), 4.43-4.04 (m, 2H), 3.92 (s, 6H), 3.69 (s, 3H), 3.64-3.51 (m, 1H), 3.48-3.31 (m, 3H), 2.94-2.78 (m, 2H), 2.41-2.13 (m, 1H), 2.09-1.89 (m, 3H); MS (ES+): 495.3 (M+1), (ES−): 529.4 (M+Cl); HPLC: 96.21%; Analysis calculated for C 24 H 30 NgO 4 (HCl) 2.5 (H 2 O) 4.5 : C, 43.23; H, 6.27; Cl, 13.29; N, 16.81. Found: C, 43.29; H, 6.11; Cl, 13.44; N, 16.37.

Preparation of 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine (186a)

Compound 186a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine (169b) (0.15 g, 0.36 mmol), pyrrolidine (0.09 mL, 1.09 mmol), DIPEA (0.19 mL, 1.09 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (12 g), eluting with DMA 80 in dichloromethane (0 to 30%)], followed by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine (186a) (43 mg, 26% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 9.23 (d, J=8.0 Hz, 1H), 8.78 (d, J=5.0 Hz, 1H), 8.43 (s, 1H), 8.12 (s, 1H), 7.51 (dd, J=8.0, 5.0 Hz, 1H), 6.97 (s, 2H), 3.96 (t, J=6.6 Hz, 2H), 3.88 (s, 6H), 3.77-3.62 (m, 5H), 2.15-1.88 (m, 4H). MS (ES+): 448.3 (M+1); MS (ES−): 446.4 (M−1). HPLC purity: 98.41%.

Preparation of N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (187b)

Compound 187b was prepared from 4-chloropyrrolo[2,1-f][1,2,4]triazine (187a) (0.1 g, 0.65 mmol; CAS #888720-29-4) in 2-Propanol (20 mL) using DIPEA (0.34 mL, 1.95 mmol) and 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (243 mg, 0.98 mmol). This gave after workup and purification by flash column chromatography [silica gel, (4 g) eluting with MeOH in DCM (0 to 30%)]; followed by reverse phase flash column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (187b) (36 mg, 15% yield) as a buff colored solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.10 (s, 2H), 7.84 (s, 1H), 7.45 (s, 1H), 7.03 (s, 2H), 6.81 (s, 1H), 3.89 (s, 6H), 3.70 (s, 3H). MS (ES+): 367.3 (M+1); MS (ES−): 401.3 (M+Cl). HPLC purity: 99.62%.

Preparation of 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (188a)

Compound 188a was prepared from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (140b) (80 mg, 0.19 mmol), pyrrolidine (0.05 mL, 0.58 mmol), DIPEA (0.1 mL, 0.58 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica gel, (12 g), eluting with DMA 80 in DCM 0 to 30%], 2-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (188a) (46 mg, 53% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 8.40 (dd, J=4.2, 1.5 Hz, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.72 (dd, J=8.6, 1.5 Hz, 1H), 7.58 (dd, J=8.5, 4.2 Hz, 1H), 6.93 (s, 2H), 3.87 (s, 6H), 3.83-3.75 (m, 2H), 3.70 (s, 3H), 3.65-3.45 (m, 2H), 2.03-1.83 (m, 4H). MS (ES+): 448.3 (M+1). HPLC purity: 97.56%.

Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (189a)

Compound 189a was prepared according to the procedure reported in step-2 of Scheme 76 from 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (75a) (500 mg, 1.19 mmol) and (S)-pyrrolidine-2-carboxamide (273 mg, 2.39 mmol) in NMP (20 mL). This gave after workup and purification by flash chromatography (Silica gel, eluting with 0-10% methanol in ethyl acetate) compound (189a) (0.16 g, 27%) as a solid. The solid was repurified by reverse phase flash column chromatography [(Silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl in water (0-50%)] to afford (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (189a) (69 mg) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 13.41 (s, 1H), 11.83 (s, 1H), 8.37 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.87 (s, 1H), 7.70-7.55 (m, 2H), 7.21 (s, 1H), 7.13 (s, 2H), 4.67 (d, J=8.7 Hz, 1H), 4.13-3.82 (m, 7H), 3.77-3.57 (m, 4H), 2.40-1.90 (m, 4H); MS (ES+): 496.3 (M+1); MS (ES−): 530.3 (M+Cl).

Preparation of (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (190a)

Compound 190a was prepared according to the procedure reported in step-2 of Scheme 76 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)-pyrrolidine-2-carboxamide (0.85 g, 7.46 mmol) in NMP (20 mL). This gave after workup and purification by flash chromatography (silica gel, eluting with 0-10% methanol in ethyl acetate) compound 190a (90 mg, 24%) free base as a solid. This was re-purified by reverse phase flash column chromatography [silica gel C-18 column, (24 g) eluting with acetonitrile and 0.1% HCl water (0-50%) followed by lyophilization to afford (S)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)furo[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (190a) (40 mgs) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d): δ 11.84 (s, 1H), 8.53-8.34 (m, 2H), 7.90 (s, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 7.16-7.03 (m, 3H), 4.61 (d, J=8.6 Hz, 1H), 4.08-3.83 (m, 7H), 3.74-3.54 (m, 4H), 2.40-1.87 (m, 4H); MS (ES+): 480.3 (M+1); MS (ES−): 514.3 (M+Cl). HPLC purity: 98.13%.

Preparation of (S)-1-(5-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191b) and (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191c)

Step-1: Preparation of (S)-1-(2-chloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191a)

Compound 191a was prepared from 2,4-dichloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidine (160a) (1.91 g, 5.58 mmol) in IPA (15 mL), (S)-pyrrolidine-2-carboxamide (0.64 g, 5.58 mmol), DIPEA (1.46 mL, 8.38 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] (S)-1-(2-chloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191a) (1.6 g, 68% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.89 (d, J=3.7 Hz, 1H), 7.52-7.40 (m, 2H), 7.34-7.20 (m, 3H), 7.08 (s, 1H), 6.69 (d, J=3.7 Hz, 1H), 4.83 (s, 1H), 4.11-3.94 (m, 1H), 3.79-3.65 (m, 1H), 2.41-2.33 (m, 1H), 2.31 (s, 3H), 2.01-1.76 (m, 3H).

Step-2: Preparation of (S)-1-(5-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191b) and (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191c)

Compound 191b and 191c was prepared from (S)-1-(2-chloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191a) (400 mg, 0.95 mmol) in tert-BuOH (15 mL), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (261 mg, 1.05 mmol), BrettPhos Palladacycle (43 mg, 0.048 mmol), BrettPhos (77 mg, 0.14 mmol), Pd 2 (dba) 3 (174 mgs, 0.19 mmol) and Cs 2 CO 3 (621 mg, 1.91 mmol) according to the procedure reported in Scheme 178. This gave after workup and purification by flash column chromatography [silica (40 g), eluting with DMA80 in DCM from 0-60%], followed by reverse phase flash column chromatography [(silica gel C-18 column, 24 g) eluting with acetonitrile and 0.1% HCl water (0-50%)] and lyophilization (S)-1-(5-tosyl-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191b) (16 mg, 3% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.49 (brs, 1H, D 2 O exchangeable), 10.46 (s, 1H, 1H, D 2 O exchangeable), 8.26 (s, 1H), 8.00 (d, J=8.0 Hz, 2H), 7.63 (s, 1H), 7.57-7.41 (m, 3H, 1H is D 2 O exchangeable), 7.26-6.96 (m, 5H, 1H is D 2 O exchangeable), 4.83-4.73 (m, 1H), 4.43-4.30 (m, 1H), 4.08-3.97 (m, 1H), 3.91 (s, 6H), 3.68 (s, 3H), 2.40 (s, 3H), 2.30-2.23 (m, 1H), 2.14-1.98 (m, 3H); MS (ES+): 633.3 (M+1); 655.3 (M+Na); (ES−): 631.4 (M−1); 667.3 (M+Cl), and (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (191c) (15 mg, 3% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.58 (s, 1H, D 2 O exchangeable), 11.97 (s, 1H, D 2 O exchangeable), 10.21 (s, 1H, D 2 O exchangeable), 8.29-8.20 (m, 1H), 7.71-7.66 (m, 1H), 7.63 (t, J=3.1 Hz, 1H, D 2 O exchangeable), 7.56 (s, 1H), 7.23-7.16 (m, 1H, D 2 O exchangeable), 7.10 (s, 2H), 6.51-6.40 (m, 1H), 4.85-4.72 (m, 1H), 4.40-4.30 (m, 1H), 3.92 (s, 6H), 3.76-3.73 (m, 2H), 3.69 (s, 3H), 2.31-2.23 (m, 1H), 2.15-2.02 (m, 3H); MS (ES+): 479.3 (M+1); 493.5 (M+Na); (ES−): 513.3 (M+Cl).

Preparation of 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-2-amine (192b)

Step-1: Preparation of 2-chloro-4-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidine (192a)

Compound 192a was prepared from 2,4-dichloropyrido[2,3-d]pyrimidine (169a) (0.5 g, 2.50 mmol) in 2-Propanol (10 mL) using pyrrolidine (0.21 mL, 2.5 mmol) and DIPEA (1.31 mL, 7.5 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in dichloromethane 0 to 30%] 2-chloro-4-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidine (192a) (0.41 g, 70% yield) as a white solid; MS (ES+): 235.2 & 237.1 (M+1).

Step-2: Preparation of 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-2-amine (192b)

Compound 192b was prepared from 2-chloro-4-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidine (192a) (0.15 g, 0.64 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (160 mg, 0.64 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 180 mg, 0.38 mmol), Pd 2 (dba) 3 (180 mg, 0.19 mmol) and cesium carbonate (630 mg, 1.92 mmol) in dioxane (5 mL) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrido[2,3-d]pyrimidin-2-amine (192b) (50 mg, 16% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.86 (s, 1H), 9.06-8.64 (m, 2H), 8.59-8.13 (m, 1H), 7.98-7.66 (m, 1H), 7.64-7.31 (m, 1H), 6.96 (s, 2H), 4.47-3.25 (m, 13H), 2.26-1.81 (m, 4H). MS (ES+): 448.3 (M+1); MS (ES−): 446.0 (M−1).

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (193c)

Step-1: Preparation of (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (193a)

Compound 193a was prepared from tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (181a) (2.0 g, 6.58 mmol) in 2-Propanol (20 mL) using (S)-pyrrolidine-2-carboxamide (0.75 g, 6.58 mmol) and DIPEA (1.72 mL, 9.86 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with DMA-80 in chloroform (0 to 50%)] (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (193a) (1.8 g, 72% yield) as an oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.43 (s, 1H), 6.95 (s, 1H), 4.75 (d, J=16.1 Hz, 1H), 4.61 (d, J=16.1 Hz, 1H), 4.50 (m, 1H), 3.92-3.70 (m, 2H), 3.69-3.41 (m, 2H), 2.67 (t, J=6.1 Hz, 2H), 2.13 (m, 1H), 1.88 (m, 3H), 1.42 (s, 9H).

Step-2: Preparation of (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (193b)

Compound 193b was prepared from (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (193a) (0.52 g, 1.35 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (422 mg, 1.69 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 0.29 g, 0.61 mmol), cesium carbonate (1.33 g, 4.07 mmol) and Pd 2 (dba) 3 (186 mg, 0.2 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (80 g), eluting with DMA 80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(C18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (193b) (340 mg, 42% yield) HCl salt as a white solid; MS (ES+): 595.4 (M+1), (ES−): 593.5 (M−1).

Step-3: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (193c)

Compound 193c was prepared by hydrolysis of Boc of (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (193b) (250 mg, 0.42 mmol) in DCM (5 mL) using trifluoroacetic acid (0.65 mL, 8.41 mmol) according to the procedure reported in Scheme 122. This gave after purification by reverse phase column chromatography [(silica gel C-18, 100 g) eluting with 0.1% HCl and acetonitrile] (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (193c) (42 mg, 20% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.30 (s, 2H, D 2 O exchangeable), 9.72 (s, 1H, D 2 O exchangeable), 8.49 (s, 1H), 7.86 (s, 1H), 7.66 (s, 1H), 7.20 (s, 2H), 4.72-4.57 (m, 2H), 4.44-4.27 (m, 1H), 4.19-4.02 (m, 1H), 3.91 (s, 6H), 3.85-3.69 (m, 1H), 3.69 (s, 3H), 3.52-3.37 (m, 1H), 3.36-3.19 (m, 1H), 3.11-2.95 (m, 2H), 2.34-2.21 (m, 1H), 2.11-1.78 (m, 3H); MS (ES+): 495.4 (M+1), (ES−): 529.4 (M+Cl).

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (194c)

Step-1: Preparation of (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (194a)

Compound 194a was prepared from tert-butyl 2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (182a) (2.0 g, 6.58 mmol) in 2-Propanol (20 mL) using (S)-pyrrolidine-2-carboxamide (0.75 g, 6.58 mmol) and DIPEA (1.72 mL, 9.86 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with DMA 80 in chloroform (0 to 50%)] (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (194a) (0.51 g, 21% yield) as an oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.37 (s, 1H), 6.95 (s, 1H), 4.52 (m, 1H), 4.38 (d, J=18.6 Hz, 1H), 4.22 (d, J=18.9 Hz, 1H), 3.97-3.75 (m, 2H), 3.66 (m, 1H), 3.35-3.21 (m, 1H), 2.99-2.75 (m, 2H), 2.20-2.05 (m, 1H), 1.99-1.73 (m, 3H), 1.43 (s, 9H).

Step-2: Preparation of (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (194b)

Compound 194b was prepared from (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (194a) (0.52 g, 1.35 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (422 mg, 1.69 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 29 mg, 0.61 mmol), cesium carbonate (1.33 g, 4.07 mmol) and Pd 2 (dba) 3 (186 mg, 0.203 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (80 g), eluting with DMA-80 in CH 2 Cl 2 ], (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (194b) (320 mg, 40% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.13, 9.94 (2s, 1H, rotamers), 8.77, 8.42 (2s, 1H, rotamers), 7.86, 7.79 (2s, 1H, rotamers), 7.52 (s, 1H), 7.22 (s, 1H), 7.18-7.03 (m, 2H), 4.68 (m, 1H), 4.57 (d, J=18.7 Hz, 1H), 4.36 (d, J=18.5 Hz, 1H), 4.09 (d, J=49.7 Hz, 1H), 3.91 (s, 6H), 3.85-3.69 (m, 1H), 3.69 (m, 3H), 3.56-3.17 (m, 2H), 3.17-2.93 (m, 1H), 2.93-2.69 (m, 1H), 2.35-2.16 (m, 1H), 2.06-1.74 (m, 3H), 1.60 (s, 3H), 1.45 (s, 6H); MS (ES−): 593.5 (M−1), 629.4 (M+Cl).

Step-3: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (194c)

Compound 194c was prepared by hydrolysis of Boc of (S)-tert-butyl 4-(2-carbamoylpyrrolidin-1-yl)-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (194b) (251 mg, 0.42 mmol) in DCM (5 mL) using trifluoroacetic acid (0.65 mL, 8.44 mmol) according to the procedure reported in Scheme 122. This gave after purification by reverse phase column chromatography [(silica gel C-18, 100 g) eluting with 0.1% HCl and acetonitrile] (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (194c) (60 mg, 29% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 9.95 (s, 3H), 8.77 (s, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.22 (s, 2H), 7.13 (s, 1H), 4.73-4.58 (m, 1H), 4.25-4.04 (m, 2H), 3.91 (s, 6H), 3.85-3.74 (m, 1H), 3.70 (s, 3H), 3.55-3.37 (m, 1H), 3.15 (d, J=27.5 Hz, 4H), 2.33-2.14 (m, 1H), 2.09-1.76 (m, 3H); MS (ES+): 495.4 (M+1), (ES−): 529.4.

Preparation of N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)isoquinolin-3-amine (195b)

Compound 195b was prepared from 3-chloroisoquinoline (195a) (0.125 g, 0.76 mmol; CAS #19493-45-9), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (190 mg, 0.76 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 150 mg, 0.31 mmol), Pd 2 (dba) 3 (140 mg, 0.195 mmol) and cesium carbonate (0.5 g, 1.53 mmol) in t-BuOH/toluene (12 mL, 1:3 ratio) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with EtOAc/MeOH (9:1) in hexane from 0-100%] followed by reverse phase column chromatography [(silica gel C-18, 50 g) eluting with acetonitrile and 0.1% HCl water] N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)isoquinolin-3-amine (195b) (22 mg, 8% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.73 (s, 1H, D 2 O exchangeable), 9.11 (s, 1H), 9.08 (s, 1H), 8.04-7.93 (m, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.69-7.59 (m, 1H), 7.43-7.35 (m, 1H), 7.27 (s, 1H), 7.12 (s, 2H), 3.90 (s, 6H), 3.72 (s, 3H); MS (ES+): 377.3 (M+1); 399.3 (M+Na); (ES−): 411.3 (M+Cl).

Preparation of (S)-1-(5-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)pyrrolidine-2-carboxamide (196b)

Step-1: Preparation of (S)-1-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)pyrrolidine-2-carboxamide (196a) Compound 196a was prepared from 5,7-dichlorothiazolo[5,4-d]pyrimidine (150a) (0.2 g, 0.97 mmol) in 2-Propanol (10 mL) using (S)-pyrrolidine-2-carboxamide (0.11 g, 0.97 mmol) and DIPEA (0.51 mL, 2.91 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DCM in methanol (0 to 30%)] (S)-1-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)pyrrolidine-2-carboxamide (196a) (0.17 g, 61% yield) as a yellow solid; MS (ES+): 306.1 (M+Na); MS (ES−): 282.3 (M−1), 318.1 & 320.1 (M+Cl).

Step-2: Preparation of (S)-1-(5-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)pyrrolidine-2-carboxamide (196b)

Compound 196b was prepared from (S)-1-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)pyrrolidine-2-carboxamide (196a) (0.17 g, 0.6 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (150 mg, 0.6 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 0.17 g, 0.36 mmol), cesium carbonate (0.58 g, 1.79 mmol) and Pd 2 (dba) 3 (160 mg, 0.18 mmol) in 1,4-dioxane (5 mL) and toluene (5 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA 80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water](S)-1-(5-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)pyrrolidine-2-carboxamide (196b) (10 mg, 4% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.01 (s, 1H), 9.23 (s, 1H), 9.04-8.67 (m, 1H), 7.96 (s, 1H), 7.53-6.81 (m, 4H), 4.77-4.03 (m, 3H), 4.02-3.50 (m, 9H), 2.32-1.83 (m, 4H). MS (ES+): 497.3 (M+1); MS (ES−): 495.3 (M−1).

Preparation of 5-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thiazolo[5,4-d]pyrimidin-7-amine (197a)

Compound 197a was prepared from 5-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thiazolo[5,4-d]pyrimidin-7-amine (158a) (0.15 g, 0.36 mmol), pyrrolidine (0.09 mL, 1.07 mmol), DIPEA (0.19 mL, 1.07 mmol) in 2-Propanol (5 mL) according to the procedure reported in Scheme 2. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with DMA 80 in CH 2 Cl 2 from 0 to 30%] 5-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thiazolo[5,4-d]pyrimidin-7-amine (197a) (0.11 g, 68% yield) as a brown solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 8.78 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 6.93 (s, 2H), 3.87 (s, 6H), 3.81-3.43 (m, 7H), 2.02-1.84 (m, 4H); MS (ES+): 454.3 (M+1); MS (ES−): 452.4 (M−1).

Preparation of N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-2-amine (198b)

Compound 198b was prepared from 2-chloroquinazoline (198a) (0.1 g, 0.61 mmol; CAS #6141-13-5), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (151 mg, 0.61 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 116 mg, 0.24 mmol), Pd 2 (dba) 3 (111 mg, 0.12 mmol) and cesium carbonate (396 mg, 1.53 mmol) in t-BuOH/toluene (12 mL, 1:3 ratio) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with EtOAc/MeOH (9:1) in hexane from 0-100%] followed by reverse phase column chromatography [(silica gel C-18, 50 g) eluting with acetonitrile and 0.1% HCl water] N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-2-amine (198b) (13 mg, 6% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.29 (s, 1H, D 2 O exchangeable), 9.33 (s, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.47-7.34 (m, 1H), 7.02 (s, 2H), 3.91 (s, 6H), 3.71 (s, 3H); MS (ES+): 378.3 (M+1); 400.3 (M+Na); (ES−): 376.3 (M−1).

Preparation of 4-(pyrrolidin-1-yl)-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (199b)

Step-1: Preparation of 2-chloro-4-(pyrrolidin-1-yl)-5-tosyl-5H-pyrrolo[3,2-d]pyrimidine (199a)

Compound 199a was prepared from 2,4-dichloro-5-tosyl-5H-pyrrolo[3,2-d]pyrimidine (160a) (1.4 g, 4.09 mmol) in IPA (10 mL), pyrrolidine (290 mg, 4.09 mmol), DIPEA (1.07 mL, 6.14 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with ethyl acetate/MeOH (9:1) in hexane from 0-70%] 2-chloro-4-(pyrrolidin-1-yl)-5-tosyl-5H-pyrrolo[3,2-d]pyrimidine (199a) (1.3 g, 84% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.95 (d, J=8.4 Hz, 2H), 7.56 (d, J=4.0 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 6.87 (d, J=4.1 Hz, 1H), 3.78-3.63 (m, 2H), 3.60-3.45 (m, 2H), 2.37 (s, 3H), 2.07-1.92 (m, 2H), 1.92-1.78 (m, 2H).

Step-2: Preparation of 4-(pyrrolidin-1-yl)-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (199b)

Compound 199b was prepared from 2-chloro-4-(pyrrolidin-1-yl)-5-tosyl-5H-pyrrolo[3,2-d]pyrimidine (199a) (350 mg, 0.93 mmol) in DMA (15 mL), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (231 mg, 0.93 mmol), Pd 2 (dba) 3 (170 mg, 0.19 mmol), X-Phos (177 mg, 0.37 mmol) and Cs 2 CO 3 (756 mg, 2.32 mmol) according to the procedure reported in Scheme 178. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with DMA-80 in DCM from 0-60%], 4-(pyrrolidin-1-yl)-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (199b) (95 mg, 17% yield) free base as an off white solid. Free base (28 mg) was taken and mixed with 1% HCl for 1 h, excess HCl was then removed, and the residue was taken up with water/CH 3 CN and lyophilized to give 4-(pyrrolidin-1-yl)-5-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (199b) (29 mg) HCl salt as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.07 (s, 1H, D 2 O exchangeable), 9.06 (s, 1H), 8.38 (s, 1H, D 2 O exchangeable), 7.96 (d, J=8.0 Hz, 2H), 7.44-7.30 (m, 3H), 7.11 (s, 2H), 6.83 (d, J=4.0 Hz, 1H), 3.84 (s, 6H), 3.75-3.62 (m, 7H), 2.31 (s, 3H), 2.02-1.85 (m, 4H); MS (ES+): 590.3 (M+1); 612.3 (M+Na); (ES−): 588.3 (M−1).

Preparation of (S)-(1-(8-isopropoxy-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidin-2-yl)methanol (200b)

Step-1: Preparation of (S)-(1-(2-chloro-8-isopropoxyquinazolin-4-yl)pyrrolidin-2-yl)methanol (200a) Compound 200a was prepared from 2,4-dichloro-8-isopropoxyquinazoline (143f) (0.5 g, 1.95 mmol) in 2-DCM (10 mL) using (S)-pyrrolidin-2-ylmethanol (0.98 g, 9.76 mmol) and DIPEA (0.756 g, 5.85 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (25 g), eluting with DCM in methanol (0 to 30%)] (S)-(1-(2-chloro-8-isopropoxyquinazolin-4-yl)pyrrolidin-2-yl)methanol (200a) (0.6 g, 96% yield) as an off-white solid; MS (ES+): 322.3 (M+1), 344.3 (M+Na); MS (ES−): 320.3 (M−1).

Step-2: Preparation of (S)-(1-(8-isopropoxy-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidin-2-yl)methanol (200b)

Compound 200b was prepared from (S)-(1-(2-chloro-8-isopropoxyquinazolin-4-yl)pyrrolidin-2-yl)methanol (200a) (0.25 g, 0.78 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (190 mg, 0.78 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 220 mg, 0.47 mmol), cesium carbonate (0.76 g, 2.33 mmol) and Pd 2 (dba) 3 (210 mg, 0.23 mmol) in 1,4-dioxane (5 mL) and toluene (5 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-(1-(8-isopropoxy-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidin-2-yl)methanol (200b) (50 mg, 11% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.78-13.65 and 11.98 (2m, 1H), 11.65 and 11.32 (2s, 1H), 8.51-8.32 (m, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.49-7.29 (m, 2H), 7.00 (s, 2H), 4.90 (s, 1H), 4.29-4.04 (m, 1H), 3.99-3.49 (m, 13H), 2.27-1.86 (m, 4H), 1.56-1.29 (m, 6H); MS (ES+): 535.3 (M+1); MS (ES−): 569.4 (M+Cl). HPLC purity: 98.33%.

Preparation of 6-benzyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (201b)

Compound 201b was prepared from 6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (201a) (0.26 g, 1.0 mmol, prepared according to the procedure reported by Sun, Hao-Peng et al; in European Journal of Medicinal Chemistry, 79, 399-412; 2014), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (312 mg, 1.25, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 215 mg, 0.45 mmol), Pd 2 (dba) 3 (137 mg, 0.15 mmol) and cesium carbonate (978 mg, 3.0 mmol) in dioxane (10 mL) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (80 g), eluting with DMA-80 in dichloromethane] followed by reverse phase column chromatography [(silica gel C-18, 50 g) eluting with acetonitrile and 0.1% HCl water] 6-benzyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (201b) (124 mg, 26% yield) HCl salt as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.79-11.52 (m, 1H, D 2 O exchangeable), 10.22 (s, 1H, D 2 O exchangeable), 8.83 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.75-7.60 (m, 2H), 7.58-7.43 (m, 3H), 7.03 (s, 2H), 4.58-4.33 (m, 2H), 4.23 (s, 2H), 3.88 (s, 6H), 3.70 (s, 3H), 3.54-3.19 (m, 3H), 3.19-2.95 (m, 1H); MS (ES+) 473.3 (M+1), (ES−) 507.2 (M+Cl); HPLC purity 98.29%0.

Preparation of 7-benzyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (202b)

Step-1: Preparation of 7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (202a)

To a solution of 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (153a) (2 g, 6.80 mmol) in ethanol (35 mL) was added zinc (3.56 g, 54.4 mmol) and ammonium hydroxide (4.73 mL, 34.0 mmol) and heated at 90° C. for 15 h. The reaction was cooled, filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated and purified by flash column chromatography (silica gel, 25 g, eluting with 0 to100% ethyl acetate in hexanes) to afford 7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (202a) (800 mg, 45% yield) as thick syrup; 1 H NMR (300 MHz, Chloroform-d) δ 8.35 (d, J=3.1 Hz, 1H), 7.40-7.25 (m, 5H), 3.73 (s, 2H), 3.67 (s, 2H), 2.86 (d, J=5.4 Hz, 2H), 2.80 (t, J=5.5 Hz, 2H).

Step-2: Preparation of 7-benzyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (202b)

Compound 202b was prepared from 7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (202a) (0.26 g, 1.0 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (312 mg, 1.25 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 215 mg, 0.45 mmol), Pd 2 (dba) 3 (137 mg, 0.15 mmol) and cesium carbonate (977 mg, 3.0 mmol) in 1,4-dioxane (10 mL) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (80 g), eluting with DMA-80 in dichloromethane] followed by reverse phase column chromatography [(silica gel C-18, 50 g) eluting with acetonitrile and 0.1% HCl water] 7-benzyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (202b) (145 mg, 31% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.76 (s, 1H, D 2 O exchangeable), 10.18 (s, 1H, D 2 O exchangeable), 8.74 (s, 1H), 8.46 (s, 1H), 7.85 (s, 1H), 7.70 (t, J=4.6 Hz, 2H), 7.55-7.41 (m, 3H), 7.00 (s, 2H), 4.48 (s, 2H), 4.34-4.11 (m, 2H), 3.88 (s, 6H), 3.70 (s, 3H), 3.45-3.06 (m, 3H), 3.02-2.86 (m, 1H); MS (ES+): 473.3 (M+1), (ES−): 507.3 (M+Cl); HPLC: 98.06%.

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (203b)

Step-1: Preparation of (S)-1-(2-chloropyrido[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (203a)

Compound 203a was prepared from 2,4-dichloropyrido[2,3-d]pyrimidine (169a) (0.5 g, 2.50 mmol) in 2-Propanol (10 mL) using (S)-pyrrolidine-2-carboxamide (0.29 g, 2.5 mmol) and DIPEA (1.31 mL, 7.5 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in dichloromethane 0 to 30%] (S)-1-(2-chloropyrido[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (203a) (0.51 g, 73% yield) as a white solid; MS (ES+): 278.2 & 280.2 (M+1).

Step-2: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (203b)

Compound 203b was prepared from (S)-1-(2-chloropyrido[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (203a) (0.25 g, 0.9 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (220 mg, 0.9 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 280 mg, 0.54 mmol), Pd 2 (dba) 3 (0.25 g, 0.27 mmol) and cesium carbonate (0.88 g, 2.7 mmol) in dioxane (5 mL) and toluene (5 mL) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with DMA −0 in CH 2 Cl 2 from 0 to 30%], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)pyrrolidine-2-carboxamide (203b) (30 mg, 6% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.73 (s, 1H), 8.81 (s, 2H), 8.32 (s, 1H), 7.83 (s, 1H), 7.71-7.41 (m, 2H), 7.35-6.84 (m, 3H), 5.00-4.77 (m, 1H), 4.52-4.06 (m, 2H), 3.92 (s, 6H), 3.69 (s, 3H), 2.42-1.94 (m, 4H). MS (ES+): 591.3 (M+1), 513.3 (M+Na); MS (ES−): 525.3 (M+Cl).

Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidine-2-carboxamide (204b)

Step-1: Preparation of (S)-1-(2-chloroquinazolin-4-yl)pyrrolidine-2-carboxamide (204a)

Compound 204a was prepared from 2,4-dichloroquinazoline (21a) (0.5 g, 2.51 mmol) in 2-Propanol (10 mL) using (S)-pyrrolidine-2-carboxamide (0.29 g, 2.5 mmol) and DIPEA (1.31 mL, 7.5 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in dichloromethane 0 to 30%] (S)-1-(2-chloroquinazolin-4-yl)pyrrolidine-2-carboxamide (204a) (0.27 g, 39% yield) as a white solid; MS (ES−): 311.2 & 313.2 (M+Cl).

Step-2: Preparation of (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidine-2-carboxamide (204b)

Compound 204b was prepared from (S)-1-(2-chloroquinazolin-4-yl)pyrrolidine-2-carboxamide (204a) (0.25 g, 0.9 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (230 mg, 0.9 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 0.26 g, 0.54 mmol), Pd 2 (dba) 3 (0.25 g, 0.27 mmol) and cesium carbonate (0.88 g, 2.7 mmol) in dioxane (5 mL) and toluene (5 mL) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in CH 2 Cl 2 from 0 to 30%], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidine-2-carboxamide (204b) (0.03 g, 7% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 8.68 (s, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.71-7.54 (m, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.36-7.10 (m, 3H), 4.93-4.83 (m, 1H), 4.54-4.38 (m, 1H), 4.31-4.14 (m, 1H), 3.92 (s, 6H), 3.70 (s, 3H), 2.42-1.86 (m, 4H); MS (ES+): 490.3 (M+1), 512.2 (M+Na); MS (ES−): 524.3 (M+Cl). HPLC purity: 95.00%.

Preparation of (S)-1-(8-isopropoxy-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidine-2-carboxamide (205b)

Step-1: Preparation of (S)-1-(2-chloro-8-isopropoxyquinazolin-4-yl)pyrrolidine-2-carboxamide (205a) Compound 205a was prepared from 2,4-dichloro-8-isopropoxyquinazoline (143f) (0.50 g, 1.94 mmol) in 2-Propanol (10 mL) using (S)-pyrrolidine-2-carboxamide (1.1 g, 9.72 mmol) and DIPEA (0.75 g, 5.83 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (25 g), eluting with ethyl acetate in hexanes (10 to 80%)] (S)-1-(2-chloro-8-isopropoxyquinazolin-4-yl)pyrrolidine-2-carboxamide (205a) (0.615 g, 95%) as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.82 (d, J=8.2 Hz, 1H), 7.55 (s, 1H), 7.46-7.21 (m, 2H), 7.04 (s, 1H), 4.78 (dt, J=15.0, 7.5 Hz, 2H), 4.07 (d, J=20.4 Hz, 2H), 2.10-1.72 (m, 4H), 1.33 (d, J=6.0 Hz, 6H); MS (ES+) 335.0 (M+1); HPLC purity: 99.1%.

Step-2: Preparation of (S)-1-(8-isopropoxy-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidine-2-carboxamide (205b)

Compound 205b was prepared from (S)-1-(2-chloro-8-isopropoxyquinazolin-4-yl)pyrrolidine-2-carboxamide (205a) (0.25 g, 0.78 mmol), 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (190 mg, 0.78 mmol, free base), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 210 mg, 0.45 mmol), cesium carbonate (0.73 g, 2.24 mmol) and Pd 2 (dba) 3 (210 mg, 0.23 mmol) in 1,4-dioxane (5 mL) and toluene (5 mL) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in CH 2 Cl 2 ], followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] (S)-1-(8-isopropoxy-2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-4-yl)pyrrolidine-2-carboxamide (205b) (20 mg, 5% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.51 (s, 1H), 8.50-8.25 (m, 1H), 7.99-7.79 (m, 2H), 7.68-7.54 (m, 2H), 7.42 (d, J=8.6 Hz, 1H), 7.27-7.12 (m, 2H), 6.99 (s, 1H), 5.00-4.79 (m, 2H), 4.57-4.09 (m, 2H), 3.91 (s, 6H), 3.70 (s, 3H), 2.43-1.90 (m, 4H), 1.56-1.35 (m, 6H). MS (ES+): 548.3 (M+1), 570.4 (M+Na); MS (ES−): 582.3 (M+Cl); HPLC purity: 95.12%.

Preparation of (S)-4-(2-(trifluoromethyl)pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (206b)

Step-1: Preparation of (S)-2-chloro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine (206a)

Compound 206a was prepared from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4a) (400 mg, 2.13 mmol) in IPA (40 mL), (S)-2-(trifluoromethyl)pyrrolidine (296 mg, 2.13 mmol), DIPEA (0.74 mL, 4.25 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate in hexane from 0-50%] (S)-2-chloro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine (206a) (590 mg, 95% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.88-7.80 (m, 1H), 7.14-7.05 (m, 1H), 6.82-6.74 (m, 1H), 5.48-5.33 (m, 1H), 4.16-4.08 (m, 1H), 4.09-3.95 (m, 1H), 2.23-2.09 (m, 4H); 19 F NMR (282 MHz, DMSO) δ −71.87.

Step-2: Preparation of (S)-4-(2-(trifluoromethyl)pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (206b)

Compound 206b was prepared from (S)-2-chloro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine (206a) (300 mg, 1.03 mmol) in toluene/t-BuOH (25 mL, Ratio: 5:2) using 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (309 mg, 1.24 mmol), Pd 2 (dba) 3 (309 mg, 1.24 mmol), X-Phos (197 mg, 0.41 mmol) and Cs 2 CO 3 (1177 mg, 3.61 mmol) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification twice by flash column chromatography [silica gel (40 g), eluting with DMA-80 in DCM from 0-100%] followed by [silica gel (12 g), eluting with EtOAc/MeOH (9:1) in hexane from 0-100%] free base of compound 206b. The free base was converted into HCl salt using 5% HCl, followed by lyophilization to give (S)-4-(2-(trifluoromethyl)pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (206b) (276 mg, 50% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.49 (s, 1H, D 2 O exchangeable), 9.14 (s, 1H), 7.90 (s, 1H, D 2 O exchangeable), 7.73 (d, J=2.3 Hz, 1H), 7.11 (s, 2H), 6.99-6.91 (m, 1H), 6.66-6.56 (m, 1H), 5.58-5.44 (m, 1H), 4.20-4.06 (m, 1H), 4.06-3.94 (m, 1H), 3.90 (s, 6H), 3.72 (s, 3H), 2.23-2.09 (m, 4H); 19 F NMR (282 MHz, DMSO) δ −71.95; MS (ES+): 504.3 (M+1), 526.3 (M+Na); (ES−): 538.3 (M+Cl).

Preparation of 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-2-amine (207b)

Step-1: Preparation of 2-chloro-4-(pyrrolidin-1-yl)thieno[3,2-d]pyrimidine (207a)

Compound 207a was prepared from 2,4-dichlorothieno[3,2-d]pyrimidine (12a) (1 g, 4.88 mmol) in IPA (10 mL), pyrrolidine (0.4 mL, 4.88 mmol), DIPEA (2.56 mL, 14.63 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DCM and methanol (0 to 30%)] 2-chloro-4-(pyrrolidin-1-yl)thieno[3,2-d]pyrimidine (207a) (0.97 g, 83% yield) as a white solid; MS (ES+): 240.1 & 242.1 (M+1), 262.1 & 264.1 (M+Na).

Step-2: Preparation of 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-2-amine (207b)

Compound 207b was prepared from 2-chloro-4-(pyrrolidin-1-yl)thieno[3,2-d]pyrimidine (207a) (400 mg, 1.67 mmol) in toluene/1,4-dioxane (10 mL, Ratio: 1:1) using 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (420 g, 1.67 mmol), Pd 2 (dba) 3 (460 mg, 0.50 mmol), X-Phos (480 mg, 1.0 mmol) and Cs 2 CO 3 (1630 mg, 5.01 mmol) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0-100%] followed by reverse phase column chromatography [(silica gel C-18, 24 g) eluting with acetonitrile and 0.1% HCl water] 4-(pyrrolidin-1-yl)-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-2-amine (207b) (40 mg, 5% yield) HCl salt as an off white solid; 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.69 (s, 1H), 8.41 (d, J=5.5 Hz, 1H), 8.35 (s, 1H), 7.76 (s, 1H), 7.46 (d, J=5.5 Hz, 1H), 6.96 (s, 2H), 4.10-3.91 (m, 4H), 3.88 (s, 6H), 3.69 (s, 3H), 2.30-1.78 (m, 4H). MS (ES+): 453.3 (M+1), 475.3 (M+Na); MS (ES−): 487.4 (M+Cl).

Preparation of N 2 ,N 7 -bis(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)naphthalene-2,7-diamine (208b)

Compound 208b was prepared from 2,7-dibromonaphthalene (208a) (400 mg, 1.4 mmol, CAS #58556-75-5) in toluene/1,4-dioxane (25 mL, Ratio: 1:5) using 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (523 mg, 2.1 mmol), Pd 2 (dba) 3 (128 mg, 0.14 mmol), X-Phos (200 mg, 0.42 mmol) and Cs 2 CO 3 (912 mg, 2.8 mmol) according to the procedure reported in step-3 of Scheme 101. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0-100%] followed by reverse phase column chromatography [(silica gel C-18, 50 g) eluting with acetonitrile and 0.1% HCl water]N 2 ,N 7 -bis(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)naphthalene-2,7-diamine (208b) (35 mg, 4% yield) HCl salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.97 (s, 2H), 8.76 (s, 2H, D 2 O exchangeable), 7.89 (s, 2H, D 2 O exchangeable), 7.68-7.58 (m, 2H), 7.25-7.20 (m, 2H), 7.14-7.01 (m, 6H), 3.87 (s, 12H), 3.71 (s, 6H); MS (ES+): 623.4 (M+1); 645.3 (M+Na); (ES−): 657.4 (M+Cl).

Preparation of (R)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol (209b)

Step-1: Preparation of (R)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol (209a)

Compound 209a was prepared from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4a) (520 mg, 2.77 mmol) in IPA (40 mL), (R)-pyrrolidin-3-ol (241 mg, 2.77 mmol), DIPEA (0.97 mL, 5.53 mmol) according to the procedure reported in step-1 of Scheme 96. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with ethyl acetate in hexane from 0-50%] (R)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol (209a) (601 mg, 91% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.70 (t, J=2.0 Hz, 1H), 7.03-6.90 (m, 1H), 6.70-6.64 (m, 1H), 5.21-4.98 (m, 1H, D 2 O exchangeable), 4.53-4.29 (m, 1H), 4.10-3.92 (m, 2H), 3.86-3.75 (m, 1H), 3.70-3.62 (m, 1H), 2.16-1.88 (m, 2H); MS (ES+): 239.3 (M+1); (ES−): 237.3 (M−1).

Step-2: Preparation of (R)-1-(2-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol (209b)

Compound 209b was prepared from (R)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol (209a) (300 mg, 1.26 mmol) in toluene/t-BuOH (25 mL, Ratio: 5:2) using 1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-amine (57a) (376 mg, 1.51 mmol), Pd 2 (dba) 3 (173 mg, 0.19 mmol), X-Phos (240 mg, 0.50 mmol) and Cs 2 CO 3 (1433 mg, 4.40 mmol) according to